(2001). "Alzheimer's disease: recent progress and prospects--Part III." Harv Ment Health Lett 18(6): 1-4.

(2001). "New tools for taking control of Alzheimer disease." Johns Hopkins Med Lett Health After 50 13(10): 4-5.

(2001). "Alzheimer's disease: recent progress and prospects--Part I." Harv Ment Health Lett 18(4): 1-4.

Abdulla, Y. H. (2001). "A plausible function of the prion protein: conjectures and a hypothesis." Bioessays 23(5): 456-62.
Amyloid beta precursor protein (APP) and prion protein (PrP) are cell membrane elements implicated in neurodegenerative diseases. Both proteins undergo endoproteolysis. Evidence is adduced from the literature hinting that the process in the two proteins could be related, their functions may overlap and their distributions coincide. It is proposed that PrP catalyses its own cleavage, the C-terminal fragment functions as an alpha secretase and the N-terminal segment chaperones the active site; the alpha secretase releases anticoagulant and neurotrophic ectodomains from APP. The proposals explain some features of spongiform encephalopathies.

Abe, K. and H. Saito (2001). "Effects of basic fibroblast growth factor on central nervous system functions." Pharmacol Res 43(4): 307-12.
Basic fibroblast growth factor (bFGF), initially identified as mitogens with prominent angiogenic properties, is now recognized as multifunctional growth factors with notable actions on neuronal cells. bFGF promotes the survival and neurite growth of brain neurons in vitro and in vivo, suggesting that it functions as a neurotrophic factor. This effect of bFGF could be beneficial for improving the survival of grafted neurons in transplantation. Furthermore, bFGF acutely modulates synaptic transmission in the hippocampus, suggesting that it has a role like a neurotransmitter or neuromodulator. In this article, we make a brief review of multiple biological activities of bFGF for brain neurons and discuss its potential usefulness for the treatment of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease.

Abraham, C. R. (2001). "Reactive astrocytes and alpha1-antichymotrypsin in Alzheimer's disease." Neurobiol Aging 22(6): 931-6.
There is ample genetic, biochemical, cellular and molecular evidence to show that the amyloid beta peptide (Abeta), a proteolytic fragment of the amyloid precursor protein (APP), plays an important, if not causative role in Alzheimer's disease (AD). An additional hallmark of AD is the neuroinflammatory response that is associated with the amyloid deposition. We discovered that the acute phase protein alpha1-antichymotrypsin (ACT) is overexpressed by reactive astrocytes, and is tightly associated with virtually all amyloid plaques in the AD brain. It has also been shown that Abeta and ACT bind in vitro. Recently, we have reported that astrocytic expression of ACT in APP transgenic mice leads to an increased plaque deposition in ACT/APP doubly transgenic mice compared to the APP mice alone, suggesting that ACT interferes with Abeta clearance. The main objective of this review is to summarize the role of astrocytosis and ACT in the pathogenesis of AD.

Ada, G. (2001). "Vaccines and vaccination." N Engl J Med 345(14): 1042-53.

Adams, L. L., R. J. Gatchel, et al. (2001). "Complementary and alternative medicine: applications and implications for cognitive functioning in elderly populations." Altern Ther Health Med 7(2): 52-61.
OBJECTIVE: Aged populations in the United States are growing in numbers, and stand to be affected most by the changing shape of healthcare delivery. Within these elderly populations, the problem of decreased cognitive functioning due to dementing disorders is rising. Recent compelling research on complementary and alternative medicine interventions targeted at cognitive deficits in the elderly is reviewed in this survey. DATA SOURCES: A literature review was undertaken to identify original clinical research studies, review articles, chapters, and books on treating cognitive deficits in the elderly. Contact with complementary and alternative medicine researchers provided additional information concerning developments in this field. STUDY SELECTION: Research studies that were methodologically sound were selected for review. More purely clinical studies also were included to provide a thorough overview of the limited amount of accumulated knowledge in this field. DATA SYNTHESIS: A qualitative synthesis of the above data was used to comprehensively present all information accumulated to date in this field. CONCLUSIONS: Although still in the preliminary stages of development, clinical research exploring the benefits of complementary and alternative therapies for cognitive deficits among the elderly shows a significant level of promise that warrants a further investment of resources.

Agostoni, A. and M. Cugno (2001). "[The kinin system: biological mechanisms and clinical implications]." Recenti Prog Med 92(12): 764-73.
The discovery of the kinin system is not recent, but its study in clinical field has been done only in the last years. This system is composed by substrates (kininogens) and plasma and tissue kallikreins are the specific activators of these substrates producing two vasoactive peptides called bradykinin and kallidin. The biologic effects of kinins are mediated by specific receptors called B1 and B2. The activation of this system is particularly important in blood pressure regulation and in inflammatory reactions. The kinin system is involved in many clinical situations including respiratory allergic reactions, septic shock, hypertension and its treatment, hypotensive transfusion reactions, heart diseases, pancreatitis, hereditary and acquired angioedema, Alzheimer's disease and liver cirrhosis with ascites. The study of the kinin system in clinical field, which had been limited by methodological difficulties, has now received an important stimulus by the recent availability of specific and sensitive methods of dosage.

Ahmed, M. B. (2001). "Alzheimer's disease: recent advances in etiology, diagnosis, and management." Tex Med 97(12): 50-8.
Alzheimer's disease is a chronic and progressive neurodegenerative disorder characterized by cognitive and functional deficit and by behavior disturbance. This disease presents a major clinical and social challenge. Increasing evidence suggests that early intervention can delay the progression of the disease and improve symptoms and cognitive functioning. Recent research focuses on genetic susceptibility. Genetic testing may eventually prove to be useful in identifying persons at risk before the onset of symptoms, but at this stage, this testing plays a limited role in identifying and confirming the diagnosis and in genetic counseling. The diagnostic work in all suspected cases of dementia should be started by family physicians; confirmed cases should be treated as soon as possible by the family physician or referred to a psychiatrist or neurologist for appropriate treatment. Donepezil, new cholinesterase inhibitors, and vitamin E have proved effective in delaying progression of Alzheimer's disease.

Albers, D. S. and S. J. Augood (2001). "New insights into progressive supranuclear palsy." Trends Neurosci 24(6): 347-53.
Increased oxidative damage and mitochondrial dysfunction have been suggested to play crucial roles in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. In this review, we will focus on progressive supranuclear palsy (PSP), a rare parkinsonian disorder with tau pathology. Particular emphasis is placed on the genetic and biochemical data that has emerged, offering new perspectives into the pathogenesis of this devastating disease, especially the contributory roles of oxidative damage and mitochondrial dysfunction.

Alexander, M. (2001). "The charms of music. Step by step prescription for patients." N C Med J 62(2): 91-4.

Allain, H., S. Schuck, et al. (2001). "Comparative effects of pharmacotherapy on the maintenance of cognitive function." Eur Psychiatry 16 Suppl 1: 35s-41s.
The quality of human cognitive performance appears today as one of the main components of quality of life, whatever the age. Ageing by itself and most of the diseases affecting the central nervous system alter higher brain functions such as memory, vigilance and attention. Dementia is the most acute example, with a cascade of behavioral and psychological consequences (BPSD), which are the main cause of the caregiver's burden and need specific pharmacotherapy. In this respect, the problem will be the choice of the best drug in situations such as wandering, agitation, violence, and screaming. The psychotropics, however, should not deteriorate the already disturbed cognition of the patients. This is the reason why we propose to establish for each drug, and notably for the antipsychotics, a precise and exact "cognitive mapping"; in other words, to measure the effects of drugs on the different components of cognition. The results of such studies will be predictive of the future phase III clinical trials and therapeutic responses. As an illustration of this approach we shall relate two studies, TIATEM (phase I) and TIAGE (phase III/IV), leading to the determination of a good cognitive safety profile of an atypical neuroleptic drug, tiapride.

Allison, A. C., R. Cacabelos, et al. (2001). "Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease." Prog Neuropsychopharmacol Biol Psychiatry 25(7): 1341-57.
In the brains of patients with Alzheimer's disease (AD) signs of neuronal degeneration are accompanied by markers of microglial activation, inflammation, and oxidant damage. The presence of nitrotyrosine in the cell bodies of neurons in AD suggests that peroxynitrite contributes to the pathogenesis of the disease. A drug with antioxidant and anti-inflammatory activity may prevent neuronal degeneration in AD. Celastrol, a plant-derived triterpene, has these effects. In low nanomolar concentrations celastrol was found to suppress the production by human monocytes and macrophages of the pro-inflammatory cytokines TNF-alpha and IL-1beta. Celastrol also decreased the induced expression of class II MHC molecules by microglia. In macrophage lineage cells and endothelial cells celastrol decreased induced but not constitutive NO production. Celastrol suppressed adjuvant arthritis in the rat, demonstrating in vivo anti-inflammatory activity. Low doses of celastrol administered to rats significantly improved their performance in memory, learning and psychomotor activity tests. The potent antioxidant and anti-inflammatory activities of celastrol, and its effects on cognitive functions, suggest that the drug may be useful to treat neurodegenerative diseases accompanied by inflammation, such as AD.

Allsop, D., L. J. Twyman, et al. (2001). "Modulation of beta-amyloid production and fibrillization." Biochem Soc Symp(67): 1-14.
Alzheimer's disease (AD) is the most common cause of dementia in old age and presently affects an estimated 4 million people in the U.S.A. and 0.75 million people in the U.K. It is a relentless, degenerative brain disease, characterized by progressive cognitive impairment. In the final stages of the disease, patients are often bedridden, doubly incontinent and unable to speak or to recognize close relatives. Pathological changes of Alzheimer's disease include extensive neuronal loss and the presence of numerous neurofibrillary tangles and senile plaques in the brain. The senile plaques contain amyloid fibrils derived from a 39-43-amino-acid peptide referred to as beta-amyloid or A beta. The basic theory of the so-called 'amyloid hypothesis' is that the deposition of aggregated forms of A beta in the brain parenchyma triggers a pathological cascade of events that leads to neurofibrillary tangle formation, neuronal loss and the associated dementia [1]. Here we discuss progress towards the identification of inhibitors of A beta production and fibrillization.

Allt, G. and J. G. Lawrenson (2001). "Pericytes: cell biology and pathology." Cells Tissues Organs 169(1): 1-11.
Pericytes are perivascular cells with multifunctional activities which are now being elucidated. The functional interaction of pericytes with endothelial cells (EC) is now being established, using current molecular and cytochemical techniques. The detailed morphology of the pericyte has been well described. Pericytes extend long cytoplasmic processes over the surface of the EC, the two cells making interdigitating contacts. At points of contact, communicating gap junctions, tight junctions and adhesion plaques are present. Pericytes appear to show both structural and functional heterogeneity. The coverage of EC by pericytes varies considerably between different microvessel types and the location of pericytes on the microvessel is not random but appears to be functionally determined. Interaction between pericytes and EC is important for the maturation, remodelling and maintenance of the vascular system via the secretion of growth factors or modulation of the extracellular matrix. There is also evidence that pericytes are involved in the transport across the blood-brain barrier and the regulation of vascular permeability. The long-standing view that pericytes are the microvessel equivalent of larger vessel smooth muscle cells and are contractile is being reassessed using current methods. An important role for pericytes in pathology, and neuropathology in particular, has been indicated in hypertension, diabetic retinopathy, Alzheimer's disease, multiple sclerosis and CNS tumour formation.

Amenta, F., L. Parnetti, et al. (2001). "Treatment of cognitive dysfunction associated with Alzheimer's disease with cholinergic precursors. Ineffective treatments or inappropriate approaches?" Mech Ageing Dev 122(16): 2025-40.
The observations of the loss of cholinergic function in neocortex and hippocampus in Alzheimer's disease (AD) developed the hypothesis that replacement of cholinergic function may be of therapeutic benefit to AD patients. The different approaches proposed or tested included intervention with acetylcholine (ACh) precursors, stimulation of ACh release, use of muscarinic or nicotinic receptor agonists and acetylcholinesterase (AChE) or cholinesterase (ChE) inhibition. Inhibition of endogenous ACh degradation through ChE inhibitors and precursor loading were treatments more largely investigated in clinical trials. Of the numerous compounds in development for the treatment of AD, AChE and ChE inhibitors are the most clinically advanced, although clinical trials conducted to date did not always confirm a significant benefit of these drugs on all symptom domains of AD. The first attempts in the treatment of AD with cholinergic precursors did not confirm a clinical utility of this class of compounds in well controlled clinical trials. However, cholinergic precursors most largely used such as choline and phosphatidylcholine (lecithin) were probably not suitable for enhancing brain levels of ACh. Other phospholipids involved in choline biosynthetic pathways such as CDP-choline, choline alphoscerate and phosphatidylserine clearly enhanced ACh availability or release and provided a modest improvement of cognitive dysfunction in AD, these effects being more pronounced with choline alphoscerate. Although some positive results cannot be generalized due to the small numbers of patients studied, they probably would justify reconsideration of the most promising molecules in larger carefully controlled trials.

Andoh, T. (2001). "[Effects of general anesthetics on neuronal nicotinic acetylcholine receptors and their roles in the mechanism of anesthesia]." Masui 50(10): 1072-84.
Neuronal nicotinic acetylcholine receptors (nAchRs) are widely expressed in the central and autonomic nervous systems and have subunit compositions with biophysical and pharmacological properties distinct from those of the receptors at the neuromuscular junction. They are thought to modulate synaptic transmission in the central nervous system (CNS) mainly by regulating the release of neurotransmitters. Although roles of neuronal nAchRs in the CNS are poorly understood, these receptors are involved in cognitive performance, nociception and psychoneurological disorders such as Alzheimer's and Parkinson disease. It is known that both central and peripheral neuronal nAchRs are sensitive to various types of anesthetics. Among those, barbiturates, ketamine, volatile and gaseous anesthetics depress neuronal nAchRs at or below clinical concentrations. Inhibition of neuronal nAchRs by barbiturates is unlikely to contribute to the anesthetic action of barbiturates, since this effect does not correlate with the anesthetic potencies of barbiturate stereoisomers. Relevance of inhibition of these receptors is controversial for anesthetic effects of other anesthetics, because conflicting results have been obtained from comparison of this effect with anesthetic actions of stereoisomers or structurally related compounds. However, it is possible that inhibition of central nAchRs contributes to secondary effects attributed to anesthesia such as impairment in memory and cognitive performance.

Andrews, G. R. (2001). "The priority of basic research on ageing vulnerability in a comprehensive research agenda on ageing for the 21st century." Novartis Found Symp 235: 4-9; discussion 9-10.
The prospects for individual and population ageing as we enter a new century pose some of the greatest social, economic and humanitarian challenges humankind as a whole has ever faced. The basic biological mechanisms that control human ageing remain ill understood but it is clear that for many individuals exhibiting predisposition to risk factors for certain chronic diseases, such as coronary heart disease, diabetes, osteoporosis, certain cancers and Alzheimer's disease, such predisposition is mediated through genetic processes that operate at a most fundamental biomolecular level interacting with nongenetic attributes. The prospect of improved understanding of the fundamental processes underlying the pathogenesis of common age-related diseases that may lead to identification of interventions that are effective in preventing, delaying or ameliorating the diseases and their consequences is compelling. It is this prospect that provides the prime justification for giving high priority to research on ageing vulnerability in a comprehensive research agenda on ageing for the 21st century.

Anthony, M., J. K. Williams, et al. (2001). "What would be the properties of an ideal SERM?" Ann N Y Acad Sci 949: 261-78.
Selective estrogen receptor modulators (SERMs) are drugs that bind to the estrogen receptor (ER); in some tissues they act like estrogen (agonists), while in other tissues they oppose the action of estrogen (antagonists). The SERM tamoxifen acts as an estrogen antagonist in the breast in that it prevents and treats breast cancer, but it acts as an estrogen agonist in the endometrium, where it can induce cancer. Estrogen, and to a lesser extent SERMs, are effective in preventing and treating osteoporosis. Contrary to the prevalent hypothesis that estrogen provides benefit to women with regard to secondary prevention of coronary heart disease (CHD), randomized clinical trials have demonstrated that estrogen is associated with an increased risk of CHD in this population of women. Conflicting results have been reported on the effect of estrogens on cognitive function. The latest and largest randomized clinical trials have demonstrated a beneficial role in short-term memory in nondemented women, in contrast to the absence of such benefit in improving symptoms in women with Alzheimer's disease. Although estrogens have been used successfully to treat some menopausal symptoms such as hot flashes, the SERMs tamoxifen and raloxifene actually induce or increase hot flashes. Data on the beneficial and adverse effects of estrogen and SERMs are reported along with an elaboration of the constellation of properties that would characterize an ideal SERM working through the ER.

Apfel, S. C. (2001). "Neurotrophic factor therapy--prospects and problems." Clin Chem Lab Med 39(4): 351-5.
Over the past 15 years neurotrophic factors have generated considerable excitement for their potential as therapy for a wide variety of degenerative neurological disorders, for which there is currently no treatment. The first part of this period was marked by the discovery, characterization, and cloning of many new growth factors, and by successful testing of these factors in animal models of neurological disease. In recent years the biotechnology industry and pharmaceutical industry have attempted to replicate the success of the animal studies in clinical trials. Although some studies have demonstrated moderate efficacy, for the most part the clinical trials have been less successful at demonstrating the therapeutic efficacy of this new class of drugs. For example, nerve growth factor appeared to be efficacious in two phase II clinical trials for peripheral neuropathy, but failed in a large scale phase III trial. Ciliary neurotrophic factor, brain derived neurotrophic factor and insulin like growth factor-1 have all been tested in clinical trials for the treatment of amyotrophic lateral sclerosis, with at best, variable indications of efficacy. Nevertheless, there are still many reasons to be optimistic that some of these agents may be useful clinically. Many technical and pharmacological issues remain to be adequately addressed, before neurotrophic factors can live up to their potential. Our collective experience with them has re-adjusted previously wild expectations, so that they are now much more realistic. This is necessary and beneficial for the maturation of this field of study.

Arendt, T. (2001). "Disturbance of neuronal plasticity is a critical pathogenetic event in Alzheimer's disease." Int J Dev Neurosci 19(3): 231-45.
Brain areas affected by AD pathology are primarily those structures that are invovled in the regulation of "higher brain functions". The functions these areas subserve such as learning, memory, perception, self-awareness, and consciousness require a life-long re-fittng of synaptic contacts that allows for the acquistion of new epigenetic information, a process based on a particularly high degree of structural plasticity. Here, we outline a hypothesis that it is the "labile state fo differentiation" of a subset of neurons in the adult brain that allows for ongoing neuroplastic processes after development is completed but at the same time renders these neurons particularly vulnerable. Mechanisms of molecular and cellular control of neuronal differentiation and proliferation might, thus, not only play a role during development but critically involved in the pathogenesis of neurodegeneration.

Arendt, T. (2001). "Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization." Neuroscience 102(4): 723-65.
Mental function has as its cerebral basis a specific dynamic structure. In particular, cortical and limbic areas involved in "higher brain functions" such as learning, memory, perception, self-awareness and consciousness continuously need to be self-adjusted even after development is completed. By this lifelong self-optimization process, the cognitive, behavioural and emotional reactivity of an individual is stepwise remodelled to meet the environmental demands. While the presence of rigid synaptic connections ensures the stability of the principal characteristics of function, the variable configuration of the flexible synaptic connections determines the unique, non-repeatable character of an experienced mental act. With the increasing need during evolution to organize brain structures of increasing complexity, this process of selective dynamic stabilization and destabilization of synaptic connections becomes more and more important. These mechanisms of structural stabilization and labilization underlying a lifelong synaptic remodelling according to experience, are accompanied, however, by increasing inherent possibilities of failure and may, thus, not only allow for the evolutionary acquisition of "higher brain function" but at the same time provide the basis for a variety of neuropsychiatric disorders. It is the objective of the present paper to outline the hypothesis that it might be the disturbance of structural brain self-organization which, based on both genetic and epigenetic information, constantly "creates" and "re-creates" the brain throughout life, that is the defect that underlies Alzheimer's disease (AD). This hypothesis is, in particular, based on the following lines of evidence. (1) AD is a synaptic disorder. (2) AD is associated with aberrant sprouting at both the presynaptic (axonal) and postsynaptic (dendritic) site. (3) The spatial and temporal distribution of AD pathology follows the pattern of structural neuroplasticity in adulthood, which is a developmental pattern. (4) AD pathology preferentially involves molecules critical for the regulation of modifications of synaptic connections, i.e. "morphoregulatory" molecules that are developmentally controlled, such as growth-inducing and growth-associated molecules, synaptic molecules, adhesion molecules, molecules involved in membrane turnover, cytoskeletal proteins, etc. (5) Life events that place an additional burden on the plastic capacity of the brain or that require a particularly high plastic capacity of the brain might trigger the onset of the disease or might stimulate a more rapid progression of the disease. In other words, they might increase the risk for AD in the sense that they determine when, not whether, one gets AD. (6) AD is associated with a reactivation of developmental programmes that are incompatible with a differentiated cellular background and, therefore, lead to neuronal death. From this hypothesis, it can be predicted that a therapeutic intervention into these pathogenetic mechanisms is a particular challenge as it potentially interferes with those mechanisms that at the same time provide the basis for "higher brain function".

Armstrong, R. A., N. J. Cairns, et al. (2001). "What does the study of the spatial patterns of pathological lesions tell us about the pathogenesis of neurodegenerative disorders?" Neuropathology 21(1): 1-12.
Discrete pathological lesions, which include extracellular protein deposits, intracellular inclusions and changes in cell morphology, occur in the brain in the majority of neurodegenerative disorders. These lesions are not randomly distributed in the brain but exhibit a spatial pattern, that is, a departure from randomness towards regularity or clustering. The spatial pattern of a lesion may reflect pathological processes affecting particular neuroanatomical structures and, therefore, studies of spatial pattern may help to elucidate the pathogenesis of a lesion and of the disorders themselves. The present article reviews first, the statistical methods used to detect spatial patterns and second, the types of spatial patterns exhibited by pathological lesions in a variety of disorders which include Alzheimer's disease, Down syndrome, dementia with Lewy bodies, Creutzfeldt-Jakob disease, Pick's disease and corticobasal degeneration. These studies suggest that despite the morphological and molecular diversity of brain lesions, they often exhibit a common type of spatial pattern (i.e. aggregation into clusters that are regularly distributed in the tissue). The pathogenic implications of spatial pattern analysis are discussed with reference to the individual disorders and to studies of neurodegeneration as a whole.

Arnold, S. E. (2001). "Contributions of neuropathology to understanding schizophrenia in late life." Harv Rev Psychiatry 9(2): 69-76.
The neurobiological basis of cognitive and functional deterioration commonly observed in elderly persons with schizophrenia is unclear. Despite superficial similarities in the clinical and neuropsychological profiles of schizophrenia in late life with neurodegenerative dementias, extensive neuropathological investigations have failed to find any evidence of neurodegeneration or neural injury beyond what is typically observed in brains of individuals without neuropsychiatric illness. In contrast, growing neuropathological data indicate aberrant brain development and connectivity in schizophrenia (including abnormalities in cytoarchitecture, innervation, and synaptic integrity) and abnormal molecular signaling pathways important in the formation of the nervous system and ongoing plasticity in maturity. These developmental abnormalities may represent a state of decreased cerebral reserve that causes persons with schizophrenia to be more vulnerable to the toxic effects of even "normal" accumulations of age-related neurodegenerative lesions.

Ashe, K. H. (2001). "Learning and memory in transgenic mice modeling Alzheimer's disease." Learn Mem 8(6): 301-8.
Recent advances in behavioral analyses of transgenic mouse models of Alzheimer's disease (AD) are discussed, and their impact on our understanding of the molecular basis of cognitive impairment in AD is considered. Studies of the relationship between memory and Ass in transgenic mice expressing the amyloid precursor protein (APP) and its variants suggest that aging promotes the formation of soluble Ass assemblies mediating negative effects on memory. A significant component of memory loss in APP transgenic mice is apparently caused by soluble Ass assemblies, but whether and how much of the dementia within individuals afflicted with AD is caused by these Ass species is unclear. Future studies in composite transgenic mice developing amyloid plaques, neurofibrillary tangles, and other AD pathology may allow for the determination of the relative contribution of Ass and non-Ass components to dementia.

Askanas, V. and W. K. Engel (2001). "Inclusion-body myositis: newest concepts of pathogenesis and relation to aging and Alzheimer disease." J Neuropathol Exp Neurol 60(1): 1-14.
We review the newest advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis (s-IBM) and present the pathologic diagnostic criteria of s-IBM. We discuss the possible pathogenic role of several themes, such as 1) increased amyloid-beta precursor protein (AbetaPP) and of its fragment Abeta; 2) phosphorylation of tau protein; 3) oxidative stress; 4) abnormal a) signal-transduction, b) transcription, and c) RNA accumulation; 5) "junctionalization" and myogenous" denervation; and 6) lymphocytic inflammation. Evidence is provided supporting our hypothesis that overexpression of AbetaPP within the aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. The remarkable pathologic similarities between s-IBM muscle and Alzheimer disease (AD) brain are discussed, and the possible cause and significance are addressed.

Auchus, A. P. and C. P. Chen (2001). "Asia regional meeting of the International Working Group for the Harmonization of Dementia Drug Guidelines: meeting report." Alzheimer Dis Assoc Disord 15(2): 66-8.
This meeting successfully catalyzed the establishment of a new working alliance between clinical dementia researches in Asia and identified common goals for the group to attain. The progress toward achieving these goals will be examined at the next Asia regional meeting, which is being planned for October 2002 in Beijing, China. This new regional working group will work with the IWG to overcome the existing methodological and regulatory obstacles impeding dementia treatment trials in Asia.

Auchus, A. P. and C. P. Chen (2001). "Asia-Pacific Consensus Statement on dementia." Alzheimer Dis Assoc Disord 15(2): 63-5.
The 12 national Alzheimer's Associations that contributed to this Consensus Statement will continue to network with one another regionally and will continue to share relevant expertise and practical resources. It is expected that regional consensus on dementia will evolve in individual member countries and in the Asia-Pacific region as a whole. It is the hope of the participating members of these two consensus conferences that this document will provide the inspiration, direction, and practical ideas to further advance the goals of national Alzheimer's Associations and to further advance dementia-related medical and service activities within the Asia-Pacific region.

Autret, A., B. Lucas, et al. (2001). "Sleep and brain lesions: a critical review of the literature and additional new cases." Neurophysiol Clin 31(6): 356-75.
We present a comprehensive review of sleep studies performed in patients with brain lesions complemented by 16 additional personal selected cases and by discussion of the corresponding animal data. The reader is cautioned about the risk of establishing an erroneous correlation between abnormal sleep and a given disorder due to the important inter and intra variability of sleep parameters among individuals. Salient points are stressed: the high frequency of post-stroke sleep breathing disorders is becoming increasingly recognised and may, in the near future, change the way this condition is managed. Meso-diencephalic bilateral infarcts induce a variable degree of damage to both waking and non-REM sleep networks producing and abnormal waking and sometimes a stage 1 hypersomnia reduced by modafinil or bromocriptine, which can be considered as a syndrome of cathecholaminergic deficiency. Central pontine lesions induce REM and non-REM sleep insomnia with bilateral lateral gaze paralysis. Bulbar stroke leads to frequent sleep breathing disorders. Polysomnography can help define the extent of involvement of various degenerative diseases. Fragmented sleep in Parkinson's disease may be preceded by REM sleep behavioural disorders. Multiple system atrophies are characterised by important sleep disorganization. Sleep waking disorganization and a specific ocular REM pattern are often seen in supra-nuclear ophtalmoplegia. In Alzheimer patients, sleep perturbations parallel the mental deterioration and are possibly related to cholinergic deficiency. Fronto-temporal dementia may be associated with an important decrease in REM sleep. Few narcoleptic syndromes are reported to be associated with a tumour of the third ventricle or a multiple sclerosis or to follow a brain trauma; all these cases raise the question whether this is a simple coincidence, a revelation of a latent narcolepsy or, as in non-DR16/DQ5 patients, a genuine symptomatic narcolepsy. Trypanosomiasis and the abnormal prion protein precociously after sleep patterns. Polysomnography is a precious tool for evaluating brain function provided it is realised under optimal conditions in stable patients and interpreted with caution. Several unpublished cases are presented: one case of pseudohypersomnia due to a bilateral thalamic infarct and corrected by modafinil, four probable late-onset autosomal recessive cerebellar ataxias without sleep pattern anomalies, six cases of fronto-temporal dementia with strong reduction in total sleep time and REMS percentage on the first polysomnographic night, one case of periodic hypersomnia associated with a Rathke's cleft cyst and four cases of suspected symptomatic narcolepsy with a DR16-DQ5 haplotype, three of which were post-traumatic without MRI anomalies, and one associated with multiple sclerosis exhibiting pontine hyper signals on MRI.

Aviel-Ronen, S., B. Shalmon, et al. (2001). "[Alzheimer disease and estrogen--the connection, modes of influence and the therapy]." Harefuah 140(2): 139-43.

Bachurin, S. O. (2001). "[Medicinal and chemical approaches to focused search of agents for treatment and therapy of Alzheimer disease]." Vopr Med Khim 47(2): 155-97.
The analysis and justification of medicinal chemistry approaches for focused search of novel agents for Alzheimer's disease (AD) and related disorders treatment and prevention have been reviewed. The systematization of modern biochemical and structural date related to the action of physiologically active compounds on the nervous system apparatus engaged in the AD-like disorders pathogenesis was performed. The major attention was paid to the cholinomimetic, anti-amyloid and antimetabolic approaches, basing on the results published in scientific literature in 3-4 last years and results of preclinical and clinical trials, presented in the internet database in the fall of 2000.

Bajetto, A., R. Bonavia, et al. (2001). "Chemokines and their receptors in the central nervous system." Front Neuroendocrinol 22(3): 147-84.
Chemokines are a family of proteins associated with the trafficking of leukocytes in physiological immune surveillance and inflammatory cell recruitment in host defence. They are classified into four classes based on the positions of key cystiene residues: C, CC, CXC, and CX3C. Chemokines act through both specific and shared receptors that all belong to the superfamily of G-protein-coupled receptors. Besides their well-established role in the immune system, several recent reports have demonstrated that these proteins also play a role in the central nervous system (CNS). In the CNS, chemokines are constitutively expressed by microglial cells, astrocytes, and neurons, and their expression can be increased after induction with inflammatory mediators. Constitutive expression of chemokines and chemokine receptors has been observed in both developing and adult brains, and the role played by these proteins in the normal brain is the object of intense study by many research groups. Chemokines are involved in brain development and in the maintenance of normal brain homeostasis; these proteins play a role in the migration, differentiation, and proliferation of glial and neuronal cells. The chemokine stromal cell-derived factor 1 and its receptor, CXCR4, are essential for life during development, and this ligand-receptor pair has been shown to have a fundamental role in neuron migration during cerebellar formation. Chemokine and chemokine receptor expression can be increased by inflammatory mediators, and this has in turn been associated with several acute and chronic inflammatory conditions. In the CNS, chemokines play an essential role in neuroinflammation as mediators of leukocyte infiltration. Their overexpression has been implicated in different neurological disorders, such as multiple sclerosis, trauma, stroke, Alzheimer's disease, tumor progression, and acquired immunodeficiency syndrome-associated dementia. An emerging area of interest for chemokine action is represented by the communication between the neuroendocrine and the immune system. Chemokines have hormone-like actions, specifically regulating the key host physiopathological responses of fever and appetite. It is now evident that chemokines and their receptors represent a plurifunctional family of proteins whose actions on the CNS are not restricted to neuroinflammation. These molecules constitute crucial regulators of cellular communication in physiological and developmental processes.

Balin, B. J. and D. M. Appelt (2001). "Role of infection in Alzheimer's disease." J Am Osteopath Assoc 101(12 Suppl Pt 1): S1-6.
Alzheimer's disease (AD) is a chronic condition in which inflammation has been shown to contribute to neurodegeneration. Current thinking suggests that deposition of beta-amyloid in the brain promotes inflammation resulting in neuronal damage/death. Alternatively, our data suggest that chronic inflammation observed in late-onset sporadic AD may be stimulated by infection with the obligate, intracellular bacterium, Chlamydia pneumoniae. Our results indicate that C. pneumoniae is found in high frequency in glial cells in areas of neuropathology within the brains of patients with AD. Based on our evidence, nervous system infection with C. pneumoniae should be considered a risk factor for sporadic AD.

Ball, M. J., R. Mathews, et al. (2001). "Latent HSV 1 virus in trigeminal ganglia: the optimal site for linking prevention of Alzheimer's disease to vaccination." Neurobiol Aging 22(5): 705-9; discussion 717-9.

Bamberger, M. E. and G. E. Landreth (2001). "Microglial interaction with beta-amyloid: implications for the pathogenesis of Alzheimer's disease." Microsc Res Tech 54(2): 59-70.
The etiology of Alzheimer's disease (AD) involves a significant inflammatory component as evidenced by the presence of elevated levels of a diverse range of proinflammatory molecules in the AD brain. These inflammatory molecules are produced principally by activated microglia, which are found to be clustered within and adjacent to the senile plaque. Moreover, long-term treatment of patients with non-steroidal anti-inflammatory drugs has been shown to reduce risk and incidence of AD and delay disease progression. The microglia respond to beta-amyloid (Abeta) deposition in the brain through the interaction of fibrillar forms of amyloid with cell surface receptors, leading to the activation of intracellular signal transduction cascades. The activation of multiple independent signaling pathways ultimately leads to the induction of proinflammatory gene expression and production of reactive oxygen and nitrogen species. These microglial inflammatory products act in concert to produce neuronal toxicity and death. Therapeutic approaches focused on inhibition of the microglial-mediated local inflammatory response in the AD brain offer new opportunities to intervene in the disease.

Ban, T. A. (2001). "Pharmacotherapy of mental illness--a historical analysis." Prog Neuropsychopharmacol Biol Psychiatry 25(4): 709-27.
The history of pharmacotherapy of mental illness can be divided into three periods. Introduction of morphine, potassium bromide, chloral hydrate, hyoscine, paraldehyde, etc., during the second half of the 19th century (first period), led to the replacement of physical restraint by pharmacological means in behavior control. Introduction of nicotinic acid, penicillin, thiamine, etc., during the first half of the 20th century (second period), led to significant changes in the diagnostic distribution of psychiatric patients; psychoses due to cerebral pellagra, and dementia due to syphilitic general paralysis virtually disappeared from psychiatric hospitals, and the prevalence of dysmnesias markedly decreased. Treatment with therapeutically effective drugs of mania, schizophrenia, depression, bipolar disorder, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, Alzheimer's disease, etc., during the second half of the 20th century (third period), brought to attention the heterogeneity of the populations within the diagnostic categories of schizophrenia and depression. Introduction of the first set of psychotropics and the spectrophotofluorimeter during the 1950s triggered the development of neuropsychopharmacology. Introduction of genetic technology for the separation of receptor subtypes in the 1980s opened the path for the "tailoring" of psychotropic drugs by the dawn of the 21st century, to receptor affinities.

Banaclocha, M. M. (2001). "Therapeutic potential of N-acetylcysteine in age-related mitochondrial neurodegenerative diseases." Med Hypotheses 56(4): 472-7.
Increasing lines of evidence suggest a key role for mitochondrial damage in neurodegenerative diseases. Brain aging, Parkinson's disease, Alzheimer's disease, Huntington's disease and Friedreich's ataxia have been associated with several mitochondrial alterations including impaired oxidative phosphorylation. Mitochondrial impairment can decrease cellular bioenergetic capacity, which will then increase the generation of reactive oxygen species resulting in oxidative damage and programmed cell death. This paper reviews the mechanisms of N-acetylcysteine action at the cellular level, and the possible usefulness of this antioxidant for the treatment of age-associated neurodegenerative diseases. First, this thiol can act as a precursor for glutathione synthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration. Second, N-acetylcysteine can act by direct reaction between its reducing thiol group and reactive oxygen species. Third, it has been shown that N-acetylcysteine can prevent programmed cell death in cultured neuronal cells. And finally, N-acetylcysteine also increases mitochondrial complex I and IV specific activities both in vitro and in vivo in synaptic mitochondrial preparations from aged mice. In view of the above, and because of the ease of its administration and lack of toxicity in humans, the potential usefulness of N-acetylcysteine in the treatment of age-associated mitochondrial neurodegenerative diseases deserves investigation.

Baranano, D. E. and S. H. Snyder (2001). "Neural roles for heme oxygenase: contrasts to nitric oxide synthase." Proc Natl Acad Sci U S A 98(20): 10996-1002.
The heme oxygenase (HO) and nitric oxide (NO) synthase (NOS) systems display notable similarities as well as differences. HO and NOS are both oxidative enzymes using NADPH as an electron donor. The constitutive forms of the enzyme are differentially activated, with calcium entry stimulating NOS by binding to calmodulin, whereas calcium entry activates protein kinase C to phosphorylate and activate HO2. Although both NO and carbon monoxide (CO) stimulate soluble guanylyl cyclase to form cGMP, NO also S-nitrosylates selected protein targets. Both involve constitutive and inducible biosynthetic enzymes. However, functions of the inducible forms are virtual opposites. Macrophage-inducible NOS generates NO to kill other cells, whereas HO1 generates bilirubin to exert antioxidant cytoprotective effects and also provides cytoprotection by facilitating iron extrusion from cells. The neuronal form of HO, HO2, is also cytoprotective. Normally, neural NO in the brain seems to exert some sort of behavioral inhibition. However, excess release of NO in response to glutamate's N-methyl-d-aspartate receptor activation leads to stroke damage. On the other hand, massive neuronal firing during a stroke presumably activates HO2, leading to neuroprotective actions of bilirubin. Loss of this neuroprotection after HO inhibition by mutant forms of amyloid precursor protein may mediate neurotoxicity in Familial Alzheimer's Disease. NO and CO both appear to be neurotransmitters in the brain and peripheral autonomic nervous system. They also are physiologic endothelial-derived relaxing factors for blood vessels. In the gastrointestinal pathway, NO and CO appear to function as coneurotransmitters, both stimulating soluble guanylyl cyclase to cause smooth muscle relaxation.

Barber, R., A. Panikkar, et al. (2001). "Dementia with Lewy bodies: diagnosis and management." Int J Geriatr Psychiatry 16 Suppl 1: S12-8.
OBJECTIVE: To summarize the clinical, pathological, imaging and treatment aspects of dementia with Lewy bodies (DLB). METHOD: Review of literature (MEDLINE). RESULTS: DLB is the second most common form of degenerative dementia, accounting for up to 20% of cases in the elderly. It is characterized by fluctuating cognitive impairment, spontaneous parkinsonism and recurrent visual hallucinations. Consensus clinical criteria have been published and have been shown to have high specificity, but they may still lack sensitivity. Pathologically, DLB may be classified as a Lewy body (LB) disorder and/or as an alpha-synucleinopathy. It is probable that a spectrum of LB disorders exists with the clinical features reflecting the distribution and severity of pathology. Although both DLB and Alzheimer's disease (AD) show a reduction in pre-synaptic cholinergic transmission from the basal forebrain, in DLB there are also deficits in cholinergic transmission from brain stem nuclei. Post-synaptic cortical muscarinic receptors are more functionally intact in DLB suggesting potential responsiveness to cholinergic enhancement. Neuroimaging findings indicate a relative preservation of medial temporal lobe structures in DLB but similar distribution of white matter changes on MRI compared with AD. Defects in nigrostriatal dopamine pathways in DLB have been demonstrated with functional neuroimaging using ligands highlighting pre- and post-synaptic dopaminergic systems. Preliminary studies also indicate subtle differences in perfusion patterns on SPECT with a greater degree of occipital hypoperfusion in DLB compared with AD. Accurate diagnosis of DLB is clinically important as the management of psychosis and behavioural disturbances is complicated by sensitivity to neuroleptic medication. There is accumulating evidence to suggest that DLB may be particularly amenable to cholinergic enhancers. The clinical management of DLB is considered using a four step approach: making a diagnosis; identification of problem symptoms; appropriate non-pharmacological interventions; and pharmacological interventions. CONCLUSIONS: Consensus criteria for probable DLB have high specificity-a positive clinical diagnosis is likely to be correct. Treatment choices must consider effects upon motor, cognitive and psychiatric symptoms. Non-pharmacological management is an essential first step, as is reduction or withdrawal of drugs with potential adverse effects. Neuroleptic sensitivity reactions appear less likely to occur with the newer atypical antipsychotics. Cholinesterase inhibitors have been shown in open-label studies and one placebo RCT to be well tolerated and effective in treating cognitive and psychiatric symptoms in DLB. They may become first-line treatments.

Barbieri, S., K. Hofele, et al. (2001). "Mouse models of alpha-synucleinopathy and Lewy pathology. Alpha-synuclein expression in transgenic mice." Adv Exp Med Biol 487: 147-67.

Barolin, G. S. (2001). "[Psychotherapy in senile dementia?!]." Wien Med Wochenschr 151(15-17): 342-7.
Psychotherapy for senile demented patients is feasible and should become a routine. However, it must be integrated psychotherapy that is not school-centred but patient-centered. Especially in the work with senile demented patients it must closely cooperate with all health professions that are in the field. These endeavours must be systematically coordinated. Analytic psychotherapy in the classical sense is not feasable. However, in old (and demented) patients sometimes a strong desire persists to tell out of the past. The therapist's task there is mainly listening and not interpreting. Children, animals, plush-animals, music and dance-therapy are not so well-known possibilities to find a psychotherapeutic approach to senile demented persons. The basic psychotherapy should be known to all health professions. Professional psychotherapy should be given more attention as to the psychotherapy of old people.

Baxter, M. G. (2001). "Effects of selective immunotoxic lesions on learning and memory." Methods Mol Biol 166: 249-65.

Belanoff, J. K., K. Gross, et al. (2001). "Corticosteroids and cognition." J Psychiatr Res 35(3): 127-45.
The brain is a major target organ for corticosteroids. It has been observed that excessive circulatory levels of endogenous and exogenous corticosteroids are frequently associated with cognitive impairment in a wide variety of clinical disease states. Cognition and low levels of corticosteroids have been less well studied. In this paper we review the literature on glucocorticosteroid effects on cognition and delineate specific functions that appear to be causally affected. We draw a possible connection to specific areas of brain perturbation, including the hippocampus and frontal lobe regions. The possibility that cognitive dysfunction caused by glucocorticoids can be pharmacologically managed is introduced.

Bennett, D. (2001). "Public health importance of vascular dementia and Alzheimer's disease with cerebrovascular disease." Int J Clin Pract Suppl(120): 41-8.
Vascular dementia (VaD) refers to a heterogeneous group of conditions that include all dementia syndromes resulting from ischaemic, haemorrhagic, anoxic or hypoxic brain damage. VaD is the second most common cause of dementia in the elderly after Alzheimer's disease. Persons with VaD are at greater risk of morbidity and mortality compared with those without dementia or those with Alzheimer's disease, and appear to be at greater risk of institutionalisation. Despite the importance of the problem posed by VaD, few placebo-controlled, double-blind, randomised clinical trials have been conducted. Although dementia may result solely from the accumulation of brain damage from cerebrovascular disease (CVD), recent data suggest that VaD often results from a combination of both CVD and Alzheimer's disease ('mixed' dementia). This raises the possibility that persons with VaD may respond to medications that are commonly used to treat Alzheimer's disease.

Benveniste, E. N., V. T. Nguyen, et al. (2001). "Immunological aspects of microglia: relevance to Alzheimer's disease." Neurochem Int 39(5-6): 381-91.
Alzheimer's disease (AD) is a progressive dementing neurologic illness, and the most frequent cause of dementia in the elderly. Neuritic plaques are one of the main neuropathological findings in AD, and the major protein component is the beta-amyloid protein (A beta). Another striking feature of neuritic plaques is the presence of activated microglia, cytokines, and complement components, suggestive of "inflammatory foci" within AD brain. In this review, we will examine the mechanisms by which microglia become activated in AD, emphasizing the role in the A beta protein and proinflammatory cytokines. As well, pathways for suppression of microglial activation by immunosuppressive cytokines will be described. Inflammation mediated by activated microglia is an important component of AD pathophysiology, and strategies to control this response could provide new therapeutic approaches for the treatment of AD.

Bianchetti, A. and M. Trabucch (2001). "Clinical aspects of Alzheimer's disease." Aging (Milano) 13(3): 221-30.
Alzheimer's disease (AD) is the most common of the dementing disorders. AD begins insidiously and progresses gradually; it is characterized clinically not only by an impairment in cognition, but also by a decline in global function, a deterioration in the ability to perform activities of daily living, and the appearance of behavioral disturbances. No definitive tests for the diagnosis are available, and AD is a diagnosis of inclusion based on patient history, physical examination, neuropsychological testing, and laboratory studies. Disease progression is highly variable, and median survival after the onset of dementia ranges from 5 to 9.3 years. Early recognition of AD allows time to plan for the future, and to treat patients before marked deterioration occurs.

Bickel, H. (2001). "[Dementia in advanced age: estimating incidence and health care costs]." Z Gerontol Geriatr 34(2): 108-15.
Based on results from large-scale epidemiological field studies in the western industrial countries, 930,000 elderly people in Germany were estimated to suffer from a dementing disorder at the end of 1996. Following the most recent population projection, a population increase of the number of elderly people (65 yrs. and above) from 12.9 million (mio.) in 1996 to more than 20 mio. in 2030 is anticipated. Based on the assumption that age-specific prevalence rates of dementia will remain stable, a steep rise in patient numbers by an average of 20,000 per year can thus be expected, reaching 1.56 mio. in 2030 and more than 2 mio. in 2050. Studies on the cost of illness point to an enormous economic burden caused by dementia. The unpaid informal care provided by relatives and the high expenses for long-term institutional care can be considered as the most significant components of total costs. Currently, the medical costs associated with diagnosis and treatment, however, appear as an almost negligible fraction of the total costs.

Bieber, E. J. and D. P. Cohen (2001). "Estrogens and hormone replacement therapy: is there a role in the preservation of cognitive function?" Int J Fertil Womens Med 46(4): 206-9.
Alzheimer's disease affects as many as 40% of Americans over the age of 80 and, as such, is a major public health issue. Interestingly, there is a two- to threefold greater prevalence in women than in men. It has been estimated that the prevalence of Alzheimer's disease will quadruple over the next half century. There have been implications of an effect of estrogen on neurological function for many years. As long as 50 years ago a study published in the gerontology literature suggested that the administration of i.m. estrogen in a nursing home population was associated with improvement in memory and a delay in progression of memory loss. Most recently there has been great interest in the effect of estrogen on both neurons and the CNS vasculature. A study evaluating verbal memory and abstract reasoning in over 700 women without dementia demonstrated that women who had used estrogen for as little as 1 year had significant improvements in baseline cognitive testing. The pathogenesis of Alzheimer's disease and neurodementia is better understood today but remains incompletely elucidated. It has been suggested that inflammation exists both within the neurovasculature and the stroma and that beta-amyloid creates an inflammatory reaction. In Alzheimer's patients there are abnormal deposits of proteins such as beta-amyloid, presenelin, and apolipoprotein E-4. Estrogen may act as a protectant against these inflammatory mediating proteins. While a recent trial demonstrated no impact of estrogen in patients diagnosed with mild to moderate Alzheimer's, other studies have suggested that estrogen use significantly delays disease onset. One study followed over 1,100 subjects who were free of disease at trial initiation over a period of 1 to 5 years. Even short-term use of estrogen imparted protection, although longer-term estrogen use was associated with greater protection. Unfortunately, most women are unaware of the potential beneficial effect of estrogen on cognitive function. Prospective studies are under way to try to delineate how estrogen impacts Alzheimer's disease.

Bigler, E. D. (2001). "Premorbid brain volume and dementia." Arch Neurol 58(5): 831-3.

Billiard, M. and B. Ondze (2001). "[Disorders of awakening. Second part: secondary disorders]." Rev Neurol (Paris) 157(5): 480-96.
Secondary disorders of awakening should be distinguished from primary disorders, narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, the causes of which are still unknown despite regular progress in the knowledge of the pathophysiology of narcolepsy. By definition secondary disorders of awakening are due to clearly identified causes of various origins. Two main types of secondary disorders of awakening have been distinguished: those depending on more or less voluntary sleep curtailment or on psychotropic or non psychotropic medications and those consecutive to different disorders, respiratory, neurologic, traumatic, psychotropic, infectious, metabolic, endocrinologic, and insomnia. Some of these disorders, frequent or very frequent, are polysomnographically investigated, night and day, enabling to assess in each case the type and severity of sleepiness. Others are only clinically evaluated. Disorders of awakening secondary to neurologic conditions and to a lesser extent to infectious conditions offer a special opportunity to study the anatomical basis of these disorders. They are granted more space.

Birge, S. J., B. S. McEwen, et al. (2001). "Effects of estrogen deficiency on brain function. Implications for the treatment of postmenopausal women." Postgrad Med Spec No: 11-6.
A growing body of evidence suggests that postmenopausal estrogen deficiency accelerates brain aging and increases the risk of various neurodegenerative processes, including Alzheimer's disease. Recent preclinical and clinical studies have indicated that estrogen has positive effects on brain homeostasis by preserving neural plasticity and the neurotransmitter pathways involved in learning, memory, and balance. In this article, Dr Birge and his coauthors address the effects of estrogen on brain function and discuss their implications for the use of selective estrogen receptor modulators, particularly tamoxifen and raloxifene, in postmenopausal women.

Birkenhager, W. H., F. Forette, et al. (2001). "Blood pressure, cognitive functions, and prevention of dementias in older patients with hypertension." Arch Intern Med 161(2): 152-6.
The prevalence and incidence of degenerative and vascular dementias increase exponentially with age, from 70 years onward. In view of the increasing longevity of humans, both varieties are bound to evolve into a major problem worldwide. According to several longitudinal studies, hypertension appears to predispose individuals to the development of cognitive impairment and ensuing dementia, after a period varying from a few years to several decades. Antihypertensive drug treatment, according to preliminary evidence, may serve to reduce the rates of such events. Such findings await to be confirmed by formal therapeutic trials against a backdrop of "historical" observational sources.

Black, S. E., C. Patterson, et al. (2001). "Preventing dementia." Can J Neurol Sci 28 Suppl 1: S56-66.
Primary prevention will become increasingly important as dementia prevalence increases and effective retardive therapies are developed. To date, only one randomized controlled trial (involving treatment of systolic hypertension) has demonstrated that the incidence of dementia can be reduced. Physicians should remain alert to possible secondary causes of dementia and correct these whenever possible. Primary and secondary prevention of stroke should reduce dementia related to cerebrovascular disease either directly or as a comorbid factor in Alzheimer's disease (AD). Epidemiological studies have revealed a number of risk factors for AD including genetic mutation, susceptibility genes, positive family history, Down's syndrome, age, sex, years of education, head trauma and neurotoxins. In case-control studies non-steroidal anti-inflammatory medication and estrogen replacement therapy appear to decrease the relative risk of developing AD. Further research to develop and test preventative therapies in AD and other dementias should be strongly encouraged.

Blasko, I., G. Ransmayr, et al. (2001). "Does IFNgamma play a role in neurodegeneration?" J Neuroimmunol 116(1): 1-4.

Blass, J. P. (2001). "Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia?" J Neurosci Res 66(5): 851-6.
The potential of impairments in oxidative/energy metabolism to cause diseases of the brain had been proposed even before the major pathways of oxidative/energy metabolism were described. Deficiencies associated with disease are known in all the pathways of oxidative/energy metabolism and are associated with some of the most common disorders of the nervous system, including Alzheimer's disease (AD) and Parkinson's disease. A common mechanism in these conditions appears to be a downward mitochondrial spiral, involving abnormalities in energy metabolism, calcium metabolism, and free radicals (reactive oxygen and nitrogen species). In AD, the spiral appears to interact with abnormalities in the metabolism of the Alzheimer amyloid precursor protein (APP) and its Abeta fragment. Several lines of evidence indicate that the mitochondrial spiral may be a proximate cause of the clinical disabilities in AD. Decreases in cerebral metabolic rate (CMR) characteristically occur in AD and in other dementias. Inducing decreases in CMR leads to clinical disabilities characteristically associated with AD and with analogous problems in experimental animals. Treatments directed toward normalizing CMR appear to help at least some patients. Further studies of this possibility and of treatments designed to ameliorate the mitochondrial spiral may prove useful for treating AD and perhaps some other dementing disorders.

Bleys, R. L. and T. Cowen (2001). "Innervation of cerebral blood vessels: morphology, plasticity, age-related, and Alzheimer's disease-related neurodegeneration." Microsc Res Tech 53(2): 106-18.
The light microscopical and ultrastructural morphology of the innervation of the major cerebral arteries and pial vessels is described, including the origins of the different groups of nerve fibres and their characteristic neurotransmitter phenotype. Species and region specific variations are described and novel data regarding the parasympathetic innervation of cerebral vessels are presented. The dynamic nature, or plasticity, of cerebrovascular innervation is emphasized in describing changes affecting particular subpopulations of neurons during normal ageing and in Alzheimer's disease. The molecular controls on plasticity are discussed with particular reference to target-associated factors such as the neurotrophins and their neuronal receptors, as well as extracellular matrix related factors such as laminin. Hypotheses are presented regarding the principal extrinsic and intrinsic influences on plasticity of the cerebrovascular innervation.

Boada Rovira, M. (2001). "[Strategies for the treatment of Alzheimer's disease. The 'ad continuum' concept]." Rev Neurol 32(11): 1074-84.
The patient with dementia suffers a chronic disorder, with no specific treatment and little therapeutic response, which is accompanied by high co morbidity and additional complications which cause multiple symptoms which limit the patient s autonomy still further, modify the environment and create progressive dependence. Thus, from all angles, approach is very difficult both in seeking the cause and in prevention and also for treatment. The objective of this review is to establish the guidelines for treatment in view of the long term course of the disorder, in accordance with the specific weight and intensity of symptoms from the onset of the illness by means of precise diagnosis of the deficits and control of the commonest disorders which occur over time, such as psycho affective, psychotic, sleep disorders or treatment of a state of confusion and control of the diseases which are most frequent in this population. Finally, we briefly analyze the health care and social requirements of these patients and suggest general recommendations for carers to improve management, classifying the states of dementia into three degrees of severity.

Boddeke, E. W. (2001). "Involvement of chemokines in pain." Eur J Pharmacol 429(1-3): 115-9.
It is well established that neuroinflammation plays an important role in neurodegenerative diseases like Alzheimer's disease, stroke, traumatic brain- and spinal cord injury and demyelinating diseases. Likewise, it has been suggested that neuroinflammation plays an important role in nociception and hyperalgesia. Most research concerning inflammatory aspects of pain has concerned the effects of proinflammatory cytokines, prostaglandins and growth factors. Recently, it has been suggested that chemokines play a role in inflammatory pain. Chemokines do not only attract blood leukocytes to the site of injury but also contribute directly to nociception.

Boller, F. and G. D. Barba (2001). "Neuropsychological tests in Alzheimer's disease." Aging (Milano) 13(3): 210-20.
The recent development of symptomatic pharmacological treatment for Alzheimer's disease (AD) and the probable introduction of new therapies in a near future make the assessment of dementia at its different stages an even greater scientific and public health challenge. Neuropsychological tests, together with clinical data, are at present the only in vivo non-invasive screening and diagnostic tools for AD and related disorders. This chapter reviews the application to AD of standard batteries and short screening tests. It also analyzes the tests to be applied to detect and assess the specific deficits of the disease, and discusses the advantages and flaws of current screening and diagnostic tests of dementia. Emphasis is placed on the need to devise and use tests developed in a rational manner, with high sensitivity and specificity, not only in the moderate stages of the disease, but also in the very early and even "preclinical" stages, as well as during the late stages (severe dementia). It is known that neuropsychological tests allow one to determine various patients' profiles. Future research should determine the possible predictive value of these profiles. This has important implications for therapeutic trials. The current implicit assumption that all patients with AD tend to evolve and decline in a similar fashion needs to be critically re-examined.

Borek, C. (2001). "Antioxidant health effects of aged garlic extract." J Nutr 131(3s): 1010S-5S.
Oxidative modification of DNA, proteins and lipids by reactive oxygen species (ROS) plays a role in aging and disease, including cardiovascular, neurodegenerative and inflammatory diseases and cancer. Extracts of fresh garlic that are aged over a prolonged period to produce aged garlic extract (AGE) contain antioxidant phytochemicals that prevent oxidant damage. These include unique water-soluble organosulfur compounds, lipid-soluble organosulfur components and flavonoids, notably allixin and selenium. Long-term extraction of garlic (up to 20 mo) ages the extract, creating antioxidant properties by modifying unstable molecules with antioxidant activity, such as allicin, and increasing stable and highly bioavailable water-soluble organosulfur compounds, such as S-allylcysteine and S-allylmercaptocysteine. AGE exerts antioxidant action by scavenging ROS, enhancing the cellular antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and increasing glutathione in the cells. AGE inhibits lipid peroxidation, reducing ischemic/reperfusion damage and inhibiting oxidative modification of LDL, thus protecting endothelial cells from the injury by the oxidized molecules, which contributes to atherosclerosis. AGE inhibits the activation of the oxidant-induced transcription factor, nuclear factor (NF)-kappa B, which has clinical significance in human immunodeficiency virus gene expression and atherogenesis. AGE protects DNA against free radical--mediated damage and mutations, inhibits multistep carcinogenesis and defends against ionizing radiation and UV-induced damage, including protection against some forms of UV-induced immunosuppression. AGE may have a role in protecting against loss of brain function in aging and possess other antiaging effects, as suggested by its ability to increase cognitive functions, memory and longevity in a senescence-accelerated mouse model. AGE has been shown to protect against the cardiotoxic effects of doxorubicin, an antineoplastic agent used in cancer therapy and against liver toxicity caused by carbon tetrachloride (an industrial chemical) and acetaminophen, an analgesic. Substantial experimental evidence shows the ability of AGE to protect against oxidant-induced disease, acute damage from aging, radiation and chemical exposure, and long-term toxic damage. Although additional observations are warranted in humans, compelling evidence supports the beneficial health effects attributed to AGE, i.e., reducing the risk of cardiovascular disease, stroke, cancer and aging, including the oxidant-mediated brain cell damage that is implicated in Alzheimer's disease.

Brandt, R. (2001). "Cytoskeletal mechanisms of neuronal degeneration." Cell Tissue Res 305(2): 255-65.
The cytoskeleton is the major intracellular determinant of neuronal morphology and is required for fundamental processes during the development and maintenance of a neuron. Thus, it is not surprising that many neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis (motor neuron disease) are characterized by typical abnormalities in the organization of the cytoskeleton. However, the role of the cytoskeletal changes during the development of the disease, e.g., whether they have a causative role during neuronal degeneration or represent an epiphenomenon of neurons that degenerate by other means, is still disputed. In this review, recent results on the development and the role of cytoskeletal abnormalities during neurodegenerative diseases are discussed and a mechanistic framework for the involvement of cytoskeletal changes during neurodegenerative processes is presented.

Brandt, J. (2001). "Mild cognitive impairment in the elderly." Am Fam Physician 63(4): 620, 622, 625-6.

Brinton, R. D. (2001). "Cellular and molecular mechanisms of estrogen regulation of memory function and neuroprotection against Alzheimer's disease: recent insights and remaining challenges." Learn Mem 8(3): 121-33.
This review focuses on recent advances in our knowledge of estrogen action in the brain. The greatest amount of attention was devoted to those studies that impact our understanding of estrogen regulation of memory function and prevention of degenerative diseases associated with memory systems, such as Alzheimer's disease. A review of recent advances in our understanding of estrogen receptors, both nuclear and membrane, is also presented. Finally, these data are considered in regard to their relevancy to the use of estrogen replacement therapy for cognitive health throughout menopause and the development of an estrogen replacement therapy designed for the unique requirements of the brain.

Brodaty, H., D. Ames, et al. (2001). "Pharmacological treatment of cognitive deficits in Alzheimer's disease." Med J Aust 175(6): 324-9.
Clinical trials and independent reviews support the use of cholinesterase inhibitors for treating the symptoms of patients with mild to moderate Alzheimer's disease (AD). Before initiating cholinesterase inhibitor therapy, patients should be thoroughly assessed, and the diagnosis confirmed, preferably by a specialist. Compliance with cholinesterase inhibitor therapy should be monitored and the response (in global, cognitive, functional and behavioural domains) reassessed after 2-3 months of treatment. Vitamin E may be protective against AD, and therapy with 1000 IU twice daily may be considered. There is insufficient evidence to support the use of other antioxidant agents, anti-inflammatory agents, monoamine oxidase B inhibitors, folate/homocysteine or antihypertensive drugs in patients with AD, or hormone replacement therapy in affected women.

Brody, J. A. and M. D. Grant (2001). "Age-associated diseases and conditions: implications for decreasing late life morbidity." Aging (Milano) 13(2): 64-7.
We discuss two types of age-associated diseases; aging-dependent such as Alzheimer's disease and congestive heart failure which increase logarithmically with age, versus age-dependent such as multiple sclerosis and amyotrophic lateral sclerosis which occur at proscribed ages, and then occurrence of new cases ceases or diminishes with further aging. Prevention strategies with both types emphasize postponement or delay of onset. The non-fatal aging-dependent diseases and conditions are an accumulating burden as we age, and increase overall morbidity in late years. These include Alzheimer's disease and other dementias, Parkinson's disease, loss of vision and hearing, incontinence, osteoporosis and hip fracture, osteoarthritis and depression. With mortality postponed, we will be living for many years at old and vulnerable ages. Life's quality will be reasonable for most. Still, increasing the chance that all will experience this desirable outcome requires pursuing the means to delay the onset of the physical and social events which we categorize as the non-fatal aging-dependent diseases and conditions. We must recognize that each added year occurs at the tip of an exponential curve where risk is maximal.

Bruno, V., G. Battaglia, et al. (2001). "Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs." J Cereb Blood Flow Metab 21(9): 1013-33.
Metabotropic glutamate (mGlu) receptors have been considered as potential targets for neuroprotective drugs, but the lack of specific drugs has limited the development of neuroprotective strategies in experimental models of acute or chronic central nervous system (CNS) disorders. The advent of potent and centrally available subtype-selective ligands has overcome this limitation, leading to an extensive investigation of the role of mGlu receptor subtypes in neurodegeneration during the last 2 years. Examples of these drugs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and LY379268. Pharmacologic blockade of mGlu1 or mGlu5 receptors or pharmacologic activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a variety of in vitro or in vivo models. MGlu1 receptor antagonists are promising drugs for the treatment of brain ischemia or for the prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity of N-methyl-d-aspartate (NMDA) receptors, because mGlu5 and NMDA receptors are physically and functionally connected in neuronal membranes. A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer disease. MGlu2/3 receptor agonists inhibit glutamate release, but also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprotective agents in a variety of CNS disorders. Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders. The advantage of all these drugs with respect to NMDA or AMPA receptor agonists derives from the evidence that mGlu receptors do not "mediate," but rather "modulate" excitatory synaptic transmission. Therefore, it can be expected that mGlu receptor ligands are devoid of the undesirable effects resulting from the inhibition of excitatory synaptic transmission, such as sedation or an impairment of learning and memory.

Bruunsgaard, H., M. Pedersen, et al. (2001). "Aging and proinflammatory cytokines." Curr Opin Hematol 8(3): 131-6.
Aging is associated with increased inflammatory activity reflected by increased circulating levels of TNF-alpha, IL-6, cytokine antagonists and acute phase proteins in vivo. Epidemiologic studies suggest that chronic low-grade inflammation in aging promotes an atherogenic profile and is related to age-associated disorders (eg, Alzheimer disease, atherosclerosis, type 2 diabetes, etc.) and enhanced mortality risk. Accordingly, a dysregulated production of inflammatory cytokines has an important role in the process of aging. Studies of age-related differences in the production of proinflammatory cytokines in response to acute stimulations in vitro have yielded inconsistent results. However, in vivo infectious models show delayed termination of inflammatory activity and a prolonged fever response in elderly humans, suggesting that the acute phase response is altered in aging. However, a causal relation between the acute phase response and the increased mortality because of bacterial infections in older patients remains to be demonstrated.

Bryant, J., A. Clegg, et al. (2001). "Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer's disease: a rapid and systematic review." Health Technol Assess 5(1): 1-137.
BACKGROUND: Alzheimer's disease is the most common cause of dementia and is characterised by an insidious onset and slow deterioration. The estimated prevalence of Alzheimer's disease for a standard health authority (500,000 people) is about 3330. Current service involves a wide range of agencies, and drug therapy for some patients. OBJECTIVES: To provide a rapid and systematic review of the clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine in the symptomatic treatment of people suffering from Alzheimer's disease. METHODS: A systematic review of the literature was undertaken. METHODS - DATA SOURCES: Searches were made of electronic databases, including MEDLINE, EMBASE, The Cochrane Library, Database of Abstracts of Reviews of Effectiveness, NHS Economic Evaluation Database, National Research Register, Science Citation Index, BIOSIS, EconLit, MRC Trials database, Early Warning System, Current Controlled Trials, TOXLINE, Index of Scientific and Technical Proceedings, and Getting Easier Access to Reviews. All sources were searched over the period covered by the databases up to March/July 2000. Bibliographies of related papers were assessed for relevant studies and experts were contacted for advice and peer review, and to identify additional published and unpublished references. Manufacturer submissions to the National Institute for Clinical Excellence (NICE) were reviewed. METHODS - STUDY SELECTION: Studies were included if they fulfilled the following criteria: (1) Intervention: donepezil, rivastigmine or galantamine used to treat Alzheimer's disease. (2) Participants: people diagnosed with Alzheimer's disease who meet the criteria for treatment with donepezil, rivastigmine and galantamine. (3) Outcomes: measures assessing changes in cognition, function, behaviour and mood, quality of life (including studies assessing carer well-being and carer-input), and time to institutionalisation. (4) Design: systematic reviews of randomised controlled trials (RCTs) and RCTs comparing donepezil, rivastigmine or galantamine with placebo or each other or non-drug comparators were included in the review of effectiveness. Economic studies of donepezil, rivastigmine or galantamine used to treat Alzheimer's disease that included a comparator (or placebo) and both the costs and consequence (outcomes) of treatment were included in the review of cost-effectiveness. Studies in non-English language, and abstracts and conference poster presentations of systematic reviews, RCTs and economic evaluations were excluded. Two reviewers identified studies by independently screening study titles and abstracts, and then by examining the full text of selected studies to decide inclusion. METHODS - DATA EXTRACTION AND QUALITY ASSESSMENT: Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer, with any disagreements resolved through discussion. The quality of RCTs was assessed using the Jadad scale and the quality of systematic reviews was assessed using criteria developed by the NHS Centre for Reviews and Dissemination. The quality of economic evaluation studies was assessed by their internal validity (i.e. the methods used) using a standard checklist, and external validity (i.e. the generalisability of the economic study to the population of interest) using a series of relevant questions. METHODS - DATA SYNTHESIS: The clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine were synthesised through a narrative review with full tabulation of results of all included studies. In the economic evaluation, the reviewers assessed whether adjustments could be made to existing models to reflect the current situation in England and Wales. RESULTS - CLINICAL EFFECTIVENESS: (1) Donepezil--three systematic reviews and five RCTs (plus four studies from industry (unpublished data, submitted as commercial in confidence)) were found. Results suggest that donepezil is beneficial when assessed using global and cognitive outcome measures. (2) Rivastigmine--three systematic reviews and five RCTs (plus two studies from industry (unpublished data, submitted as commercial in confidence)) were found. Results suggest that rivastigmine is beneficial in terms of global outcome measures. (3) Galantamine--one systematic review and three RCTs (plus three studies from industry (unpublished data, submitted as commercial in confidence)) were found. Results suggest that galantamine is beneficial in terms of global, cognitive and functional scales. RESULTS - SUMMARY OF BENEFITS: It is difficult to quantify benefits from the evidence available in the literature. Statistically significant improvements in tests such as ADAS-cog (Alzheimer's Disease Assessment Scale cognitive subscale) may not be reflected in changes in daily life. (ABSTRACT TRUNCATED)

Bu, G. (2001). "The roles of receptor-associated protein (RAP) as a molecular chaperone for members of the LDL receptor family." Int Rev Cytol 209: 79-116.
Members of the LDL receptor family mediate endocytosis and signal transduction of many extracellular ligands which participate in lipoprotein metabolism, protease regulation, embryonic development, and the pathogenesis of disease (e.g., Alzheimer's disease). Structurally, these receptors share common motifs and modules that are highlighted with clusters of cysteine-rich ligand-binding repeats. Perhaps, the most significant feature that is shared by members of the LDL receptor family is the ability of a 39-kDa receptor-associated protein (RAP) to universally inhibit ligand interaction with these receptors. Under physiological conditions, RAP serves as a molecular chaperone/escort protein for these receptors to prevent premature interaction of ligands with the receptors and thereby ensures their safe passage through the secretory pathway. In addition, RAP promotes the proper folding of these receptors, a function that is likely independent from its ability to inhibit ligand binding. The molecular mechanisms underlying these functions of RAP, as well as the molecular determinants that contribute to RAP-receptor interaction will be discussed in this review. Elucidation of these mechanisms should help to clarify how a specialized chaperone promotes the biogenesis of LDL receptor family members, and may provide insights into how the expression and function of these receptors can be regulated via the expression of RAP under pathological states.

Burkman, R. T., J. A. Collins, et al. (2001). "Current perspectives on benefits and risks of hormone replacement therapy." Am J Obstet Gynecol 185(2 Suppl): S13-23.
Hormone replacement therapy with estrogen alone or with added progestin relieves menopausal symptoms and physical changes associated with depleted endogenous estrogen levels. Estrogen replacement has also demonstrated a clear benefit in the prevention of osteoporosis. Hormone replacement therapy with added progestin maintains spinal bone density, protects against postmenopausal hip fractures, and provides these benefits even when therapy is started after age 60. More recently, additional benefits have emerged. Current estrogen and hormone replacement therapy users have a 34% reduction in the risk of colorectal cancer and a 20% to 60% reduction in the risk of Alzheimer's disease. Until recently, the body of evidence indicated that hormone replacement therapy with estrogen only reduced cardiovascular disease risk by 40% to 50% in healthy patients; whether the findings of 3 ongoing trials will change this conclusion is pending availability of the final results. The many benefits of estrogen and hormone replacement therapy must be weighed against a slight increase in the risk of breast cancer diagnosis with use for 5 or more years, but which disappears following cessation of therapy. Overall, estrogen and hormone replacement therapy improves the quality of life and increases life expectancy for most menopausal women.

Bush, A. I. and L. E. Goldstein (2001). "Specific metal-catalysed protein oxidation reactions in chronic degenerative disorders of ageing: focus on Alzheimer's disease and age-related cataracts." Novartis Found Symp 235: 26-38; discussion 38-43.
Abnormalities of protein aggregation and deposition may play an important role in the pathophysiology of a diverse set of chronically progressive degenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and age-related cataracts. We propose that aberrant metalloprotein reactions may be a common denominator in these diseases. In these instances, an abnormal reaction between a protein and redox active metal ions (especially copper or iron) promotes the generation of reactive oxygen species, and possibly, protein radicalization. These products then lead to chemical modification of the protein, alterations in protein structure and solubility, and oxidative damage to surrounding tissue. In this review, we explore these ideas by focusing on two common diseases of ageing, Alzheimer's disease and age-related cataracts. Understanding the metalloprotein biochemistry in both diseases may lead to a better understanding of the underlying pathophysiology in both disorders and suggest novel targets for therapeutic agents.

Butterfield, D. A., J. Drake, et al. (2001). "Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide." Trends Mol Med 7(12): 548-54.
Amyloid beta-peptide (Abeta) is heavily deposited in the brains of Alzheimer's disease (AD) patients. Free-radical oxidative stress, particularly of neuronal lipids, proteins and DNA, is extensive in those AD brain areas in which Abeta is abundant. Recent research suggests that these observations might be linked, and it is postulated that Abeta-induced oxidative stress leads to neurodegeneration in AD brain. Consonant with this postulate, Abeta leads to neuronal lipid peroxidation, protein oxidation and DNA oxidation by means that are inhibited by free-radical antioxidants. Here, we summarize current research on phospholipid peroxidation, as well as protein and DNA oxidation, in AD brain, and discuss the potential role of Abeta in this oxidative stress.

Butterfield, D. A., B. J. Howard, et al. (2001). "Brain oxidative stress in animal models of accelerated aging and the age-related neurodegenerative disorders, Alzheimer's disease and Huntington's disease." Curr Med Chem 8(7): 815-28.
Oxidative stress in brain is emerging as a potential causal factor in aging and age-related neurodegenerative disorders. Brain tissue from living patients is difficult to acquire; hence, animal models of aging and age-related neurodegenerative disorders, though not perfect models, have provided tissue to study the role of oxidative stress in these disorders. In this review, the central role of oxidative damage in brain in models of accelerated aging (progeria and Werner's syndrome) and the age-related neurodegenerative disorders, Alzheimer's disease and Huntington's disease, will be presented and evaluated. To the extent that the animal models faithfully mirror their respective disorders, and based on the totality of the studies, it is apparent that oxidative stress, the excess of free radicals over the means of scavenging these harmful agents, may play critical roles in the molecular basis of accelerated aging, Alzheimer's disease, and Huntington's disease.

Butterfield, D. A. and J. Kanski (2001). "Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins." Mech Ageing Dev 122(9): 945-62.
Protein oxidation, one of a number of brain biomarkers of oxidative stress, is increased in several age-related neurodegenerative disorders or animal models thereof, including Alzheimer's disease, Huntington's disease, prion disorders, such as Creutzfeld-Jakob disease, and alpha-synuclein disorders, such as Parkinson's disease and frontotemporal dementia. Each of these neurodegenerative disorders is associated with aggregated proteins in brain. However, the relationship among protein oxidation, protein aggregation, and neurodegeneration remain unclear. The current rapid progress in elucidation of mechanisms of protein oxidation in neuronal loss should provide further insight into the importance of free radical oxidative stress in these neurodegenerative disorders.

Byerly, M. J., M. T. Weber, et al. (2001). "Antipsychotic medications and the elderly: effects on cognition and implications for use." Drugs Aging 18(1): 45-61.
Despite being frequently prescribed in the elderly, antipsychotic medications are commonly associated with adverse effects in this population, including sedative, orthostatic and extrapyramidal adverse effects. Growing evidence suggests that antipsychotics can also cause deleterious cognitive effects in some elderly patients. Preclinical and growing clinical evidence indicates that inhibitory effects on dopaminergic, cholinergic and histaminergic neurochemical systems may account for antipsychotic-associated cognitive impairment in the elderly. A review of published reports of the cognitive effects of antipsychotics in the elderly suggests that newer antipsychotic medications may possess a more favourable cognitive profile than that of traditional agents in this population. The cognitive effect that a specific antipsychotic will have in the elderly, however, is likely better predicted by considering the pharmacodynamic action of an individual agent in combination with the pathophysiology of the condition being treated. Agents with relatively weak dopamine inhibiting effects (e.g. clozapine and quetiapine), for example, would theoretically have a cognitive profile superior to that of agents with higher degrees of dopaminergic inhibition (all traditional agents, risperidone, olanzapine and ziprasidone) when used for conditions associated with diminished dopamine function (e.g. idiopathic Parkinson's disease). Drugs with weak anticholinergic effects (high-potency traditional agents, risperidone, quetiapine and ziprasidone) would theoretically be less likely to cause cognitive impairment than agents with high degrees of cholinergic receptor blocking actions (clozapine and olanzapine) when treating patients with impaired cholinergic function (e.g. Alzheimer's disease). Cholinergic agonist effects of clozapine and olanzapine may, however, mitigate potential adverse cognitive effects associated with the cholinergic blocking actions of these agents. Large, rigorous trials comparing the cognitive effects of antipsychotics with diverse pharmacodynamic actions are lacking in the elderly and are needed.

Calabrese, V., G. Scapagnini, et al. (2001). "Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity." Neurochem Res 26(6): 739-64.
It is becoming increasingly evident that the mitochondrial genome may play a key role in neurodegenerative diseases. Mitochondrial dysfunction is characteristic of several neurodegenerative disorders, and evidence for mitochondria being a site of damage in neurodegenerative disorders is partially based on decreases in respiratory chain complex activities in Parkinson's disease, Alzheimer's disease, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant balance perturbation, are thought to underlie defects in energy metabolism and induce cellular degeneration. Efficient functioning of maintenance and repair process seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of genes termed vitagenes. A promising approach for the identification of critical gerontogenic processes is represented by the hormesis-like positive effect of stress. In the present review, we discuss the role of energy thresholds in brain mitochondria and their implications in neurodegeneration. We then review the evidence for the role of oxidative stress in modulating the effects of mitochondrial DNA mutations on brain age-related disorders and also discuss new approaches for investigating the mechanisms of lifetime survival and longevity.

Calabrese, E. J. (2001). "Amyloid beta-peptide: biphasic dose responses." Crit Rev Toxicol 31(4-5): 605-6.
This article summarizes recent findings indicating that amyloid beta-peptide displays neurotoxic and neurotrophic effects, depending on concentration. Mechanistic findings revealed that reactive oxygen species mediate both the toxic and neurotropic responses as a function of concentration with low doses being neutotrophic, while higher doses were toxic. The data reveal a potential biological function for amyloid beta-peptide within an optimal concentration zone. These findings suggest the critical role of dose in understanding disease causation and clinical therapeutics for Alzheimer's disease.

Canales, J. J., R. Corbalan, et al. (2001). "Aluminium impairs the glutamate-nitric oxide-cGMP pathway in cultured neurons and in rat brain in vivo: molecular mechanisms and implications for neuropathology." J Inorg Biochem 87(1-2): 63-9.
Aluminium (Al) is a neurotoxicant and appears as a possible etiological factor in Alzheimer's disease and other neurological disorders. The mechanisms of Al neurotoxicity are presently unclear but evidence has emerged suggesting that Al accumulation in the brain can alter neuronal signal transduction pathways associated with glutamate receptors. In cerebellar neurons in culture, long term-exposure to Al added 'in vitro' impaired the glutamate-nitric oxide (NO)-cyclic GMP (cGMP) pathway, reducing glutamate-induced activation of NO synthase and NO-induced activation of the cGMP generating enzyme, guanylate cyclase. Prenatal exposure to Al also affected strongly the function of the glutamate-NO-cGMP pathway. In cultured neurons from rats prenatally exposed to Al, we found reduced content of NO synthase and of guanylate cyclase, and a dramatic decrease in the ability of glutamate to increase cGMP formation. Activation of the glutamate-NO-cGMP pathway was also strongly impaired in cerebellum of rats chronically treated with Al, as assessed by in vivo brain microdialysis in freely moving rats. These findings suggest that the impairment of the Glu-NO-cGMP pathway in the brain may be responsible for some of the neurological alterations induced by Al.

Capone, G. T. (2001). "Down syndrome: advances in molecular biology and the neurosciences." J Dev Behav Pediatr 22(1): 40-59.
The entire DNA sequence for human chromosome 21 is now complete, and it is predicted to contain only about 225 genes, which is approximately three-fold fewer than the number initially predicted just 10 years ago. Despite this remarkable achievement, very little is known about the mechanism(s) whereby increased gene copy number (gene dosage) results in the characteristic phenotype of Down syndrome. Although many of the phenotypic traits show large individual variation, neuromotor dysfunction and cognitive and language impairment are observed in virtually all individuals. Currently, there are no efficacious biomedical treatments for these central nervous system-associated impairments. To develop novel therapeutic strategies, the effects of gene dosage imbalance need to be understood within the framework of those critical biological events that regulate brain organization and function.

Carlson, L. A. and B. Winblad (2001). "[Reduced prevalence of dementia in patients treated with antilipemic agents. An overview of cholesterol metabolism in the brain and actions]." Lakartidningen 98(36): 3795-7.

Carpenter, D. O. (2001). "Effects of metals on the nervous system of humans and animals." Int J Occup Med Environ Health 14(3): 209-18.
Several metals have toxic actions on nerve cells and neurobehavorial functioning. These toxic actions can be expressed either as developmental effects or as an increased risk of neurodegenerative diseases in old age. The major metals causing neurobehavioral effects after developmental exposure are lead and methylmercury. Lead exposure in young children results in a permanent loss of IQ of approximately 5 to 7 IQ points, and also results in a shortened attention span and expression of anti-social behaviors. There is a critical time period (<2 years of age) for development of these effects, after which the effects do not appear to be reversible even if blood lead levels are lowered with chelation. Methylmercury has also been found to have effects on cognition at low doses, and prenatal exposure at higher levels can disrupt brain development. Metals have also been implicated in neurodegenerative diseases, although it is unlikely that they are the sole cause for any of them. Elevated aluminum levels in blood, usually resulting from kidney dialysis at home with well water containing high aluminum, result in dementia that is similar to but probably different from that of Alzheimer's disease. However, there is some epidemiological evidence for elevated risk of Alzheimer's in areas where there is high concentration of aluminum in drinking water. Other metals, especially lead, mercury, manganese and copper, have been implicated in amvotrophic lateral sclerosis and Parkinson's disease.

Castellano, C., V. Cestari, et al. (2001). "NMDA receptors and learning and memory processes." Curr Drug Targets 2(3): 273-83.
In the first part of this review studies are considered in which pre- or post-training peripheral or intracerebroventricular administrations of competitive or noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were carried out in a variety of animal species tested in different experimental conditions, in order to investigate the effects of these drugs on acquisition and memory processes. In particular, post-training treatments, which are known to affect memory consolidation, ruling out the possible "aspecific effects" linked to the pre-training administrations, show that the NMDA receptor antagonists impair memory in animals tested in various tasks. Memory impairments are also evident when the NMDA antagonists (in particular AP5) are injected into different brain structures, including amygdala and hippocampus. In a second part of this review some recent studies are considered showing the existence of: a) cholinergic-glutamatergic interactions; b) interactions between NMDA receptors and opioid system, and c) interactions between NMDA receptor antagonists (MK-801) and cocaine, in the modulation of memory processes of laboratory animals. The results of some studies showing the involvement of glutamatergic mechanisms in Alzheimer's disease are finally reported, and the therapeutic efficacy of glutamatergic drugs in the treatment of this disease is considered.

Cechetto, D. F. (2001). "Role of nuclear factor kappa B in neuropathological mechanisms." Prog Brain Res 132: 391-404.

Chadha, S. and J. Young (2001). "Key developments in geriatric medicine." Practitioner 245(1626): 698-700, 702, 704-5 passim.

Chan, P. L. and N. H. Holford (2001). "Drug treatment effects on disease progression." Annu Rev Pharmacol Toxicol 41: 625-59.
Degenerative diseases are characterized by a worsening of disease status over time. The rate of deterioration is determined by the natural rate of progression of the disease and by the effect of drug treatments. A goal of drug treatment is to slow disease progression. Drug treatments can be categorized as symptomatic or protective. Symptomatic treatments do not affect the rate of disease progression whereas protective treatments have the ability to slow disease progression down. Many current methods for describing disease progression have two common drawbacks: a linear relationship between time and disease status is assumed, and within- and between-subject variability is ignored. Disease progress models combined with pharmacokinetic pharmacodynamic models and hierarchical random effects statistical models provide insights into understanding the time course and management of degenerative disease.

Chapman, P. F., A. M. Falinska, et al. (2001). "Genes, models and Alzheimer's disease." Trends Genet 17(5): 254-61.
Alzheimer's disease (AD) is a neurodegenerative disorder that is claiming an increasing number of victims as the world population ages. The identification of gene mutations and polymorphisms that either cause AD or significantly increase the risk for developing it enabled the creation of a whole generation of realistic rodent models of the disease. Animals expressing mutated human amyloid precursor protein and presenilin 1 show dramatic parallels to AD, although none of the models appear to capture the full range of pathologies that characterize the human disease. Increased refinement of these models will enhance the already tantalizing possibility of treatment.

Checler, F. (2001). "The multiple paradoxes of presenilins." J Neurochem 76(6): 1621-7.

Chen, M. and H. L. Fernandez (2001). "Alzheimer movement re-examined 25 years later: is it a "disease" or a senile condition in medical nature?" Front Biosci 6: E30-40.
Dementia in the elderly used to be rare, but why has it become a major social threat today? There can be many potential answers, but an ultimate one is clear: the longer life expectancy today. This knowledge indicates that "advanced aging" is a primary suspect in the origin of senile dementia. If so, then why can many elderly remain healthy at the same old age? We know, for example, that elderly people commonly have a certain degree of atherosclerosis and osteoporosis, but only some of them develop severe clinical symptoms at the same age. These different outcomes generally can be explained by "risk factors" in life (exercise, diet, individual background, etc). It thus appears to be a general pattern that advanced aging (after age 80) will set the stage for various senile disorders, but risk factors largely determine the onset age as well as individual specificity of their clinical manifestations. In this context, senile disorders including senile dementia would differ fundamentally from the pathogen-caused conventional diseases (AIDS, polio, cancer, Down's, etc.) by origin, incidence, and intervention strategy. This view would call into question the current definition of senile dementia as a conventional "disease" (Alzheimer's). The term "Alzheimer's disease" originally referred to "midlife" dementia, but it is defined today to be the same medical entity as senile dementia on the basis that they both display the same hallmarks and symptoms despite their onset age difference. Now, after in-depth scrutiny, we finally come to realize that they are not the same disease, but as different as heart failure at midlife versus the "same" failure at advanced age (i.e., a conventional disease versus a senile condition). Thus, by eliminating the age difference, the new definition has converted a senile condition into a conventional "disease", thereby changing the course of its scientific inquiry to miss the main targets. This may be why after extensive studies for 25 years, the origin of senile dementia has remained an enigma.

Chen, M. and H. L. Fernandez (2001). "Where do Alzheimer's plaques and tangles come from? Aging-induced protein degradation inefficiency." Front Biosci 6: E1-E11.
Amyloid plaques and neurofibrillary tangles are prominent lesions in the aging brain and they may be responsible for cell death in Alzheimer's disease. But a basic question has not been answered: why and how are plaques and tangles formed during aging? In this study, we approach this question by first examining what happens in the aging body. Plaques and tangles do not come alone, but together with many other aging markers in the body (cholesterol deposition, gallstones, hair graying, and bone loss, etc.). Because these aging markers occur to a certain extent in all elderly and at about the same time in life, it is reasonable to conceive that they originate from a common cause, that is, aging-induced metabolic inefficiency. If cholesterol and gallstone depositions are the results of inefficient degradation/clearance of lipids and minerals, then similarly plaque and tangle formation in most people would be the results of inefficient normal degradation of ?-amyloid precursor protein (APP) and tau, respectively. By this view, our studies should focus on the enzymes responsible for APP and tau normal degradation and their natural changes in aging, rather than on presumed pathological factors. Whatever precise mechanisms underlying their depositions, plaques and tangles are the natural products of aging, thus fundamentally different from pathological events such as cancer growth in concept.

Chertkow, H., H. Bergman, et al. (2001). "Assessment of suspected dementia." Can J Neurol Sci 28 Suppl 1: S28-41.
At the Second Canadian Consensus Conference on Dementia (CCCD) (February, 1998), a group of neurologists, geriatricians, and psychiatrists met to consider guidelines for evaluation of dementia in Canada. This review paper formed a background paper for their discussion of dementia diagnosis. These experts from across the country concluded that diagnosis of suspected dementia cases continued to rest on skilled clinical assessment. Mental status exam, preferably in some quantifiable form, has become an essential part of the assessment. Selected laboratory tests are advisable in all cases (CBC, TSH, electrolytes, calcium, and glucose), but the CCCD continued to advise that CT scanning was mandatory only in selected cases where clinical findings pointed to another possibility besides Alzheimer's disease. The growing list of other diagnostic measures with potential usefulness in diagnosis of Alzheimer's disease or dementia in general was reviewed, but the evidence was judged as insufficient to support routine use of these tests by physicians. As new treatments for Alzheimer's disease become available, neurologists face new diagnostic challenges--differentiating Mild Cognitive Impairment, Frontotemporal dementias and Mixed dementias, and Lewy Body Dementia. Guidelines to aid in differential diagnosis are presented.

Chodobski, A. and J. Szmydynger-Chodobska (2001). "Choroid plexus: target for polypeptides and site of their synthesis." Microsc Res Tech 52(1): 65-82.
Choroid plexus (CP) is an important target organ for polypeptides. The fenestrated phenotype of choroidal endothelium facilitates the penetration of blood-borne polypeptides across the capillary walls. Thus, both circulating and cerebrospinal fluid (CSF)-borne polypeptides can reach their receptors on choroidal epithelium. Several polypeptides have been demonstrated to regulate CSF formation by controlling blood flow to choroid plexus and/or the activity of ion transport in choroidal epithelium. However, many ligand-receptor interactions occurring in the CP are not involved in the regulation of fluid secretion. Increasing evidence suggests that the choroidal epithelium plays an important role in hormonal signaling via a receptor-mediated transport into the brain (e.g., leptin) and helps to clear certain CSF-borne polypeptides (e.g., soluble amyloid beta-protein). Thus, impaired choroidal transport or insufficient clearance of polypeptides may contribute to pathogenesis of systemic or central nervous system (CNS) disorders, such as obesity or Alzheimer's disease. CP epithelium is not only a target but is also a source of neuropeptides, growth factors, and cytokines in the CNS. These polypeptides following their release into the CSF may exert distal, endocrine-like effects on target cells in the brain due to bulk flow of this fluid. Distinct temporal patterns of choroidal expression of several polypeptides are observed during brain development and in various CNS disorders, including traumatic brain injury and ischemia. Therefore, it is proposed that the CP plays an integral role not only in normal brain functioning, but also in the recovery from the injury. This review attempts to critically analyze the available data to support the above hypothesis.

Chorsky, R. L., F. Yaghmai, et al. (2001). "Alzheimer's disease: a review concerning immune response and microischemia." Med Hypotheses 56(1): 124-7.
Alzheimer's disease (AD), as we think of it today, is the idiopathic progressive loss of cognitive function over a period of several years. The risk of late onset dementia increases significantly with each decade of life such that half of the population over the age of 80 is vulnerable to this disease (1). We know that proper functioning of the central nervous system is dependent on adequate blood flow to remove harmful metabolic products and supply nutrients such as glucose and oxygen to the brain. It has been suggested that cerebral hypoperfusion causes AD (2). Mean cerebral blood flow decreases with age and with sclerosis of cerebral blood vessels. Blood flow appears to increase in stimulated areas of the brain during different activities. However, there is a derangement of blood flow in disease states; this has been documented in the temporal lobes of AD patients, (3,4). English language journal articles located by a MEDLINE search (1960-1999) were reviewed with consideration to the hypothesis that Alzheimer's disease is an autoimmune disease initiated by low oxygen tension and microischemia. Inflammation is thought to be a known contributor to the pathology of AD (5,6). Recent reports support the concept of autoimmunity as a final common pathway of neuron death, particularly for cholinergic in Alzheimer's disease (6). A model of Alzheimer's disease is proposed and related research and treatment modalities are discussed.

Chui, H. (2001). "Dementia due to subcortical ischemic vascular disease." Clin Cornerstone 3(4): 40-51.
Ischemic vascular disease (IVD) is the second most common cause of dementia in the Western world. This article focuses on dementia resulting from subcortical ischemic vascular disease (SIVD), a subtype of IVD, which in many cases may be prevented. Hypertension and diabetes are the leading causes of small-artery disease, subcortical brain ischemia, and stepwise or slowing progressive decline in cognitive function. The pattern of cognitive impairment in SIVD, as compared with Alzheimer's disease, is characterized by greater impairment of executive function but better preservation of recognition memory. Structural neuroimaging studies, such as computed tomography and especially magnetic resonance imaging, are more sensitive than the clinical examination and can enable detection of subcortical lacunes and deep white matter changes that are clinically silent. Often the brain can be protected against SIVD by early diagnosis and management of risk factors. Once end-organ damage has occurred, however, treatment outcome is less satisfactory. The most common risk factors for SIVD--hypertension and diabetes mellitus--are best detected and managed in primary care settings.

Clippingdale, A. B., J. D. Wade, et al. (2001). "The amyloid-beta peptide and its role in Alzheimer's disease." J Pept Sci 7(5): 227-49.
Amyloid formation plays a central role in the cause and progression of Alzheimer's disease. The major component of this amyloid is the amyloid-beta (A beta) peptide, which is currently the subject of intense study. This review discusses some recent studies in the area of A beta synthesis, purification and structural analysis. Also discussed are proposed mechanisms for A beta-induced neurotoxicity and some recent advances in the development of A beta-related therapeutic strategies.

Clostre, F. (2001). "[Mitochondria: recent pathophysiological discoveries and new therapeutic perspectives]." Ann Pharm Fr 59(1): 3-21.
Until about a decade ago, few researchers in clinical or evolutionary biology paid much attention to mitochondria. But over the years, as technological advances in molecular biology made nuclear functions more accessible to them, interest in mitochondria began to revive. First, geneticists started tracing certain rare inherited disorders to mutations in the mitochondria's circular genome. More recently, other researchers have speculated that mitochondria might contribute to aging, either by releasing tissue-damaging reactive oxygen molecules or by impairing and depriving the cell of the energy it needs to function. One the most important recent developments has been the recognition that mitochondria play a central role in the regulation of programmed cell death, or apoptosis. Now, we know that mitochondria play a decisive role in life-death decisions for the cell and may choose between the apoptotic and necrotic pathways. Mitochondria can trigger cell death in a number of ways: by disrupting electron transport and energy metabolism, by activating the mitochondrial permeability transition, by releasing and/or activating proteins that mediate apoptosis. Any or all of these mechanisms may help to explain how mitochondrial defects contribute to the pathogenesis of neuronal death or dysfunction in ischemia/reperfusion injury as well as in human degenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. This has opened up new avenues for understanding the pathogenesis of neurodegeneration and may lead to new and more effective therapeutic approaches to these diseases.

Coelho, F. and J. Birks (2001). "Physostigmine for Alzheimer's disease." Cochrane Database Syst Rev(2): CD001499.
BACKGROUND: The main pharmacological approach for the treatment of Alzheimer's disease (AD) has been based on the use of agents potentiating cholinergic transmission, particularly by inhibiting acetylcholinesterase (AChE), the enzyme that destroys acetylcholine after it has been secreted into the synaptic clefts. Physostigmine is an AChE inhibitor originally extracted from calabar beans. It is licensed in many countries as an agent for reversing the effect of drugs and poisons causing the anticholinergic syndrome. Studies conducted more than 20 years ago suggested that physostigmine could improve memory in people with or without dementia. Investigation of this property has been limited by the very short half-life of physostigmine. Various forms of administering the drug have been tried to overcome this problem, most recently a controlled-release (CR) oral formulation, and a skin patch. It has been proposed as a potential drug for the symptomatic treatment of AD. OBJECTIVES: To determine whether there is evidence of beneficial effects for the use of physostigmine in Alzheimer's disease. To assess the incidence and severity of adverse effects. SEARCH STRATEGY: The Cochrane Controlled Trials Register was searched using the following terms: 'physostigmine', 'physostigmine salicylate', 'Synapton' and 'Antilirium' in accordance with the Cochrane Dementia and Cognitive Improvement Group's search strategy. The pharmaceutical company was contacted. SELECTION CRITERIA: All relevant unconfounded, double-blind, randomized, placebo-controlled trials in which physostigmine was administered for more than one day to patients with dementia of Alzheimer type. Trials in which the allocation to the treatment was not randomized, or in which the allocation to the treatment was not concealed were excluded. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers (JMC & JB), pooled where appropriate and possible, and the weighted or standardized mean differences or Peto odds ratios (95% CI) were estimated. Where possible, intention-to-treat analysis was used. MAIN RESULTS: Fifteen studies were included using four different methods of administration of physostigmine. Four studies, involving 29 people in total, used intravenous infusion; seven, involving 131 people, used a conventional oral form; four, involving 1456 participants, used a controlled-release oral form, and one study of 181 people used a verum skin patch. There are no usable results from the intravenous infusion trials, and the few results from the conventional oral form showed no benefit of physostigmine compared with placebo. The results from two of the four studies of the controlled-release physostigmine apply only to a group of patients identified as responders in a pre-randomization titration period. The best dose physostigmine (mean 25mg/day) was associated with a 1.75 point improvement on ADAS-Cog score (mean difference -1.75, 95% confidence interval -2.90, -0.60 on an intention-to-treat basis) and a 0.26 point improvement on the CGIC score (treated as a continuous scale) (mean difference -0.26, 95% confidence interval 0.06, 0.46 on an intention-to-treat basis) compared with placebo at 6 weeks. There were statistically significantly higher numbers of patients from the physostigmine group withdrawing from the trial (22/183 vs 2/183)(OR 5.92, 95% confidence limits 2.59, 13.54) and suffering at least one event of nausea, vomiting, diarhoea, anorexia, dizziness, stomach pain, flatulence or sweating compared with placebo at 6 weeks. The best dose physostigmine (mean 27mg/day) was associated with a 2.0 point improvement on ADAS-Cog score (mean difference -2.02, 95% confidence interval -3.59, -0.45 on an intention to treat basis) compared with placebo at 12 weeks. There were statistically significantly higher numbers of patients from the physostigmine group withdrawing from the trial due to adverse events (13/83 vs 5/93)(OR 3.05, 95% confidence limits 1.15, 8.07) and suffering at least one event of nausea, vomiting, diarhoea, anorexia, dizziness, stomach pain, tremor, asthenia or sweating compared with placebo at 12 weeks. When no attempt was made to identify responders and all relevant patients with Alzheimer's disease were randomized, fixed dose physostigmine (mean 33 mg/day) was associated with a statistically significantly higher number withdrawing (234/358 vs 31/117)(OR 4.82, 95% confidence limits 3.17, 7.33), withdrawing due to adverse events (196/358 vs 10/117) (OR 6.54, 95%confidence limits 4.29, 9.95) and suffering at least one event of nausea, vomiting, diarhoea, anorexia, dizziness, stomach pain, dyspepsia, sweating, asthenia, dyspnoea or abnormal dreaming compared with placebo at 24 weeks. The results from the study of the verum patch physostigmine show that the double dose (delivering mean dose 12mg/day) was associated with statistically significantly higher numbers suffering at least one adverse event of vomiting, nausea or abdominal cramps compared with placebo at 24 weeks, but placebo was associated with statistically significantly greater numbers of gastrointestinal complaints at 24 weeks compared with single-dose physostigmine. REVIEWERS' CONCLUSIONS: The evidence of effectiveness of physostigmine for the symptomatic treatment of Alzheimer's disease is limited. Even in a controlled release formulation designed to overcome the short half-life, physostigmine showed no convincing benefit and adverse effects remained common leading to a high rate of withdrawal.

Cohen-Mansfield, J. (2001). "Nonpharmacologic interventions for inappropriate behaviors in dementia: a review, summary, and critique." Am J Geriatr Psychiatry 9(4): 361-81.
Inappropriate behaviors are very common in dementia and impose an enormous toll both emotionally and financially. Three main psychosocial theoretical models have generally been utilized to explain inappropriate behaviors in dementia: the "unmet needs" model, a behavioral/learning model, and an environmental vulnerability/reduced stress-threshold model. A literature search yielded 83 nonpharmacological intervention studies, which utilized the following categories of interventions: sensory, social contact (real or simulated), behavior therapy, staff training, structured activities, environmental interventions, medical/nursing care interventions, and combination therapies. The majority are reported to have a positive, albeit not always significant, impact. Better matching of the available interventions to patients' needs and capabilities may result in greater benefits to patients and their caregivers.

Collins, S., C. A. McLean, et al. (2001). "Gerstmann-Straussler-Scheinker syndrome,fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies." J Clin Neurosci 8(5): 387-97.
Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru constitute major human prion disease phenotypes. Each has been successfully transmitted in animal models and all are invariably fatal neurodegenerative disorders, with the brains of affected individuals harbouring variable amounts of an abnormal, protease-resistant form of the prion protein (PrPres), which is inextricably linked to pathogenesis and transmissibility. Classical sporadic CJD is the most common human transmissible spongiform encephalopathy (TSE), but recently the variant form (vCJD), first described in the UK in 1996, has drawn considerable attention. In contrast to sporadic CJD, FFI and GSS are almost invariably genetically determined TSEs, caused by a range of mutations within the open reading frame of the prion protein gene (PRNP) on chromosome 20. By definition, the nosologic term FFI is reserved for patients manifesting prominent insomnia, generally in combination with dysautonomia, myoclonus, and eventual dementia, with the predominant pathologic changes lying within the thalami and a specific underlying mutation in PRNP. GSS, however, encompasses a more diverse clinical spectrum ranging from progressive cerebellar ataxia or spastic paraparesis (both usually in combination with dementia), to isolated cognitive impairment resembling Alzheimer's disease. Additional extra-pyramidal features, which may respond to dopaminergic therapy can also be seen. Neuropathological findings are also relatively diverse, partly overlapping with those found in Alzheimer's disease, especially the presence of neurofibrillary tangles (NFTs). Although GSS and FFI in their classical forms are differentiable clinical profiles, such divisions may have no intrinsic biological validity given the considerable intra-familial clinico-pathological diversity so commonly seen. Kuru constitutes a horizontally transmitted prion disease, which after a lengthy incubation period, presents clinically as a progressive cerebellar ataxia associated with tremors. It has now almost disappeared since the cessation of ritualistic endocannibalism in the late 1950s but was previously exclusively endemic amongst the Fore linguistic group and neighbouring tribes in the Eastern Highlands of New Guinea. Uniform topographical central nervous system histopathology includes spongiform change and neuronal loss, with amyloid (kuru) plaques in approximately 75% of cases.

Conn, D. K. (2001). "Cholinesterase inhibitors. Comparing the options for mild-to-moderate dementia." Geriatrics 56(9): 56-7.
Cholinesterase inhibitors can be used as one element of a comprehensive approach to management of mild-to-moderate AD. Benefits include modest cognitive improvement, increased activation, and improved mood and behavior. Patients with other disorders, such as Lewy-body dementia, may also improve. The most common side effects include GI disturbances, insomnia, dizziness, fatigue, and muscle cramps. Adverse effects can be significantly reduced by waiting 4 to 6 weeks before increasing doses. Insomnia may be alleviated by having the patient take the medication early in the day.

Cooke, D. D., L. McNally, et al. (2001). "Psychosocial interventions for caregivers of people with dementia: a systematic review." Aging Ment Health 5(2): 120-35.
The content of interventions for caregivers of dementia patients is highly varied. None of the reviews conducted to date have focused on evaluating the effects of the content of interventions exclusively for dementia caregivers, and this issue is not well understood. The purpose of this review was to first identify the type of components (e.g. education, counselling) that have been utilized in psychosocial/psycho-educational interventions for dementia caregivers, and to evaluate the success of the different components or combination of components in producing positive outcomes for dementia caregivers. Forty studies were included in the review. Approximately two-thirds of the interventions did not show improvements in any outcome measures. Among those studies, which did demonstrate improvements, the inclusion of social components (e.g. social support) or a combination of social and cognitive (e.g. problem solving) components seemed to be relatively effective. It is important to note, however, that these analyses were based on small numbers and the review was limited by a number of methodological issues (e.g. poor description of interventions). To advance our understanding of the efficacy of psychosocial interventions for caregivers of people with dementia, a more systematic approach is required. Intervention components need to be carefully contrasted in appropriately designed studies of sufficient size.

Cooper, B. (2001). "Nature, nurture and mental disorder: old concepts in the new millennium." Br J Psychiatry Suppl 40: s91-101.
BACKGROUND: Evidence from twin and adoption studies has highlighted the importance of gene-environment interaction in the aetiology of mental disorders, and advances in molecular genetics have raised hopes of more rapid progress in this field of investigation. AIMS: To review epidemiological knowledge concerning genetic and environmental risk factors for a cross-section of psychiatric conditions, and evidence of interaction between the two types. METHOD: Searches of the literature in genetic and psychiatric epidemiology, including contributions to this supplement. RESULTS: Overall, firm knowledge on both genetic and environmental causal factors is still fragmentary, although progress has varied among diagnostic categories. Environmental aspects have been dealt with only perfunctorily in most genetic epidemiological research. CONCLUSIONS: Better definition and classification of environmental hazards, and closer inter-disciplinary cooperation, will be necessary in future. Specific gene-environment interaction effects seem likely to prove most important in neuropsychiatric syndromes, and a less specific genetic influence on susceptibility to environmental stress among the common mental disorders.

Court, J., C. Martin-Ruiz, et al. (2001). "Nicotinic receptor abnormalities in Alzheimer's disease." Biol Psychiatry 49(3): 175-84.
Loss of cortical nicotinic acetylcholine receptors with high affinity for agonists (20-50%) in patients with Alzheimer's disease is a common finding. Recent immunochemical analyses indicate that this deficit is predominantly associated with the loss of alpha4 subunits (30-50%), although modest reductions of alpha3 may occur in some individuals (25-29%). No reduction of beta2 subunit protein expression or levels of alpha3 and alpha4 messenger RNA has been reported. Decline in cortical [(125)I]alpha-bungarotoxin binding and alpha7 protein expression does not appear to be as extensive or widespread as the loss of alpha4 (0-40%), with no reduction in messenger RNA expression. In the thalamus, there was a trend for reduced [(3)H]nicotine binding in the majority of nuclei (0-20%) in Alzheimer's disease; however, there was a significant decline in [(125)I]alpha-bungarotoxin binding in the reticular nucleus. In the striatum [(3)H]nicotine binding was reduced in Alzheimer's disease, and although neuroleptic medication accentuated this change, it occurred in those free of neuroleptics. Changes in nicotinic acetylcholine receptors in Alzheimer's disease are distinct from those in normal aging and are likely to contribute to clinical features and possibly neuropathology.

Cowburn, R. F., C. O'Neill, et al. (2001). "Receptor-G-protein signalling in Alzheimer's disease." Biochem Soc Symp(67): 163-75.
Based on radioligand binding studies, it has long been assumed that the neurochemical pathology of Alzheimer's disease (AD) does not involve widespread changes in post-synaptic neurotransmitter function. However, more recent studies suggest that receptor function in AD may be compromised due to disrupted post-receptor signal transduction, in particular that mediated by the G-protein regulated phosphoinositide hydrolysis and adenylate cyclase (AC) pathways. The phosphoinositide hydrolysis pathway has been shown to be altered at a number of levels in AD post-mortem brains, including impaired agonist and G-protein regulation of phospholipase C, decreased protein kinase C (PKC) levels and activity, and a reduced number of receptor sites for the second messenger, Ins(1,4,5)P3. Of these, loss of Ins(1,4,5)P3 receptors and PKC in the entorhinal cortex and hippocampus correlates with AD-related neurofibrillary changes, as staged according to Braak's protocol. Disregulation of the phosphoinositide hydrolysis pathway may therefore have consequences for the progression of AD pathology. In contrast to the extensive pattern of disruption seen with the phosphoinositide hydrolysis pathway, changes to AC signalling in AD appear more circumscribed. Disruptions include a lesion at the level of Gs-protein stimulation of AC and, at least in the hippocampus, reduced enzyme activities in response to forskolin stimulation. Of these, the latter change has been shown to precede neurofibrillary changes. Apart from a loss of calcium/calmodulin sensitive AC isoforms, other components of this signalling pathway, including G-protein levels, Gi-protein mediated inhibition and protein kinase A levels and activity, remain relatively preserved in the disorder.

Cox, C. and K. Albisu (2001). "The Alzheimer's Connections Demonstration Program: instituting a national case management program." Am J Alzheimers Dis Other Demen 16(5): 279-84.
The Alzheimer's Connections Demonstration Program was designed to study the most effective ways of linking families with needed services and resources. The five-year demonstration, begun in 1995, funded case management programs in 29 Alzheimer's Association chapters and served 2,313 families. This paper reports on the final two years of the project when all programs were operational. During this period, 800 families were served. The findings indicate that the programs complement the existing chapter services by offering a specific intervention with caregivers. At the end of the demonstration, all chapters planned to continue the program as case management increased their visibility in the community through their ability to offer direct services.

Coyle, J. and P. Kershaw (2001). "Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimer's disease." Biol Psychiatry 49(3): 289-99.
Despite the proven efficacy of acetylcholinesterase inhibitors in Alzheimer's disease, there is a need for new and more effective treatments. Galantamine is a novel treatment for Alzheimer's disease that inhibits acetylcholinesterase and modulates nicotinic receptors. In randomized, double-blind, placebo-controlled studies of up to 6 months duration, galantamine significantly improved cognitive function. Galantamine also had beneficial effects on instrumental and basic activities of daily living, and postponed the progression of behavioral symptoms. Patients who completed one of the 6-month, placebo-controlled studies were eligible to enter a 6-month, open-extension study of the 24-mg/day dose of galantamine. At the end of 12 months, cognitive function and activities of daily living were preserved in those patients who had been treated throughout the study with galantamine 24 mg/day. At 12 months, this group of patients had significantly better cognitive functions than patients who had been treated with a placebo for 6 months before receiving galantamine. These studies indicate that galantamine postpones the progression of symptoms in Alzheimer's disease. Since galantamine shows the greatest benefits when treatment is started early, its long-term benefits may result from an effect on the underlying disease process; such an effect might be mediated by galantamine's concomitant action on nicotinic receptors.

Croom, J. and I. L. Taylor (2001). "Neuropeptide Y, peptide YY and aluminum in Alzheimer's disease: is there an etiological relationship?" J Inorg Biochem 87(1-2): 51-6.
Neuropeptide Y (NPY) and peptide YY (PYY) are members of the pancreatic polypeptide family which have a high degree of primary and tertiary structural homology. They function as neurotransmitters and humoral agents in central nervous system and gastrointestinal function. During the last two decades, NPY body fluid concentrations and NPY/PYY brain receptor numbers have been demonstrated to be altered during the course of Alzheimer's disease. Recent research has shown that both NPY and PYY may be involved in aluminum metabolism in animal models. A brief discussion of the structure, biological activity and possible involvement of these peptides in aluminum metabolism and Alzheimer's disease is contained herein.

Cucchiara, B. and S. E. Kasner (2001). "Use of statins in CNS disorders." J Neurol Sci 187(1-2): 81-9.
It is well established that 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") reduce cholesterol levels and prevent coronary heart disease (CHD). Although a causal relation between elevated cholesterol levels and stroke has not been well defined, a number of large secondary prevention studies and meta-analyses have shown that statin therapy reduces stroke in patients with CHD and hypercholesterolemia. In addition to the vascular effects of statins (stabilization of atherosclerotic plaques, decreased carotid intimal-medial thickness), there are increasing data to suggest that these agents have additional properties that are potentially neuroprotective. These include endothelial protection via actions on the nitric oxide synthase system, as well as antioxidant, anti-inflammatory and anti-platelet effects. These actions of statins might have potential uses in other neurological disorders such as Alzheimer's disease and certain types of brain tumors.

Cummings, J. L. and S. McPherson (2001). "Neuropsychiatric assessment of Alzheimer's disease and related dementias." Aging (Milano) 13(3): 240-6.
Alzheimer's disease (AD) patients exhibit a variety of behavioral alterations including agitation, apathy, depression, anxiety, delusions, irritability and disinhibition. Most patients with AD exhibit neuropsychiatric symptoms, and behavioral changes become more frequent with advancing disease severity. The NPI is a valid and reliable means of assessing neuropsychiatric symptoms in patients with dementia. The NPI correlates with increasing disability in activities of daily living and increasing cognitive impairment. Physical illness contributes little to behavioral symptoms measured by the NPI. Reduced frontal lobe metabolism and perfusion have been identified in patients with apathy, agitation, psychosis and depression. Patients with elevated agitation scores on the NPI have a higher burden of frontal lobe neurofibrillary tangles than patients without agitation. The NPI is sensitive to behavioral improvements following treatment with cholinesterase inhibitors and psychotropic agents. Neuropsychiatric symptom profiles differ among dementia syndromes, and the NPI provides a means of assessing neuropsychiatric symptoms that may aid in differential diagnosis. Evaluation of neuropsychiatric symptoms is a critical aspect of dementia diagnosis and management.

Cummings, J. L. (2001). "Treatment of Alzheimer's disease." Clin Cornerstone 3(4): 27-39.
A growing consensus indicates that Alzheimer's disease (AD) results from an increase in the production or accumulation of beta-amyloid protein (A beta) leading to nerve cell death. Mechanisms by which A beta accumulation leads to neuronal death include oxidative damage and inflammation. This article discusses the management of AD patients with antioxidants, cholinesterase inhibitors, and psychotropic agents. Studies show that these agents can slow the progression of the disease, improve cognition, and reduce behavioral disturbances. A therapeutic alliance between physician and caregiver is an essential element in successfully managing the AD patient. The 3Rs--repeat, reassure, and redirect--can help caregivers reduce behavioral disturbances in patients with AD and limit the need for pharmacologic management.

Cunnane, G. (2001). "Amyloid precursors and amyloidosis in inflammatory arthritis." Curr Opin Rheumatol 13(1): 67-73.
Recent data demonstrating the multifunctional role of serum amyloid A (SAA) in the pathogenesis of amyloidosis have yielded important insights into this potentially fatal consequence of chronic inflammation. SAA has been shown to participate in chemotaxis, cellular adhesion, cytokine production, and metalloproteinase secretion and is thus integrally involved in the disease process. In addition to its production by the liver as part of the acute phase response, SAA is also expressed by several pathologic tissues such atherosclerotic plaques, rheumatoid synovitis and in the brains of patients with Alzheimer disease. Its constitutive production in normal tissue suggests a role for SAA in host defense and tissue turnover. Many pathways are involved in the regulation of SAA, and as more becomes known about these, potential therapeutic targets may be identified. However, the prevention of secondary amyloidosis is best achieved by early and adequate treatment of patients with chronic inflammatory disorders. Suppression of the acute phase response and normalization of SAA levels are likely to significantly impact on the incidence of amyloidosis in inflammatory arthritis.

Cutler, N. R. and J. J. Sramek (2001). "Review of the next generation of Alzheimer's disease therapeutics: challenges for drug development." Prog Neuropsychopharmacol Biol Psychiatry 25(1): 27-57.
1. AD is believed to stem from dysfunctional cholinergic signaling in the regions of the brain associated with memory and cognition. 2. The occurrence of AD in afflicted individuals correlates with an increase in the accumulation of A beta-rich senile plaques and neurofibrillary tangles in the brain. 3. Currently, the only FDA-approved AD therapies are a group of acetylcholinesterase inhibitors which slow the turnover of the neurotransmitter acetylcholine in the synapse. 4. Many other compounds which target other aspects of the disease, such as reducing neuronal damage and limiting oxidation, are in clinical trials. These include monoamine oxidase (MAO-B) inhibitors, NSAIDs, antioxidants and estrogen, among others. 5. Recent research discoveries have more completely defined the molecular nature of AD, and are generating new approaches for treatment. One idea is to limit the ability of the protein tau to become phosphorylated in hopes that this will limit the formation of neurofibrillary tangles in the brain. 6. A separate approach that is being pursued is to prevent formation and accumulation of A beta plaques. This may be accomplished by either regulating gamma-secretase activity, or using anti-beta-amyloid antibodies to reduce the size of existing plaques. 7. Employing improved procedural and technological approaches during clinical trials, such as bridging studies, dynabridge studies and PET analysis, promises to streamline the drug development process. 8. The use of biomarkers and MRI analysis may be an effective means by which to identify the disease early. Consequently, early intervention treatment therapies may be an effective way of delaying onset of the disease. 9. Long term AD studies, particularly those focusing on the MCI population, are likely to provide statistically valid results using a smaller study population.

Danbolt, N. C. (2001). "Glutamate uptake." Prog Neurobiol 65(1): 1-105.
Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons. The transporter proteins represent the only (significant) mechanism for removal of glutamate from the extracellular fluid and their importance for the long-term maintenance of low and non-toxic concentrations of glutamate is now well documented. In addition to this simple, but essential glutamate removal role, the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission. They may modify the time course of synaptic events, the extent and pattern of activation and desensitization of receptors outside the synaptic cleft and at neighboring synapses (intersynaptic cross-talk). Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, and actual amino acid transport activity and associated ion channel activities. A variety of soluble compounds (e.g. glutamate, cytokines and growth factors) influence glutamate transporter expression and activities. Neither the normal functioning of glutamatergic synapses nor the pathogenesis of major neurological diseases (e.g. cerebral ischemia, hypoglycemia, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, epilepsy and schizophrenia) as well as non-neurological diseases (e.g. osteoporosis) can be properly understood unless more is learned about these transporter proteins. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.

Dani, J. A. (2001). "Overview of nicotinic receptors and their roles in the central nervous system." Biol Psychiatry 49(3): 166-74.
Alzheimer's disease is a complex disorder affecting multiple neurotransmitters. In particular, the degenerative progression is associated with loss within the cholinergic systems. It should be anticipated that both muscarinic and nicotinic mechanisms are affected as cholinergic neurons are lost. This review focuses on the basic roles of neuronal nicotinic receptors, some subtypes of which decrease during Alzheimer's disease. Nicotinic acetylcholine receptors belong to a superfamily of ligand-gated ion channels that play key roles in synaptic transmission throughout the central nervous system. Neuronal nicotinic receptors, however, are not a single entity, but rather there are many different subtypes constructed from a variety of nicotinic subunit combinations. This structural diversity and the presynaptic, axonal, and postsynaptic locations of nicotinic receptors contribute to the varied roles these receptors play in the central nervous system. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, and postsynaptic nicotinic receptors mediate a small minority of fast excitatory transmission. In addition, some nicotinic receptor subtypes have roles in synaptic plasticity and development. Nicotinic receptors are distributed to influence many neurotransmitter systems at more than one location, and the broad, but sparse, cholinergic innervation throughout the brain ensures that nicotinic acetylcholine receptors are important modulators of neuronal excitability.

Dannhardt, G. and W. Kiefer (2001). "Cyclooxygenase inhibitors--current status and future prospects." Eur J Med Chem 36(2): 109-26.
Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase and subsequent downstream synthetases. Two closely related forms of the cyclooxygenase have been identified which are now known as COX-1 and COX-2. Both isoenzymes transform arachidonic acid to prostaglandins, but differ in their distribution and their physiological roles. Meanwhile, the responsible genes and their regulation have been clarified. COX-1, the pre-dominantly constitutive form of the enzyme, is expressed throughout the body and performs a number of homeostatic functions such as maintaining normal gastric mucosa and influencing renal blood flow and platelet aggregation. In contrast, the inducible form is expressed in response to inflammatory and other physiological stimuli and growth factors, and is involved in the production of the prostaglandins that mediate pain and support the inflammatory process. All the classic NSAIDs inhibit both COX-1 and COX-2 at standard anti-inflammatory doses. The beneficial anti-inflammatory and analgesic effects are based on the inhibition of COX-2, but the gastrointestinal toxicity and the mild bleeding diathesis are a result of the concurrent inhibition of COX-1. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and could represent a major advance in the treatment of rheumatoid arthritis and osteoarthritis. Apart from its involvement in inflammatory processes, COX-2 seems to play a role in angiogenesis, colon cancer and Alzheimer's disease, based on the fact that it is expressed during these diseases. The benefits of specific and selective COX-2 inhibitors are currently under discussion and offer a new perspective for a further use of COX-2 inhibitors.

Danysz, W. (2001). "Neurotoxicity as a mechanism for neurodegenerative disorders: basic and clinical aspects." Expert Opin Investig Drugs 10(5): 985-9.
This three day meeting focused on chronic neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amylotrophic lateral sclerosis (ALS). It attracted 69 participants from 10 countries with dominance of Chile and USA. Neurodegeneration and its prevention increasingly gain in importance as the number of people affected increases year-by-year. The meeting addressed various basic aspects having pragmatic implications such as: oxidative stress, inflammatory reaction, glial activation, role of glutamatergic system and apoptosis using a plethora of in vitro and in vivo methods.

Das, U. N. (2001). "Essential fatty acids as possible mediators of the actions of statins." Prostaglandins Leukot Essent Fatty Acids 65(1): 37-40.
Statins and polyunsaturated fatty acids have similar actions: both enhance endothelial nitric oxide synthesis, inhibit the production of pro-inflammatory cytokines, lower cholesterol levels, prevent atherosclerosis and are of benefit in coronary heart disease, stroke and osteoporosis. Statins enhance the conversion of linoleic acid and eicosapentaenoic acid to their long chain derivatives. Animals with essential fatty acid deficiency show an increase in HMG-CoA reductase activity, which reverts to normalcy following topical application of linoleic acid. Similarly to statins, polyunsaturated fatty acids also inhibit HMG-CoA reductase activity. In view of the similarity in their actions and as statins influence essential fatty acid metabolism, it is suggested that essential fatty acids and their metabolites may serve as second messengers of the actions of statins.

Datar, R. H. (2001). "Nucleic acids in diagnosis (Part II): Genetic testing and screening." Natl Med J India 14(2): 93-8.

De Deyn, P. P. and W. C. Wirshing (2001). "Scales to assess efficacy and safety of pharmacologic agents in the treatment of behavioral and psychological symptoms of dementia." J Clin Psychiatry 62 Suppl 21: 19-22.
Advances in the assessment of the behavioral and psychological symptoms of dementia (BPSD) have been employed in large-scale clinical trials of new antipsychotic medications such as risperidone. These scales can be used to assess drug efficacy and to compare different treatment regimens. We review 3 valid and reliable scales, the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the Cohen-Mansfield Agitation Inventory (CMAI), and the Neuropsychiatric Inventory (NPI). Extrapyramidal side effects (EPS) associated with the treatment of BPSD have also been assessed using a number of rating instruments. The design of the most comprehensive of these, the Extrapyramidal Symptom Rating Scale (ESRS), is exhaustive, and it successfully quantifies EPS and distinguishes toxic from nontoxic medications. This publication serves as an aid to researchers and clinicians in their interpretation of qualitative and quantitative data from trials evaluating antipsychotic agents in the treatment of BPSD.

De Vreese, L. P., M. Neri, et al. (2001). "Memory rehabilitation in Alzheimer's disease: a review of progress." Int J Geriatr Psychiatry 16(8): 794-809.
BACKGROUND: Memory rehabilitation is a sadly misrepresented area of applied research in Alzheimer's disease. OBJECTIVES: To gather and evaluate recent evidence for the clinical effectiveness or ecologically validity of memory rehabilitation for mild to moderate Alzheimer's patients. METHODS: Computerised searches and some handsearching were conducted spanning the last five years, from 1995 to 2000, inclusively. Criteria for inclusion in this overview involved the use of a precise memory rehabilitation technique within an experimental study design applied to Alzheimer's patients with pre- and post-treatment evaluation. FINDINGS: Three potential levels of memory rehabilitation procedures with proven clinical or pragmatic efficacy were identified. The first level bears on the facilitation of residual explicit memory with structured support both at encoding and at subsequent recall; the second level of memory rehabilitation exploits the relatively intact implicit memory system (priming and procedural memory); the last deals with finding ways of coping with the patient's limited explicit memory capacities through the use of external memory aids. A proposal of suggestions for good practice and future research in memory rehabilitation is also offered with the hope to spur further development in this rapidly expanding area of applied research. CONCLUSION: The available evidence shows that alternative and innovative ways of memory rehabilitation for Alzheimer's patients can indeed be clinically effective or pragmatically useful with a great potential for use within the new culture of a more graded and proactive type of Alzheimer's disease care.

DeCarli, C. (2001). "The role of neuroimaging in dementia." Clin Geriatr Med 17(2): 255-79.
Potential new therapies for the treatment of Alzheimer's disease demand early and accurate diagnosis. Although clinical evaluation is generally sufficient when the disease is well established, neuroimaging tools are helpful to detect the earliest changes of Alzheimer's disease or differentiate Alzheimer's disease from the other forms of dementia. This article reviews the basic concepts of brain imaging and clinical application. It concludes with a brief discussion of future directions in neuroimaging for the diagnosis and longitudinal follow-up of Alzheimer's disease.

DeKosky, S. T. (2001). "Epidemiology and pathophysiology of Alzheimer's disease." Clin Cornerstone 3(4): 15-26.
Researchers in Alzheimer's disease (AD) have made remarkable strides in the past 2 decades in characterizing the disorder, understanding its pathophysiology, and developing models for assessing treatment. With these successes and the promise of others to come, researchers and policy makers alike are keeping a nervous eye on the "demographic clock," which predicts that with the aging of the US population (and indeed the world), a massive increase in the number of AD cases and related dementias will emerge, flooding our medical care system and overwhelming our ability to care for these patients and their caregivers. This article explores some of the data underlying the explosion of AD and discusses the clinical disorder, its manifestations, and our advances in understanding the underlying pathobiology. Our growing knowledge of AD pathophysiology will lead us to the development of more effective medications to slow the progression or even prevent the emergence of this dreaded disorder.

Delacourte, A. (2001). "The molecular parameters of tau pathology. Tau as a killer and a witness." Adv Exp Med Biol 487: 5-19.

Demeunynck, M., F. Charmantray, et al. (2001). "Interest of acridine derivatives in the anticancer chemotherapy." Curr Pharm Des 7(17): 1703-24.
DNA is considered as one of the main targets for anticancer drug design. The planar structure of acridines confers to the molecules the ability to bind DNA by intercalation and therefore to interfere with metabolic processes. A large number of natural alkaloids and synthetic acridine derivatives have been tested as anticancer agents. So far, a few molecules have entered clinical trials and have been approved for chemotherapy. The mechanisms of action are not fully understood. Cytotoxicity may be related to potent enzyme inhibition. Topoisomerase and telomerase activities may be strongly affected by acridines. The affinity of acridines for DNA has also been used to design new active compounds in which a DNA modifying group is tethered to the acridine nucleus. Acridine derivatives display other pharmacological properties such as antibacterial and antimalarial activities. They are also tested for Alzheimer's disease.

Deschamps, V., P. Barberger-Gateau, et al. (2001). "Nutritional factors in cerebral aging and dementia: epidemiological arguments for a role of oxidative stress." Neuroepidemiology 20(1): 7-15.
There is increasing evidence that oxidative stress is involved in cerebral aging and dementia. The objective of this review is to give a progress report on the more recent results of the various epidemiologic cohorts studied for the association between nutrition of older people, the evolution of cognitive performances and the risk of later occurrence of dementia or stroke. The oxidative theory of pathological brain ageing is supported by animal laboratory experiments. Furthermore, experimental research has consistently suggested that diet-related factors play an important role in cognitive functions in ageing. In humans, a number of epidemiological case-control and prospective studies analyzed the association between nutrition, particularly fatty acids and antioxidant molecules (vitamins A, E, C, beta-carotene and polyphenols) and cognition. In the context of evidence already available, further studies are needed to identify the specific role of various nutrients, their interactions and the influence of genetic factors and living habits on cerebral aging and dementia. Vascular dementia and Alzheimer's disease, that share several risk factors, might be targets for primary prevention through nutritional recommendations and/or supplementation.

Dhingra, K. (2001). "Selective estrogen receptor modulation: the search for an ideal hormonal therapy for breast cancer." Cancer Invest 19(6): 649-59.
Female hormones, especially estrogens, play an important role in the pathogenesis of breast neoplasms and are a principal determinant of their biological behavior. Endocrine manipulation through medical or surgical means can often lead to objective shrinkage of breast tumors. Tamoxifen, a triphenylethylene estrogen receptor modulator, is currently the most widely used hormonal treatment for breast cancer. It has been conclusively demonstrated to reduce the risk of relapse following definitive local therapy (and systemic chemotherapy, when indicated) of invasive or noninvasive breast cancer. Recently, it has also been shown to reduce the incidence of breast cancer in healthy women who are at high risk of developing the disease. In addition, it can prevent osteoporosis and reduce the risk of fractures in postmenopausal women. However, its use is also complicated by an increased incidence of endometrial hyperplasia/carcinoma, venous thromboembolism, cataracts, and in some cases, emergence of tamoxifen-dependent clones of breast cancer. These side effects (except cataracts) are believed to be related to estrogen-agonist effects of tamoxifen. Newer drugs, which are "pure antiestrogens" or inhibitors of estrogen biosynthesis, are devoid of such estrogen-agonist activity and may not have the liability of many of these side effects. However, these agents would also be expected to lack the potentially beneficial effects of tamoxifen on lipids and skeletal system. The ability of tamoxifen to act as an estrogen-agonist or estrogen-antagonist in a tissue-specific fashion has led to the concept of selective estrogen-receptor modulation. Selective estrogen receptor modulators (SERMs), which are devoid of estrogen-agonist effects on the uterus or breast cancer cells but retain potentially beneficial effects on bones and lipids, have been described as "ideal" SERMs. A number of such compounds are currently being tested. Raloxifene is already approved for prevention of osteoporosis and has potential efficacy for prevention and treatment of breast cancer. An analogue of raloxifene, LY353381, is currently in Phase II clinical trials for treatment of breast cancer, with promising early results. EM800 and CP336156 are other promising ideal SERMs in clinical trials. These compounds may provide better treatment and chemoprevention alternatives for breast cancer as compared to tamoxifen, aromatase inhibitors, and pure antiestrogens. In addition, they may also prove to be useful for the treatment and prevention of prostate cancer as well as for treating benign gynecological diseases such as fibroids and endometriosis. Future laboratory efforts should focus on further broadening the efficacy profile of SERMs (e.g., prevention of Alzheimer's disease and elevation of high-density lipoproteins to improve the likelihood of cardiovascular benefit) and narrowing their side-effect profile (e.g., risk of thromboembolism and hot flashes).

Diaz-Arrastia, R. and F. Baskin (2001). "New biochemical markers in Alzheimer disease." Arch Neurol 58(3): 354-6.

Dickson, D. W. (2001). "Neuropathology of Alzheimer's disease and other dementias." Clin Geriatr Med 17(2): 209-28.
Clinical differentiation of neurodegenerative diseases that produce dementia is imprecise. Neuropathology offers the only way to make a definite diagnosis. The CNS autopsy is also important for clinical quality control and for providing tissue that furthers research into these disabling disorders. This brief article summarizes the major neuropathologic features of largely sporadic disorders that present with late-life dementia. The common causes of dementia discussed are Alzheimer's disease, Lewy body disease, and vascular dementia; less common disorders described are dementia lacking distinctive histopathology, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, and Creutzfeldt-Jakob disease.

Dierssen, M., C. Fillat, et al. (2001). "Murine models for Down syndrome." Physiol Behav 73(5): 859-71.
The availability of the recently published DNA sequence of human chromosome 21 (HSA21) is a landmark contribution that will have an immediate impact on the study of the role of specific genes to Down syndrome (DS). Trisomy 21 or DS is the only autosomal aneuploidy that is not lethal in the fetal or early postnatal period. DS phenotypes show variable penetrance, affecting many different organs, including brain (mental retardation, early onset of Alzheimer's disease, AD), muscle (hypotonia), skeleton, and blood. DS phenotypes may stem directly from the cumulative effect of overexpression of specific HSA21 gene products or indirectly through the interaction of these gene products with the whole genome, transcriptome, or proteome. Mouse genetic models have played an important role in the elucidation of the contribution of specific genes to the DS phenotype. To date, the strategies used for modeling DS in mice have been three: (1) to assess single-gene contributions to DS phenotype, using transgenic techniques to create models overexpressing single or combinations of genes, (2) to assess the effects of overexpressing large foreign DNA pieces, introduced on yeast artificial chromosomes (YACs) or bacterial artificial chromosomes (BACs) into transgenic mice, and (3) mouse trisomies that carry all or part of MMU16, which has regions of conserved homology with HSA21. Here we review the existing murine models and the relevance of their contribution to DS research.

Dietschy, J. M. and S. D. Turley (2001). "Cholesterol metabolism in the brain." Curr Opin Lipidol 12(2): 105-12.
The central nervous system accounts for only 2% of the whole body mass but contains almost a quarter of the unesterified cholesterol present in the whole individual. This sterol is largely present in two pools comprised of the cholesterol in the plasma membranes of glial cells and neurons and the cholesterol present in the specialized membranes of myelin. From 0.02% (human) to 0.4% (mouse) of the cholesterol in these pools turns over each day so that the absolute flux of sterol across the brain is only approximately 0.9% as rapid as the turnover of cholesterol in the whole body of these respective species. The input of cholesterol into the central nervous system comes almost entirely from in situ synthesis, and there is currently little evidence for the net transfer of sterol from the plasma into the brain of the fetus, newborn or adult. In the steady state in the adult, an equivalent amount of cholesterol must move out of the brain and this output is partly accounted for by the formation and excretion of 24S-hydroxycholesterol. This cholesterol turnover across the brain is increased in neurodegenerative disorders such as Alzheimer's disease and Niemann-Pick type C disease. Indirect evidence suggests that large amounts of cholesterol also turn over among the glial cells and neurons within the central nervous system during brain growth and neuron repair and remodelling. This internal recycling of sterol may involve ligands such as apolipoproteins E and AI, and one or more membrane transport proteins such as members of the low density lipoprotein receptor family. Changes in cholesterol balance across the whole body may, in some way, cause alterations in sterol recycling and apolipoprotein E expression within the central nervous system, which, in turn, may affect neuron and myelin integrity. Further elucidation of the processes controlling these events is very important to understand a variety of neurodegenerative disorders.

Dingwall, C. (2001). "Spotlight on BACE: the secretases as targets for treatment in Alzheimer disease." J Clin Invest 108(9): 1243-6.

Dobson, C. M. (2001). "Protein folding and its links with human disease." Biochem Soc Symp(68): 1-26.
The ability of proteins to fold to their functional states following synthesis in the intracellular environment is one of the most remarkable features of biology. Substantial progress has recently been made towards understanding the fundamental nature of the mechanism of the folding process. This understanding has been achieved through the development and concerted application of a variety of novel experimental and theoretical approaches to this complex problem. The emerging view of folding is that it is a stochastic process, but one biased by the fact that native-like interactions between residues are, on average, more stable than non-native ones. The sequences of natural proteins have emerged through evolutionary processes such that their unique native states can be found very efficiently even in the complex environment inside a living cell. But under some conditions proteins fail to fold correctly, or to remain correctly folded, in living systems, and this failure can result in a wide range of diseases. One group of diseases, known as amyloidoses, which includes Alzheimer's disease and the transmissible spongiform encephalopathies, involves deposition of aggregated proteins in a variety of tissues. These diseases are particularly intriguing because evidence is accumulating that the formation of the highly organized amyloid aggregates is a generic property of polypeptides, and not simply a feature of the few proteins associated with recognized pathological conditions. That such aggregates are not normally found in properly functional biological systems is again a testament to evolution, in this case of a variety of mechanisms inhibiting their formation. Understanding the nature of such protective mechanisms is a crucial step in the development of strategies to prevent and treat these debilitating diseases.

Dominguez, D. I., B. De Strooper, et al. (2001). "Secretases as therapeutic targets for the treatment of Alzheimer's disease." Amyloid 8(2): 124-42.
The extracellular deposition of short amyloid peptides in the brain of patients is thought to be a central event in the pathogenesis of Alzheimer's Disease. The generation of the amyloid peptide occurs via a regulated cascade of cleavage events in its precursor protein, A beta PP. At least three enzymes are responsible for A beta PP proteolysis and have been tentatively named alpha-, beta- and gamma-secretases. The recent identification of several of these secretases is a major leap in the understanding how these secretases regulate amyloid peptide formation. Members of the ADAM family of metalloproteases are involved in the non-amyloidogenic alpha-secretase pathway. The amyloidogenic counterpart pathway is initiated by the recently cloned novel aspartate protease named BACE. The available data are conclusive and crown BACE as the long-sought beta-secretase. This enzyme is a prime candidate drug target for the development of therapy aiming to lower the amyloid burden in the disease. Finally, the gamma-secretases are intimately linked to the function of the presenilins. These multi-transmembrane domain proteins remain intriguing study objects. The hypothesis that the presenilins constitute a complete novel type of protease family, and are cleaving A beta PP within the transmembrane region, remains an issue of debate. Several questions remain unanswered and direct proof that they exert catalytic activity is still lacking. The subcellular localization of presenilins in neurons, their integration in functional multiprotein complexes and the recent identification of additional modulators of gamma-secretase, like nicastrin, indicate already that several players are involved. Nevertheless, the rapidly increasing knowledge in this area is already paving the road towards selective inhibitors of this secretase as well. It is hoped that such drugs, possibly in concert with the experimental vaccination therapies that are currently tested, will lead to a cure of this inexorable disease.

Duckett, L. (2001). "Alzheimer's dementia: morbidity and mortality." J Insur Med 33(3): 227-34.
OBJECTIVES: To evaluate the morbidity and mortality of Alzheimer's disease in early onset and late onset disease. BACKGROUND: Comprehensive literature review to provide historic and demographic background on the disease as well as to determine the pertinent factors for risk assessment. METHODS: Abstract mortality methodology is employed to develop mortality ratios and life expectancies on those with early onset as well as late onset disease. RESULTS: Mortality ratios and morbidity are high in the early onset disease. The late onset disease has high mortality ratios in the more severe forms of the disease. Mild disease is not associated with high mortality ratios. CONCLUSIONS: Alzheimer's disease is an important impairment in an elderly individual. Early onset disease is uncommon and associated with high mortality and morbidity. The late onset disease is common and is associated with much less morbidity and mortality. Risk factors are useful in identifying high-risk individuals.

Duff, K. and M. V. Rao (2001). "Progress in the modeling of neurodegenerative diseases in transgenic mice." Curr Opin Neurol 14(4): 441-7.
Transgenic mouse models exist for the major neurodegenerative diseases, including Alzheimer's disease, tauopathy and amyotrophic lateral sclerosis. Although many of the mice do not completely replicate the human disease they are intended to model, they have provided insight into the mechanisms that underlie disease etiology. In the case of the Alzheimer's disease and amyotrophic lateral sclerosis models, the mice have also provided a therapeutic testing ground for the testing of agents that have been shown to have considerable clinical promise.

Duff, K. (2001). "Transgenic mouse models of Alzheimer's disease: phenotype and mechanisms of pathogenesis." Biochem Soc Symp(67): 195-202.
A range of transgenic mice have been created to model Alzheimer's disease. These include mice expressing human forms of the amyloid precursor protein, the presenilins and, more recently, tau. Several of the models develop features of the disease including amyloid pathology, cholinergic deficits, neurodegeneration and cognitive impairment. Progress in the characterization and use of these model animals is discussed.

Dukic-Stefanovic, S., R. Schinzel, et al. (2001). "AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs?" Biogerontology 2(1): 19-34.
In Alzheimer's disease, age-related cellular changes such as compromised energy production and increased radical formation are worsened by the presence of AGEs as additional, AD specific stress factors. Intracellular AGEs (most likely derived from methylglyoxal) crosslink cytoskeletal proteins and render them insoluble. These aggregates inhibit cellular functions including transport processes and contribute to neuronal dysfunction and death. Extracellular AGEs, which accumulate in ageing tissue (but most prominently on long-lived protein deposits like the senile plaques) exert chronic oxidative stress on neurons. In addition, they activate glial cells to produce free radicals (superoxide and NO) and neurotoxic cytokines such as TNF-alpha. Drugs, which inhibit the formation of AGEs by specific chemical mechanisms (AGE-inhibitors), including aminoguanidine, carnosine, tenilsetam, OPB-9195 and pyridoxamine, attenuate the development of (AGE-mediated) diabetic complications. Assuming that 'carbonyl stress' contributes significantly to the progression of Alzheimer's disease, AGE-inhibitors might also become interesting novel therapeutic drugs for treatment of AD.

Dumery, L., F. Bourdel, et al. (2001). "beta-Amyloid protein aggregation: its implication in the physiopathology of Alzheimer's disease." Pathol Biol (Paris) 49(1): 72-85.
beta-Amyloid protein (A beta), a 39-42 residue peptide resulting from the proteolytic processing of a membrane-bound beta-amyloid precursor protein (APP), is one of the major components of the fibrillar deposits observed in Alzheimer patients. A beta fibril formation is a complex process which involves changes in A beta conformation and self-association to form cross-beta pleated sheets, protofibrils, and fibrils. Since the aggregation of soluble A beta peptide into fibrils is viewed as a critical event in the physiopathology of Alzheimer's disease (AD), preventing, altering, or reversing fibril formation may thus be of therapeutic value. This review will focus on the current state of knowledge of A beta fibril formation, with special emphasis on physiological and exogenous inhibitors which may have a therapeutic potential.

Dworetzky, B. A. (2001). "The neurology of memory." Semin Speech Lang 22(2): 95-105.
Remembering is an intrinsic and awesome aspect of human function. Memory loss, a common sequela of brain damage, has been studied extensively to understand how the brain encodes, stores and retrieves information. Important anatomic structures for memory have been identified from work in surgical therapy for epilepsy as well as other clinical syndromes where memory loss is a major feature. Beyond clinicoanatomic correlations, current research has focused on synaptic modifications and biochemical processes that underlie changes in neuronal connectivity. As Alzheimer's disease research expands our knowledge of memory, the treatment of other memory disorders will follow.

Dzielska-Olczak, M. and S. Olczak (2001). "[Clinical application of cyclooxygenase-2 inhibitors]." Pol Merkuriusz Lek 10(60): 480-2.
Nonsteroidal antiinflammatory drugs (NSAIDs) are a group of compounds with similar therapeutic and side effects. Their therapeutic effects depend on blockade of prostaglandin synthesis through enzyme cyclooxygenase (COX) inhibition. Two isoforms of the enzyme cyclooxygenase have been identified: COX-1 and COX-2. Selective COX-2 inhibitors i.e. meloxicam, nimesulid, etodolac or highly selective COX-2 inhibitors i.e. celecoxib, rofecoxib have antiinflammatory and analgesic properties with less or no gastrointestinal or other NSAIDs-typical adverse effects. Highly selective COX-2 inhibitors may also be active in colonic polyposis, colorectal cancer and Alzheimer's disease.

Ebadi, M., P. Govitrapong, et al. (2001). "Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease." Biol Signals Recept 10(3-4): 224-53.
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.

Effros, R. B. (2001). "Ageing and the immune system." Novartis Found Symp 235: 130-9; discussion 139-45, 146-9.
Immune system alterations during ageing are complex and pleiotropic, suggestive of remodelling or altered regulation, rather than simple immune deficiency. The most dramatic changes with age occur within the T cell compartment, the arm of the immune system that protects against pathogens and tumours, consistent with the increased incidence and severity of infection and cancer in the elderly. Indeed, autopsy studies confirm infection as the major cause of death in the very old. Increased serum levels of inflammatory mediators are another hallmark of ageing, suggestive of either regulatory defects or an ongoing attack on sub-clinical neoplastic disease or infection. Qualitative changes in antibody production, including those secreted by the gut mucosal immune compartment, affect responses to foreign antigens as well as to prophylactic vaccines. Innate immunity, the first line of defence that precedes the antigen-specific T and B cell responses, also undergoes changes with age. Some of the immune effects associated with ageing are secondary to overall organismic changes, such as alterations in the viscosity of cell membranes and proteolytic cellular machinery. Evidence suggesting that immune system changes may be involved in some major age-related pathologies, such as atherosclerosis and Alzheimer's disease, will be discussed.

Einat, H. and R. H. Belmaker (2001). "The effects of inositol treatment in animal models of psychiatric disorders." J Affect Disord 62(1-2): 113-21.
Clinical trials indicate that inositol may be effective in the treatment of patients with depression, panic disorder and obsessive compulsive disorder (OCD), but not in the treatment of patients with schizophrenia, Alzheimer's disease, ADHD or autism. This spectrum of clinical action parallels that of serotonin selective reuptake inhibitors (SSRIs), but inositol is a precursor in the phosphatidylinositol cycle, a second messenger system distal to the receptor for 5HT-2. To study its mechanism of therapeutic action there is a need to test inositol's activity in animal models of psychopathology. In rats, chronic inositol was demonstrated to increase activity levels, reduce immobility time in the forced swim test and in the reserpine-induced hypoactivity models of depression, and reduce anxiety-like behaviors in the elevated plus-maze. The reduction in anxiety-like behaviors appears to be related to baseline levels of activity. Inositol treatment was not observed to have any effect on amphetamine-induced hyperactivity, apomorphine-induced stereotypy, or on the performance of memory tasks by monkeys. Clinical controlled trials of inositol in patients with depression, panic disorder, and OCD were small, and positive psychoactive effects in animals clearly strengthen the case for further clinical trials and potential for general therapeutic use in humans.

Ellis, K. A. and P. J. Nathan (2001). "The pharmacology of human working memory." Int J Neuropsychopharmacol 4(3): 299-313.
Experimental studies conducted primarily on non-human primates have begun to address the anatomical and neurochemical correlates of working memory. There is an associated growing body of experimental literature investigating whether modulating key neurotransmitters can facilitate working memory in humans. This paper reviews evidence that acute modulation of dopamine in particular, but also noradrenaline, acetylcholine and serotonin may influence working-memory performance in humans. Differences in neurochemical specificity with regard to stages of working memory, type of working memory (spatial or non-spatial) and cortical effects are also discussed. This evidence has contributed to neuropharmacological understanding of working memory in humans. The important therapeutic consequences of a better understanding of facilitation of working memory is discussed in reference to schizophrenia, Parkinson's disease and Alzheimer's disease.

Emahazion, T., L. Feuk, et al. (2001). "SNP association studies in Alzheimer's disease highlight problems for complex disease analysis." Trends Genet 17(7): 407-13.
Genetic linkage and association analyses are two distinct approaches to understanding the genetic etiology of complex disease. Association analysis has become particularly popular in recent times, but the true utility of the strategy remains uncertain. To try to gain better insight into the relevant issues, we have used genetic association analysis to explore the etiology of Alzheimer's disease. Our empirical findings supplement the theoretical debate, illustrating the general doubtfulness of previous positive findings and the limited ability of typical association studies based on candidate genes to discern true medium-sized signals from false positives. Improvements in genotyping technologies and increasing the number of SNPs tested, without sophisticated allowance for all other issues, could simply lead to an unmanageable overload of false-positive signals, themselves obscuring true disease associations.

Emerich, D. F. and H. C. Salzberg (2001). "Update on immunoisolation cell therapy for CNS diseases." Cell Transplant 10(1): 3-24.
Delivery of potentially therapeutic drugs to the brain is hindered by the blood-brain barrier (BBB), which restricts the diffusion of drugs from the vasculature to the brain parenchyma. One means of overcoming the BBB is with cellular implants that produce and deliver therapeutic molecules. Polymer encapsulation, or immunoisolation, provides a means of overcoming the BBB to deliver therapeutic molecules directly into the CNS region of interest. Immunoisolation is based on the observation that xenogeneic cells can be protected from host rejection by encapsulating, or surrounding, them within an immunoisolatory, semipermeable membrane. Cells can be enclosed within a selective, semipermeable membrane barrier that admits oxygen and required nutrients and releases bioactive cell secretions, but restricts passage of larger cytotoxic agents from the host immune defense system. The selective membrane eliminates the need for chronic immunosuppression of the host and allows the implanted cells to be obtained from nonhuman sources. In this review, cell immunoisolation for treating CNS diseases is updated from considerations of device configurations, membrane manufacturing and characterization in preclinical models of Alzheimer's and Huntington's disease.

Emre, M. and N. Qizilbash (2001). "Experimental approaches and drugs in development for the treatment of dementia." Expert Opin Investig Drugs 10(4): 607-17.
Treatment of dementia can be divided as symptomatic treatment of cognitive or non-cognitive symptoms and the treatment of underlying pathology. In the last decade the thrust of symptomatic treatment of Alzheimer's disease (AD) has been enhancement of cholinergic transmission. Besides the acetycholinesterase inhibitors (AChE-I) currently in use, cholinergic agonists and enhancers are in development. Other therapeutic approaches directed towards neurotransmitter substitution or modulation include serotoninergic, noradrenergic substances, neuropeptides and those acting via excitatory amino acid receptors, such as ampakines or NMDA antagonists. Introduction of atypical neuroleptics represents the most recent development in the treatment of behavioural symptoms. Efforts to treat the underlying pathology are based on modulation of APP processing in order to decrease the accumulation of beta-amyloid, those to decrease tau hyperphosphorylation, use of nerve growth factors and those based on Apo-E modulation. Potential use of oestrogens and NSAIDs are also under investigation. Recently, vaccination with amyloid-beta peptide has been reported to be effective in an animal model of AD, this putative vaccine is now in clinical trials. Likewise, recent studies suggest that some statins may have a prophylactic effect.

Engelborghs, S. and P. P. De Deyn (2001). "Biological and genetic markers of sporadic Alzheimer's disease." Acta Med Okayama 55(2): 55-63.
With the development of new treatments, there is an increasing need for early diagnosis of sporadic Alzheimer's disease. Therefore, biological markers allowing positive diagnosis early in the course of the disease are highly desirable. Cerebrospinal fluid levels of protein tau were shown to be significantly increased in patients with Alzheimer's disease. Although sensitivity is high, poor specificity limits the diagnostic value of this marker. The same is true for the 42 amino acid isoform of beta-amyloid protein that is significantly decreased in cerebrospinal fluid of Alzheimer's disease patients. However, combining both markers could improve specificity at least allowing differentiation between Alzheimer's disease, normal ageing and depressive pseudodementia. Other biological markers such as cerebrospinal fluid levels of neurotransmitters, cytokines or superoxide dismutase were shown to have even less diagnostic value. The apolipoprotein epsilon 4 allele is a risk factor for Alzheimer's disease but not a diagnostic marker as many individuals who inherit epsilon 4 do not develop the disease. Till now, a single diagnostic marker allowing discrimination between Alzheimer's disease and other dementias does not exist. Combined cerebrospinal fluid levels of beta-amyloid protein and tau protein might be used as a marker that helps discriminating Alzheimer's disease from normal ageing and depression.

Engelhardt, E., D. M. Moreira, et al. (2001). "[Alzheimer's disease and magnetic resonance spectroscopy of the hippocampus]." Arq Neuropsiquiatr 59(4): 865-70.
OBJECTIVE: Acquisition of data of magnetic resonance metabolite spectrum of the hippocampal formation (hippocampus-hc) in the elderly, normal and with Alzheimer's disease (AD). METHOD: Subjects matched for age: a. normal sample (n=20), CDR=0, and b. AD sample (n=40), CDR 1 and 2. Technique: Signa Horizon LX-GE, 1.5T, 1H-MRS with automated software PROBE/SV, VOI: hc (right and left); single voxel (2x2x2cm); TR 1500ms/TE 50ms; PRESS; metabolites: N-acetylaspartate (Naa), choline (Cho), creatine (Cr), myo-inositol (mI). RESULTS: The present data relate to the ratios of Naa, Cho and mI, with Cr taken as reference, and the mI/Naa ratio. The study showed reduction of Naa, increase of mI and of the mI/Naa ratio, and not consistent results for Cho. The results of the whole sample of AD patients compared to the pooled normal mean +/- sd were significant for Naa, mI and mI/Naa (p<0.01). Accuracy in relation to the individual values of both samples showed satisfactory levels of sensitivity, specificity and positive predictive value. CONCLUSION: The present results can be used as a helpful tool to detect pathologic changes of the hippocampus in AD, and allowing greater accuracy and an earlier diagnosis of this disease.

Erkinjuntti, T. (2001). "Clinical deficits of Alzheimer's disease with cerebrovascular disease and probable VaD." Int J Clin Pract Suppl(120): 14-23.
Vascular dementia (VaD) describes dementia arising from cerebrovascular disease (CVD) and ischaemic brain injury, and relates to a number of different vascular mechanisms and clinical manifestations. The characterisation of brain lesions by neuroimaging analysis, and the study of their relation to clinical deficits such as cognitive and functional decline, are critical to the concept and treatment of VaD, and form an important part of widely used diagnostic criteria for this dementia type. For instance, the extent to which pathological brain lesions cause, compound or coexist with cognitive impairment is a major determinant of other clinical deficits, their nature and the rate of disease progression. Through numerous neuroimaging and epidemiological studies, VaD is now seen to encompass a heterogeneous group of clinical syndromes such as multiple-infarct (cortical) dementia, small-vessel (subcortical) dementia and, less commonly, dementia associated with strategic infarcts. Due to a large number of similarities in clinical symptoms, pathophysiological mechanisms, associated risk factors and neurochemical deficits between VaD and Alzheimer's disease, patients with coexistent Alzheimer's disease and CVD ('mixed' dementia) represent another important, but previously underestimated subgroup. This article reviews the clinical symptoms and neuroimaging findings most commonly observed in patients with VaD. Increased familiarity with the clinical picture of VaD should offer more hope of defining realistic treatment aims for future pharmacotherapy.

Esiri, M. M. (2001). "Potential for HSV-1 vaccination to reduce risk of HSV-1 encephalitis and/or Alzheimer's disease?" Neurobiol Aging 22(5): 711-3; discussion 717-9.

Esler, W. P. and M. S. Wolfe (2001). "A portrait of Alzheimer secretases--new features and familiar faces." Science 293(5534): 1449-54.
The amyloid beta-peptide (Abeta) is a principal component of the cerebral plaques found in the brains of patients with Alzeheimer's disease (AD). This insoluble 40- to 42-amino acid peptide is formed by the cleavage of the Abeta precursor protein (APP). The three proteases that cleave APP, alpha-, beta-, and gamma-secretases, have been implicated in the etiology of AD. beta-Secretase is a membrane-anchored protein with clear homology to soluble aspartyl proteases, and alpha-secretase displays characteristics of certain membrane-tethered metalloproteases. gamma-Secretase is apparently an oligomeric complex that includes the presenilins, which may be the catalytic component of this protease. Identification of the alpha-, beta-, and gamma-secretases provides potential targets for designing new drugs to treat AD.

Estol, C. J. (2001). "[Dementia: clinic and diagnosis]." Vertex 12(46): 292-302.
Decline of the cognitive functions necessary for activities of daily living results in a spectrum ranging from benign forgetfulness and minimal cognitive impairment to dementia. The latter is characterized by personality and behavioral changes. Alzheimer's disease is the most frequent cause of dementia affecting almost one of two people older than 80 years. Lewy body and cerebrovascular disease are also frequent causes of cognitive decline. Recent studies have revealed genetic aspects of Alzheimer's disease and the role of certain enzymes in the pathophysiology of fibrillary amyloid deposition. The aim in cognitive disease is an early diagnosis to initiate therapy and adapting measures in the patient's daily routines. The diagnosis is basically clinical with neuroimaging and neuropsychological tests' support. The EEG, SPECT, LP and other studies are only useful in a few specific scenarios. At present, a few promising therapies are being evaluated. Family support is of vital importance.

Eustache, F., B. Desgranges, et al. (2001). "[Contribution of positron emission tomography to functional neuroimaging in Alzheimer's disease]." Rev Neurol (Paris) 157(4): 377-83.
When combined with cognitive investigations, functional neuroimaging methods such as positron emission tomography allow to depict the neural substrates that underlie the neuropsychological alterations in Alzheimer's disease. Capitalising on the variance in both cognitive performances and resting cerebral metabolic rate of glucose (CMRGlc) in Alzheimer's disease, it is possible to correlate these two quantitative variables on a pixel-by-pixel basis and to generate maps showing the significant correlations in stereotaxic space. Some examples using this approach in the domain of memory disorders are presented in this brief review. We notably show that the localisation of the significant correlations differs from one memory system to another, as evaluated by clinical memory tasks. This approach also unravels the compensatory mechanisms that take place with evolution of the disease. Over and above its interest in clinical neuropsychology, this method constitutes a new source of inferences complementary to the classic activation paradigm in normal subjects, as the latter identifies the cerebral structures that are involved with, but not necessarily indispensable for, the normal execution of the task. This approach highlights the interest of combining functional neuroimaging and neuropsychology to better understand the neural substrates of cognitive deficits in both patients with memory disorders and elderly normal subjects.

Evans, J. P., C. Skrzynia, et al. (2001). "The complexities of predictive genetic testing." Bmj 322(7293): 1052-6.

Evseev, V. A., T. V. Davydova, et al. (2001). "Dysregulation in neuroimmunopathology and perspectives of immunotherapy." Bull Exp Biol Med 131(4): 305-8.
Dysregulation of neuroimmune connections is a primary or secondary pathogenic factor of some CNS diseases. Autoimmune aggression is typical of multiple sclerosis, Alzheimer's disease, and epilepsy, while dysregulation characterized by enhanced production of autoantibodies to neurotransmitters and activation of cell factors is characteristic of alcoholism and drug abuse. In experimental models of alcoholism and drug addiction, protective effects of antiserotonin antibodies are mediated by immune cells stimulated by these antibodies. These effects can be used in the therapy of various forms of neuroimmunopathology by the method of adoptive immunotherapy.

Farkas, E. and P. G. Luiten (2001). "Cerebral microvascular pathology in aging and Alzheimer's disease." Prog Neurobiol 64(6): 575-611.
The aging of the central nervous system and the development of incapacitating neurological diseases like Alzheimer's disease (AD) are generally associated with a wide range of histological and pathophysiological changes eventually leading to a compromised cognitive status. Although the diverse triggers of the neurodegenerative processes and their interactions are still the topic of extensive debate, the possible contribution of cerebrovascular deficiencies has been vigorously promoted in recent years. Various forms of cerebrovascular insufficiency such as reduced blood supply to the brain or disrupted microvascular integrity in cortical regions may occupy an initiating or intermediate position in the chain of events ending with cognitive failure. When, for example, vasoconstriction takes over a dominating role in the cerebral vessels, the perfusion rate of the brain can considerably decrease causing directly or through structural vascular damage a drop in cerebral glucose utilization. Consequently, cerebral metabolism can suffer a setback leading to neuronal damage and a concomitant suboptimal cognitive capacity. The present review focuses on the microvascular aspects of neurodegenerative processes in aging and AD with special attention to cerebral blood flow, neural metabolic changes and the abnormalities in microvascular ultrastructure. In this context, a few of the specific triggers leading to the prominent cerebrovascular pathology, as well as the potential neurological outcome of the compromised cerebral microvascular system are also going to be touched upon to a certain extent, without aiming at total comprehensiveness. Finally, a set of animal models are going to be presented that are frequently used to uncover the functional relationship between cerebrovascular factors and the damage to neural networks.

Farkas, R. H. and C. L. Grosskreutz (2001). "Apoptosis, neuroprotection, and retinal ganglion cell death: an overview." Int Ophthalmol Clin 41(1): 111-30.

Farooqu, A. A. and L. A. Horrocks (2001). "Plasmalogens, phospholipase A2, and docosahexaenoic acid turnover in brain tissue." J Mol Neurosci 16(2-3): 263-72; discussion 279-84.
Plasmalogens are glycerophospholipids of neural membranes containing vinyl ether bonds. Their synthetic pathway is located in peroxisomes and endoplasmic reticulum. The rate-limiting enzymes are in the peroxisomes and are induced by docosahexaenoic acid (DHA). Plasmalogens often contain arachidonic acid (AA) or DHA at the sn-2 position of the glycerol moiety. The receptor-mediated hydrolysis of plasmalogens by cytosolic plasmalogen-selective phospholipase A2 generates AA or DHA and lysoplasmalogens. AA is metabolized to eicosanoids. The mechanism of signaling with DHA is not known. The plasmalogen-selective phospholipase A2 differs from other intracellular phospholipases A2 in molecular mass, kinetic properties, substrate specificity, and response to glycosaminoglycans, gangliosides, and sialoglycoproteins. A major portion of [3H]DHA incorporated into neural membranes is found at the sn-2 position of ethanolamine glycerophospholipids. Studies with a mutant cell line defective in plasmalogen biosynthesis indicate that the incorporation of DHA is reduced in this RAW 264.7 cell line by 50%. In contrast, the incorporation of AA remains unaffected. This is reversed completely when the growth medium is supplemented with sn-1-hexadecylglycerol, suggesting that DHA can be selectively targeted for incorporation into plasmalogens. We suggest that deficiencies of DHA and plasmalogens in peroxisomal disorders, Alzheimer's disease (AD), depression, and attention deficit hyperactivity disorders (ADHD) may be responsible for abnormal signal transduction associated with learning disability, cognitive deficit, and visual dysfunction. These abnormalities in the signal-transduction process can be partially corrected by supplementation with a diet enriched with DHA.

Farooqui, A. A. and L. A. Horrocks (2001). "Plasmalogens: workhorse lipids of membranes in normal and injured neurons and glia." Neuroscientist 7(3): 232-45.
Plasmalogens are unique glycerophospholipids because they have an enol ether double bond at the sn-1 position of the glycerol backbone. They are found in all mammalian tissues, with ethanolamine plasmalogens 10-fold higher than choline plasmalogens except in muscles. The enol ether double bond at the sn-1 position makes plasmalogens more susceptible to oxidative stress than the corresponding ester-bonded glycerophospholipids. Plasmalogens are not only structural membrane components and a reservoir for second messengers but may also be involved in membrane fusion, ion transport, and cholesterol efflux. Plasmalogens may also act as antioxidants, thus protecting cells from oxidative stress. Receptor-mediated degradation of plasmalogens by plasmalogen-selective phospholipase A2 results in the generation of arachidonic acid, eicosanoids, and platelet activating factor. Low levels of these metabolites have trophic effects, but at high concentration they are cytotoxic and may be involved in allergic response, inflammation, and trauma. Levels of plasmalogens are decreased in several neurological disorders including Alzheimer's disease, ischemia, and spinal cord trauma. This may be due to the stimulation of plasmalogen-selective phospholipase A2. A deficiency of plasmalogens in peroxisomal disorders and Niemann-Pick type C disease indicates that this deficiency may be due to the decreased activity of plasmalogen synthesizing enzymes that occur in peroxisomes.

Fassbender, K., C. Masters, et al. (2001). "Alzheimer's disease: molecular concepts and therapeutic targets." Naturwissenschaften 88(6): 261-7.
The beta amyloid peptide is the major component of the neuritic plaques, the characteristic lesions in Alzheimer's disease. Mutations in three genes (APP, PS-1, and PS-2) cause familial Alzheimer's disease by alteration of the rate of generation of amyloid peptide or the length of this peptide. However, in the 90% non-familial cases, other factors play a major pathogenetic role. These include the apolipoprotein E genotype, the "plaque-associated" proteins promoting the formation of toxic fibrillar aggregates or the chronic inflammatory responses. The aim of this review is to explain the steps in the complex cascade leading to Alzheimer's disease and, based on this, to report the current efforts to intervene in these different pathophysiological events in order to prevent progression of Alzheimer's disease. Whereas acetylcholine substitution is currently used in clinical practice, future therapeutical strategies to combat Alzheimer's disease may include anti-inflammatory treatments, vaccination against beta amyloid peptide, or treatment with cholesterol-lowering drugs.

Fehder, W. P. and S. D. Douglas (2001). "Interactions between the nervous and immune systems." Semin Clin Neuropsychiatry 6(4): 229-40.
Substantial morphologic and functional evidence exists that supports the reciprocal interactions that occur between the nervous and immune systems. The nervous and immune systems have been increasingly found to use a common chemical language in the form of neuropeptides, cytokines, and hormones. Sophisticated immunologic techniques such as the identification and detection of immune cell surface markers enable researchers to determine the origin and activity of diverse cells in the blood and central nervous system. These techniques have elucidated the activity of immune cells in the central nervous system (CNS) that was previously thought to be privileged from immune surveillance in the presence of an intact blood brain barrier. Immune cells in the CNS play a central role in several degenerative diseases such as Alzheimer's disease, Huntington's disease, Multiple sclerosis, AIDS dementia complex, and nerve destruction associated with trauma. Immune cells also play a role in demyelinating peripheral nerve disorders. Cytokines and neuropeptides secreted by peripheral immune cells have profound effects on behavior that is mediated by the CNS. The close integration between immune and nervous system responses is being increasingly recognized in physiologic and pathologic conditions.

Feldman, H. and A. Kertesz (2001). "Diagnosis, classification and natural history of degenerative dementias." Can J Neurol Sci 28 Suppl 1: S17-27.
The release of the first approved medications for the treatment of Alzheimer's disease in Canada has highlighted the renewed need and importance of diagnostic accuracy and understanding of the spectrum of the dementias. The epidemiological scope of the problem of dementia in Canada including risk factors, caregiving patterns and costs of care have been well-characterized through the Canadian Study of Health and Aging (CSHA 1991-1996) with some of the key findings reviewed here. Beyond Alzheimer's disease the phenotypes and genotypes of the other degenerative dementias have been emerging with proposed operational diagnostic criteria that should facilitate their recognition in clinical practice. This paper reviews the clinical phenotypes of the most common causes of dementia with a proposed classification scheme and with discussion of their relevance from a differential treatment standpoint. This paper served as a background document for the working group of the Consensus Conference on Dementia (C3D) in February 1998 and has been revised subsequently for this publication.

Ferencik, M., M. Novak, et al. (2001). "Alzheimer's disease, inflammation and non-steroidal anti-inflammatory drugs." Bratisl Lek Listy 102(3): 123-32.
Alzheimer's disease (AD) is a degenerative disease of the brain, which causes dementia. The disease is characterised by three main pathogenic factors: senile plaques, neurofibrillary tangles and inflammation. the participation of the local inflammatory reaction is confirmed especially by the results of studies dealing with activated microglia, reactive astrocytes, complement system, cytokines, reactive mediators of oxygen and nitrogen (free radicals), all of which participate significantly in inflammatory processes. These inflammatory markers are locally produced by brain cells, and occur in close proximity of beta-amyloid and tau protein deposits. Moreover, some epidemiologic and pilot clinical studies have proven that long-term administration of anti-inflammatory drugs have a protective effect on the onset of AD. Out of them, non-steroidal anti-inflammatory drugs (NSAIDs) are most extensively investigated medicaments. Despite some contradictory findings, the prevalent majority of these studies prove that long-term application of anti-inflammatory treatment can delay the onset, or at least slow down the progression of AD, namely in people between 65 and 75 years of age. The most appropriate prophylactic effect seems to be achieved by specific inhibitors of cyclooxygenase-2 (COX-2), namely celecoxib and rofecoxib. These preparations protect the gastrointestinal tract better than classical NSAIDs which inhibit both isoenzymes--COX-1 and COX-2. COX-2 is expressed in higher concentrations in the degenerating cells of the brain and this excessive expression can be decreased by selective inhibitors. The latter decrease also the excessive activation of some transcription factors (PPARgama and the nuclear factor kapa-B), which are responsible for the initiation of transcription of a number of pro-inflammatory genes. The selective inhibitors COX-2 can thereby have an anti-inflammatory effect operating on several levels. (Tab. 1, Fig. 1, Ref. 75.)

Fernandez-Novoa, L. and R. Cacabelos (2001). "Histamine function in brain disorders." Behav Brain Res 124(2): 213-33.
The neurotransmitter histamine (HA) has been implicated in the regulation of numerous and important activities of the central nervous system as arousal, cognition, circadian rhythms and neuroendocrine regulation. The data presented here indicate the participation of the histaminergic system in central nervous system disorders, such as Alzheimer's disease and schizophrenia. We also present experimental data on histamine in an animal model of neurodegeneration and the cytotoxic effects of histamine on cultured rat endothelial cells. More studies are needed to investigate the role of the histaminergic system in central nervous system disorders. Peripheral cellular studies in health and disease, molecular studies on receptors and in vivo pharmacological studies may help us to better understand the function of the histaminergic system in health and disease.

Ferrari, E., D. Casarotti, et al. (2001). "Age-related changes of the adrenal secretory pattern: possible role in pathological brain aging." Brain Res Brain Res Rev 37(1-3): 294-300.
The biosynthetic dissociation of the adrenocortical secretion occurring with age may have a pathogenetic role in the pathophysiology of brain aging. We studied cortisol and DHEAS secretion in healthy old and young subjects, in senile dementia, in major depression of elderly subjects and in healthy centenarians. A clear age-related decline of DHEAS secretion was well evident in healthy centenarians, and a further decrease in DHEAS concentration was found in old depressed patients and moreover in the demented ones, by comparison with age-matched controls. The circadian profile of serum cortisol was clearly flattened in old subjects, due to the selective increase in the cortisol nocturnal levels, particularly evident in demented subjects; on the other hand, the morning serum cortisol levels were not significantly different among centenarians, young and old controls. The molar ratio between cortisol and DHEAS showed a significant age-related increase; the occurrence of senile dementia and of major depression played an additive role, by comparison to physiological aging. The qualitative and quantitative modifications of the adrenocortical secretion occurring with aging seem mainly dependent on age itself, but the occurrence of pathological conditions may amplify these changes. Since cortisol and DHEAS play opposite effects on the central nervous system, the evaluation of the ratio between cortisol and DHEAS seems to be a good marker of the neuroendocrine features in old subjects.

Ferreira, S. T. and F. G. De Felice (2001). "PABMB Lecture. Protein dynamics, folding and misfolding: from basic physical chemistry to human conformational diseases." FEBS Lett 498(2-3): 129-34.
Proteins exhibit a variety of motions ranging from amino acid side-chain rotations to the motions of large domains. Recognition of their conformational flexibility has led to the view that protein molecules undergo fast dynamic interconversion between different conformational substates. This proposal has received support from a wide variety of experimental techniques and from computer simulations of protein dynamics. More recently, studies of the subunit dissociation of oligomeric proteins induced by hydrostatic pressure have shown that the characteristic times for subunit exchange between oligomers and for interconversion between different conformations may be rather slow (hours or days). In such cases, proteins cannot be treated as an ensemble of rapidly interconverting conformational substates, but rather as a persistently heterogeneous population of different long-lived conformers. This is reminiscent of the deterministic behavior exhibited by macroscopic bodies, and may have important implications for our understanding of protein folding and biological functions. Here, we propose that the deterministic behavior of proteins may be closely related to the genesis of conformational diseases, a class of pathological conditions that includes transmissible spongiform encephalopathies, Alzheimer's disease and other amyloidosis.

Finiels, H., D. Strubel, et al. (2001). "[Deglutition disorders in the elderly. Epidemiological aspects]." Presse Med 30(33): 1623-34.
THE PREVALENCE: The exact prevalence of deglutition disorders in the elderly is not known. It appears frequent in very old patients and in those suffering from polypathological symptoms, affecting 50% of the populations in long-term care units. THE EFFECTS OF AGING: Physiological aging alters various parameters of swallowing, however it seems that these modifications related to age have little effect on healthy subjects. However, they may increase vulnerability in those presenting with intercurrent pathologies. CONCOMITANT DISORDERS: Other than the decrease in efficient mastication and the existence of xerostomia, frequently observed contributing factors, many diseases may be responsible for dysphagia in the elderly. Neurological disorders, particularly cerebral vascular diseases, central nervous system degenerative disorders and neuro-motor diseases predominate. In the aging, muscular disorders and after effects of various diseases can set-in. Modifications in oropharyngeal anatomy generally results from cancerous lesions of the aero-digestive junction, but also, occasionally from extrinsic compression that does not necessarily reflect a neoplastic etiology. Zenker's diverticulitis represents a cause of dysphagia specific to the elderly. Problems in swallowing of iatrogenic origin are also frequent, following cervical radiotherapy or after oropharyngeal surgery, during tracheal intubation or when using feeding tubes and also during various medical treatments. UNDERRATED CONSEQUENCES: Dysphagia leads to multiple morbid after effects, primarily alteration in quality of life, dehydration, undernutrition, asphyxia and congestion and recurrent infections of the respiratory tract. The responsibility of deglutition disorders in the occurrence of these complications is difficult to assess in weak elderly subjects because of the frequent concomitance with multiple deficiencies and incapacities.

Finkel, S. I. (2001). "Behavioral and psychological symptoms of dementia: a current focus for clinicians, researchers, and caregivers." J Clin Psychiatry 62 Suppl 21: 3-6.
Behavioral and psychological symptoms of dementia are an important aspect of dementing illness. They represent a growing burden to caregivers and health care institutions and an increasing financial burden as the proportion of elderly patients, and consequently those with dementia, increases throughout the world. Behavioral and psychological symptoms of dementia can be recognized and assessed using a number of rating scales. Management of the symptoms is then possible for the benefit of patients, family members, caregivers, and the health care system.

Flaten, T. P. (2001). "Aluminium as a risk factor in Alzheimer's disease, with emphasis on drinking water." Brain Res Bull 55(2): 187-96.
Aluminium (Al) is clearly a powerful neurotoxicant. Considerable evidence exists that Al may play a role in the aetiology or pathogenesis of Alzheimer's disease (AD), but whether the link is causal is still open to debate. This paper reviews the epidemiological evidence linking Al and AD. Nine out of 13 published epidemiological studies of Al in drinking water and AD have shown statistically significant positive relations. Given the difficulty in producing high-quality data for the occurrence of AD and also for Al exposure, with the resulting unavoidable misclassification errors biasing any true association towards the null value, these studies are remarkably consistent. A major problem in their interpretation is that drinking water, even at high Al concentrations, only contributes a fraction of the total dietary intake of Al. In particular, regular consumers of antacids ingest gram amounts of Al daily, thousands of times the amounts taken in through drinking water, and epidemiological studies of antacid exposure and AD have been largely negative. However, Al is very poorly absorbed in the gastrointestinal tract, and the possibility that some Al fractions present in drinking water may be particularly bioavailable cannot be dismissed at present. The combined evidence linking Al and AD warrants substantial research efforts. Such efforts should focus on clarification of the cellular and molecular mechanisms in Al toxicity and of the basic metabolism and kinetics of Al in the human body, and on further epidemiological studies including diverse routes of Al exposure and also variables that are known or suspected to influence the individuals' susceptibility to AD, such as apolipoprotein E allele status and family history of AD.

Flicker, L. and G. Grimley Evans (2001). "Piracetam for dementia or cognitive impairment." Cochrane Database Syst Rev(2): CD001011.
OBJECTIVES: To determine the clinical efficacy of piracetam for the features of dementia or cognitive impairment, classified according to the major subtypes of dementia: vascular, Alzheimer's disease or mixed vascular and Alzheimer's disease, or unclassified dementia, or cognitive impairment not fulfilling the criteria for dementia. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 10 November 2000 using the term spiracetam, nootropic and 2-Oxo-1-pyrrolidine. In addition the pharmaceutical company responsible for marketing most of the piracetam worldwide, UCB Pharma, provided a comprehensive list of abstracts, which included many unpublished studies. As many of these unpublished, placebo-controlled studies will be reviewed as possible. SELECTION CRITERIA: All unconfounded trials specified as randomized in which treatment with piracetam was administered for more than a day and compared with placebo in patients with dementia of Alzheimer type, vascular dementia,or mixed vascular and Alzheimer's disease, or unclassified dementia, or cognitive impairment not fulfilling the criteria for dementia. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. Each study was independently verified as fulfilling the inclusion criteria. Studies were rated for methodological quality by assessment of blinding and loss before analysis as described by Jadad et al. (1996). Studies were pooled if appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat analyses were undertaken. Sensitivity analyses were performed to determine if successive elimination of those studies performing most poorly on these quality criteria changed the effect estimate. MAIN RESULTS: Unfortunately, many of the studies were of cross-over design and first-phase data were unavailable, or could not be extracted. Global Impression of Change was the only outcoeme for which there was a significant volume of evidence from the pooled data. There was evidence of heterogeneity in the results from the individual studies, chi-square test = 20.8 (df=5). Using a fixed effects model the odds ratio for improvement in the piracetam group compared with the placebo group was 3.55, [95% CI][2.45, 5.16]. If a random effects model was used the odds ratio was 3.47 [1.29, 9.30]. If one single-blind study was excluded, the fixed effects model yielded an odds ratio of 3.36 [2.29, 4.99] and if a random effects model was applied then the odds ratio was 2.89 [1.01, 8.24]. The evidence of effects on cognition and other measures, was inconclusive. REVIEWER'S CONCLUSIONS: At this stage the evidence available from the published literature does not support the use of piracetam in the treatment of people with dementia or cognitive impairment. Although effects were found on global impression of change, no benefit was shown by any of the more specific measures. There is a need for further evaluation of piracetam by : 1) Obtaining the data from the identified studies for an individual patient database review, 2) Performing a randomized trial of piracetam in patients with diagnoses made by currently accepted diagnostic criteria. The trial should extend over for a period of at least 6 months and preferably longer. Specific cognitive instruments which are sensitive to change, Clinician Global Impression of Change, levels of dependency and caregiver quality of life scales should also be incorporated in such a study.

Fortini, M. E. (2001). "Notch and presenilin: a proteolytic mechanism emerges." Curr Opin Cell Biol 13(5): 627-34.
Presenilins are needed for proteolytic processing of transmembrane proteins of the Notch/Lin-12 family and for cleavage of the amyloid precursor protein. Accumulating evidence now strongly implicates Presenilin as the catalytic core of a multiprotein complex that executes an unusual intramembranous cleavage of its substrates. In the case of amyloid precursor protein, this cleavage contributes to the generation of small, toxic amyloid peptides that trigger the pathological development of Alzheimer's disease. In the Notch/Lin-12 pathway, Presenilin-mediated cleavage of the receptor is a crucial feature of ligand-induced receptor activation and signal transduction. In this pathway, the Presenilins perform a regulated cleavage event that follows additional processing steps during receptor maturation and ligand-induced ectodomain removal.

Fosslien, E. (2001). "Mitochondrial medicine--molecular pathology of defective oxidative phosphorylation." Ann Clin Lab Sci 31(1): 25-67.
Different tissues display distinct sensitivities to defective mitochondrial oxidative phosphorylation (OXPHOS). Tissues highly dependent on oxygen such as the cardiac muscle, skeletal and smooth muscle, the central and peripheral nervous system, the kidney, and the insulin-producing pancreatic beta-cell are especially susceptible to defective OXPHOS. There is evidence that defective OXPHOS plays an important role in atherogenesis, in the pathogenesis of Alzheimer's disease, Parkinson's disease, diabetes, and aging. Defective OXPHOS may be caused by abnormal mitochondrial biosynthesis due to inherited or acquired mutations in the nuclear (n) or mitochondrial (mt) deoxyribonucleic acid (DNA). For instance, the presence of a mutation of the mtDNA in the pancreatic beta-cell impairs adenosine triphosphate (ATP) generation and insulin synthesis. The nuclear genome controls mitochondrial biosynthesis, but mtDNA has a much higher mutation rate than nDNA because it lacks histones and is exposed to the radical oxygen species (ROS) generated by the electron transport chain, and the mtDNA repair system is limited. Defective OXPHOS may be caused by insufficient fuel supply, by defective electron transport chain enzymes (Complexes I - IV), lack of the electron carrier coenzyme Q10, lack of oxygen due to ischemia or anemia, or excessive membrane leakage, resulting in insufficient mitochondrial inner membrane potential for ATP synthesis by the F0F1-ATPase. Human tissues can counteract OXPHOS defects by stimulating mitochondrial biosynthesis; however, above a certain threshold the lack of ATP causes cell death. Many agents affect OXPHOS. Several nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit or uncouple OXPHOS and induce the 'topical' phase of gastrointestinal ulcer formation. Uncoupled mitochondria reduce cell viability. The Helicobacter pylori induces uncoupling. The uncoupling that opens the membrane pores can activate apoptosis. Cholic acid in experimental atherogenic diets inhibits Complex IV, cocaine inhibits Complex I, the poliovirus inhibits Complex II, ceramide inhibits Complex III, azide, cyanide, chloroform, and methamphetamine inhibit Complex IV. Ethanol abuse and antiviral nucleoside analogue therapy inhibit mtDNA replication. By contrast, melatonin stimulates Complexes I and IV and Gingko biloba stimulates Complexes I and III. Oral Q10 supplementation is effective in treating cardiomyopathies and in restoring plasma levels reduced by the statin type of cholesterol-lowering drugs.

Foster, J. K. (2001). "Selective attention in Alzheimer's disease." Front Biosci 6: D135-53.
This chapter presents a review of selective attention functioning in Alzheimer's disease (AD). The primary focus is on work conducted into this complex topic within the author and colleagues' laboratories (i.e. studies of simple and conjoined visual search). Findings obtained by the author and colleagues investigating simple and conjoined feature visual search in AD are related to findings obtained in the same laboratories in the healthy elderly and in patients with Parkinson's disease. Selective attention is a complex, multifactorial entity. Impairment of selective attention may be an early feature of AD and a prominent clinical characteristic of some patients. However, there are currently few reliable clinical measures of attentional dysfunction in AD. The experimental literature implicates some aspects of selective attention more reliably in AD than others. With respect to our own empirical studies, more effortful or controlled aspects of selective attention (as characterized by conjoined feature visual search) are impaired in AD. Furthermore, on the basis of our experimental observations, these aspects of selective attention appear to be disproportionately impaired relative to deficits in other cognitive domains that have previously been reported in the AD literature. By contrast, conjoined feature visual search deficits were not observed in our studies in patients with Parkinson's disease. The selective attention deficits that we have noted in AD patients represent an extension of the types of impairments that we have also observed in healthy aging; that is, compared with the healthy elderly, AD patients were quantitatively but not qualitatively more impaired on conjoined feature visual search. This is an important observation. The ways in which these findings relate to the wider AD selective attention literature are also considered, drawing out several common theoretical strands across a range of empirical studies.

Foy, M. R. (2001). "17beta-estradiol: effect on CA1 hippocampal synaptic plasticity." Neurobiol Learn Mem 76(3): 239-52.
An understanding of synaptic plasticity in the mammalian brain has been one of R. F. Thompson's major pursuits throughout his illustrious career. A current series of experiments of significant interest to R. F. Thompson is an examination of the interactions between sex hormones, synaptic plasticity, aging, and stress. This research is contained within a broader project whose aim is to investigate animal models that evaluate estrogen interactions with Alzheimer's disease. This paper reviews the recent results that have led to a better understanding of how the sex hormone estrogen influences synaptic plasticity in an important structure within the mammalian brain responsible for learning and memory: the hippocampus. In this review, a number of experiments have been highlighted that investigate the molecular mechanisms that underlie estrogen's effect on two specific forms of synaptic plasticity commonly studied in neurophysiology and the behavioral neurosciences: long-term potentiation and long-term depression.

Franceschi, C., S. Valensin, et al. (2001). "Neuroinflammation and the genetics of Alzheimer's disease: the search for a pro-inflammatory phenotype." Aging (Milano) 13(3): 163-70.
The role of interleukin 1 (IL-1) and interleukin 6 (IL-6) in the pathogenesis of Alzheimer's disease (AD) is reviewed within the framework of "inflamm-aging", i.e., the characteristic chronic pro-inflammatory status which develops in old age, and neuroinflammation, i.e., the peculiar inflammatory process which is present in the brain of AD patients. In particular, the data suggesting that several IL-1 and IL-6 gene polymorphisms can contribute to the risk of developing AD are reviewed. The possibility as well as the difficulty in identifying a pro-inflammatory phenotype, and its importance for the prevention, diagnosis and therapy of AD and other age-related pathologies are discussed.

Frey, J. (2001). "[Is there sugar in the Alzheimer's disease?]." Ann Biol Clin (Paris) 59(3): 253-7.
Epidemiological and immunohistochemical studies focus the interest on the contribution of carbohydrates in the pathophysiology of Alzheimer's disease. Diabetes mellitus increases the risk. In the extracellular (senile) plaques, which contain aggregates of amyloid proteins, and in the neurofibrillary tangles within the cytoplasm of neurons, advanced glycation end products were detected. It is discussed whether it is a cause or an effect of the Alzheimer's disease. The vascular origin of the lesions is also considered.

Frisoni, G. B. (2001). "Treatment of Alzheimer's disease with acetylcholinesterase inhibitors: bridging the gap between evidence and practice." J Neurol 248(7): 551-7.
Views on drug therapy with acetylcholinesterase inhibitors of the cognitive symptoms of Alzheimer's disease are not uniform, varying from excitement at the possibility of significantly improving the personal and social burden of the disease to skeptical and nihilistic attitudes. Clinical practice from generous prescription to evidence-based guidelines and advising much stricter rules, mirror these attitudes. The epidemiological and clinical relevance of the issue requires understanding of the factors responsible for such discrepancies. Randomized clinical trials have only been able to address a few of the many variables that can affect the response to acetylcholinesterase inhibitors. The effect on behavioral symptoms, severe Alzheimer's dementia, and non-Alzheimer's forms of degenerative dementia need to be clarified as well as the modulating effect of frequently associated conditions such as cognitive changes due to physical diseases and cerebrovascular disease. The gap between evidence and clinical practice might be closed with appropriately designed observational studies rather than randomized clinical trials.

Froehlich, T. E., S. T. Bogardus, Jr., et al. (2001). "Dementia and race: are there differences between African Americans and Caucasians?" J Am Geriatr Soc 49(4): 477-84.
This study provides an overview of racial differences in etiology and prevalence of dementia. Preliminary findings indicate that the clinical and molecular etiologies of dementia differ between races. African Americans have a higher prevalence of vascular dementia and a lower prevalence of Parkinsonian dementia than do Caucasians. The genetic etiologies of Alzheimer's-type dementia appear to differ between African Americans and Caucasians. The variations in dementia etiologies and in cognitive testing accuracy between races suggests the urgent need to develop racially appropriate cognitive assessment methods and to develop preventive and treatment etiologies differently according to racial background of individual patients.

Galasko, D. (2001). "New approaches to diagnose and treat Alzheimer's disease: a glimpse of the future." Clin Geriatr Med 17(2): 393-410.
An explosion of scientific and clinical knowledge about Alzheimer's disease now provides a basis for selecting targets for treatment aimed at slowing progression of dementia or delaying the onset of or preventing Alzheimer's disease. The rationale that underlies several promising approaches to treatment are reviewed. Novel forms of treatment are most effective when combined with sensitive clinical methods to diagnose Alzheimer's disease as early as possible and to track its progression over time. Therefore, this article highlights findings concerning biological markers for Alzheimer's disease and the mild cognitive impairment syndrome and attempts to define a prodromal stage of Alzheimer's disease.

Galluzzi, S., L. Cimaschi, et al. (2001). "Mild cognitive impairment: clinical features and review of screening instruments." Aging (Milano) 13(3): 183-202.
Clinical criteria to recognize subjects with cognitive impairment in the pre-dementia stage are becoming available. These are frail subjects, at risk of adverse outcomes, such as death, institutionalization, and functional and cognitive deterioration. Early identification of these subjects has a great importance in order to start rehabilitative or pharmacological interventions that could slow the progression of cognitive impairment, and the onset of disability. In this regard, cognitive screening tests might be helpful in different clinical settings (general practice, acute care, rehabilitation, and nursing home). We describe the most frequent clinical presentations of cognitive impairment in the pre-dementia stage, and review eleven screening tests to provide recommendations on which should be preferred in each setting.

Galvin, J. E., V. M. Lee, et al. (2001). "Synucleinopathies: clinical and pathological implications." Arch Neurol 58(2): 186-90.
The synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathologic lesion composed of aggregates of insoluble alpha-synuclein protein in selectively vulnerable populations of neurons and glia. Growing evidence links the formation of abnormal filamentous aggregates to the onset and progression of clinical symptoms and the degeneration of affected brain regions in neurodegenerative disorders. These disorders may share an enigmatic symmetry, i.e., missense mutations in the gene encoding for the disease protein (alpha-synuclein) cause familial variants of Parkinson disease as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild-type brain protein in the more common sporadic varieties of Parkinson disease. It is likely that clarification of this enigmatic symmetry in 1 form of synucleinopathy will have a profound impact on understanding the mechanisms underlying all these disorders. Furthermore, these efforts will likely lead to novel diagnostic and therapeutic strategies in regard to the synucleinopathies.

Gandy, S. and S. Petanceska (2001). "Regulation of alzheimer beta-amyloid precursor trafficking and metabolism." Adv Exp Med Biol 487: 85-100.

Garcia, M. L. and D. W. Cleveland (2001). "Going new places using an old MAP: tau, microtubules and human neurodegenerative disease." Curr Opin Cell Biol 13(1): 41-8.
The microtubule-associated protein tau was originally identified as a protein that co-purified with tubulin in vitro, stimulated assembly of tubulin into microtubules and strongly stabilized microtubules. Recognized now as one of the most abundant axonal microtubule-associated proteins, a convergence of evidence implicates an overlapping in vivo role of tau with other axonal microtubule-associated proteins (e.g. MAP1B) in establishing microtubule stability, axon elongation and axonal structure. Missense and splice-site mutations in the human tau gene are now known to be causes of inherited frontotemporal dementia and parkinsonism linked to chromosome 17, a cognitive disorder of aging. This has provided direct evidence for the hypothesis that aberrant, filamentous assembly of tau, a frequent hallmark of a series of human cognitive diseases, including Alzheimer's disease, can directly provoke neurodegeneration.

Garcia-Segura, L. M., I. Azcoitia, et al. (2001). "Neuroprotection by estradiol." Prog Neurobiol 63(1): 29-60.
This review highlights recent evidence from clinical and basic science studies supporting a role for estrogen in neuroprotection. Accumulated clinical evidence suggests that estrogen exposure decreases the risk and delays the onset and progression of Alzheimer's disease and schizophrenia, and may also enhance recovery from traumatic neurological injury such as stroke. Recent basic science studies show that not only does exogenous estradiol decrease the response to various forms of insult, but the brain itself upregulates both estrogen synthesis and estrogen receptor expression at sites of injury. Thus, our view of the role of estrogen in neural function must be broadened to include not only its function in neuroendocrine regulation and reproductive behaviors, but also to include a direct protective role in response to degenerative disease or injury. Estrogen may play this protective role through several routes. Key among these are estrogen dependent alterations in cell survival, axonal sprouting, regenerative responses, enhanced synaptic transmission and enhanced neurogenesis. Some of the mechanisms underlying these effects are independent of the classically defined nuclear estrogen receptors and involve unidentified membrane receptors, direct modulation of neurotransmitter receptor function, or the known anti-oxidant activities of estrogen. Other neuroprotective effects of estrogen do depend on the classical nuclear estrogen receptor, through which estrogen alters expression of estrogen responsive genes that play a role in apoptosis, axonal regeneration, or general trophic support. Yet another possibility is that estrogen receptors in the membrane or cytoplasm alter phosphorylation cascades through direct interactions with protein kinases or that estrogen receptor signaling may converge with signaling by other trophic molecules to confer resistance to injury. Although there is clear evidence that estradiol exposure can be deleterious to some neuronal populations, the potential clinical benefits of estrogen treatment for enhancing cognitive function may outweigh the associated central and peripheral risks. Exciting and important avenues for future investigation into the protective effects of estrogen include the optimal ligand and doses that can be used clinically to confer benefit without undue risk, modulation of neurotrophin and neurotrophin receptor expression, interaction of estrogen with regulated cofactors and coactivators that couple estrogen receptors to basal transcriptional machinery, interactions of estrogen with other survival and regeneration promoting factors, potential estrogenic effects on neuronal replenishment, and modulation of phenotypic choices by neural stem cells.

Gauthier, S. (2001). "Cholinergic adverse effects of cholinesterase inhibitors in Alzheimer's disease: epidemiology and management." Drugs Aging 18(11): 853-62.
Cholinergic adverse effects of acetylcholinesterase inhibitors (AChEIs) are caused by their central and peripheral pharmacological actions on a variety of organ tissues. Gastrointestinal adverse effects predominate and these were relatively common in the phase II and III randomised clinical trials of AChEIs for the treatment of probable Alzheimer's disease. However, in these studies forced and rapid titration of drugs was used, which is not the case in clinical practice. Although there is a risk of pharmacodynamic interactions with other drugs leading to enhanced cholinergic adverse effects, very few of these interactions have proven to be clinically significant. Unresolved issues include the mechanism of syncope and neuromuscular weakness, which should be resolved through structured pharmacovigilance programmes and clinical studies. Loss of bodyweight may prove to be a long term significant complication. As a class, the AChEIs have proven to be well tolerated in the symptomatic treatment of Alzheimer's disease in its mild-to-moderately severe stages. The incidence and clinical significance of cholinergic adverse events will need to be carefully studied if the drugs are used for indications other than Alzheimer's disease.

Gauthier, S. and S. Ferris (2001). "Outcome measures for probable vascular dementia and Alzheimer's disease with cerebrovascular disease." Int J Clin Pract Suppl(120): 29-39.
Vascular dementia (VaD) can be defined as dementia associated with cerebrovascular disease (CVD), and accounts for a large proportion of all dementia cases. There is substantial overlap in the clinical symptomatology, pathophysiology and neurochemical mechanisms in VaD compared with Alzheimer's disease, suggesting that an effective treatment for Alzheimer's disease may also offer benefit as a symptomatic treatment in VaD. However, there are currently no explicit guidelines for conducting clinical pharmacotherapy trials in VaD patients. Two important requirements for assessing therapeutic benefits in such trials are 1) the inclusion of appropriate patients and 2) the use of appropriate outcome measures. Debate on the precise definition of VaD in relation to patient selection criteria continues, but many of the recommendations for outcome measures in Alzheimer's disease are already applicable to VaD. There is consensus that cognitive and global function measures, and assessments of abilities to perform activities of daily living (ADL) must be included as part of the optimal assessment battery in VaD trials. A measure of reduced behavioural symptoms with associated reductions in demands on caregivers would also be desirable. However, care must be taken in extrapolating Alzheimer's disease-specific evaluations to VaD, in that important differences in specific domains affected and characteristics of disease course must be taken into account. Between them, measures such as the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog; perhaps with supplemental tests of attention and other frontal lobe functions), evaluations of clinical global impression of change and a functional assessment addressing instrumental as well as basic ADL, e.g. Disability Assessment in Dementia (DAD) scale, should provide a good overall description of VaD-related deficits and sufficient appraisal of treatment effects. The Neuropsychiatric Inventory has also been shown to have good potential utility for measuring behavioural alterations in VaD. These and other assessments are reviewed to provide a balanced and realistic view of the type of treatment outcomes that can be expected in VaD pharmacotherapy trials, and to address the best ways of measuring these outcomes.

Gauthier, S. (2001). "Alzheimer's disease: current and future therapeutic perspectives." Prog Neuropsychopharmacol Biol Psychiatry 25(1): 73-89.
1. A better understanding of the pathophysiology of AD has been made possible through population-based epidemiological studies, human genetic and post-mortem studies, leading to a number of testable hypothesis towards delaying progression. 2. A number of disease milestones have been identified as therapeutic targets, such as conversion from MCI to diagnosable dementia. 3. Clinicians caring for patients with AD have currently available a number of symptomatic drugs, and will have in the future the ability to predict the risk for asymptomatic individuals to develop AD, and provide advice towards prevention.

Gebicke-Haerter, P. J., O. Spleiss, et al. (2001). "Microglial chemokines and chemokine receptors." Prog Brain Res 132: 525-32.

Gebicke-Haerter, P. J. (2001). "Microglia in neurodegeneration: molecular aspects." Microsc Res Tech 54(1): 47-58.
Inflammatory events in the CNS are associated with injuries as well as with well-known chronic degenerative diseases, such as Multiple Sclerosis, Parkinson's, or Alzheimer's disease. Compared to inflammation in peripheral tissues, inflammation in brain appears to follow distinct pathways and time-courses, which likely has to do with a relatively strong immunosuppression in that organ. For this reason, it is of great importance to get insights into the molecular mechanism governing immune reactions in brain tissue. This task is hard to achieve in vivo, but can be approached by studying the major cell type responsible for brain inflammation, the microglia, in culture. Since these cells are the only professional antigen-presenting cells resident in brain parenchyma, molecular mechanisms of antigen presentation are being discussed first. After covering the expression and regulation of anti- and proinflammatory cytokines, induction and regulation of two key enzymes and their products-COX-2 and iNOS-are summarized. Possibly, pivotal molecular targets for drug therapies of brain disorders will be discovered in intracellular signaling pathways leading to activation of transcription factors. Finally, the impact of growth factors, of neurotrophins in particular, is highlighted. It is concluded that the presently available data on the molecular level is far from being statisfying, but that only from better insights into molecular events will we obtain the information required for more specific therapies.

Genazzani, A. R., P. Monteleone, et al. (2001). "Clinical implications of circulating neurosteroids." Int Rev Neurobiol 46: 399-419.

Georgopoulou, N., M. McLaughlin, et al. (2001). "The role of post-translational modification in beta-amyloid precursor protein processing." Biochem Soc Symp(67): 23-36.
The beta-amyloid precursor protein (APP) plays a pivotal role in the early stages of neurodegeneration associated with Alzheimer's disease. An alteration in the processing pattern of the protein results in an increase in the generation of the 40-42-amino-acid beta-amyloid (A beta) peptide, which coalesces to form insoluble, extracellular amyloid deposits. A greater understanding of the factors that influence APP processing may assist in the design of effective therapeutic agents to halt progression of Alzheimer's disease. APP is a sialoglycoprotein with two potential N-linked glycosylation sites, one of which may contain a complex oligosaccharide chain. An alteration in the glycosylation state of APP by the generation of oligomannosyl oligosaccharides results in a decrease in the secretion of the neuroprotective, soluble form of the protein and a parallel increase in the deposition of the cellular protein within the perinuclear region of the cell. Conversely, the attachment of additional terminal sialic acid residues on to the oligosaccharide chain results in an increase in secretion of soluble APP (sAPP alpha). One factor that has been widely reported to alter APP processing is the activation of protein kinase C (PKC). This process has been characterized using synaptosomal preparations, which suggests that the PKC action is occurring at the level of the plasma membrane. Furthermore, when cells are transfected with the sialyltransferase enzyme, there is a direct relationship between the sialylation potential of APP and the fold stimulation of sAPP alpha, after PKC activation. These results suggest that the post-translational modification of APP by glycosylation is a key event in determining the processing of the protein.

Giacobini, E. (2001). "Do cholinesterase inhibitors have disease-modifying effects in Alzheimer's disease?" CNS Drugs 15(2): 85-91.
During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) has resulted in drugs being registered for the first time in the US and Europe for this specific indication. The 3 agents registered are cholinesterase inhibitors (ChEIs). The major therapeutic effect of ChEIs in patients with AD is the maintenance of cognitive function, as compared with placebo, during a 6-month to 1-year period of treatment. Additional drug effects that may occur are the slowing of cognitive deterioration and improvement of behaviour and daily living activities. Comparison of clinical effects of 6 ChEIs demonstrates a rather similar magnitude of improvement in cognitive outcome measures. For some drugs, this level may represent an upper limit, while for others it may be possible to increase the benefit further. In order to maximise and prolong positive drug effects it is important to start treatment early and adjust the dosage during treatment. Recent studies that used this administration strategy have shown that in many patients, the stabilisation effect produced by ChEIs can be prolonged for as long as 36 months. This long-lasting effect suggests mechanisms of action other than symptomatic ones. In this article, the effects of ChEIs on beta-amyloid metabolism are postulated to explain the stabilising (i.e. disease-modifying) effects of the drugs. Evidence for such a mechanism is available at the experimental but not yet at the clinical level.

Giacobini, E. (2001). "Is anti-cholinesterase therapy of Alzheimer's disease delaying progression?" Aging (Milano) 13(3): 247-54.
During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer's disease (AD) resulted in three drugs being registered for the first time in the US and Europe. All three compounds are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a stable level during a 6-month to 1-year period of treatment, as compared to placebo. Additional drug effects are to slow down cognitive deterioration and improve behavioral and daily living activity. Recent studies show that in many patients the cognitive stabilization effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic, and directly cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and amyloid precursor protein (APP) metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and cholinergic synaptic function; the effect of such lesions can be reversed by ChEI treatment. A reduction in cholinergic neurotransmission, experimental or pathological, leads to amyloidogenic metabolism and contributes to the development of neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, for which evidence is available on an experimental as well as clinical level, a mechanism based on beta-amyloid metabolism is postulated. The question whether cholinergic stabilization implies simply slowing down progression of disability or also involves delay of disease progression is discussed.

Gimenez y Ribotta, M. (2001). "Gene therapy strategies in neurodegenerative diseases." Histol Histopathol 16(3): 883-93.
Treatment of neurodegenerative diseases by classical pharmacotherapy is restricted by blood-brain barrier which prevents access to the brain of potentially therapeutic molecules. Recent progress in the knowledge of pathophysiological molecular processes, and in the development of molecular biotechnology have opened the way to new therapeutic interventions for these disorders. This chapter reviews the most recent gene therapy strategies using experimental models for neurodegenerative diseases.

Gjedde, A. (2001). "[Receptor mapping in living human beings by means of positron emission tomography]." Ugeskr Laeger 163(38): 5199-205.
PET can map neurotransmitter synthesis, storage, release, binding to receptors, and re-uptake in the brain with tracer concentrations in the picomolar or nanomolar range. Tracers are analogues of naturally occurring precursors or ligands, or are drugs, which bind with varying degrees of specificity to receptor subtypes in the brain. Tracers have been synthesised for many transmitter systems, but dopaminergic and serotonergic neurotransmissions are the main foci of current efforts to selectively trace synthesis, storage, re-uptake, or post-synaptic binding of neurotransmitters. Common measures of the tracer uptake and binding include precursor clearance (k3), a measure of transmitter synthesis and trapping, and binding potential (pB), a measure of the receptor binding per unit of unbound tracer, and hence a measure of the release of the endogenous transmitter, or the occupancy of a drug. Dopamine tracers are used in diseases of the basal ganglia, whereas serotonin, benzodiazepine, and opiate tracers are used in lesions of the cerebral cortex. PET has revealed loss of dopaminergic terminals and dopamine synthetic capacity in Parkinson's disease, MPTP intoxication, and Lesch-Nyhan's syndrome; release of dopamine after administration of cocaine and amphetamine, and in motor activity and cognition; increased synaptic dopamine and release of dopamine, and the 70-90% neuroleptic occupancy of dopamine receptors in the striatum, in patients with schizophrenia; loss of muscarinic and nicotinergic receptors in Alzheimer's disease, and benzodiazepine and opiate receptors in stroke, epilepsy, and Huntington's chorea; altered opiate receptors in chronic pain and drug abuse; and release of opiates in analgesia; but changes in serotonin synthesis, transport, and binding in affective or psychotic disorders remain elusive.

Goedert, M. and M. G. Spillantini (2001). "Tau gene mutations and neurodegeneration." Biochem Soc Symp(67): 59-71.
Abundant neurofibrillary lesions made of the microtubule-associated protein tau constitute a defining neuropathological characteristic of Alzheimer's disease. Filamentous tau protein deposits are also the defining neuropathological characteristic of other neurodegenerative diseases, many of which are frontotemporal dementias or movement disorders, such as Pick's disease, progressive supranuclear palsy and corticobasal degeneration. It is well established that the distribution of tau pathology correlates with the presence of symptoms of disease. However, until recently, there was no genetic evidence linking dysfunction of tau protein to neurodegeneration and dementia. This has now changed with the discovery of close to 20 mutations in the tau gene in frontotemporal dementia with Parkinsonism linked to chromosome 17. All cases with tau mutations examined to date have shown an abundant filamentous tau pathology in brain cells. Pathological heterogeneity is determined to a large extent by the location of mutations in tau. Known mutations are either coding region or intronic mutations located close to the splice-donor site of the intron downstream of exon 10. Most coding region mutations produce a reduced ability of tau to interact with microtubules. Several of these mutations also promote sulphated glycosaminoglycan-induced assembly of tau into filaments. Intronic mutations and some coding region mutations produce increased splicing in of exon 10, resulting in an overexpression of four-repeat tau isoforms. Thus a normal ratio of three-repeat to four-repeat tau isoforms is essential for preventing the development of tau pathology. The new work has shown that dysfunction of tau protein can cause neurodegeneration and dementia.

Goethals, M. and P. Santens (2001). "Posterior cortical atrophy. Two case reports and a review of the literature." Clin Neurol Neurosurg 103(2): 115-9.
We present two cases of progressive early-onset dementia with apraxia and visuospatial disability as initial manifestations. In the later stages of the illness Gerstmann's and Balint's syndromes developed. Structural neuroimaging demonstrated parieto-occipital atrophy and functional imaging revealed bilateral hypometabolism and hypoperfusion in these areas. These cases fulfil the diagnostic criteria of posterior cortical atrophy (PCA). Frontal lobe involvement became evident as the disease progressed. Alzheimer's disease also typically features this anterior spread and possibly this is the underlying pathological substrate for this clinical syndrome, although definite pathology is lacking. In this report, we describe longitudinal evolution in these two cases of PCA.

Golde, T. E. and S. G. Younkin (2001). "Presenilins as therapeutic targets for the treatment of Alzheimer's disease." Trends Mol Med 7(6): 264-9.
Studies demonstrating that accumulation and aggregation of the amyloid beta protein (Abeta) within the brain is likely to cause Alzheimer's disease (AD) have provided the rationale for therapeutic strategies aimed at influencing Abeta production, aggregation and clearance. gamma-secretase catalyzes the final cleavage that releases the Abeta from its precursor; therefore, it is a potential therapeutic target for the treatment of AD. Recent data show that the polytopic membrane proteins presenilin 1 and presenilin 2 are either catalytic components or essential co-factors of a membrane-bound proteolytic complex that possesses gamma-secretase activity. Although recent findings demonstrating that gamma-secretase inhibitors bind directly to presenilins (PSs) further support a catalytic role for PSs in gamma-secretase cleavage, additional studies are still needed to clarify the role of PSs in gamma-secretase cleavage and the use of targeting PSs to reduce Abeta production.

Goldstein, L. S. (2001). "Kinesin molecular motors: transport pathways, receptors, and human disease." Proc Natl Acad Sci U S A 98(13): 6999-7003.
Kinesin molecular motor proteins are responsible for many of the major microtubule-dependent transport pathways in neuronal and non-neuronal cells. Elucidating the transport pathways mediated by kinesins, the identity of the cargoes moved, and the nature of the proteins that link kinesin motors to cargoes are areas of intense investigation. Kinesin-II recently was found to be required for transport in motile and nonmotile cilia and flagella where it is essential for proper left-right determination in mammalian development, sensory function in ciliated neurons, and opsin transport and viability in photoreceptors. Thus, these pathways and proteins may be prominent contributors to several human diseases including ciliary dyskinesias, situs inversus, and retinitis pigmentosa. Kinesin-I is needed to move many different types of cargoes in neuronal axons. Two candidates for receptor proteins that attach kinesin-I to vesicular cargoes were recently found. One candidate, sunday driver, is proposed to both link kinesin-I to an unknown vesicular cargo and to bind and organize the mitogen-activated protein kinase components of a c-Jun N-terminal kinase signaling module. A second candidate, amyloid precursor protein, is proposed to link kinesin-I to a different, also unknown, class of axonal vesicles. The finding of a possible functional interaction between kinesin-I and amyloid precursor protein may implicate kinesin-I based transport in the development of Alzheimer's disease.

Gonzalez Gonzalez, J. A. (2001). "[Drug treatment of Alzheimer's disease]." An R Acad Nac Med (Madr) 118(3): 527-41; discussion 541-4.
The Alzheimer's disease is caused by a today unknown plurietiopathology that does not allow to establish an effective treatment. In the last years, important advances about neuronal physiology and its molecular bases of functioning has been attempt. At the same time, the research and finding of medicaments which used individually or together allow us to advance from a symptomatic treatment to influence and be effective etiopathologically in the Alzheimer's disease. A few are trying to maintain the structure and function of the neurons (synapsis). Others are concentrated on prevent their death or substitute the damaged cells by embryonic mother cells. Nowadays, there are important projects in an experimental stage of research with the hope that "they will be useful for everything" or unless to slow down or stop the Alzheimer's disease. We are going to talk about these medicaments in this article.

Gonzalez-Gross, M., A. Marcos, et al. (2001). "Nutrition and cognitive impairment in the elderly." Br J Nutr 86(3): 313-21.
As the number of older people is growing rapidly worldwide and the fact that elderly people are also apparently living longer, dementia, the most common cause of cognitive impairment is getting to be a greater public health problem. Nutrition plays a role in the ageing process, but there is still a lack of knowledge about nutrition-related risk factors in cognitive impairment. Research in this area has been intensive during the last decade, and results indicate that subclinical deficiency in essential nutrients (antioxidants such as vitamins C, E and beta-carotene, vitamin B(12), vitamin B(6), folate) and nutrition-related disorders, as hypercholesterolaemia, hypertriacylglycerolaemia, hypertension, and diabetes could be some of the nutrition-related risk factors, which can be present for a long time before cognitive impairment becomes evident. Large-scale clinical trials in high-risk populations are needed to determine whether lowering blood homocysteine levels reduces the risk of cognitive impairment and may delay the clinical onset of dementia and perhaps of Alzheimer's disease. A curative treatment of cognitive impairment, especially Alzheimer's disease, is currently impossible. Actual drug therapy, if started early enough, may slow down the progression of the disease. Longitudinal studies are required in order to establish the possible link of nutrient intake--nutritional status with cognitive impairment, and if it is possible, in fact, to inhibit or delay the onset of dementia.

Gotz, J. (2001). "Tau and transgenic animal models." Brain Res Brain Res Rev 35(3): 266-86.
Advances in genetics and transgenic approaches have a continuous impact on our understanding of Alzheimer's disease (AD) and related disorders, especially as aspects of the histopathology and neurodegeneration can be reproduced in animal models. AD is characterized by extracellular Abeta peptide-containing plaques and neurofibrillary aggregates of hyperphosphorylated isoforms of microtubule-associated protein tau. A causal link between Abeta production, neurodegeneration and dementia has been established with the identification of familial forms of AD which are linked to mutations in the amyloid precursor protein APP, from which the Abeta peptide is derived by proteolysis. No mutations have been identified in the tau gene in AD until today. Tau filament formation, in the absence of Abeta production, is also a feature of several additional neurodegenerative diseases including progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The identification of mutations in the tau gene which are linked to FTDP-17 established that dysfunction of tau can, as well as Abeta formation, lead to neurodegeneration and dementia. In this review, newly recognized cellular functions of tau, and the neuropathology and clinical syndrome of FTDP-17 will be presented, as well as recent advances that have been achieved in studies of transgenic mice expressing tau and AD-related kinases and phosphatases. These models link neurofibrillary lesion formation to neuronal loss, provide an in vivo model in which therapies can be assessed, and may contribute to determine the relationship between Abeta production and tau pathology.

Gouras, G. K. and M. F. Beal (2001). "Metal chelator decreases Alzheimer beta-amyloid plaques." Neuron 30(3): 641-2.
Transgenic mice developing beta-amyloid (Abeta) plaques are advancing experimental treatment strategies for Alzheimer's disease. The metal chelator, clioquinol, is reported by Cherny et al. (2001) to reduce Abeta plaques, presumably by chelation of Abeta-associated zinc and copper. This and other recent Abeta-modulating treatment approaches are discussed.

Gozes, I. (2001). "Neuroprotective peptide drug delivery and development: potential new therapeutics." Trends Neurosci 24(12): 700-5.
Alzheimer's disease and related neurodegenerative disorders are prevalent among the elderly and might be considered as the plague of the 21st century. It is thus imperative to find cures for these conditions. The use of nerve growth factor proteins as neuroprotective therapeutics is limited by their hindered mobility through the blood-brain barrier. Peptides provide an attractive alternative. However, do peptide derivatives retain the activity of the entire protein? Are they stable? Would peptides cross the blood-brain barrier and what are the potential side effects? Examples are put forth to strengthen our opinion that peptides are important candidates for future drug development.

Graf, R. A. (2001). "Detouring destruction: a role for inhibitory neuronal activity in preventing neuronal loss--implications for Alzheimer's disease." J Am Osteopath Assoc 101(12 Suppl Pt 1): S7-10.
Recent results from the author's efforts and others have indicated approaches that may eventually lead to new therapeutic strategies for combating neurodegenerative effects associated with dementia and Alzheimer's disease (AD). These strategies include unraveling mechanisms that decrease senile plaque accumulation and delay or slow the neurodegenerative progression associated with AD. Recent work addresses whether normally functioning inhibitory brain circuitry can protect and detour neurodegeneration. The aim of these research efforts is that one or a combination of these approaches will develop into an applied therapy that will enhance brain protection mechanisms and add to quality of life for patients with AD.

Greenlee, W., J. Clader, et al. (2001). "Muscarinic agonists and antagonists in the treatment of Alzheimer's disease." Farmaco 56(4): 247-50.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.

Gregersen, N., P. Bross, et al. (2001). "The role of chaperone-assisted folding and quality control in inborn errors of metabolism: protein folding disorders." J Inherit Metab Dis 24(2): 189-212.
Molecular chaperones are present in the various compartments of the cell and assist the folding of newly synthesized proteins. Compared to wild-type proteins, missense mutant proteins are generally synthesized in a normal fashion, but may be impaired in their folding. A broad array of diseases that are due to misfolding of mutant proteins may be labelled conformational diseases: aggregation diseases, such as Alzheimer disease; diseases caused by negative dominance from misfolded structural proteins, such as hypertrophic cardiomyopathy; and disorders where the misfolded protein is degraded by intracellular proteases. Many metabolic disorders belong to this last category, where the so-called protein quality control systems, comprising chaperones and proteases, attempt to eliminate folding intermediates or misfolded proteins. On the basis of in vitro experiments with a limited number of missense mutations identified in patients with phenylalanine hydroxylase and fatty acid oxidation deficiencies, we discuss the cellular fate of missense mutant proteins. We find that the balance between folding to functional conformers, retention (holding) and degradation of folding intermediates or misfolded proteins is dependent on the nature of the mutation and on the efficiency of the quality control. For example, low temperature may promote formation of functional conformers, while elevated temperature usually promotes retention and degradation. We conclude that disorders caused by many missense mutations are complex diseases in which the mutation itself is a necessary major primary component, but that its effect may be modified by cellular conditions and possibly by genetic variations in the quality control systems. We suggest that this new knowledge about cell handling may open new avenues of understanding of the cell pathology and treatment of patients with metabolic disorders.

Grimes, C. A. and R. S. Jope (2001). "The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling." Prog Neurobiol 65(4): 391-426.
Glycogen synthase kinase-3beta (GSK3beta) is a fascinating enzyme with an astoundingly diverse number of actions in intracellular signaling systems. GSK3beta activity is regulated by serine (inhibitory) and tyrosine (stimulatory) phosphorylation, by protein complex formation, and by its intracellular localization. GSK3beta phosphorylates and thereby regulates the functions of many metabolic, signaling, and structural proteins. Notable among the signaling proteins regulated by GSK3beta are the many transcription factors, including activator protein-1, cyclic AMP response element binding protein, heat shock factor-1, nuclear factor of activated T cells, Myc, beta-catenin, CCAAT/enhancer binding protein, and NFkappaB. Lithium, the primary therapeutic agent for bipolar mood disorder, is a selective inhibitor of GSK3beta. This raises the possibility that dysregulation of GSK3beta and its inhibition by lithium may contribute to the disorder and its treatment, respectively. GSK3beta has been linked to all of the primary abnormalities associated with Alzheimer's disease. These include interactions between GSK3beta and components of the plaque-producing amyloid system, the participation of GSK3beta in phosphorylating the microtubule-binding protein tau that may contribute to the formation of neurofibrillary tangles, and interactions of GSK3beta with presenilin and other Alzheimer's disease-associated proteins. GSK3beta also regulates cell survival, as it facilitates a variety of apoptotic mechanisms, and lithium provides protection from many insults. Thus, GSK3beta has a central role regulating neuronal plasticity, gene expression, and cell survival, and may be a key component of certain psychiatric and neurodegenerative diseases.

Grutzendler, J. and J. C. Morris (2001). "Cholinesterase inhibitors for Alzheimer's disease." Drugs 61(1): 41-52.
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and has become an urgent public health problem in most areas of the world. Substantial progress has been made in understanding the basic neurobiology of AD and, as a result, new drugs for its treatment have become available. Cholinesterase inhibitors (ChEIs), which increase the availability of acetylcholine in central synapses, have become the main approach to symptomatic treatment. ChEIs that have been approved or submitted to the US Food and Drug Administration (FDA) include tacrine, donepezil, metrifonate, rivastigmine and galantamine. In this review we discuss their pharmacology, clinical experience to date with their use and their potential benefits or disadvantages. ChEIs have a significant, although modest, effect on the cognitive status of patients with AD. In addition to their effect on cognition, ChEIs have a positive effect on mood and behaviour. Uncertainty remains about the duration of the benefit because few studies of these compounds beyond one year have been published. Although ChEIs are generally well tolerated, all patients should be followed closely for possible adverse effects. There is no substantial difference in the effectivenes of the various ChEIs, however, they may have different safety profiles. We believe the benefits of their use outweigh the risks and costs and, therefore, ChEls should be considered as primary therapy for patients with mild to moderate AD.

Gu, H. F. (2001). "[Single nucleotide polymorphisms(SNPs)and SNP databases]." Zhonghua Yi Xue Yi Chuan Xue Za Zhi 18(6): 479-81.
Along the rapid development of human genome sequencing project, the variation data of human DNA sequence has become more and more useful not only for studying the origin, evolution and the mechanisms of maintenance of genetic variability in human populations, but also for detection of genetic association in complex disease such as diabetes, obesity, hypertension, Alzheimer's disease, etc. In recent two years, the databases such as dbSNP, CGAP, HGBASE, JST and Go!Poly etc. to collect and exploit data of genomic polymorphisms mainly single nucleotide polymorphisms (SNPs) have been respectively established in the United States, European countries, Japan and China. This overview summarized the development and applications of those SNP databases and also discussed some issues regarding the potential improvement of accuracy of SNP data collected. China has one fifth population in the world. Therefore, development of the SNP database for Chinese populations is of importance in developing complete SNP databases of human genome and may also stimulate the further development of biomedical research and production in China.

Guhaniyogi, J. and G. Brewer (2001). "Regulation of mRNA stability in mammalian cells." Gene 265(1-2): 11-23.
The regulation of mRNA decay is a major control point in gene expression. The stability of a particular mRNA is controlled by specific interactions between its structural elements and RNA-binding proteins that can be general or mRNA-specific. Regulated mRNA stability is achieved through fluctuations in half-lives in response to developmental or environmental stimuli like nutrient levels, cytokines, hormones and temperature shifts as well as environmental stresses like hypoxia, hypocalcemia, viral infection, and tissue injury. Furthermore, in specific disorders like some forms of neoplasia, thalassemia and Alzheimer's disease, deregulated mRNA stability can lead to the aberrant accumulation of mRNAs and the proteins they encode. This review presents a discussion of some recently identified examples of regulated and deregulated mRNA stability in order to illustrate the diversity of genes regulated by alterations in the degradation rates of their mRNAs.

Gulcher, J., A. Kong, et al. (2001). "The genealogic approach to human genetics of disease." Cancer J 7(1): 61-8.
The goal of modern human genetics is to correlate genes with disease or, more specifically, relate genetic variation to phenotypic variation. Although this correlation is usually straightforward in the Mendelian disorders, it has proved to be much more difficult to find in the common diseases because they appear to be more complex, likely involving an interplay among multiple genes and between genes and the environment. Although the strategy of linkage mapping of families was very successful when it was applied to the rare monogenic diseases, few common diseases have been mapped to statistical significance. Many investigators are now abandoning linkage analysis altogether and are moving to a candidate gene case-control strategy. In this article, we describe a genealogic approach to mapping human disease genes and provide three examples of how we have used it to map common diseases to statistical significance. We focus on a simple population with little historic migration and use a computerized genealogy database to increase the number of patients who can be compared with other affected relatives through high-density microsatellite genotyping. The genealogy helps determine which phenotypic classification is inherited and therefore possible to map. It may represent a more efficient strategy than candidate gene case-control studies for determination of what alleles or haplotypes are shared by patients in a population. We suggest that the genetics community not give up on linkage analysis, nor should it assume that the common diseases are too complex to map.

Haan, J., E. Bakker, et al. (2001). "[From gene to disease; amyloid-beta precursor protein gene instrumental in hereditary cerebral amyloid angiopathies]." Ned Tijdschr Geneeskd 145(34): 1639-41.
Hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D) is an autosomal dominant disease caused by a mutation in the amyloid precursor protein gene on chromosome 21. The disease is characterised by amyloid deposition in cerebral blood vessels, which results in cerebral haemorrhages, leucencephalopathy, dementia and death. In the same gene, mutations have also been found for other rare diseases which also result in dementia and haemorrhages, as well as familial Alzheimer's disease (different mutations in different families). The majority of familial Alzheimer cases, however, are associated with mutations in the PS1 gene (more than 70 different mutations) or the PS2 gene (4 mutations).

Hake, A. M. (2001). "Use of cholinesterase inhibitors for treatment of Alzheimer disease." Cleve Clin J Med 68(7): 608-9, 613-4, 616.
The four cholinesterase inhibitors now available for treatment of Alzheimer disease (AD) may be most beneficial, especially in the long run, if started early in the course of the disease. This paper reviews the efficacy, pharmacokinetics, metabolism, side effects, dosage, and precautions for the use of these agents, which may produce modest improvements in cognition, behavior, and the ability to perform activities of daily living.

Hannequin, D. and D. Campion (2001). "[Dominant forms of Alzheimer's disease: from genotype to phenotype]." Rev Neurol (Paris) 157(4): 384-92.
This review is devoted to the relationships between phenotype and genotype of the autosomal dominant forms of Alzheimer's disease caused by mutations of presenilins (PSs) and amyloid precursor protein (APP) genes. A first part examines the clinical characteristics mainly the early age of onset and argues about the diversity of age of onset between different mutations and also between patients bearing the same mutation in large families. The second part reports several arguments demonstrating that the main effect of the PSs and APP mutations is the elevation of Ab42 peptide. The pathological and behavioral effects observed in transgenic APP or PSs animals suggest that intra cellular deposits of Ab42 play a role in the pathophysiological process.

Hardy, J. (2001). "Genetic dissection of primary neurodegenerative diseases." Biochem Soc Symp(67): 51-7.
Neurodegenerative diseases have traditionally been defined as clinico-pathological entities. The clinician observes characteristic clusters of symptoms that relate to the anatomical distribution of the lesion. Typically, these symptoms progress in a characteristic sequence allowing the clinician to make a provisional diagnosis. At autopsy, the pathologist examines the nature and distribution of the lesions, reads the clinical report and makes a definitive diagnosis. This structure is so deeply embedded in our concepts of neurodegenerative disease that we are hardly aware of it. It has become deeply embedded because it has been a useful construct that allows grouping of patients for research, especially in treatment trials. However this success has served to hide its limitations and molecular genetic analysis has clearly shown that there are other ways of thinking about neurodegenerative disease. In this review, I will summarize the limitations of the clinicopathological approach, and discuss how molecular genetics offers an alternative way of thinking about neurodegeneration. My intention is not to suggest that we should replace the clinicopathological approach (Newtonian physics is a perfectly good way of thinking about the world on a day-to-day basis even though we know it is only an approximation to the truth) but rather, to suggest that future treatments for these most devastating diseases may come from a deeper understanding of their related pathogenesis.

Harvey, P. D. (2001). "Cognitive impairment in elderly patients with schizophrenia: age related changes." Int J Geriatr Psychiatry 16 Suppl 1: S78-85.
Cognitive impairment in schizophrenia is a major feature of the illness. Like many of the other aspects of the illness, however, it has not been studied extensively in older patients. Several studies of older patients with a lifetime course of poor outcome and chronic institutional stay have indicated that some patients manifest evidence of profound cognitive impairments on a cross-sectional basis and cognitive and functional decline over longitudinal follow-ups of 30 months or longer. Risk factors for this decline include lower educational attainment and more severe positive symptoms, but do not include more severe symptoms of physical illness. These impairments have been shown to be discriminable from normal age-related changes and from the changes associated with Alzheimer's Disease. In contrast, studies of patients with no history of lifetime institutional stay find no such evidence of either age-related changes in cognitive functioning or longitudinal decline in cognitive or functional status. Since there is accumulating evidence of progressive brain changes over the lifespan in patients with schizophrenia, the course of cognitive deficits in later life will remain an important topic, both for understanding the lifetime course of schizophrenia and for developing interventions aimed at reduction of disability in the illness.

Hayashida, K. (2001). "[Usefulness of SPECT images in helping radiologists understand brain diseases]." Nippon Igaku Hoshasen Gakkai Zasshi 61(5): 208-14.
Nuclear brain imaging is able to show functional abnormalities of lesions that are not detectable by CT and MR images. The diagnostic keys of nuclear-imaging in terms of clinical usefulness are its early detection of lesions and determination of the efficacy of drug and surgical therapies. In dementic patients, F-18 FDG brain images can be diagnosed as Alzheimer's disease 12 months earlier than is possible on CT and MRI images, and can provide information for effective drug therapy. O-15 water CBF images can predict the effect of Nicholin by assessing transient increases in cerebral blood flow (CBF), thereby facilitating improvement in higher brain functions such as orientation. In stroke patients, brain SPECT images with Tc-99m HMPAO can predict fatal cerebral hemorrhage caused by anti-thrombic therapy by showing the decrease in count ratio (count ratio of infarcted to contralateral area of < 0.34) in the acute phase and identifying disruption of the blood brain barrier by showing hyperfixation in the subacute phase. Brain SPECT with I-123 IMP can also identify "misery" perfused areas resulting from reduced CBF and decreased vasoreactivity in the chronic phase. This criterion is utilized for patient selection for extracranial/intracranial bypass surgery, because patients with areas of poor perfusion might be indicated for such surgery. Since nuclear medicine images can accurately select candidates for drug or surgical therapies, they will be beneficial in reducing Medicare costs as well as in enhancing patients' quality of life as a result of the successful treatment. With the advancement of technology, nuclear medicine units that can simultaneously obtain CT images and can combine functional with anatomical images will provide more useful information for the diagnosis of brain disease.

Heneka, M. T. and D. L. Feinstein (2001). "Expression and function of inducible nitric oxide synthase in neurons." J Neuroimmunol 114(1-2): 8-18.
Enzymatically derived nitric oxide (NO) has been implicated in numerous physiological and pathological processes in the brain. Whereas during development NO participates in developmental and maturation processes, excess NO production in the adult in response to inflammation, injury, or trauma participates in both cell death and repair. The expression and activity of the inducible isoform of NO synthase (iNOS) play a pivotal role in sustained and elevated NO release. Recent evidence suggests that neurons can respond to proinflammatory stimuli and take part in brain inflammation. Neuronal iNOS expression has been described in different experimental settings, including cytokine stimulation of neuronal cell lines and primary neurons in vitro as well as in animal models of stroke and neurodegeneration. This article outlines different conditions leading to iNOS gene transcription and expression in neurons and neuronal cells and highlights the potential impact on human brain inflammation and neurodegeneration.

Herz, J. and D. K. Strickland (2001). "LRP: a multifunctional scavenger and signaling receptor." J Clin Invest 108(6): 779-84.

Herz, J. (2001). "The LDL receptor gene family: (un)expected signal transducers in the brain." Neuron 29(3): 571-81.

Herz, J. (2001). "Lipoprotein receptors: beacons to neurons?" Trends Neurosci 24(4): 193-5.
Lipoprotein receptors were originally considered simply as cellular transporters for cholesterol and other lipids. This view is rapidly changing. Signaling functions have recently been recognized in several members of the low-density lipoprotein receptor gene family. These Apolipoprotein E receptors are highly expressed in the developing and in the mature nervous system, in which they regulate crucial developmental processes and might also participate in synaptic neurotransmission.

Hidalgo, J., M. Aschner, et al. (2001). "Roles of the metallothionein family of proteins in the central nervous system." Brain Res Bull 55(2): 133-45.
Metallothioneins (MTs) constitute a family of proteins characterized by a high heavy metal [Zn(II), Cu(I)] content and also by an unusual cysteine abundance. Mammalian MTs are comprised of four major isoforms designated MT-1 trough MT-4. MT-1 and MT-2 are expressed in most tissues including the brain, whereas MT-3 (also called growth inhibitory factor) and MT-4 are expressed predominantly in the central nervous system and in keratinizing epithelia, respectively. All MT isoforms have been implicated in disparate physiological functions, such as zinc and copper metabolism, protection against reactive oxygen species, or adaptation to stress. In the case of MT-3, an additional involvement of this isoform in neuromodulatory events and in the pathogenesis of Alzheimer's disease has also been suggested. It is essential to gain insight into how MTs are regulated in the brain in order to characterize MT functions, both in normal brain physiology, as well as in pathophysiological states. The focus of this review concerns the biology of the MT family in the context of their expression and functional roles in the central nervous system.

Hirai, S. (2001). "[Recent development of anti-dementia drugs]." No To Shinkei 53(3): 235-40.

Hirano, K. and H. Sugie (2001). "[Osteodysplasia, lipomembranous polycystic-dementia]." Ryoikibetsu Shokogun Shirizu(34 Pt 2): 405-6.

Hirsch, R. D. (2001). "[Socio- and psychotherapy in patients with Alzheimer disease]." Z Gerontol Geriatr 34(2): 92-100.
Symptoms presented by patients with Alzheimer-type dementia do not only reflect organic disturbances only but require a holistic and person-oriented view. Affective and behavioral disturbances are not necessarily secondary to cognitive impairment. Guidelines are presented for a multidimensional treatment involving the significant other. Socio- and psychotherapy are essential for this treatment. Their approaches have greatly increased in number and diversity in the past few years. Sociotherapy is based on milieu therapy and includes different training- and group activities. Several psychosocial treatment modalities are available, including validation, dementia care mapping, reminiscence therapy, cognitive training and psychoeducational group work. Psychotherapeutic approaches include relaxation techniques, and psychodynamic oriented- and behavioral modalities. The indication for a specific modality is based on an assessment of the disturbances present and available resources. Of special importance are also services to family carers, including counseling, psychotherapy, as well as support and modification of the care-setting. Even though there are only limited empirical data available on the effects of socio- and psychotherapy for patients with Alzheimer-type dementia, the available evidence is indicative of a positive influence on symptoms of this illness. Diversity of symptoms and individualized, variable course of the illness may point to the importance of psychological and social factors in this illness, by far larger than presently recognized.

Hock, B. J., Jr. and B. T. Lamb (2001). "Transgenic mouse models of Alzheimer's disease." Trends Genet 17(10): S7-12.
Recent advances in the understanding of the genetic basis of Alzheimer's disease have enabled the production of transgenic mouse models of the disease. Utilizing both cDNA- and genomic-based approaches, these mouse models for Alzheimer's disease have already provided valuable insights into the pathogenesis of the disease and potential therapeutic interventions.

Holinka, C. F. (2001). "Design and conduct of clinical trials in hormone replacement therapy." Ann N Y Acad Sci 943: 89-108.
Postmenopausal hormone replacement therapy represents an area of outstanding importance in preventive medicine that greatly affects personal well-being as well as public health. The number of women living in the United States who are 50 years or older has been estimated at nearly 50 million. Many of those women are likely to be eligible for postmenopausal hormone replacement, which may consist either of estrogen replacement therapy (ERT) in women without a uterus or, more frequently, estrogen/progestin combination therapy (HRT) in women with a uterus. This chapter first presents an overview of general regulatory requirements pertaining to the design and conduct of clinical studies in support of marketing approval for a drug product. These requirements include, but are not restricted to, studies in HRT. The chapter next discusses the design and conduct of clinical trials in support of marketing approval for the indications: treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy; prevention of osteoporosis; and protection by adjunctive progestin against estrogen-induced endometrial hyperplasia/cancer in women with a uterus. Finally, data related to the potential cardioprotective action of HRT and its protection against Alzheimer's disease and colon cancer are discussed.

Holroyd, S. and M. L. Shepherd (2001). "Alzheimer's disease: a review for the ophthalmologist." Surv Ophthalmol 45(6): 516-24.
Alzheimer's disease is the most prevalent dementia. Definitive diagnosis is made only at autopsy, although "probable" diagnoses are made using clinical criteria. Patients with Alzheimer's disease demonstrate severe deficits in memory with cortical features of language difficulty and visuomotor spatial deficits. They also may present with psychotic symptoms of delusions and hallucinations, and personality and behavioral changes. Advancing age, genetics, and environmental risk factors are important in the development of Alzheimer's disease. Visual abnormalities have been described in Alzheimer's disease and may be related to the development of visual hallucinations. Although palliative treatments exist for the cognitive loss and behavioral symptoms, future treatments will focus on both delay of onset and slowing of progression of the disease. Continued research is needed to further understand this devastating disorder, which may in turn lead to more successful treatments.

Honig, L. S. and R. Mayeux (2001). "Natural history of Alzheimer's disease." Aging (Milano) 13(3): 171-82.
Alzheimer's disease (AD) is the principal cause of dementia in the elderly, and affects about 15 million people worldwide. The earliest symptom is usually an insidious impairment of memory. As the disease progresses, there is increasing impairment of language and other cognitive functions. Problems occur with naming and word-finding, and later with verbal and written comprehension and expression. Visuospatial, analytic and abstract reasoning abilities, judgment, and insight become affected. Behavioral changes may include delusions, hallucinations, irritability, agitation, verbal or physical aggression, wandering, and disinhibition. Ultimately, there is loss of self-hygiene, eating, dressing, and ambulatory abilities, and incontinence and motor dysfunction. Before diagnosis of AD, individuals may have memory complaints, which represent a period of mild cognitive impairment (MCI). Before MCI, there is a prodromal, ill-defined presymptomatic period of disease ('pre-MCI"). In this review, we particularly focus on these earliest stages. We also discuss the more advanced stages of AD, and address factors that may influence disease course. Understanding the natural history of AD will allow better targeting of the disease-modifying treatments that are on the horizon.

Honjo, H., N. Kikuchi, et al. (2001). "Alzheimer's disease and estrogen." J Steroid Biochem Mol Biol 76(1-5): 227-30.
The preventive effect of estrogen on Alzheimer's disease (AD) has become clear with epidemiological data. Therapeutic effects of estrogen have not yet been established. In this presentation, we report our new basic and clinical data. The estrogen receptor, (ER)alpha, and ERbeta mRNA were investigated in rat brain. Estradiol-17beta (E(2)) treatment following OVX reduced the levels of ERalpha mRNA in the hypothalamus. In the substantia innominata (SI), the number of choline acetyltransferase immunoreacive cells increased significantly in the estrogen treatment rat. The neurons in SI projecting to the forebrain cortex contained ERalpha. Increasing amounts of intracellular calcium, peroxidation, and apoptosis with amyloid beta were suppressed in neuronal cells from rat pheochromocytoma (PC12) cells with E(2). ERalpha cDNA transfected PC 12 cells elaborated more neurite-like processes with E(2). In clinics, we are currently preparing vaginal progesterone tablets, which essentially may concentrate in the endometrium to prevent endometrial cancer, with few general circulation of progesterone inviting less depression. The therapeutic effects of cyclic estrogen, such as its preventive effect, are suggested in these studies, at least on mild AD.

Hoogendijk, W. J., G. Meynen, et al. (2001). "[Increased activity of stress-regulating systems in Alzheimer disease]." Tijdschr Gerontol Geriatr 32(1): 17-23.
Behavioral, i.e. non-cognitive, disturbances, such as anxiety, agitation, sleep disturbances and depression occur in the majority of Alzheimer's disease (AD) patients, but their neurobiological basis is unknown. Disturbance of stress regulating systems, like the locus coeruleus, could play an important role. The locus coeruleus, the main production site of noradrenaline in the central nervous system, is involved in phenomena like attention, arousal and the response to the environment. In Alzheimer's disease, there is a marked reduction of noradrenergic neurons in the locus coeruleus. We studied the activity in the remaining locus coeruleus neurons and found an inverse relationship between the number of remaining neurons and the noradrenergic activity. This could indicate compensatory activity and loss of flexibility of this system. Clinically, the loss of flexibility could result in an impairment to focus attention and to respond to the environment. These results can be related to another stress related system, the hypothalamo-pituitary-adrenal-(HPA)axis. This means that further evaluation of both of these systems is necessary.

Hoozemans, J. J., A. J. Rozemuller, et al. (2001). "Immunological aspects of alzheimer's disease: therapeutic implications." BioDrugs 15(5): 325-37.
Alzheimer's disease (AD) is a chronic neurodegenerative disease causing progressive impairment of memory and cognitive function. The amyloid cascade hypothesis suggests that mismetabolism of the beta-amyloid (A beta) precursor protein (APP) followed by subsequent formation of non-fibrillar and fibrillar A beta deposits leads to glial activation and eventually to neurotoxicity, causing cognitive impairment. Several lines of evidence indicate that an inflammatory process contributes to the pathology of AD. First, inflammatory proteins have been identified as being associated with neuritic plaques and in glial cells surrounding these plaques. Second, certain polymorphisms of acute-phase proteins and cytokines associated with AD plaques increase the risk or predispose for earlier onset of developing AD. Third, epidemiological studies indicate that anti-inflammatory drugs can retard the development of AD. Several steps in the pathological cascade of AD have been identified as possible targets for actions of nonsteroidal anti-inflammatory drugs. For instance, microglia are considered a target because this cell type is closely involved in AD pathology through secretion of neurotoxic substances and by modulating a positive feedback loop of the inflammatory mechanism that may be involved in the pathological cascade in AD. On the basis of studies in APP transgenic mice, immunisation with A beta was recently suggested as a novel immunological approach for the treatment of AD. Immunisation elicits A beta-specific antibodies that could affect several early steps of the amyloid-driven cascade. Antibodies could prevent A beta from aggregating into fibrils and accelerate clearance of A beta by stimulating its removal by microglial cells. This review outlines the pathological and genetic evidence that an inflammatory mechanism is involved in AD and the therapeutic approaches based on inhibition or mediation of inflammation.

Horvath, S. (2001). "[The use of vinpocetine in chronic disorders caused by cerebral hypoperfusion]." Orv Hetil 142(8): 383-9.
The clinical signs and symptoms of so-called "cerebrovascular insufficiency" or "cerebral vascular dysfunction" have the characteristics of those of chronic cerebral hypoperfusion. The clinical features of chronic cerebral hypoperfusion often show the symptoms of cognitive impairment and organic psychosyndromes. Cerebral hypoperfusion could be found in dementias of different origin (subcortical arteriosclerotic leucoencephalopathy [Binswanger], vascular dementia, Alzheimer's disease, etc.). Pathological changes caused by chronic cerebral hypoperfusion often confined only to the white matter (demyelisation, glial activation, damage of oligodendroglial cells, as well as scattered cell death). Each therapy has an influence on the biochemical and pathophysiological alterations caused by chronic cerebral hypoperfusion can be used with reason in these disorders. The mechanism of action of vinpocetine is interfering on many aspects with the biochemical and pathophysiological processes attributable to chronic cerebral hypoperfusion, independently of the original alteration responsible for hypoperfusion. This fact might give an explanation on the beneficial effect of vinpocetine on clinical signs and symptoms of chronic cerebrovascular insufficiency.

Hsu, Y. Y., A. T. Du, et al. (2001). "Magnetic resonance imaging and magnetic resonance spectroscopy in dementias." J Geriatr Psychiatry Neurol 14(3): 145-66.
This article reviews recent studies of magnetic resonance imaging and magnetic resonance spectroscopy in dementia, including Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, idiopathic Parkinson's disease, Huntington's disease, and vascular dementia. Magnetic resonance imaging and magnetic resonance spectroscopy can detect structural alteration and biochemical abnormalities in the brain of demented subjects and may help in the differential diagnosis and early detection of affected individuals, monitoring disease progression, and evaluation of therapeutic effect.

Huang, Y. and K. K. Wang (2001). "The calpain family and human disease." Trends Mol Med 7(8): 355-62.
The number of mammalian calpain protease family members has grown to 14 on last count. Overactivation of calpain 1 and calpain 2 (and their small subunit) has long been tied to acute neurological disorders (e.g. stroke and traumatic brain injury) and recently to Alzheimer's disease. Loss-of-function mutations of the calpain 3 gene have now been identified as the cause of limb-girdle muscular dystrophy 2A. Calpain 10 was recently identified as a susceptibility gene for type 2 diabetes, whereas calpain 9 appears to be a gastric cancer suppressor. This review describes our current understanding of the calpain family members and their mechanistic linkages to the aforementioned diseases as well as other emerging pathological conditions.

Huber, J. D., R. D. Egleton, et al. (2001). "Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier." Trends Neurosci 24(12): 719-25.
Disruption of the tight junctions (TJs) of the blood-brain barrier (BBB) is a hallmark of many CNS pathologies, including stroke, HIV encephalitis, Alzheimer's disease, multiple sclerosis and bacterial meningitis. Furthermore, systemic-derived inflammation has recently been shown to cause BBB tight junctional disruption and increased paracellular permeability. The BBB is capable of rapid modulation in response to physiological stimuli at the cytoskeletal level, which enables it to protect the brain parenchyma and maintain a homeostatic environment. By allowing the "loosening" of TJs and an increase in paracellular permeability, the BBB is able to "bend without breaking"; thereby, maintaining structural integrity.

Hughes, D. A. and T. Walley (2001). "Economic evaluations during early (phase II) drug development: a role for clinical trial simulations?" Pharmacoeconomics 19(11): 1069-77.
Faced with increasing demands on demonstrating cost effectiveness, pharmaceutical companies are required to conduct pharmacoeconomic evaluations throughout the drug development programme. At present, there is particular emphasis in the literature on burden-of-illness studies and on economic evaluations conducted alongside phase III clinical trials but not on those conducted during phase II clinical trials. This article describes modelling techniques, namely clinical trial simulations (CTS), which are gaining popularity in the clinical research community, but which might also prove to be beneficial during the conduct of these early pharmacoeconomic evaluations. The basic concepts and structure of CTS are described by using published examples of simulations of antipsychotic and anticancer drugs. With the use of an illustrative example of a hypothetical cholinesterase inhibitor for Alzheimer's disease, an integrated CTS-based pharmacoeconomic evaluation is presented. The results demonstrate how the modelling may be of value in 'go/no-go' decisions during the drug development programme.

Huppert, F. A. and J. K. Van Niekerk (2001). "Dehydroepiandrosterone (DHEA) supplementation for cognitive function." Cochrane Database Syst Rev(2): CD000304.
BACKGROUND: In view of the theoretical rationale for beneficial effects of DHEA and DHEAS on cognitive function in ageing and dementia, we have undertaken a thorough investigation of well-conducted studies in this area. This will provide a basis for confirmation of any effect of DHEA/S administration in humans in properly controlled trials. The review will also provide a scientific basis for effective dosage, acceptable route and duration of administration, and side effect profiles. This review is especially pertinent at this time as DHEA is currently being sold in large quantities in health food stores, particularly in the USA. In some cases the recommended dose is different for men and women (50mg/day for men and 25mg/day for women) and the basis for this recommendation needs to be explored. OBJECTIVES: To establish whether administration of DHEA, or its sulphate, DHEAS, improves cognitive function or reduces the rate of decline of cognitive function in normal older adults or in individuals with dementia. SEARCH STRATEGY: Relevant electronic databases, journals, personal communications and conference abstracts were searched for randomised controlled trials investigating the effects of DHEA/S on cognition in older adults. SELECTION CRITERIA: All relevant randomised controlled trials of DHEA/S were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Data for the specified outcomes were independently extracted by two reviewers (FAH & JvN) and cross-checked. Any discrepancies were discussed and resolved. No data pooling was undertaken owing to the lack of availability of the relevant statistics. MAIN RESULTS: There are four included studies, three cognition in normal older people, and Barnhart 1999 in perimenopausal women with decreased well-being. There were no studies in dementia. There were a few significant findings. Wolf 1997 found significant improvement following DHEA compared with placebo in both immediate recall (MD 0.8, 95% CI 0.16, 1.44) and delayed recall (MD 0.9, 95% CI 0.09, 1.71) of a visual memory test in women, estimated in a crossover trial after 2 weeks of treatment with each of DHEA and placebo. However there was no significant improvement in men, nor a significant effect on a verbal memory test. There was also no significant effect on four other cognitive tests. Wolf 1998 (2) found that placebo group performance deteriorated significantly on a test of selective attention following a psychosocial stressor (p<0.05), while deterioration was not evident in the DHEA group (p=0.85) after two weeks of treatment. However, when compared to placebo, DHEA produced a significant impairment on a visual memory test (p<0.01) following the stressor. No significant effect was found on a third cognitive task. Effects were not found on tasks when administered in the absence of a stressor. Barnhart 1999 employed three cognitive measures and found no significant effect of DHEA compared with placebo at 3 months. Findings to date suggest that DHEA replacement seems to be well tolerated with an absence of significant side-effects. REVIEWER'S CONCLUSIONS: The data offer no support at present for an improvement in memory or other aspects of cognitive function following DHEA treatment in normal older people. In view of the growing public enthusiasm for DHEA supplementation, particularly in the USA, and the possibility that any neuroprotective effect of DHEA/S may only be evident in the long term, there is a need to undertake high quality trials in which the duration of DHEA treatment is longer than one year, and the number of participants is large enough to detect effects if they exist. Recently, trials of DHEA supplementation in Alzheimer's Disease (USA), post-menopausal women (USA), normal older men (UK), and a one-year trial in normal older men and women (France) have been completed. As soon as the results are available these studies will be included in the review.

Huse, J. T. and R. W. Doms (2001). "Neurotoxic traffic: uncovering the mechanics of amyloid production in Alzheimer's disease." Traffic 2(2): 75-81.
Alzheimer's disease (AD) is thought by many to result from the accumulation of the neurotoxic amyloid-beta (A beta) peptide in brain parenchyma. The process by which A beta is proteolytically derived from the larger amyloid precursor protein (APP) has been the focus of much attention in the AD research field over the past decade. Recently, several of the proteins directly involved in the generation of A beta have been identified and characterized providing a number of viable therapeutic targets for the treatment of AD. However, the cellular mechanisms by which these proteins interact in the proteolytic processing of APP have not been well defined, nor are they readily apparent when one considers what is known about the intracellular localization and trafficking of the various participants. This article will review the underlying cell biology of A beta production and discuss the mechanistic options for APP processing given the current knowledge of the proteases involved.

Hutton, M., J. Lewis, et al. (2001). "Analysis of tauopathies with transgenic mice." Trends Mol Med 7(10): 467-70.
Intraneuronal filamentous inclusions composed of the microtubule-associated protein tau are a feature of several neurodegenerative diseases (including Alzheimer's disease) known as tauopathies. A pivotal finding was the identification in 1998 of mutations in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. This demonstrated that tau dysfunction is sufficient to cause neurodegeneration, and indicated that tau is likely to play a crucial role in the pathogenesis of other tauopathies. However, the mechanism by which tau filamentous lesions form and their role in neurodegeneration remains uncertain. Recent progress in the development of transgenic mouse models of human tauopathy is allowing these questions to be addressed.

Hyman, B. T. (2001). "Molecular and anatomical studies in Alzheimer's disease." Neurologia 16(3): 100-4.
This chapter builds on the themes developed during the last 10 years of studying the neuroanatomical basis of Alzheimer's disease (AD) from a neural systems perspective. Indirect evidence suggests that Abeta deposits are a dynamic lesion, and that a subset of Abeta deposits that stain for thioflavine S (thioS) are a critical lesion in terms of effects on neurons and their processes. Parallel studies in transgenic mice point to the same conclusion. Finally, we will discuss recent studies, using a remarkable microscropy tool that we have developed -an application of multiphoton microscopy- for in vivo histology, and in vivo functional imaging in living, anesthetized transgenic mice. Resolution is well below a micrometer, and cortical depths up to approximately 300 microns beneath the skull can be imaged; the mice recover uneventfully and can be reimaged days to months later. With this new technique, we can, for the first time, study dynamic processes of A beta deposition and resolution in a living brain.

Ikemoto, S. (2001). "[Apolipoprotein D]." Nippon Rinsho 59 Suppl 2: 131-5.

Ikemoto, M. and H. Arai (2001). "[Scavenger receptor family and molecular mechanism of xenobiotic removal]." Seikagaku 73(3): 161-6.

Imaizumi, K., K. Miyoshi, et al. (2001). "The unfolded protein response and Alzheimer's disease." Biochim Biophys Acta 1536(2-3): 85-96.
Disruption of calcium homeostasis, inhibition of protein glycosylation, and reduction of disulfide bonds provoke accumulation of unfolded protein in the endoplasmic reticulum (ER), and are therefore a type of 'ER stress'. Normal cells respond to ER stress by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP, GRP94 and protein disulfide isomerase to facilitate protein folding. This induction system is termed the unfolded protein response. Familial Alzheimer's disease-linked presenilin-1 (PS1) mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress transducers such as IRE1, PERK and ATF6.

Imam, S. Z., J. el-Yazal, et al. (2001). "Methamphetamine-induced dopaminergic neurotoxicity: role of peroxynitrite and neuroprotective role of antioxidants and peroxynitrite decomposition catalysts." Ann N Y Acad Sci 939: 366-80.
Oxidative stress, reactive oxygen (ROS), and nitrogen (RNS) species have been known to be involved in a multitude of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Both ROS and RNS have very short half-lives, thereby making their identification very difficult as a specific cause of neurodegeneration. Recently, we have developed a high performance liquid chromatography/electrochemical detection (HPLC/EC) method to identify 3-nitrotyrosine (3-NT), an in vitro and in vivo biomarker of peroxynitrite production, in cell cultures and brain to evaluate if an agent-driven neurotoxicity is produced by the generation of peroxynitrite. We show that a single or multiple injections of methamphetamine (METH) produced a significant increase in the formation of 3-NT in the striatum. This formation of 3-NT correlated with the striatal dopamine depletion caused by METH administration. We also show that PC12 cells treated with METH has significantly increased formation of 3-NT and dopamine depletion. Furthermore, we report that pretreatment with antioxidants such as selenium and melatonin can completely protect against the formation of 3-NT and depletion of striatal dopamine. We also report that pretreatment with peroxynitrite decomposition catalysts such as 5, 10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) and 5, 10, 15, 20-tetrakis (2,4,6-trimethyl-3,5-sulfonatophenyl) porphinato iron III (FETPPS) significantly protect against METH-induced 3-NT formation and striatal dopamine depletion. We used two different approaches, pharmacological manipulation and transgenic animal models, in order to further investigate the role of peroxynitrite. We show that a selective neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI), significantly protect against the formation of 3-NT as well as striatal dopamine depletion. Similar results were observed with nNOS knockout and copper zinc superoxide dismutase (CuZnSOD)-overexpressed transgenic mice models. Finally, using the protein data bank crystal structure of tyrosine hydroxylase, we postulate the possible nitration of specific tyrosine moiety in the enzyme that can be responsible for dopaminergic neurotoxicity. Together, these data clearly support the hypothesis that the reactive nitrogen species, peroxynitrite, plays a major role in METH-induced dopaminergic neurotoxicity and that selective antioxidants and peroxynitrite decomposition catalysts can protect against METH-induced neurotoxicity. These antioxidants and decomposition catalysts may have therapeutic potential in the treatment of psychostimulant addictions.

Imbimbo, B. P. (2001). "Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer's disease." CNS Drugs 15(5): 375-90.
According to the cholinergic hypothesis, the impairment of cognitive function and the behavioural disturbances that affect patients with Alzheimer's disease are mainly due to cortical deficiencies in cholinergic transmission. Numerous cholinesterase inhibitors have been investigated for treatment of this disease, the rationale being to support the cholinergic system by blocking the degradation of acetylcholine released from presynaptic neurons. These drugs can be classified as reversible (tacrine, donepezil and galantamine), pseudo-reversible (physostigmine, eptastigmine and rivastigmine) or irreversible (metrifonate) enzyme inhibitors. This article reviews efficacy and tolerability results from 6-month placebo-controlled studies of 7 cholinesterase inhibitors: tacrine (80 to 160 mg/day), donepezil (5 to 10 mg/day), rivastigmine (1 to 12 mg/day), metrifonate (30 to 80 mg/day), eptastigmine (30 to 60 mg/day), physostigmine (30 to 36 mg/day) and galantamine (8 to 32 mg/day). All these agents have demonstrated a statistically significant, although modest, effect versus placebo on the cognitive and global performance of patients with Alzheimer's disease. Dramatic clinical response has been seen in only 3 to 5% of patients. There are no major differences in terms of efficacy between the different drugs. The mean difference between drug and placebo effects on standardised psychometric scales is about 2 to 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog; a 70-point cognitive scale) and 0.2 to 0.5 points on the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus; a 7-point global scale), or 5 to 14% of the average value of the scales. The most common adverse effects observed after administration of cholinesterase inhibitors are nausea, vomiting, diarrhoea, dizziness, asthenia and anorexia, all symptoms linked to cholinergic overstimulation. These effects are dose related and largely depend on the degree of cholinesterase inhibition. Also important is the rate of onset of cholinesterase inhibition, which depends on the kinetics of enzyme inhibition, the presence and rate of titration, and the pharmacodynamic peak-to-trough fluctuations. A model predicting the incidence of nausea based on acetylcholinesterase inhibition and the half-life of acetylcholinesterase recovery is proposed. In conclusion, cholinesterase inhibitors are the only pharmacological agents proved to be effective for the treatment of Alzheimer's disease in large, long term, double-blind, placebo-controlled trials. While the efficacy of different cholinesterase inhibitors is similar, their tolerability profiles differ. For example, the incidence of nausea (in excess of that seen with placebo) at cognitively effective dosages ranges from 1% with eptastigmine 60 mg/day to 53% with physostigmine 30 mg/day. Differences in tolerability profile may be due to the extent of peripheral acetylcholinesterase inhibition needed to reach clinical efficacy. Other contributing pharmacodynamic factors are the rate of onset of and fluctuations in acetylcholinesterase inhibition at steady state.

Inagaki, C., N. Hattori, et al. (2001). "Cl(-)-ATPase in rat brain and kidney." J Exp Zool 289(4): 224-31.
Cl(-)-stimulated ATPase/ATP-dependent Cl(-) pump (Cl(-)-ATPase/pump) has been found as a candidate for an active outwardly directed Cl(-) transporter in brain neurons. (1) A 520-kDa protein complex with Cl(-)-ATPase/pump activity was isolated from rat brain. It consisted of four protein subunits (51, 55, 60, and 62 kDa proteins), the 51-kDa protein being a covalent phosphorylenzyme subunit. (2) An antiserum against the 51-kDa protein inhibited Cl(-)-ATPase/pump activity. Western blot analysis showed an immunoreactive 51-kDa protein in the brain, spinal cord, and kidney. By enzyme histochemistry and immunohistochemistry, Cl(-)-ATPase-like activity or immunoreactivity was observed on the plasma membranes of brain neurons, and on the baso-lateral membranes of type A intercalated cells of renal collecting ducts. (3) Reconstituted Cl(-)-ATPase/pump activity was highest in liposomes with phosphatidylinositol-4-monophosphate. LiCl, an inhibitor of inositolphosphatase, reduced Cl(-)-ATPase activity and increased intracellular Cl(-) concentrations in cultured rat hippocampal neurons with increased phosphatidylinositol turnover. (4) In the brains of patients with Alzheimer's disease (AD), where phosphatidylinositol 4-kinase activity is reduced, Cl(-)-ATPase activity was also reduced. Thus, Cl(-)-ATPase is likely an outwardly directed ATP-dependent Cl(-) transporter that consists of four subunits and is regulated by phosphatidylinositol-4-monophosphate. Changes in Cl(-)-ATPase activity may be related to the pathophysiology of human neurodegenerative diseases. J. Exp. Zool. 289:224-231, 2001.

Ince, P. (2001). "Dementia with Lewy bodies." Adv Exp Med Biol 487: 135-45.

Irizarry, M. C. and B. T. Hyman (2001). "Alzheimer disease therapeutics." J Neuropathol Exp Neurol 60(10): 923-8.
Alzheimer disease (AD) is characterized pathologically by cholinergic deficits, amyloid plaques, neurofibrillary tangles, gliosis, and neuronal and synaptic loss. The primary therapeutic approach that has arisen from the pathological analysis of AD brain has been cholinergic augmentation by cholinesterase inhibitors, which modestly improve cognitive function. Research on the underlying pathophysiological dysfunction have focussed on AD-specific processes such as amyloid precursor protein, tau, and cerebral apolipoprotein E metabolism, and more general neurodegenerative processes such as inflammation, oxidation, excitotoxicity, and apoptosis. Rational neuroprotective approaches have led to recent trials of estrogen, antioxidant and anti-inflammatory medications in AD, and to the development of anti-amyloid strategies for delaying progression or preventing development of AD.

Irminger-Finger, I. and C. Sieber (2001). "Aging research in Switzerland." Exp Gerontol 36(8): 1251-63.
The present review on aging research in Switzerland describes ongoing gerontological and geriatric research in the field of both basic science and clinical research. Although Switzerland is situated at the rear end of the scale in regard of size or number of inhabitants, the number of high quality research groups per inhabitant positions it amongst the leading countries in the Western world. Being a small country Switzerland counts only five universities with clinical affiliations. Aging research in Switzerland therefore does not cover all areas of this rapidly developing discipline but some of the scientific contributions are mirrored in highest scored journals or others focus on topics that clearly bridge geriatric research and research on cellular and molecular mechanisms of aging.

Jacquier, M., D. Arango, et al. (2001). "APOE epsilon4 and Alzheimer's disease: positive association in a Colombian clinical series and review of the Latin-American studies." Arq Neuropsiquiatr 59(1): 11-7.
OBJECTIVE: As the strength of the association between the APOE epsilon4 allele and Alzheimer's disease (AD) varies across ethnic groups, we studied if there was such an association in Colombian patients. METHOD: We performed apolipoprotein E (APOE) genotyping in a clinical sample of 83 unrelated AD patients, predominantly late-onset (>65 yrs) including familial ( n =30) and sporadic AD cases (n= 53) diagnosed according to NINCDS-ADRDA criteria and assessed by a multi-disciplinary team. Control subjects (n = 44) had no significant cognitive impairment by medical interview and neuro-psychological testing. RESULTS: We found a high association (OR= 5.1 95%CI 1.9 -13.6) between APOE epsilon4 and AD, in this series with predominantly late-onset cases with familial aggregation in 24 cases (28.9%). A significant negative association was found between epsilon2 and AD (OR= 0.2 95% CI 0.05-0.75). CONCLUSION: Further population-based surveys in Colombia are warranted to precise a possible dose effect of APOE epsilon4.

Janciauskiene, S. (2001). "Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles." Biochim Biophys Acta 1535(3): 221-35.
Serine proteinase inhibitors (Serpins) are irreversible suicide inhibitors of proteases that regulate diverse physiological processes such as coagulation, fibrinolysis, complement activation, angiogenesis, apoptosis, inflammation, neoplasia and viral pathogenesis. The molecular structure and physical properties of serpins permit these proteins to adopt a number of variant conformations under physiological conditions including the native inhibitory form and several inactive, non-inhibitory forms, such as complexes with protease or other ligands, cleaved, polymerised and oxidised. Alterations of a serpin which affect its structure and/or secretion and thus reduce its functional levels may result in pathology. Serpin dysfunction has been implicated in thrombosis, emphysema, liver cirrhosis, immune hypersensitivity and mental disorders. The loss of inhibitory activity of serpins necessarily results in an imbalance between proteases and their inhibitors, but it may also have other physiological effects through the generation of abnormal concentrations of modified, non-inhibitory forms of serpins. Although these forms of inhibitory serpins are detected in tissues and fluids recovered from inflammatory sites, the important questions of which conditions result in generation of different molecular forms of serpins, what biological function these forms have, and which of them are directly linked to pathologies and/or may be useful markers for characterisation of disease states, remain to be answered. Elucidation of the biological activities of non-inhibitory forms of serpins may provide useful insights into the pathogenesis of diseases and suggest new therapeutic strategies.

Janevic, M. R. and C. M. Connell (2001). "Racial, ethnic, and cultural differences in the dementia caregiving experience: recent findings." Gerontologist 41(3): 334-47.
PURPOSE: This research reviewed studies that compare two or more racial, ethnic, national, or cultural groups on aspects of the dementia caregiving experience. DESIGN AND METHODS: Electronic databases were searched to find studies published between 1996 and 2000 in peer-reviewed journals that met the above criteria. RESULTS: Twenty-one studies based on 18 samples were identified. These articles included comparisons involving the following groups of caregivers: African Americans, Chinese, Chinese Americans, Koreans, Korean Americans, Latinos, Whites, and residents of 14 European Union countries. Consistent with previous research, White caregivers were more likely to be spouses when compared to other groups. White caregivers tended to report greater depression and appraised caregiving as more stressful than African American caregivers. Findings were mixed regarding differences in coping and social support, but suggested that minority groups may not have more available support than Whites. Common methodological limitations were a lack of noncaregiving control groups and failure to test specific pathways by which the grouping variable (e.g., race) exerts its impact on outcome variables. IMPLICATIONS: Future studies in this area should use both quantitative and qualitative research methods to specify the pathways by which race, ethnicity, and culture affect the caregiving experience, and should expand their focus beyond the primary caregiver to include the effects of caregiving on families and networks.

Janus, C. and D. Westaway (2001). "Transgenic mouse models of Alzheimer's disease." Physiol Behav 73(5): 873-86.
Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by a progressive loss of cognitive function. Despite considerable progress, a complete description of the molecular pathology of this disease has yet to be elucidated. In this respect, the need for an animal model that develops some or all aspects of this uniquely human disease in a reproducible fashion is crucial for the development and testing of potential treatments. A valid animal model for AD should exhibit (1) progressive AD-like neuropathology and (2) cognitive deficits, and (3) should be verified in several laboratories. Transgenic models should be able to (4) discern pathogenic effects of familial forms (FAD) mutations from those of transgene overexpression. Models derived from microinjection of FAD mutant alleles should (5) encompass more than one Tg line. At present, however, no model that replicates all of these desirable features exists. In this review, we discuss transgenic mouse models with well-characterized AD-like neuropathology that show some form of cognitive impairment. We argue that conclusions drawn from a limited selection of cross-sectional experiments should be verified in longitudinally designed experiments. Future studies should attempt to establish a closer relationship between molecular pathology and the degree of cognitive impairment. While exact replication of AD in mice may not attainable (due to phylogenetic differences and fundamental differences in behavioral ecology), rigorous comparative analysis of cognitive behavior observed in various mouse models of AD should provide a framework for better understanding of molecular mechanisms underlying cognitive impairment observed in AD patients.

Jhee, S., T. Shiovitz, et al. (2001). "Beta-amyloid therapies in Alzheimer's disease." Expert Opin Investig Drugs 10(4): 593-605.
Neurones in the brain produce beta-amyloid fragments from a larger precursor molecule termed the amyloid precursor protein (APP). When released from the cell, these protein fragments may accumulate in extracellular amyloid plaques and consequently hasten the onset and progression of Alzheimer's disease (AD). A beta fragments are generated through the action of specific proteases within the cell. Two of these enzymes, beta- and gamma-secretase, are particularly important in the formation of A beta as they cleave within the APP protein to give rise to the N-terminal and C-terminal ends of the A beta fragment, respectively. Consequently, many researchers are investigating therapeutic approaches that inhibit either beta- or gamma-secretase activity, with the ultimate goal of limiting A beta; production. An alternative AD therapeutic approach that is being investigated is to employ anti-A beta antibodies to dissolve plaques that have already formed. Both of these approaches focus on the possibility that accrual of A beta leads to neuronal degeneration and cognitive impairment characterised by AD and test the hypothesis that limiting A beta deposition in neuritic plaques may be an effective treatment for AD.

Jodar-Vicente, M. (2001). "[Initial deficits in Alzheimer's disease: 3 practical examples]." Rev Neurol 32(12): 1173-7.
INTRODUCTION: The aim of the first studies to determine the neuropsychological features of Alzheimer's disease (AD) were based on the concept of the disease as an homogeneous entity. However, clinical observations and the most recent research studies have demonstrated that Alzheimer's disease may present several other neuropsychological deficits on its clinical onset. DEVELOPMENT: in the initial process of cognitive function loss, memory deficits are seen as a consequence of hippocampal degeneration; however, a great interindividual variability is observed in the appearance of other cortical deficits. In addiction, new advances in epidemiology, neurochemistry and neuropathology support the idea that AD represents a neuropsychologically heterogeneous disorder. In AD three different subgroups have been established: patients with initial deficits in visuospatial abilities, patients with a major deterioration of linguistic abilities, and a third group with altered visuospatial and linguistic abilities. The most sensitive neuropsychological tests capable of distinguish among these differences were The Boston Naming Test (BNT) and the copy of a drawing. These results have been confirmed with single photon emission computed tomography (SPECT) images, and has been observed that patients with a pattern of a elevated right-hemispheric deterioration presented also a higher right-hipofunctionality. At the same time, patients with an elevated linguistic deficit showed a higher hipofunctionality image in the left hemisphere. CONCLUSIONS: In this work we present three patients from a prospective study in course, who have similar background, education, gender and disease evolution, but with an onset of the illness corresponding to each of the patterns previously described All three patients were explored with an extense neuropsychological battery of tests specially chosen for this study.

Johansson, J. (2001). "Membrane properties and amyloid fibril formation of lung surfactant protein C." Biochem Soc Trans 29(Pt 4): 601-6.
Pulmonary surfactant is essential for respiration and lung host defence and is composed of 80-90% lipids, mainly dipalmitoylphosphatidylcholine (DPPC). Surfactant protein C (SP-C) constitutes 1-2% of the surfactant mass, and is one of the most hydrophobic peptides yet isolated. SP-C residues 9-34 form an alpha-helix with a central poly-valine segment, which perfectly matches the thickness of a fluid DPPC bilayer. The palmitoyl groups linked to Cys-5 and Cys-6 of SP-C increase the capacity of the peptide to promote lipid adsorption at an air/liquid interface, and augment the mechanical stability of SP-C/lipid mixtures. SP-C undergoes alpha-helix-->beta-sheet transition and forms amyloid fibrils. NMR and MS studies show that the poly-valine helix is kinetically stabilized, and that once it unfolds, formation of beta-sheet aggregates is significantly faster than refolding. alpha-Helix unfolding is accelerated after removal of the palmitoyl groups. Secondary structure prediction of SP-C yields beta-strand conformation of the poly-valine part. A database search revealed similar discordance between experimentally determined helices and predicted beta-strands for other amyloid-forming proteins, including the prion protein associated with spongiform encephalopathies, and the amyloid-beta (Abeta) peptide associated with Alzheimer's disease. For Abeta and SP-C, removal of the helix/strand discordance by residue replacements abrogates fibril formation in vitro.

Jonker, C., D. L. Gerritsen, et al. (2001). "[Quality of life and dementia. I. Model of assessment of wellbeing in dementia patients]." Tijdschr Gerontol Geriatr 32(6): 252-8.
The introduction of cholinesterase inhibitors to improve the cognitive function and activities of daily living in patients with Alzheimer disease, raises the question whether these drugs also have the potential to improve the quality of life of these patients. In this article a model is presented to measure quality of life in patients with dementia, in which psychological well-being is chosen as the central measure. The presented model might be the starting point to develop instruments to measure quality of life in dementia. After a short introduction concerning the developments in quality of life research, the two most important characteristics of the concept--multidimensionality and subjectivity--are discussed against the background of the relevant literature on dementia. The dementia-specific dimensions--individual characteristics, psychological, social and physical dimension, and environment--and domains are presented, and put in a hierarchical model.

Joosten, E. (2001). "Homocysteine, vascular dementia and Alzheimer's disease." Clin Chem Lab Med 39(8): 717-20.
There is some evidence from recent observational studies that hyperhomocysteinemia is a risk factor for cognitive dysfunction, including Alzheimer's disease and vascular dementia. There are only a few intervention studies, and the results are disappointing for such a frequent disease. Prospective double-blind and placebo-controlled intervention studies are not available. If homocysteine-lowering therapy will be in the running for the prevention and treatment of dementia, we must be able to diagnose the disease at a preclinical stage (i.e. 5 or 10 or 20 years before the disease becomes clinically overt for Alzheimer's disease). At the moment, there are insufficient data to support a vitamin B12, B6 or folate therapy in the prevention or treatment of patients with dementia.

Joseph, J., B. Shukitt-Hale, et al. (2001). "Copernicus revisited: amyloid beta in Alzheimer's disease." Neurobiol Aging 22(1): 131-46.
The beta-amyloid hypothesis of Alzheimer's Disease (AD) has dominated the thinking and research in this area for over a decade and a half. While there has been a great deal of effort in attempting to prove its centrality in this devastating disease, and while an enormous amount has been learned about its properties (e.g., putative toxicity, processing and signaling), Abeta has not proven to be both necessary and sufficient for the development, neurotoxicity, and cognitive deficits associated with this disease. Instead, the few treatments that are available have emerged from aging research and are primarily directed toward modification of acetylcholine levels. Clearly, it is time to rethink this position and to propose instead that future approaches should focus upon altering the age-related sensitivity of the neuronal environment to insults involving such factors as inflammation and oxidative stress. In other words "solve the problems of aging and by extension those of AD will also be reduced." This review is being submitted as a rather Lutherian attempt to "nail an alternative thesis" to the gate of the Church of the Holy Amyloid to open its doors to the idea that aging is the most pervasive element in this disease and Abeta is merely one of the planets.

Juurlink, B. H. (2001). "Therapeutic potential of dietary phase 2 enzyme inducers in ameliorating diseases that have an underlying inflammatory component." Can J Physiol Pharmacol 79(3): 266-82.
Many diseases associated with ageing have an underlying oxidative stress and accompanying inflammatory component, for example, Alzheimer's disease or atherosclerosis. Reviewed in this manuscript are: the role of oxidative stress in activating the transcription factor nuclear factor kappa B (NFkappaB), the role of NFkappaB in activating proinflammatory gene transcription, strong oxidants produced by cells, anti-oxidant defense systems, the central role of phase 2 enzymes in the anti-oxidant defense, dietary phase 2 enzyme inducers and evidence that dietary phase 2 enzymes decrease oxidative stress. It is likely that a diet containing phase 2 enzyme inducers may ameliorate or even prevent diseases that have a prominent inflammatory component to them. Research should be directed into the potential therapeutic effects of dietary phase 2 enzyme inducers in ameliorating diseases with an underlying oxidative stress and inflammatory component to them.

Kagan, B. L., Y. Hirakura, et al. (2001). "The channel hypothesis of Huntington's disease." Brain Res Bull 56(3-4): 281-4.
Extended tracts of polyglutamine (PG) have been implicated in the pathogenicity of the mutant protein huntingtin and have been shown to form ion channels in planar lipid bilayers. These lines of evidence suggest that huntingtin and other PG mutant proteins may damage cells via a channel mechanism. This mechanism could cause damage to the plasma membrane by running down ionic gradients, discharging membrane potential; or allowing influx of toxic ions such as Ca(2+). PG damage to intracellular membranes such as the lysosomal membrane or the mitochondrial membrane could also injure cells via leakage of toxic enzymes or triggering of apoptosis. The channel mechanism is well-established for microbial toxins, and the existence of at least six other "amyloid" channels relevant to diseases such as Alzheimer's and Creutzfeld-Jakob, suggests that this may be a widespread pathogenic mechanism.

Kalaria, R. N., C. G. Ballard, et al. (2001). "Multiple substrates of late-onset dementia: implications for brain protection." Novartis Found Symp 235: 49-60; discussion 60-5.
Age is the single most important risk factor for progressive dementia in populations worldwide. In developed countries the prevalence of dementia is estimated to be 3-5% at age 65 years and expected to double every decade thereafter. Although there is ageing-related attrition of neural tissue accompanied by profound changes in brain glia, marked neuronal loss and severe cognitive impairment are associated with pathological changes. Accelerated somatic ageing of the vasculature comprising endothelial and smooth muscle cells and slowed glial replacement are also likely to pre-dispose to degenerative processes. Approximately 90% of patients with late-onset dementia have neuropathological features of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), alone or in combination. Both AD and DLB reveal extensive amyloid beta deposition within senile plaques. Neurofibrillary tangles evident as tau pathology are much reduced in DLB where symptoms may be more related to cholinergic transmitter abnormalities than structural pathology. Depletion of brain acetylcholine is also encountered in VaD, which like AD and DLB may respond to cholinergic therapy. Cerebrovascular pathology, ischaemic brain damage and neurovascular instability resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementia. The apolipoprotein E epsilon 4 allele, a major genetic susceptibility factor for AD also associated with cardiovascular pathology, may contribute to neurodegenerative changes through vascular mechanisms. The interrelationships of these multiple substrates of late-onset dementia have major implications for neuroprotective and disease slowing therapies. Measures that improve cardiovascular function and increase brain perfusion would be useful to attenuate cognitive decline.

Karpus, W. J. (2001). "Chemokines and central nervous system disorders." J Neurovirol 7(6): 493-500.
Chemokines and their receptors are large families of inflammatory molecules responsible for a number of biologic functions including the accumulation of leukocytes at tissue sites. Over the past 8 years, a number of studies have indicated a role for chemokines in the pathogenesis of CNS inflammatory diseases. This minireview provides a brief summary of our current knowledge of chemokines and CNS inflammatory diseases including experimental autoimmune encephalomyelitis, multiple sclerosis, virus-induced demyelinating diseases, Alzheimer's disease, and central nervous system bacterial-induced diseases.

Kato, T. (2001). "The other, forgotten genome: mitochondrial DNA and mental disorders." Mol Psychiatry 6(6): 625-33.
This paper summarizes recent research on mitochondrial DNA (mtDNA)--which might be described as the "other, forgotten genome". Recent studies suggest the possible pathophysiological significance of mtDNA in schizophrenia and neurodegenerative and mood disorders. Decreased activity of the mitochondrial electron transport chain has been implicated in both Parkinson's and Alzheimer's disease and while age-related accumulation of mtDNA deletions has been suggested as a possible cause, there is no concrete evidence that particular mtDNA polymorphisms are responsible. In schizophrenia, the activity and/or mRNA expression of complex IV are involved, but the direction of the alteration is not the same and there is no evidence linking schizophrenia with mtDNA. In bipolar disorder, there is some evidence of parent-of-origin effects and association with mtDNA polymorphisms but further investigation is needed to elucidate the role of mtDNA in mental disorders.

Kaufer, D. I. (2001). "Long-term care in dementia: patients and caregivers." Clin Cornerstone 3(4): 52-62.
General principles of managing chronic, age-associated diseases apply as much to Alzheimer's disease (AD) and other late-life dementing disorders as they do to congestive heart failure or osteoarthritis. Beyond efforts to maintain residual tissue or organ function, important physician roles include promoting general well-being and helping patients and their caregivers adjust to disease-related limitations. Physicians provide essential information to patients and their families about the disease, its social and legal ramifications, and community resources to facilitate care. Therefore, physicians must be knowledgeable about broadly intersecting medical, legal, financial, and ethical issues surrounding the long-term management of AD and other dementias. The many challenges faced by patients with dementia and their caregivers over time underscore the need for an ongoing diagnostic and therapeutic alliance with primary care physicians. This article reviews salient aspects of long-term care for patients with AD and other dementias, highlighting the vital and varied roles of physicians in managing these chronic brain disorders.

Kenemans, P., G. A. van Unnik, et al. (2001). "Perspectives in hormone replacement therapy." Maturitas 38 Suppl 1: S41-8.
Estrogens have been convincingly shown to be highly effective in preventing and reversing menopause-related conditions, such as hot flushes, urogenital complaints, and postmenopausal bone loss. Observational studies report that long-term, estrogen-containing, postmenopausal hormone replacement therapy (HRT) leads to a substantial reduction in hip fractures, myocardial infarction, and possibly colonic cancer, with important consequences for health and quality of life. Estrogen replacement may postpone the onset of Alzheimer's disease and extend life. While many of these effects are biologically plausible, with a variety of cellular mechanisms being involved, only ongoing and future large-scale randomized clinical trials can and should define the effects of HRT more precisely. Long-term compliance is a key issue for long-term benefits, and offering women a choice of administration routes and regimens can only be beneficial in this respect. Pills, patches, gels, and implants are all widely prescribed. Intravaginal or intranasal forms of administration, which are very easy to use and adaptable on an individual level, are among the new options which could improve long-term continuation of HRT use. Fear of breast cancer and recurrence of vaginal bleeding are real concerns for many women considering HRT. This has led to research into lower-dose, estrogen-containing regimens, into continuous combined regimens, and into the potential of estrogen receptor alpha or beta binding molecules that may help to prevent such problems from arising. The prospects for safe and effective postmenopausal HRT with either estrogens or estrogen-like drugs are very promising when these drugs are used in a patient-tailored, risk profile-based manner.

Kennedy, J. S., F. P. Bymaster, et al. (2001). "A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data." Int J Geriatr Psychiatry 16 Suppl 1: S33-61.
OBJECTIVE: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available. METHOD: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed. RESULTS AND CONCLUSION: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders.

Klein, R. C. and F. J. Castellino (2001). "Activators and inhibitors of the ion channel of the NMDA receptor." Curr Drug Targets 2(3): 323-9.
The involvement of the glutamate-glycine activated ion channels of the NMDA receptor in various neurophysiological processes has made this ion channel the focus of intense research. The excessive release of glutamate in a variety of neuronal hypoxic conditions implicates the NMDA receptor in a number of neuropatholological states, such as stroke, chronic pain, Parkinson's disease, Alzheimer's disease, ALS, and epilepsy, among others, thus making this receptor a prime drug target candidate. A variety of agents are known to be effective in opening and closing of the ion channels of this receptor, among the latter group of agents is the peptidic conantokins. Through the use of electrophysiological measurements with a number of cell types containing natural and recombinant subunits of the NMDA receptor, much knowledge is evolving regarding the mechanism of action of activators and inhibitors of the NMDA receptor ion channels. In addition, structure-function studies of the conantokins in these systems have been revealing in terms of their complimentary sites on the NMDA receptor. These relationships serve as the main focus of this review.

Klein, W. L., G. A. Krafft, et al. (2001). "Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?" Trends Neurosci 24(4): 219-24.
Amyloid beta (Abeta) is a small self-aggregating peptide produced at low levels by normal brain metabolism. In Alzheimer's disease (AD), self-aggregation of Abeta becomes rampant, manifested most strikingly as the amyloid fibrils of senile plaques. Because fibrils can kill neurons in culture, it has been argued that fibrils initiate the neurodegenerative cascades of AD. An emerging and different view, however, is that fibrils are not the only toxic form of Abeta, and perhaps not the neurotoxin that is most relevant to AD: small oligomers and protofibrils also have potent neurological activity. Immuno-neutralization of soluble Abeta-derived toxins might be the key to optimizing AD vaccines that are now on the horizon.

Knoll, J. (2001). "Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain." CNS Drug Rev 7(3): 317-45.
Hundreds of millions of people now die over the age of 80 years primarily due to twentieth century progress in hygiene, chemotherapy, and immunology. With a longer average lifespan, the need to improve quality of life during the latter decades is more compelling. "Aging--The Epidemic of the New Millenium," a recent international conference (Monte Carlo, June 17-18, 2000), showed with peculiar clarity that a safe and efficient drug strategy to slow the age-related decay of brain performance is still missing. This review summarizes the physiologic and pharmacologic arguments in favor of a peculiar lifelong prophylactic medication with reasonable chances to keep in check brain aging and decrease the precipitation of age-related neurological diseases.

Knopman, D. S. (2001). "An overview of common non-Alzheimer dementias." Clin Geriatr Med 17(2): 281-301.
Approximately 20% to 40% of dementia is caused by diseases other than Alzheimer's disease. This article reviews the major categories of non-Alzheimer dementia, including dementia associated with cerebrovascular disease, dementia associated with extrapyramidal features, and the frontotemporal dementias. Dementia associated with cerebrovascular disease is a heterogeneous condition the importance of which is often misunderstood. Dementia with Lewy bodies, the most common of the dementias associated with extrapyramidal disease, is becoming better recognized for its unique management issues. At least some of the frontotemporal dementias, which in this article encompass the progressive aphasias, have mutations in the tau gene that account for some of the phenotypic variations.

Knopman, D. (2001). "Cerebrospinal fluid beta-amyloid and tau proteins for the diagnosis of Alzheimer disease." Arch Neurol 58(3): 349-50.

Kokubo, Y. and H. Tanaka (2001). "[Apolipoprotein E genetic polymorphism]." Nippon Rinsho 59 Suppl 3: 799-805.

Kontush, A. (2001). "Amyloid-beta: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer's disease." Free Radic Biol Med 31(9): 1120-31.
Elevated production of amyloid-beta (A beta) as a preventive antioxidant for brain lipoproteins under the action of increased oxidative stress in aging is postulated to represent a major event in the development of Alzheimer's disease (AD). Increase in A beta production is followed by chelation of transition metal ions by A beta, accumulation of A beta-metal lipoprotein aggregates, production of reactive oxygen species and neurotoxicity. Chelation of copper by A beta is proposed to be a most important part of this pathway, because A beta binds copper stronger than other transition metals and because copper is a more efficient catalyst of oxidation than other metals. This amyloid-binds-copper (ABC) model does not remove A beta peptide from its central place in our current thinking of AD, but rather places additional factors in the center of discussion. Most importantly, they embrace pathological mechanisms known to develop in aging (which is the major risk factor for AD), such as increased production of reactive oxygen species by mitochondria, that are positioned upstream relative to the generation of A beta.

Kourie, J. I. (2001). "Mechanisms of amyloid beta protein-induced modification in ion transport systems: implications for neurodegenerative diseases." Cell Mol Neurobiol 21(3): 173-213.
1. Alzheimer's disease (AD) is a neurodegenerative disorder that affects the cognitive function of the brain. Pathological changes in AD are characterized by the formation of amyloid plaques and neurofibrillary tangles as well as extensive neuronal loss. Abnormal proteolytic processing of amyloid precursor protein (APP) is the central step that leads to formation of amyloid plaque, neurofibrillary tangles, and neuronal loss. 2. The plaques, which accumulate extracellularly in the brain, are composed of aggregates and cause direct neurotoxic effects and/or increase neuronal vulnerability to excitotoxic insults. The aggregates consist of soluble pathologic amyloid beta peptides AbetaP[1-42] and AbetaP[1-43] and soluble nonpathologic AbetaP[1-40]. Both APP and AbetaP interact with ion transport systems. AbetaP induces a wide range of effects as the result of activating a cascade of mechanisms. 3. The major mechanisms proposed for AbetaP-induced cytotoxicity involve the loss of Ca2+ homeostasis and the generation of reactive oxygen species (ROS). The changes in Ca2+ homeostasis could be the result of (1) changes in endogenous ion transport systems, e.g. Ca2+ and K+ channels and Na+/K+-ATPase, and membrane receptor proteins, such as ligand-driven ion channels and G-protein-driven releases of second messengers, and (2) formation of heterogeneous ion channels. 4. The consequences of changes in Ca2+-homeostasis-induced generation of ROS are (a) direct modification of intrinsic ion transport systems and their regulatory mechanisms, and (b) indirect effects on ion transport systems via peroxidation of phospholipids in the membrane, inhibition of phosphorylation, and reduction of ATP levels and cytoplasmic pH. 5. We propose that in AD, AbetaP with its different conformations alters cell regulation by modifying several ion transport systems and also by forming heterogeneous ion channels. The changes in membrane transport systems are proposed as early steps in impairing neuronal function preceding plaque formation. We conclude that these changes damage the membrane by compromising its integrity and increasing its ion permeability. This mechanism of membrane damage is not only central for AD but also may explain other malfunctioned protein-processing-related pathologies.

Kourie, J. I. and C. L. Henry (2001). "Protein aggregation and deposition: implications for ion channel formation and membrane damage." Croat Med J 42(4): 359-74.
Protein deposition, aggregation, and formation of amyloids are associated with a wide range of pathologies, including several neurodegenerative diseases. Aggregation and deposition are a result of malfunction in protein folding, assembly, and transport, caused by protein mutation and/or changes in the cell environment. The mechanism of protein deposition and aggregation is triggered when the hydrophobic and positively charged regions of the misfolded proteins are exposed. The cells aim to regulate these misfolded and malfunctioning aggregation-prone proteins by degradation mechanisms, e.g., proteosomes, and/or by storing them in specialized compartments, e.g., Russell bodies and aggresomes. During these processes, however, some aggregation-prone protein intermediates are capable of aggregation and forming beta-sheet based channels in various negatively charged cellular membranes. Adverse cellular conditions, transitional metals, cellular proteins, and genetic mutations play an important role in the formation and function of these non-intrinsic channels. These channels, which can damage membrane function, are pathologic because they can disrupt the metabolic, ionic, and water homeostasis and distort signal transduction. We propose that different conformations of aggregation-prone proteins could alter cell regulation by modifying several ion transport systems and also by forming heterogeneous ion channels. The changes in membrane transport systems are proposed as early steps in impairing neuronal function preceding fibril formation. We conclude that these changes damage the membrane by compromising its integrity and increasing its ion permeability. This mechanism of membrane damage is a general mechanism that may explain other malfunctioning protein processing-related pathologies.

Kril, J. J. and G. M. Halliday (2001). "Alzheimer's disease: its diagnosis and pathogenesis." Int Rev Neurobiol 48: 167-217.
A hypothesis has been presented that links many of the identified and putative risk factors for AD and suggests a mechanism for their action. Crawford (1996, 1998) proposes an association between AD and cerebral blood flow (CBF) by citing evidence that many of the factors that are linked with an increased risk of AD also decrease CBF (e.g., old age, depression, underactivity, head trauma). Similarly, it is suggested factors that increase CBF are associated with a decreased risk of AD (e.g., education, exercise, smoking, NSAIDs). Although the authors acknowledge that reduced CBF is not sufficient to cause AD, the reported positive and negative associations provide tantalizing evidence for a common mode of action for many of the equivocal risk factors reported to date. This hypothesis is also consistent with other data that links microvascular damage and impaired blood flow (de la Torre, 1997, 2000) and low education with increased cerebrovascular disease (Del Ser et al., 1999). Gaining a better understanding of the interaction between AD and vascular disease is of great importance. Not only will it provide insights into the pathogenesis of AD, but it may also provide us with a rare opportunity for the treatment and possible prevention of AD. A great many risk factors for vascular disease have been identified and intervention programs have successfully reduced the incidence of heart disease and stroke. The potential exists to provide the same level of success with AD.

Kuchel, G. A., C. Tannenbaum, et al. (2001). "Can variability in the hormonal status of elderly women assist in the decision to administer estrogens?" J Womens Health Gend Based Med 10(2): 109-16.
Hormone replacement therapy (HRT) has been proposed for the prevention and treatment of many chronic conditions, ranging from osteoporosis, heart disease, urinary incontinence, and Alzheimer's disease. With the exception of osteoporosis, however, many of the suggested benefits remain controversial. Part of the controversy stems from the relative absence of randomized controlled trials, particularly those enrolling sufficient numbers of elderly women. We propose that another factor may also contribute, one that has been overlooked - failure to consider the variable endogenous estrogen status of elderly women. Highly variable levels of estrogens are present in nearly all postmenopausal women, even at advanced ages. Similar to other endocrine systems, estrogen deficiency and the need for its replacement are, therefore, likely to be relative rather than absolute. Recent studies indicate that elderly women who are less able to compensate for declining ovarian 17beta-estradiol production by adipose synthesis of estrone (E1) may be at greater risk for certain chronic conditions associated with relative estrogen deficiency. Because many markers of estrogen deficiency exhibit overlap between risk groups, their clinical usefulness as predictors of frailty, disability, and response to HRT has been limited. Future studies will need to focus not only on the use of highly variable circulating serum estrogen levels but also on markers of overall estrogenic effects at the level of individual target tissues (i.e., markers of bone turnover, karyopyknotic index on a vaginal wall smear). We propose that a clinical approach that takes into consideration the remarkable heterogeneity (physiological as well as psychological) of elderly women will enable us to approach the decision about HRT in a more individualized and possibly better targeted fashion.

Kurz, A. F. (2001). "What is vascular dementia?" Int J Clin Pract Suppl(120): 5-8.
Cerebrovascular disease (CVD) and dementia frequently coexist in elderly patients. The question of whether the CVD causes the dementia depends on how 'dementia' is defined. Traditional definitions specified that dementia involved a decline in intellectual ability as a core feature. However, revised definitions have since stipulated two key elements: 1) a global rather than focal neurobehavioural deficit and 2) impairment in activities of daily living (ADL). When applied to CVD, these latter concepts of dementia raise difficulty: Focal cerebrovascular lesions in the cortex generate location-specific neurobehavioural deficits that are part of the dementia syndrome, but, even in combination, do not represent a global intellectual decline. Most cerebrovascular lesions are associated with physical symptoms that make it difficult to evaluate whether cognitive impairments have an independent impact on ADL. The majority of neurobehavioural symptoms in CVD are caused by small-vessel-type subcortical lesions and are dissimilar to those seen in Alzheimer's disease. There are several pathogenetic mechanisms, however, by which large-vessel or small-vessel CVD can cause global cognitive and intellectual impairments, allowing a diagnosis of vascular dementia (VaD): An accumulation of ischaemic lesions in the cortex may produce global intellectual impairment, particularly if they affect important areas of the brain. Single small infarcts, or haemorrhages in strategic subcortical locations, may interfere with specific circuits connecting the prefrontal cortex to the basal ganglia, or with nonspecific thalamocortical projections. This may generate combinations of executive dysfunction, personality change or apathy, which are associated with hypoperfusion and hypometabolism predominantly in frontal cortical areas. Extensive white matter lesions probably affect cognitive function through a loss of axons, producing a functional disconnection of the cortex. This can manifest as significant reductions in blood flow and metabolism in frontal, temporal and parietal cortical areas, which do not show any structural damage. Given the diversity of aetiological factors, pathological changes and pathogenetic mechanisms associated with VaD, several distinct syndromes must be distinguished. Further study is needed to demonstrate that this emerging concept can improve diagnosis, guide treatment and stimulate research.

LaDu, M. J., J. A. Shah, et al. (2001). "Apolipoprotein E and apolipoprotein E receptors modulate A beta-induced glial neuroinflammatory responses." Neurochem Int 39(5-6): 427-34.
Large numbers of activated glia are a common pathological feature of many neurodegenerative disorders, including Alzheimer's disease (AD). Several different stimuli, including lipopolysaccharide (LPS), dibutyryl (db)cAMP, and aged amyloid-beta 1-42 (A beta), can induce glial activation in vitro, as measured by morphological changes and the production of pro-inflammatory cytokines and oxidative stress molecules. Only A beta-induced activation is attenuated by the addition of exogenous apolipoprotein E (apoE)-containing particles. In addition, only A beta also induces an increase in the amount of endogenous apoE, the primary apolipoprotein expressed by astrocytes in the brain. The functional significance of the increase in apoE appears to be to limit the inflammatory response. Indeed, compared to wild type mice, glial cells cultured from apoE knockout mice exhibit an enhanced production of several pro-inflammatory markers in response to treatment with A beta and other activating stimuli. The mechanism for both the A beta-induced glial activation and the increase in apoE appears to involve apoE receptors, a variety of which are expressed by both neurons and glia. Experiments using receptor associated protein (RAP), an inhibitor of apoE receptors with a differential affinity for the low-density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), revealed that LRP mediates A beta-induced glial activation, while LDLR mediates the A beta-induced changes in apoE levels. In summary, both an apoE receptor agonist (apoE) and an antagonist (RAP) inhibit A beta-induced glial cell activation. Thus, apoE receptors appear to translate the presence of extracellular A beta into cellular responses, both initiating glial cell activation and limiting its scope by inducing apoE, an anti-inflammatory agent.

Lamb, H. M. and K. L. Goa (2001). "Rivastigmine. A pharmacoeconomic review of its use in Alzheimer's disease." Pharmacoeconomics 19(3): 303-18.
Alzheimer's disease is associated with a large cost burden, of which institutionalised care constitutes a major component. Therefore, the decision to move a patient from the community to institutionalised care is associated with a significant increase in direct costs. About three-quarters of patients with Alzheimer's disease are admitted to a nursing home within 5 years of diagnosis. Unpaid or informal caregiver time is another large cost in Alzheimer's disease, especially for patients cared for in the community; informal care can account for up to three-quarters of healthcare costs in non-institutionalised patients. Several cholinesterase inhibitors, of which rivastigmine is one, are available for the treatment of patients with mild to moderate Alzheimer's disease. By improving cognitive function and slowing the rate of cognitive decline, cholinesterase inhibitor therapy may reduce a significant part of the economic burden of the disease by delaying the move to institutionalised care. In the absence of prospective long term data which focus on pharmacoeconomic end-points, modelling techniques have been used to extrapolate clinical data available for some cholinesterase inhibitors, including rivastigmine. Four economic analyses, based on a single model of cognitive decline, have been performed with rivastigmine from the perspective of the provider or society. All show that rivastigmine therapy (excluding drug-related costs) is associated with cost savings in patients with mild to moderate Alzheimer's disease by delaying the time to institutionalisation. If the acquisition cost of the drug was factored in, the cost savings completely or partially offset treatment costs. The magnitude of the cost savings increased as the time horizon increased (up to 2 years). The largest savings were realised in patients with mild disease over a 2-year time-frame, suggesting that treatment should be initiated early from an economic viewpoint. Pharmacoeonomic data comparing different cholinesterase inhibitors are, as yet, unavailable. CONCLUSION: Pharmacoeconomic analyses, based on modelled data excluding drug costs, indicate that rivastigmine completely or partially offsets the costs of treatment by delaying cognitive decline and the time to institutionalisation in patients with mild to moderate Alzheimer's disease. From a societal perspective, cost savings are realised if the drug is introduced early in the disease. Additional benefits offered by rivastigmine on behavioural symptoms, which may reduce caregiver burden, have yet to be investigated from a pharmacoeconomic perspective.

Lanctot, K. L., N. Herrmann, et al. (2001). "Role of serotonin in the behavioral and psychological symptoms of dementia." J Neuropsychiatry Clin Neurosci 13(1): 5-21.
The behavioral and psychological symptoms of dementia (BPSD) can have serious debilitating effects on the patient and increase caregiver burden. Investigations into the underlying neuropathology indicate that the serotonergic system may contribute to BPSD. In addition, serotonergic pathways are known to interact extensively with the cholinergic, noradrenergic, GABAergic, and dopaminergic systems. Hence, serotonergic therapies may be used to manipulate other neurotransmitters systems to alleviate BPSD or in combination with agents specific for the other neurotransmitter receptor sites. Neurotransmitter-modulated behaviors and evidence provided by pharmacological interventions are reviewed, focusing primarily on the serotonergic system.

Landes, A. M., S. D. Sperry, et al. (2001). "Apathy in Alzheimer's disease." J Am Geriatr Soc 49(12): 1700-7.
Apathy, or loss of motivation, is arguably the most common change in behavior in Alzheimer's disease (AD) but is underrecognized. Apathy represents a form of executive cognitive dysfunction. Patients with apathy suffer from decreased daily function and specific cognitive deficits and rely on families to provide more care, which results in increased stress for families. Apathy is one of the primary syndromes associated with frontal and subcortical pathology, and apathy in AD appears to have multiple neuroanatomical correlates that implicate components of frontal subcortical networks. Despite the profound effects of this common syndrome, only a few instruments have been designed to specifically assess apathy, and these instruments have not been directly compared. Assessment of apathy in AD requires clinicians to distinguish loss of motivation from loss of ability due to cognitive decline. Although apathy may be misdiagnosed as depression because of an overlap in symptoms, current research has shown apathy to be a discrete syndrome. Distinguishing apathy from depression has important treatment implications, because these disorders respond to different interventions. Further research is required to clarify the specific neuroanatomical and neuropsychological correlates of apathy and to determine how correct diagnosis and treatment of apathy may improve patient functioning and ease caregiver burden.

Landreth, G. E. and M. T. Heneka (2001). "Anti-inflammatory actions of peroxisome proliferator-activated receptor gamma agonists in Alzheimer's disease." Neurobiol Aging 22(6): 937-44.
The role of inflammatory processes in the brains of Alzheimer's Disease (AD) patients has recently attracted considerable interest. Indeed, the only demonstrated effective therapy for AD patients is long-term treatment with non-steroidal anti-inflammatory drugs (NSAIDs). The mechanistic basis of the efficacy of NSAIDs in AD remains unclear. However, the recent recognition that NSAIDs can bind to and activate the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), has offered an explanation for the action of these drugs in AD. PPARgamma activation leads to the inhibition of microglial activation and the expression of a broad range of proinflammatory molecules. The newly appreciated anti-inflammatory actions of PPARgamma agonists may allow novel therapies for AD and other CNS indications with an inflammatory component.

Langford, D. and E. Masliah (2001). "Crosstalk between components of the blood brain barrier and cells of the CNS in microglial activation in AIDS." Brain Pathol 11(3): 306-12.
During the progression of AIDS, a majority of patients develop cognitive disorders such as HIV encephalitis (HIVE) and AIDS dementia complex (ADC), which correlate closely with macrophage infiltration into the brain and microglial activation. Microglial activation occurs in response to infection, inflammation and neurological disorders including HIVE, Alzheimer's disease, Parkinson's disease and multiple sclerosis. Microglia can be activated by immunoreactive cells independent of, but enhanced by HIV infection, from at least two routes. Activation may occur from signals originating from activated monocytes and lymphocytes in the blood stream, which initiate a cascade of stimuli that ultimately reach microglia in the brain or from activated macrophages/microglia/astrocytes within the brain. Effects of microglial activation stemming from both systemic and CNS HIV infection act together to commence signaling feedback, leading to HIVE and increased neurodegeneration. Most recent data indicate that in AIDS patients, microglial activation in the brain with subsequent release of excitotoxins, cytokines and chemokines leads to neurodegeneration and cognitive impairment. Since the presence of HIV in the brain results from migration of infected monocytes and lymphocytes across the vascular boundary, the development of novel therapies aimed at protecting the integrity of the blood brain barrier (BBB) upon systemic HIV infection is critical for controlling CNS infection.

Larson, E. B. (2001). "Dementia in the elderly: the "silent epidemic" no more." Trans Am Clin Climatol Assoc 112: 136-46; discussion 146-8.

Lathe, R. (2001). "Hormones and the hippocampus." J Endocrinol 169(2): 205-31.
Hippocampal lesions produce memory deficits, but the exact function of the hippocampus remains obscure. Evidence is presented that its role in memory may be ancillary to physiological regulation. Molecular studies demonstrate that the hippocampus is a primary target for ligands that reflect body physiology, including ion balance and blood pressure, immunity, pain, reproductive status, satiety and stress. Hippocampal receptors are functional, probably accessible to their ligands, and mediate physiological and cognitive changes. This argues that an early role of the hippocampus may have been in sensing soluble molecules (termed here 'enteroception') in blood and cerebrospinal fluid, perhaps reflecting a common evolutionary origin with the olfactory system ('exteroception'). Functionally, hippocampal enteroception may reflect feedback control; evidence is reviewed that the hippocampus modulates body physiology, including the activity of the hypothalamus-pituitary-adrenal axis, blood pressure, immunity, and reproductive function. It is suggested that the hippocampus operates, in parallel with the amygdala, to modulate body physiology in response to cognitive stimuli. Hippocampal outputs are predominantly inhibitory on downstream neuroendocrine activity; increased synaptic efficacy in the hippocampus (e.g. long-term potentiation) could facilitate throughput inhibition. This may have implications for the role of the hippocampus and long-term potentiation in memory.

Law, A., S. Gauthier, et al. (2001). "Say NO to Alzheimer's disease: the putative links between nitric oxide and dementia of the Alzheimer's type." Brain Res Brain Res Rev 35(1): 73-96.
Alzheimer's disease (AD) is the most common form of dementia, with progressive cognitive deficits being the primary symptom. AD is neuropathologically characterized by amyloid and neurofibrillary tangle depositions, basal forebrain cholinergic deficit, and extensive neuronal loss and synaptic changes in the cortex and hippocampus. Mutations of amyloid precursor protein or presenilin genes or apolipoprotein E gene polymorphism appear to affect amyloid formation, which in turn causes neuronal death via a number of possible mechanisms, including Ca(2+) homeostasis disruption, oxidative stress, excitotoxicity, energy depletion, neuro-inflammation and apoptosis. Nitric oxide (NO) is an enzymatic product of nitric oxide synthase, which exists in three isoforms. In addition to its vasoactive and immunological properties, NO has significant neurophysiological functions. However, NO can also be neurotoxic primarily due to its free radical properties, and it has been implicated in neurodegenerative diseases. Interestingly, there is increasing evidence that NO may have a role in the aforementioned AD pathogenetic mechanisms, and putative links between NO and AD are beginning to be recognized. This review focuses on these issues highlighting the possible relevance of NO in AD, either as a neuroprotective or neurotoxic agent.

Lawlor, B. and S. N. Bhriain (2001). "Psychosis and behavioural symptoms of dementia: defining the role of neuroleptic interventions." Int J Geriatr Psychiatry 16 Suppl 1: S2-6.
Neuroleptics have a definite role in dementia but the treatment targets need to be more narrowly defined. Symptom clusters that are neuroleptic-responsive (e.g., aggression, psychomotor agitation and psychosis) appear to be emerging but need clearer definition and measurement. A number of these symptom clusters are relatively persistent over time and associated with increased risk of institutionalization, underscoring the need for treatment. The frequency, severity and persistence of the symptom or behaviour, the context in which it occurs and its impact on the carer must be considered before prescribing a neuroleptic. Given the modest effect size for neuroleptic interventions, the safety and tolerability of the agent is also a key factor in determining drug choice. Novel neuroleptics are safer and better tolerated and therefore should be used in preference to conventional agents when neuroleptic treatment is indicated for behavioural and psychological symptoms of dementia.

Layfield, R., A. Alban, et al. (2001). "The ubiquitin protein catabolic disorders." Neuropathol Appl Neurobiol 27(3): 171-9.
The ubiquitin-proteasome system of intracellular proteolysis is essential for cell viability. We propose the concept that neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as other conditions including some types of cancer, collectively represent a raft of 'ubiquitin protein catabolic disorders' in which altered function of the ubiquitin-proteasome system can cause or directly contribute to disease pathogenesis. Genetic abnormalities within the ubiquitin pathway, either in ubiquitin-ligase (E3) enzymes or in deubiquitinating enzymes, cause disease because of problems associated with substrate recognition or supply of free ubiquitin, respectively. In some cases, mutations in protein substrates of the ubiquitin-proteasome system may directly contribute to disease progression because of inefficient substrate recognition. Mutations in transcripts for the ubiquitin protein itself (as a result of 'molecular misreading') also affect ubiquitin-dependent proteolysis with catastrophic consequences. This has been shown in Alzheimer's disease and could apply to other age-associated neurodegenerative conditions. Within the nervous system, accumulation of unwanted proteins as a result of defective ubiquitin-dependent proteolysis may contribute to aggregation events, which underlie the pathogenesis of several major human neurodegenerative diseases.

Le, W. D. and J. Jankovic (2001). "Are dopamine receptor agonists neuroprotective in Parkinson's disease?" Drugs Aging 18(6): 389-96.
Dopamine receptor agonists are playing an increasingly important role in the treatment of not only patients with advanced Parkinson's disease and those with levodopa-induced motor fluctuations, but also in the early treatment of the disease. This shift has been largely due to the demonstrated levodopa-sparing effect of dopamine agonists and their putative neuroprotective effect, with evidence for the latter being based largely on experimental in vitro and in vivo studies. In this article we review the evidence for neuroprotection by the dopamine agonists pramipexole, ropinirole, pergolide, bromocriptine and apomorphine in cell cultures and animal models of injury to the substantia nigra. Most of the studies suggest that dopamine agonists may have neuroprotective effects via direct scavenging of free radicals or increasing the activities of radical-scavenging enzymes, and enhancing neurotrophic activity. However, the finding that pramipexole can normalise mitochondrial membrane potential and inhibit activity of caspase-3 in cytoplasmic hybrid cells derived from mitochondrial DNA of patients with nonfamilial Alzheimer's disease suggests an even broader implication for the neuroprotective role of dopamine agonists. Although the clinical evidence for neuroprotection by dopamine agonists is still limited, the preliminary results from several ongoing clinical trials are promising. Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progression of Parkinson's disease using various surrogate markers of neuronal degeneration such as 18F-levodopa positron emission tomography and 123I beta-CIT (carbomethoxy-beta-4-iodophenyl-nortropane) single positron emission computed tomography. The results of these experimental and clinical studies will improve our understanding of the action of dopamine agonists and provide critical information needed for planning future therapeutic strategies for Parkinson's disease and related neurodegenerative disorders.

Lee, V. M., M. Goedert, et al. (2001). "Neurodegenerative tauopathies." Annu Rev Neurosci 24: 1121-59.
The defining neuropathological characteristics of Alzheimer's disease are abundant filamentous tau lesions and deposits of fibrillar amyloid beta peptides. Prominent filamentous tau inclusions and brain degeneration in the absence of beta-amyloid deposits are also hallmarks of neurodegenerative tauopathies exemplified by sporadic corticobasal degeneration, progressive supranuclear palsy, and Pick's disease, as well as by hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Because multiple tau gene mutations are pathogenic for FTDP-17 and tau polymorphisms appear to be genetic risk factors for sporadic progressive supranuclear palsy and corticobasal degeneration, tau abnormalities are linked directly to the etiology and pathogenesis of neurodegenerative disease. Indeed, emerging data support the hypothesis that different tau gene mutations are pathogenic because they impair tau functions, promote tau fibrillization, or perturb tau gene splicing, thereby leading to formation of biochemically and structurally distinct aggregates of tau. Nonetheless, different members of the same kindred often exhibit diverse FTDP-17 syndromes, which suggests that additional genetic or epigenetic factors influence the phenotypic manifestations of neurodegenerative tauopathies. Although these and other hypothetical mechanisms of neurodegenerative tauopathies remain to be tested and validated, transgenic models are increasingly available for this purpose, and they will accelerate discovery of more effective therapies for neurodegenerative tauopathies and related disorders, including Alzheimer's disease.

Lee, S. S. (2001). "Effective screening for Alzheimer's disease in everyday practice." Jaapa 14(7): 39-48.

Lendon, C. and N. Craddock (2001). "Susceptibility gene(s) for Alzheimer's disease on chromosome 10." Trends Neurosci 24(10): 557-9.
The majority of Alzheimer's disease is inherited in a complex manner involving environmental factors and several genes. One of these genes is Apolipoprotein E where the polymorphic allele (APOE epsilon 4) has been robustly shown to modify risk and the course of Alzheimer's disease. The epsilon 4 allele however, only accounts for approximately 50% of late onset Alzheimer's disease. Here we review three quite different approaches that have led to convincing evidence that there is at least one other susceptibility gene for complex inherited forms of Alzheimer's disease on chromosome 10q. Two linkage studies give strong evidence of a locus at almost exactly the same location: one using the amyloid beta brain-deposited fragment of the amyloid precursor protein as a continuous phenotype, and the other using a categorical disease phenotype. A third candidate gene linkage and association analysis approach interestingly finds a maximum signal approximately 35-60cM distal to the previous studies.

Leonard, B. E. (2001). "Changes in the immune system in depression and dementia: causal or co-incidental effects?" Int J Dev Neurosci 19(3): 305-12.
It is now widely accepted that psychological stress and psychiatric illness can compromise immune function. Furthermore the mechanisms whereby such changes occur are probably associated with the activities of the cytokines and other inflammatory mediators of the immune system which are known to initiate changes in behaviour. This review aims to summarise the experimental and clinical evidence that implicates the pro-inflammatory cytokines in the pathological changes seen in major depression and in Alzheimer's disease (AD). In major depression, evidence is provided to show that both activation (e.g., macrophage activity, acute phase proteins) and inhibition (e.g., natural killer cell activity) of the immune system occur. Many of the behavioural changes seen in depression are simulated by three pro-inflammatory cytokines (IL-1, IL-6 and TNF-alpha), which may produce their impact on the brain by activating cyclooxygenase, nitric acid synthase and corticotrophin releasing factor. Effective antidepressant treatments largely attenuate the immune changes thereby raising the possibility that the normalisation of central biogenic amine function that are conventionally implicated in the cause of depression may be secondary to those of the pro-inflammatory cytokines.With respect to AD, while the cause(s) are unknown, there is both experimental and clinical evidence to suggest that inflammatory processes in the brain caused in particular by TNF-alpha together with the subsequent rise in free radicals, are instrumental in causing the pathological changes which underlie the disease. Evidence in favour of the inflammatory hypothesis is supported by the finding that nonsteroidal anti-inflammatory drugs slow down the progression of the disease.Although, more research is needed into the inter-relationships between the various pro-inflammatory cytokines and the behavioural changes invoked in major depression and AD, the immunological hypothesis has been important in stimulating new concepts regarding the causes of the pathological changes in these diseases and how effective drug treatments may attenuate them.

Leowattana, W. (2001). "DHEA(S): the fountain of youth." J Med Assoc Thai 84 Suppl 2: S605-12.
Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are weak androgens produced primarily by the adrenal gland. Although their plasma concentrations by far exceed those of any other adrenal product, their physiological roles have not yet been determined. In plasma, where the major portion of these hormones is present in the sulfate form, it is possible that DHEAS serves as a reservoir for DHEA. Since various tissues have been shown to contain steroid sulfatases. The peak plasma levels of DHEA and DHEAS occur at approximately age 25 years, decrease progressively thereafter, and diminish by 95 per cent around the age of 85 years. The decline of DHEAS concentrations with aging has led to the suggestion that DHEAS could play a role in itself and be implicated in longevity. Moreover, the epidemiological evidence has shown that adult men with high plasma DHEAS levels are less likely to die of cardiovascular disease. DHEA has also been shown to increase the body's ability to transform food into energy and burn off excess fat. Another recent finding involves the anti-inflammatory properties of DHEA. It has been known that DHEA can lower the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). It should be pointed out that chronic inflammation is known to play a critical role in the development of the killer diseases of aging: heart disease, Alzheimer's disease and certain types of cancer. In conclusion, DHEA or DHEAS administration combined with conventional treatment may be implicated in particular conditions to improve the quality of life.

Lev, N. and E. Melamed (2001). "Heredity in Parkinson's disease: new findings." Isr Med Assoc J 3(6): 435-8.
Multiple factors have been hypothesized over the last century to be causative or contributory for Parkinson's disease. Hereditary factors have recently emerged as a major focus of Parkinson's disease research. Until recently most of the research on the etiology of Parkinson's disease concentrated on environmental factors, and the possibility that genetic factors contribute significantly to the pathogenesis of Parkinson's disease has been neglected. However, it has become increasingly apparent that even in sporadic cases, the disease most likely reflects a combination of genetic susceptibility and an unknown environmental insult. Moreover, the identification of genes and proteins that may cause hereditary parkinsonism substantially contributes to our ability to understand the pathogenesis of Parkinson's disease and may help in the early identification of the disease and its treatment. The discovery of alpha-synuclein mutations in families with autosomal dominant Parkinson's disease sheds light on its role in sporadic Parkinson's disease. It seems that this protein tends to aggregate when the cellular milieu is altered [14-16]. The question as to the exact changes that cause its deposition remains open. One of the major possibilities is oxidative stress [16]. The role of these aggregates in neuronal cell death is also still unclear. Transgenic mice expressing wild-type human alpha-synuclein developed progressive accumulation of alpha-synuclein and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus and the substantia nigra. These alterations were associated with loss of dopaminergic terminals and motor impairments [24]. This finding suggests that accumulation of alpha-synuclein may play a causal role in sporadic Parkinson's disease as well. The parkin protein seems to be a crucial survival factor for nigral neurons [15]. The parkin protein is related to the ubiquitin pathway, which is important in the elimination of damaged proteins. Ubiquitin-mediated degradation of proteins plays a central role in the control of numerous processes, including signal transduction, receptor and transcriptional regulations, programmed cell death, and breakdown of abnormal proteins that may interfere with normal cell functions. Further studies on the function of Parkin protein and its relation to the ubiquitin pathway could elucidate at least one of the molecular mechanisms of nigral neuronal death. A mutation in the ubiquitin carboxy-teminal hydrolase L1 gene also implies the importance of the ubiquitin pathway in Parkinson's disease. Abnormal tau protein was found to be the cause of familial frontotemporal dementia and parkinsonism. It tends to form filamentous structures, which may lead to neuronal death. Elucidation of the molecular mechanism of neuronal death in this disease may contribute to our understanding of sporadic diseases with tau accumulation, such as corticobasal degeneration, progressive supranuclear palsy, Pick's disease, Alzheimer's disease and possibly also the pathogenesis of Parkinson's disease. Other genetic loci have been identified by linkage analysis of patients with familial parkinsonism. These loci conceal other genes and proteins that may be pivotal factors in the pathogenesis of Parkinson's disease. The discovery of genetic mutations in patients with parkinsonism may offer us new insights into the understanding of the pathways leading to neuronal death and development of Parkinson's disease. It may also help in the early identification of susceptible people to this disease and possibly in developing new treatment strategies.

Levine, B., T. King, et al. (2001). "Palliative pain therapy at the end of life and forensic medicine issues." Am J Forensic Med Pathol 22(1): 62-4.
An 83-year-old woman with a history of Alzheimer's disease and breast cancer died at home while receiving palliative pain therapy with oral morphine from her family for metastatic breast cancer. Allegations of mistreatment were made, and this case was ultimately referred to the Office of the Chief Medical Examiner, State of Maryland. An autopsy failed to identify any injuries or residual cancer, leaving no anatomic explanation for the pain that had been presumed to be metastatic breast carcinoma involving bone. The blood free morphine concentration was 5,200 ng/ml, and the total morphine concentration was 15,000 ng/ml. This case demonstrates the challenges and difficulties in forensic medicine when faced with the interpretation of toxicologic results at the end of life.

Li, M. and H. A. Lester (2001). "Ion channel diseases of the central nervous system." CNS Drug Rev 7(2): 214-40.
In the last decade, advances in molecular genetics and cellular electrophysiology have increased our understanding of ion channel function. A number of diseases termed "channelopathies" have been discovered that are caused by ion channel dysfunction. Channelopathies can be caused by autoimmune, iatrogenic, toxic or genetic mechanisms. Mutations in genes encoding ion channel proteins that disrupt channel function are now the most commonly identified cause of channelopathies, perhaps because gene disruption is readily detected by the methods of molecular genetics. Ion channels are abundant in the central nervous system (CNS), but CNS channelopathies are rare; however, they overlap with some important neurological disorders, such as epilepsy, ataxia, migraine, schizophrenia, Alzheimer's disease and other neurodegenerative diseases. It is possible that more CNS channelopathies will be discovered when additional ion channels are characterized and the complex mechanisms of brain function are better understood. At present, increased knowledge of the identity, structure and function of ion channels is facilitating diagnosis and treatment of many channelopathies.

Liddell, M. B., S. Lovestone, et al. (2001). "Genetic risk of Alzheimer's disease: advising relatives." Br J Psychiatry 178(1): 7-11.
BACKGROUND: Clinicians are increasingly asked by relatives of patients with Alzheimer's disease to advise on their genetic risk of developing Alzheimer's disease in later life. Many clinicians find this a difficult question to answer. AIMS: To provide information for old age psychiatrists wishing to advise relatives of their risk of developing Alzheimer's disease. METHOD: A selective review of the key literature on the genetic epidemiology of Alzheimer's disease. RESULTS: Currently a DNA diagnosis is attainable in some 70% of families with autosomal dominant Alzheimer's disease. In first-degree relatives of most cases, risk is increased some three- or four-fold relative to controls, but only one-third of this is realised in the average life span. Apolipoprotein E genotyping cannot be used as a predictive test and confers only minimal diagnostic benefit. CONCLUSIONS: Pedigrees with familial Alzheimer's disease should be referred to a Regional Centre for Medical Genetics. Accurate risk prediction is not possible in the vast majority of pedigrees with Alzheimer's disease, although it is possible for the psychiatrist to give a rough estimate of the risk, which can reasonably the couched in reassuring terms.

Link, C. D. (2001). "Transgenic invertebrate models of age-associated neurodegenerative diseases." Mech Ageing Dev 122(14): 1639-49.
Transgenic Drosophila melanogaster and Caenorhabditis elegans strains have been engineered to express human proteins associated with neurodegenerative diseases. These model systems include transgenic animals expressing beta-amyloid peptide (Alzheimer's disease), polyglutamine repeat proteins (Huntington's disease, Spinocerebellar ataxia), and alpha-synuclein (Parkinson's disease). In most of these invertebrate models, some aspects of the human diseases are reproduced. Although expression of all these proteins in transgenic mice has been instructive, the invertebrate models offer experimental advantages (e.g. forward genetic screens) that can potentially address some of the outstanding questions regarding the cellular processes underlying these diseases. This review considers what has been learned from these invertebrate models, and speculates what further insight may be gained from them.

Linn, E. S., A. M. Kaunitz, et al. (2001). "The hormone continuum: accrual of women's health benefits." Int J Fertil Womens Med 46(2): 60-72.
The hormone continuum is a treatment strategy that advocates maintaining hormone continuity, from the reproductive years into menopause and beyond. This entails the use first of oral contraceptives (OCs), which confer well-known health benefits--especially reductions in ovarian and endometrial cancers--besides effective contraception, and later, hormone replacement therapy (HRT), which provides relief of perimenopausal and menopausal symptoms and protects older women from (a) decreasing bone mineral density; (b) cardiovascular disease, according to several studies; and (c) Alzheimer's disease, as suggested by a number of studies. In perimenopause, use of OCs declines by about one-half, and then by a further four-fifths up to menopause. This is unfortunate, because in these later reproductive years women are subject to unintended pregnancy, which in 65% of cases is terminated by abortion. Furthermore, women are thereby deprived also of alleviation of dysmenorrhea and even vasomotor symptoms that often characterize the perimenopause. After menopause is well established, a "seamless" transition to HRT can be made, often with the same progestin that was contained in the OC. This paper discusses risks as well as benefits of hormone therapy, especially of HRT, with an emphasis on patient counseling and individualizing of therapy.

Liu, D. X. and L. A. Greene (2001). "Neuronal apoptosis at the G1/S cell cycle checkpoint." Cell Tissue Res 305(2): 217-28.
Apoptosis is a fundamental and essential process in development and tissue homeostasis of multicellular organisms. Roughly half of all the neurons produced during neurogenesis die apoptotically before the nervous system matures. Apoptosis is also involved in various neurodegenerative disorders such as Alzheimer's disease and neuronal trauma. Investigation of the mechanisms underlying neuronal apoptosis led to an unexpected discovery that in many cases revival of the quiescent and dormant cell cycle machinery is a common theme. Recent data suggest that uncoordinated expression of cell cycle molecules and the consequent breach of cell cycle checkpoints could be one of the primary mechanisms by which postmitotic neurons undergo apoptotic death. Evidence indicates that upregulation of cyclin-D-CDK4/6 activity and deregulation of E2F transcription factors mark key events in early stages of neuronal apoptosis. Active E2F repression by Rb family members is required for the survival of neurons. Apoptotic signals promote successive phosphorylation and dysfunction of Rb family members, resulting in sequential E2F derepression and expression of selective E2F-responsive genes. Thus, expression of derepressed E2F-responsive genes may be instrumental in propagating and amplifying the apoptotic signals instructing neuronal cells to carry out the apoptotic program.

Llorente-Vizcaino, A. and J. C. Cejudo-Bolivar (2001). "[Memories and Alzheimer's disease]." Rev Neurol 32(12): 1163-72.
INTRODUCTION: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Memory loss is generally the most pervasive cognitive symptom of AD but is not the only one and is not homogeneous in its loss. DEVELOPMENT: Memory complaint is one of the most frequent complaints in elderly people but not all complaints of memory inefficiencies in old age reflect dementing illnesses. Amnesia is the failure or lack of memory. Research in cognitive psychology and neuropsychology of memory has produced evidence than human memory is not a unitary aspect of human cognition but is organized in independent systems. Tulving (1995) and Van der Linden (1997) identified at least five major memory systems: primary memory or working memory, episodic memory, semantic memory, procedural system and perceptual priming. From a theoretical view of multiple memory systems, the purpose of the present conference is the review of multiple systems models of human memory and the memory processes, encoding, storage and retrieval in AD and memory assessment. Memory assessment is not limited by formal testing and requires ecological assessment by daily living tasks of AD patients. Appropriateness of multiple memory systems models is discussed.

Lopera, F. (2001). "[Clinical history in the study of a patient with dementia]." Rev Neurol 32(12): 1187-91.
OBJECTIVES. To carry out a detailed review of the keys to diagnosis of different types of dementia whilst taking a clinical history. DEVELOPMENT. Dementia is a syndrome with many different aetiologies. Correct diagnosis depends on recording data of the history of the dementia, particularly of complaints regarding cognition and behavior. The keys to the clinical history should be based on questions about cognitive disorders, with emphasis on how they started, their evolution and particular form of dysfunction, Although Alzheimer's dementia is the most frequent, this diagnosis should only be made when the other forms of dementia have been ruled out. In this article we describe some of the keys to a good clinical history to facilitate the etiological and differential diagnosis of dementia. CONCLUSIONS. Establishment of a full clinical history is the first and most important step in the diagnosis of dementia and cognitive disorders. On this will depend the plan to be followed to study the aetiology and most suitable treatment. Success or failure in the study of a patient with dementia depends on the quality of the clinical history obtained.

Lopez, A. and J. Birks (2001). "Nimodipine for primary degenerative, mixed and vascular dementia." Cochrane Database Syst Rev(1): CD000147.
BACKGROUND: Dementia is an age-related condition in which Alzheimer's disease (AD) and cerebrovascular disease account for the bulk of cases. The role played by calcium in regulating brain functions is well known - the calcium ion links membrane excitation to subsequent intracellular enzymatic response. Change in calcium homeostasis is one important effect of aging with repercussions on higher cortical functions. Nimodipine is an isopropyl calcium channel blocker which can easily cross the blood brain barrier. Its primary action is to reduce the number of open channels, thus restricting influx of calcium ions into the cell. The usefulness of nimodipine in patients with Alzheimer's disease and vascular dementia and unspecified dementia is still controversial with mixed results. In spite of the uncertainties about its efficacy in dementia, nimodipine is currently a frequently prescribed drug for cognitive impairment and dementia in several European countries. This review will be conducted in two phases; the current review is based on evidence from published data only. The second phase will be based on individual-patient data analysed centrally and added to this review in due course. OBJECTIVES: To determine the clinical efficacy of nimodipine for the symptoms of dementia, either unclassified or according to the major subtypes - Alzheimer's disease, vascular, or mixed Alzheimer's and vascular dementia. SEARCH STRATEGY: The Cochrane Dementia Group Register of Clinical Trials was searched using the terms 'nimodipine' and 'isopropyl (2-methoxy-ethyl) 1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate'. SELECTION CRITERIA: All unconfounded, double-blind, randomised trials in which treatment with nimodipine was administered for more than a day and compared to placebo in patients with dementia, either unclassified or according to the major subtypes - Alzheimer's disease, vascular, or mixed Alzheimer's and vascular dementia. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers and the odds ratio (95%CI) or the average difference (95%CI) were estimated. Both intention-to-treat and on-treatment results were extracted. MAIN RESULTS: This review produced no clear results. Many of the data published were not capable of being sensibly pooled. The data were compatible with nimodipine producing improvement, no change or even harm for those with Alzheimer's disease, vascular dementia, or mixed Alzheimer's and vascular dementia. It was not possible to use many of the published results in a combined analysis. For measures of overall clinical improvement, the intention-to-treat analysis, based on one study only, failed to detect any difference between nimodipine and placebo (OR 0.53; 95%CI 0.25 - 1.13). An on-treatment analysis, based on one study only, produced a statistically significant difference in favour of nimodipine (SMD 4.4; 95%CI 3.9 - 5.0). For cognitive function, the effect of nimodipine was statistically significantly different from placebo for the Mini Mental State Examination score (0-30; high =good) (SMD 0.9; 95%CI 0.59 - 1.22) and there was a statistically significant effect in favour of treatment for the Wechsler Memory Scale (SMD 0.47; 95%CI 0.17 - 0.77). These analyses were based only on those who completed the study and not intention-to-treat analyses. There were no results presented in a form suitable for pooling for functional autonomy, behaviour, quality of life dependency (eg institutionalization), effect on carer, death, acceptability of treatment (as measured by withdrawal rate, safety (as measured by the incidence of adverse effects, including side effects, leading to withdrawal). REVIEWER'S CONCLUSIONS: This review provides no convincing evidence that nimodipine is a useful treatment for the symptoms of dementia, either unclassified or according to the major subtypes - Alzheimer's disease, vascular, or mixed Alzheimer's and vascular dementia. However, as so few of the trials presented data in a format suitable for pooling, the results of this review may be modified when further data from all relevant trials are included. There is an urgent need for the independent evaluation of the data already existing in the trials but not accessible through published or grouped data. An independent meta-analysis of the individual patient data is required. Nimodipine cannot be currently recommended in patients with dementia. The results and conclusions of this update are unaltered by further searching as the additional studies do not add any further valid/eligible data.

Lopez-Arrieta, J. M., J. L. Rodriguez, et al. (2001). "Efficacy and safety of nicotine on Alzheimer's disease patients." Cochrane Database Syst Rev(2): CD001749.
BACKGROUND: Nicotine is a cholinergic agonist that also has a presynaptic effect in releasing acetylcholine. In animal model has been shown to reverse spatial memory deficits produced by lesions in the medial septal nucleus of rats, and in aged monkeys nicotine administration improves memory and alertness to visual stimuli. Observational studies have claimed a protective effect of smoking against Alzheimer's disease (AD), but recent studies have called this into question. Smoking is a risk factor for stroke and so, possibly, for vascular dementia. Because nicotine has adverse effects, it is important to conduct a systematic review to assess the clinical efficacy and safety of nicotine for patients with AD OBJECTIVES: To evaluate the efficacy and safety of nicotine, administered in any way or form, for people with Alzheimer's disease. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 24 January 2001 using the term nicotine. SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with nicotine patches or administration of nicotine intravenously or in any other way or form was administered for more than a day and compared with placebo for people with Alzheimer's disease. DATA COLLECTION AND ANALYSIS: The one included trial did not present results suitable for inclusion in the review. MAIN RESULTS: The poor quality of trials did not allow any synthesis of data across studies. REVIEWER'S CONCLUSIONS: This review is not able to provide any evidence that nicotine is a useful treatment for Alzheimer's disease.

Lopez-Garcia, C., A. Molowny, et al. (2001). "[Synaptic zinc in the central nervous system]." Rev Neurol 33(4): 341-7.
Apart from iron, zinc is the most abundant oligoelement in the nervous tissue. Although the majority of zinc constitutes a stable fraction that is tightly bound to molecules and molecular complexes (structural or metabolic zinc), a small proportion (10 15% of cerebral zinc) remains as an ion and it is stored inside membranous compartments (ionic vesicular zinc). In neurons, most of this ionic zinc can be found inside synaptic vesicles and it is released outside the neuron during synaptic transmission: this is the synaptic zinc. In the surroundings of the synapse, zinc acts over a variety of neuronal receptors and ionic channels, playing a modulatory role that is not yet fully understood. The prolonged presence of zinc in the vicinity of the synapse allows its translocation to postsynaptic neurons, which lack the defensive mechanisms (membrane transporters that store zinc into vesicles). In this case, zinc acts as a neurotoxic and it can induce neuronal cell death. Neurons and glial cells have very efficient, although not well known, cleaning mechanisms that eliminate synaptic zinc from the extracellular space; it probably is simultaneous with glutamate clearance. It is feasible that dysfunction of these zinc cleaning systems could induce compensatory mechanisms (precipitation induced by amyloid precursor protein) which in turn could potentiate ethiologic factors of Alzheimer s disease.

Lorenzo-Otero, J. (2001). "[Apraxia of ideas and movements and visual-constructive skills]." Rev Neurol 32(5): 473-7.
OBJECTIVES: To study alterations in copying behaviour in Alzheimer's disease (AD) and its relationship with other cognitive parameters. As secondary objectives, in this paper we describe the evolution of concepts, definitions and examination of ideas-movement and constructive apraxia, together with its involvement in AD and review the investigations of the Uruguayan school on the development of behaviour copying and how this is affected in patients with cerebral lesions. PATIENTS AND METHODS: We made a study of 82 consecutive patients with probable AD at stages 3 to 5 on the overall deterioration scale (GDS), registered in the Department of Neuropsychology, and a group of healthy persons, paired for age, sex and educational level. We used an extensive protocol for cognitive evaluation. We evaluated the idea-movement apraxia by means of imitation of increasingly complex gestures, and constructive apraxia using the protocol described by Mendilaharsu et al. RESULTS: At stages 4 and 5 of the GDS scale, the idea-movement apraxia was significantly correlated with digital agnosia and the anomias. Constructive apraxia was found in GDS stage 3. We found 'homogeneous cognitive deterioration' in advanced patients (GDS 5) who showed closing-in when copying figures. The closing-in correlated significantly with the presence of anomias, idea apraxia and digital agnosia. CONCLUSION: In the early stages, EA shows varied praxis profiles, but above stage 5 of the GDS scale there was a tendency to homogeneity.

Lott, I. T. and E. Head (2001). "Down syndrome and Alzheimer's disease: a link between development and aging." Ment Retard Dev Disabil Res Rev 7(3): 172-8.
A subset of aged individuals with Down syndrome (DS) exhibits the clinical features of Alzheimer's disease (AD) but our ability to detect dementia in this population is hampered by developmental differences as well as the sensitivity of existing test tools. Despite the apparent clinical heterogeneity in aged individuals with DS, age-associated neuropathology is a consistent feature. This is due to the fact that trisomy 21 leads to a dose-dependent increase in the production of the amyloid precursor protein and subsequently the production of the amyloidogenic fragments leading to early and predominant senile plaque formation. A review of the existing literature indicates that oxidative damage and neuroinflammation may interact to accelerate the disease process particularly in individuals with DS over the age of 40 years. By combining clinical information with measures of brain-region specific neuropathology we can "work backwards" and identify the earliest and most sensitive clinical change that may signal the onset of AD. For the past 50 years, investigators in the fields of mental retardation, developmental disabilities, and aging have been interested in the curious link between AD and DS. The morphologic and biochemical origins of AD are seen in the early years of the lifespan for individuals with DS. Study of the process by which AD evolves in DS affords an opportunity to understand an important link between development and aging. This review will focus on advances in the molecular and clinical basis of this association.

Lovestone, S., B. Anderton, et al. (2001). "Apolipoprotein E gene and Alzheimer's disease: is tau the link?" Biochem Soc Symp(67): 111-20.
The finding that APOE (the gene encoding apolipoprotein E) polymorphic variation was associated with an altered risk of developing Alzheimer's disease (AD) was a significant advance and immediately prompted a search for the mechanisms responsible for this alteration. Some 6 years later, a number of different hypotheses remain that might account for this influence on pathogenesis with no single mechanism being unequivocally accepted. The different approaches to understanding these mechanisms can be broadly categorized as: those suggesting a remote effect, such as different rates of vascular risk factors in those with the different APOE alleles; those proposing altered neuronal vulnerability, perhaps due to apolipoprotein E (ApoE)-isoform-specific differences in local cholesterol transport; and those hypotheses postulating an ApoE interaction with the two key lesions of AD, plaques and tangles. In this chapter we will review the evidence for and against an interaction between ApoE and the neuronal cytoskeleton, in particular with the microtubule-associated protein tau.

Lowe, J. (2001). "The pathological diagnosis of neurodegenerative diseases causing dementia." Curr Top Pathol 95: 149-77.

Ludolph, A. C., A. Sperfeld, et al. (2001). "[Tauopathies--a new class of neurodegenerative diseases]." Nervenarzt 72(2): 78-85.
Recently it was shown by several research groups that mutations in the gene encoding for the tau protein associated with microtubuli on chromosome 17 caused a distinct form of dementia named frontotemporal dementia and parkinsonism (FTDP-17). This disease includes familial asymmetrical frontal and, in the further course, frontotemporal dementia, parkinsonism, which is often initially sensitive to levodopa, signs of upper motor neuron degeneration, and, less commonly, amyotrophy. Tau is an intracellular protein of the cytoskeleton, which is responsible for the arrangement and stabilization of microtubuli. The discovery of mutations in the tau gene causing a distinct neurodegenerative disease in humans has firmly established the importance of the tau gene for neurodegenerative processes, not only in tauopathies but also in other degenerative disorders with tau pathology, such as corticobasal degeneration, supranuclear progressive paralysis, amyotropic lateral sclerosis, parkinsonism-dementia complex of Guam, and Alzheimer's disease. Our experience with patients suffering from PTDP-17 shows that its phenotype varies more than was described in the first consensus conferences. In the future, it will be important to designate the diagnostic gold standard not by clinical description, but etiologic classification.

Lue, L. F., D. G. Walker, et al. (2001). "Modeling microglial activation in Alzheimer's disease with human postmortem microglial cultures." Neurobiol Aging 22(6): 945-56.
Alzheimer's disease (AD) is a uniquely human disorder. Despite intense research, the lack of availability of model systems has hindered AD studies though in recent years transgenic mouse models have been produced, which develop AD-like amyloid beta peptide (Abeta) plaques. For the study of inflammatory changes in AD brains, these transgenic mice may have limitations due to differences in the innate immune system of humans and rodents. Many studies of inflammatory processes in AD have focused on the role of activated microglia. Over the last 8 years, our research has focused on the properties of human microglia cultured from brain tissues of AD and non-demented (ND) individuals. As these are the cells observed to be activated in AD tissues, they represent a useful system for modeling the inflammatory components of AD.In this review, we summarize data by our group and others on the use of microglia for AD-related inflammatory research, with emphasis on results using human postmortem brain microglia. A range of products have been shown to be produced by human postmortem microglia, both constitutively and in response to treatment with Abeta, including proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF) alpha, and macrophage colony stimulating factor (M-CSF), along with complement proteins, especially C1q, superoxide radicals and neurotoxic factors. In our studies, we have demonstrated that there was a significant difference between AD and ND microglia in terms of their secretion of M-CSF and C1q. We also discuss the role of putative Abeta microglial receptors, particular recent data showing a role for the receptor for advanced glycation endproducts (RAGE) in mediating the responses of human microglia to Abeta. Finally, our studies on the use of an Abeta spot paradigm to model microglia interactions with plaques demonstrated that many of the features of AD inflammation can be modeled with postmortem brain derived microglia.

Lyons, D. and D. M. McLoughlin (2001). "Recent advances: Psychiatry." Bmj 323(7323): 1228-31.

Ma, K. C. (2001). "Alzheimer-type I astrogliopathy (AIA) and its implications for dynamic plasticity of astroglia: a historical review of the significance of AIA." J Neuropathol Exp Neurol 60(2): 121-31.
Alzheimer-type I astrogliopathy (AIA) is an uncommon neuropathological phenomenon encountered in Wilson's disease and less often in acquired hepatic encephalopathy. Since its first description in 1912 it has received little attention. However, after 1971, when the nature of its morphogenesis began to be recognized and it was shown that it could be reproduced experimentally, its significance has been increasingly appreciated. Two intriguing characteristics of the dynamic plasticity of astroglia were revealed from the studies of the inter-relationships between AIA and Alzheimer-type II astrogliopathy (AIIA); normal astroglia and AIIA; and reactive astrogliosis and AIIA, namely, the compensatory "rebound" phenomenon of Alzheimer astrogliopathy, and a dual cellular origin for reactive astrogliosis taking place in both normal and dystrophic astrocytes. More recently the presence of AIA and AIIA has been reported in a case of anoxic encephalopathy, and also in a case of Marchiafava-Bignami's disease. In this review, dependable criteria for the identification of the pathological features of AIA are discussed and emphasized. Both types of Alzheimer astrogliopathy may be used as pathologic markers with specific morphological and immunocytochemical characteristics to study in detail the disturbances of metabolic interactions between the astrocyte-neuron coupling and the exact mechanisms of the dynamic plasticity of astroglia.

Maccioni, R. B., J. P. Munoz, et al. (2001). "The molecular bases of Alzheimer's disease and other neurodegenerative disorders." Arch Med Res 32(5): 367-81.
Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death. Neurodegeneration in Alzheimer's disease is a pathologic condition of cells rather than an accelerated way of aging. The senile plaques are generated by a deposition in the human brain of fibrils of the beta-amyloid peptide (Abeta), a fragment derived from the proteolytic processing of the amyloid precursor protein (APP). Tau protein is the major component of paired helical filaments (PHFs), which form a compact filamentous network described as neurofibrillary tangles (NFTs). Experiments with hippocampal cells in culture have indicated a relationship between fibrillary amyloid and the cascade of molecular signals that trigger tau hyperphosphorylations. Two main protein kinases have been shown to be involved in anomalous tau phosphorylations: the cyclin-dependent kinase Cdk5 and glycogen synthase kinase GSK3beta. Cdk5 plays a critical role in brain development and is associated with neurogenesis as revealed by studies in brain cells in culture and neuroblastoma cells. Deregulation of this protein kinase as induced by extracellular amyloid loading results in tau hyperphosphorylations, thus triggering a sequence of molecular events that lead to neuronal degeneration. Inhibitors of Cdk5 and GSK3beta and antisense oligonucleotides exert protection against neuronal death. On the other hand, there is cumulative evidence from studies in cultured brain cells and on brains that oxidative stress constitutes a main factor in the modification of normal signaling pathways in neuronal cells, leading to biochemical and structural abnormalities and neurodegeneration as related to the pathogenesis of Alzheimer's disease. This review is focused on the main protein aggregates responsible for neuronal death in both sporadic and familial forms of Alzheimer's disease, as well as on the alterations in the normal signaling pathways of functional neurons directly involved in neurodegeneration. The analysis is extended to the action of neuroprotective factors including selective inhibitors of tau phosphorylating protein kinases, estrogens, and antioxidants among other molecules that apparently prevent neuronal degeneration.

Maccioni, R. B., C. Otth, et al. (2001). "The protein kinase Cdk5. Structural aspects, roles in neurogenesis and involvement in Alzheimer's pathology." Eur J Biochem 268(6): 1518-27.
A set of different protein kinases have been involved in tau phosphorylations, including glycogen synthase kinase 3beta (GSK3 beta), MARK kinase, MAP kinase, the cyclin-dependent kinase 5 (Cdk5) system and others. The latter system include the catalytic component Cdk5 and the regulatory proteins p35, p25 and p39. Cdk5 and its neuron-specific activator p35 are essential molecules for neuronal migration and for the laminar configuration of the cerebral cortex. Recent evidence that the Cdk5/p35 complex concentrates at the leading edge of axonal growth cones, together with the involvement of this system in the phosphorylation of neuronal microtubule-asociated proteins (MAPs), provide further support to the role of this protein kinase in regulating axonal extension in developing brain neurons. Although the aminoacid sequence of p35 has little similarity with those of normal cyclins, studies have shown that its activation domain may adopt a conformation of the cyclin-folded structure. The computed structure for Cdk5 is compatible with experimental data obtained from studies on the Cdk5/p35 complex, and has allowed predictions on the protein interacting domains. This enzyme exhibits a wide cell distribution, even though a regulated Cdk5 activity has been shown only in neuronal cells. Cdk5 has been characterized as a proline-directed Ser/Thr protein kinase, that contributes to phosphorylation of human tau on Ser202, Thr205, Ser235 and Ser404. Cdk5 is active in postmitiotic neurons, and it has been implicated in cytoskeleton assembly and its organization during axonal growth. In addition to tau and other MAPs, Cdk5 phosphorylates the high molecular weight neurofilament proteins at their C-terminal domain. Moreover, nestin, a protein that regulates cytoskeleton organization of neuronal and muscular cells during development of early embryos, and several other regulatory proteins appear to be substrates of Cdk5 and are phosphorylated by this kinase. Studies also suggest, that in addition to Cdk5 involvement in neuronal differentiation, its activity is induced during myogenesis, however, the mechanisms of how this activity is regulated during muscular differentiation has not yet been elucidated. Recent studies have shown that the beta-amyloid peptide (A beta) induces a deregulation of Cdk5 in cultured brain cells, and raises the question on the possible roles of this tau-phosphorylating protein kinase in the sequence of molecular events leading to neuronal death triggered by A beta. In this context, there are evidence that Cdk5 is involved in tau hyperphosphorylation promoted by A beta in its fibrillary form. Cdk5 inhibitors protect hippocampal neurons against both tau anomalous phosphorylations and neuronal death. The links between the studies on the Cdk5/p35 system in normal neurogenesis and its claimed participation in neurodegeneration, provide the framework to understand the regulatory relevance of this kinase system, and changes in its regulation that may be implicated in disturbances such as those occurring in Alzheimer disease.

Mackenzie, I. R. (2001). "Postmortem studies of the effect of anti-inflammatory drugs on Alzheimer-type pathology and associated inflammation." Neurobiol Aging 22(6): 819-22.
Examining postmortem tissue is the most direct way of evaluating the effect of antemortem drug use on the pathological processes believed to be important in Alzheimer's disease (AD). A small number of studies have recently been published in which data from human autopsy tissue and animal models provides important insight into the mechanisms by which anti-inflammatory (AI) agents may protect against AD. These indicate that certain classes of AI drugs may be capable of reducing the chronic inflammation which is consistently seen in AD brain tissue. In addition, a recent study using a transgenic mouse model of AD, suggests that AI therapy may also influence the accumulation of senile plaques and dystrophic neurites. The results of these and future postmortem studies will be invaluable in the development of optimum treatment strategies.

Madhusoodanan, S. (2001). "Introduction: antipsychotic treatment of behavioral and psychological symptoms of dementia in geropsychiatric patients." Am J Geriatr Psychiatry 9(3): 283-8.

Maelicke, A. (2001). "The pharmacological rationale for treating vascular dementia with galantamine (Reminyl)." Int J Clin Pract Suppl(120): 24-8.
There is considerable evidence indicating that, as in Alzheimer's disease, the central cholinergic system is impaired in vascular dementia (VaD). Using lessons learned from Alzheimer's disease research, it has been proposed that enhancement of the cholinergic system is a rational approach to treating the symptoms of VaD. Galantamine's dual mode of action may provide a greater chance of success in treating patients with Alzheimer's disease through enhanced efficacy on the cognitive, functional and behavioural aspects of dementia. Trials are currently underway to see if this broad spectrum of efficacy extends to patients with Alzheimer's disease with cerebrovascular disease ('mixed' dementia) or VaD, as well as other conditions, and the results are eagerly awaited.

Maelicke, A., M. Samochocki, et al. (2001). "Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer's disease." Biol Psychiatry 49(3): 279-88.
Cholinesterase inhibitors are the only approved drug treatment for patients with mild to moderately severe Alzheimer's disease. Interestingly, the clinical potency of these drugs does not correlate well with their activity as cholinesterase inhibitors, nor is their action as short lived as would be expected from purely symptomatic treatment. A few cholinesterase inhibitors, including galantamine, produce beneficial effects even after drug treatment has been terminated. These effects assume modes of action other than mere esterase inhibition and are capable of inducing systemic changes. We have recently discovered a mechanism that could account, at least in part, for the above-mentioned unexpected properties of some cholinesterase inhibitors. We have found that a subgroup of cholinesterase inhibitors, including galantamine but excluding tacrine, directly interacts with nicotinic acetylcholine receptors. These compounds, named allosterically potentiating ligands, sensitize nicotinic receptors by increasing the probability of channel opening induced by acetylcholine and nicotinic agonists and by slowing down receptor desensitization. The allosterically potentiating ligand action, which is not necessarily associated with cholinesterase inhibition, has been demonstrated by whole-cell patch-clamp recordings to occur in natural murine and human neurons and in murine and human cell lines expressing various subtypes of neuronal nicotinic acetylcholine receptors.

Maiese, K. (2001). "The dynamics of cellular injury: transformation into neuronal and vascular protection." Histol Histopathol 16(2): 633-44.
Despite the immediate event, such as cerebral trauma, cardiac arrest, or stroke that may result in neuronal or vascular injury, specific cellular signal transduction pathways in the central nervous system ultimately influence the extent of cellular injury. Yet, it is a cascade of mechanisms, rather than a single cellular pathway, which determine cellular survival during toxic insults. Although neuronal injury associated with several disease entities, such as Alzheimer's disease, Parkinson's disease, and cerebrovascular disease was initially believed to be irreversible, it has become increasingly evident that either acute or chronic modulation of the cellular and molecular environment within the brain can prevent or even reverse cellular injury. In order to develop rational, efficacious, and safe therapy against neurodegenerative disorders, it becomes vital to elucidate the cellular and molecular mechanisms that control neuronal and vascular injury. These include the pathways of free radical injury, the independent mechanisms of programmed cell death, and the downstream signal transduction pathways of endonuclease activation, intracellular pH, cysteine proteases, the cell cycle, and tyrosine phosphatase activity. Employing the knowledge gained from investigations into these pathways will hopefully further efforts to successfully develop effective treatments against central nervous system disorders.

Maimone, D., R. Dominici, et al. (2001). "Pharmacogenomics of neurodegenerative diseases." Eur J Pharmacol 413(1): 11-29.
Current knowledge of sporadic degenerative disorders suggests that, despite their multifactorial etiopathogenesis, genetics plays a primary role in orchestrating the pathological events, and even dramatically changes the disease phenotype from patient to patient. Genes may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the magnitude and severity of pathogenic processes or the response to drug treatment. The goal of pharmacogenomics is the application of this knowledge to elaborate more specific and effective treatments and to tailor therapies to individual patients according to their genetic profile. Here, we outline the leading theories on the etiopathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer disease, and we review the potential role of genetic variations, such as gene mutations and polymorphisms, in each context. We also suggest potential targets for new therapeutic approaches and variability factors for current treatments based on genotype features. Finally, we propose a few options of preventive therapeutic interventions in patients with a high genetic risk of disease.

Mak, W. and S. L. Ho (2001). "The impact of molecular biology on clinical neurology." Hong Kong Med J 7(1): 40-9.
Advances in molecular biology have increased our understanding of both inherited and sporadic forms of neurological disease. In this review, the impact of these advances is discussed in relation to specific neurological conditions. These include the hereditary neuropathies and ataxias, Huntington's disease, and the muscular dystrophies, as well as Alzheimer's disease, Parkinson's disease, and motor neuron disease. Genetic channelopathies, such as familial hemiplegic migraine, are also described. Although knowledge in this area overall is still relatively scant, current advances in molecular biology have helped in the reclassification of some neurological disorders, thereby providing a further step towards the development of rational therapies to treat these conditions.

Maki, P. M. and S. M. Resnick (2001). "Effects of estrogen on patterns of brain activity at rest and during cognitive activity: a review of neuroimaging studies." Neuroimage 14(4): 789-801.
Animal and human studies provide evidence of systematic effects of estrogen on cerebral activity and cognitive function. In this article, we review studies of the activational effects of estrogen on cerebral activity during rest and during the performance of cognitive tasks in pre- and postmenopausal women. The goal is twofold--to better understand evidence suggesting that estrogen influences brain functioning and argue for the importance of considering hormone effects when designing neuroimaging studies. Hormone-related increases in blood flow during the resting state have been documented in healthy elderly women, elderly women with cerebrovascular disease, and middle-aged postmenopausal women with early menopause. There is no reliable influence of estrogen on blood flow during the resting state in women with Alzheimer's disease. Hormone therapy has been associated with changes in brain activation patterns in middle-aged and elderly postmenopausal women during performance of verbal and figural memory tasks, providing critical biological support for the view that estrogen might protect against age-associated changes in cognition and lower the risk of Alzheimer's disease. There is a paucity of studies examining changes in brain activation patterns across the menstrual cycle and a need for randomized studies of hormone therapy in postmenopausal women to confirm findings from observational studies. General procedural guidelines for controlling and investigating hormone effects in neuroimaging studies are discussed.

Marks, F. (2001). "[Prevention of cancer and Alzheimer disease with non-steroidal anti-inflammatory agents]." Dtsch Med Wochenschr 126(11): 308-13.

Marshall, M. J. and S. A. Hutchinson (2001). "A critique of research on the use of activities with persons with Alzheimer's disease: a systematic literature review." J Adv Nurs 35(4): 488-96.
TOPIC: The topic of this paper concerns the use of therapeutic activities with persons with Alzheimer's disease (AD). PURPOSE: The purpose is to present a critique of the research on these activities, with an emphasis on methodology. ORGANIZING CONSTRUCT AND SCOPE: Nursing literature identifies a number of purposes for activities for persons with AD. Activities should be therapeutic, enhance quality of life, arrest mental decline, and generate and maintain self-esteem. Other purposes of activities for this population are to create immediate pleasure, re-establish dignity, provide meaningful tasks, restore roles, and enable friendships. Activities may be more important to the psychological state of well-being of persons with dementia than the general physical and social environments in which they live. SOURCES: The literature reviewed was identified with the use of computer data bases (Medline - 1991-March 2001; Cumulative Index of Nursing and Allied Health Literature (CINAHL) - 1991-March 2001; and PsychLit - 1988-March 1999). In addition, data bases of Science Citation Index and Social Science Citation Indexes as they appear in the computer base, Web of Science, were searched for 1992-2001. The time period for each search was determined by the manner in which the literature was grouped for inclusion in the particular database. Hand searches of 11 selected journals included the years 1993-2001. The search dates were selected to reflect the time period when the largest number of studies on activities and AD have appeared in the professional literature. We critique a total of 33 studies. CONCLUSIONS: While researchers have demonstrated interest in the use of activities with persons with AD, theoretical and methodological difficulties, unclear findings and gaps exist, including a lack of emphasis on gender, ethnic, racial or cultural differences. Sampling issues involving diagnosis and staging complicate the research on individuals with AD. Case studies, single subject experimental designs, and tightly controlled quasi-experimental and experimental designs are needed to advance knowledge in this important area.

Martin, L. J. (2001). "Neuronal cell death in nervous system development, disease, and injury (Review)." Int J Mol Med 7(5): 455-78.
Neuronal death is normal during nervous system development but is abnormal in brain and spinal cord disease and injury. Apoptosis and necrosis are types of cell death. They are generally considered to be distinct forms of cell death. The re-emergence of apoptosis may contribute to the neuronal degeneration in chronic neurodegenerative disease, such as amyotrophic lateral sclerosis and Alzheimer's disease, and in neurological injury such as cerebral ischemia and trauma. There is also mounting evidence supporting an apoptosis-necrosis cell death continuum. In this continuum, neuronal death can result from varying contributions of coexisting apoptotic and necrotic mechanisms; thus, some of the distinctions between apoptosis and necrosis are becoming blurred. Cell culture and animal model systems are revealing the mechanisms of cell death. Necrosis can result from acute oxidative stress. Apoptosis can be induced by cell surface receptor engagement, growth factor withdrawal, and DNA damage. Several families of proteins and specific biochemical signal-transduction pathways regulate cell death. Cell death signaling can involve plasma membrane death receptors, mitochondrial death proteins, proteases, kinases, and transcription factors. Players in the cell death and cell survival orchestra include Fas receptor, Bcl-2 and Bax (and their homologues), cytochrome c, caspases, p53, and extracellular signal-regulated protein kinases. Some forms of cell death require gene activation, RNA synthesis, and protein synthesis, whereas others forms are transcriptionally-translationally-independent and are driven by posttranslational mechanisms such as protein phosphorylation and protein translocation. A better understanding of the molecular mechanisms of neuronal cell death in nervous system development, injury and disease can lead to new therapeutic approaches for the prevention of neurodegeneration and neurological disabilities and will expand the field of cell death biology.

Masliah, E., G. Ho, et al. (2001). "Functional role of TGF beta in Alzheimer's disease microvascular injury: lessons from transgenic mice." Neurochem Int 39(5-6): 393-400.
Recent studies have implicated pro- and anti-inflammatory cytokines as integral to Alzheimer's disease (AD) pathogenesis. Among them, transforming growth factor-beta (TGF-beta) is emerging as an important factor in regulating inflammatory responses. This multifunctional cytokine might be centrally involved in several aspects of AD pathogenesis by regulating beta-amyloid precursor protein synthesis and processing, plaque formation, astroglial and microglial response and neuronal cell death. Among all of these potential roles, studies in transgenic and infusion animal models have shown that TGF-beta may primarily contribute to AD pathogenesis by influencing A beta production and deposition, which in turn might result in damage to the brain microvasculature. The lessons learned from these models are of great interest not only for understanding of the role of TGF-beta in AD, but also for future treatments where testing of anti-inflammatory agents such as ibuprofen and an amyloid vaccine hold great promise. In this regard, further elucidation of the signal pathways by which TGF-beta exerts its effect in AD might lead to specific targets for further therapeutic intervention.

Massart, F., J. Y. Reginster, et al. (2001). "Genetics of menopause-associated diseases." Maturitas 40(2): 103-16.
Menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is estimated that perhaps 50 million women worldwide will go into menopause annually. Atherosclerotic cardiovascular disease, osteoporotic fractures and Alzheimer's dementia are common chronic disorders after menopause, representing major health problems in most developed countries. Apart from being influenced by environmental factors, these chronic disorders recognize a strong genetic component, and there are now considerable clinic evidences that these disorders are related to low hormonal milieu of postmenopausal women. Here, we review up-to-date available data suggesting that genetic variation may contribute to higher susceptibility to four sporadic chronic syndromes such as osteoporosis (OP), osteoarthritis (OA), Alzheimer's disease (AD) and coronary artery disease (CAD). For these four syndromes candidate genes that today appear as major loci in genetic susceptibility encode for proteins specific of a given system, as the vitamin D receptor (VDR) gene for the skeleton and, therefore, OP or angiotensin converting enzyme (ACE) for the cardiovascular system and, therefore, CAD. The investigation of gene polymorphisms in various pathological conditions typical of postmenopause offer an explanation not only of their genetic inheritance but also of their co-segregation in given individuals. In this view, it may be possible to identify a common set of genes whose variants contribute to a common genetic background for these different disorders. Ideal candidates appear genes of the estrogen response cascade [i.e. estrogen receptor (ERs), enzymes involved in estrogen metabolism or co-activators and co-inhibitors]. All together this information may represent the basis both for future recognition of individuals at risk and for the pharmacogenetic driving of drug responsiveness.

Masters, C. L. and K. Beyreuther (2001). "The Worster-Drought syndrome and other syndromes of dementia with spastic paraparesis: the paradox of molecular pathology." J Neuropathol Exp Neurol 60(4): 317-9.

Matsuda, H. (2001). "Cerebral blood flow and metabolic abnormalities in Alzheimer's disease." Ann Nucl Med 15(2): 85-92.
In this review I summarize observations of PET and SPECT studies about cerebral blood flow and metabolic abnormalities in Alzheimer's disease. In very early AD flow or metabolism reduces first in the posterior cingulate gyrus and precuneus. This reduction may arise from functional deafferentation caused by primary neural degeneration in the remote area of the entorhinal cortex that is the first to be pathologically affected in AD. Then medial temporal structures and parietotemporal association cortex show flow or metabolic reduction as disease processes. The reason why flow or metabolism in medial temporal structures shows delay in starting to reduce in spite of the earliest pathological affection remains to be elucidated. It is likely that anterior cingulate gyrus is functionally involved, since attention is the first non-memory domain to be affected, before deficits in language and visuospatial functions. However few reports have described involvement in the anterior cingulate gyrus. Relationship between cerebral blood flow or metabolism and apolipoprotein E genotype has been investigated. Especially, the APOE epsilon4 allele has been reported to increase risk and to lower onset age as a function of the inherited dose of the epsilon4 allele. Reduction of flow or metabolism in the posterior cingulate gyrus and precuneus has been reported even in presymptomatic nondemented subjects who were cognitively normal and had at least a single epsilon4 allele. On the contrary the relation of epsilon4 allele to the progression rate of AD has been controversial from neuroimaging approaches. PET and SPECT imaging has become to be quite useful for assessing therapeutical effects of newly introduced treatment for AD. Recent investigations observed significant regional flow increase after donepezil hydrochloride treatment. Most of these observations have been made by applying computer assisted analysis of three-dimensional stereotactic surface projection or statistical parametric mapping instead of a conventional regions of interest technique.

Mattox, J. H. and L. P. Shulman (2001). "Combined oral hormone replacement therapy formulations." Am J Obstet Gynecol 185(2 Suppl): S38-46.
Today, clinicians are challenged to address a woman's contraceptive needs during her reproductive and perimenopausal years and then provide her with a menopausal therapeutic option. This option should offer optimal symptom relief, noncontraceptive health benefits, and a good tolerability profile. The benefits of hormone replacement therapy include control of vasomotor symptoms, reduction of vulvovaginal atrophy, and protection against osteoporosis. Research also points to emerging hormone replacement therapy benefits such as protection against cardiovascular disease, colon cancer, and Alzheimer's disease. One of the primary considerations in the transition from oral contraceptive use to hormone replacement therapy is the tolerability profile of the progestin component of the hormone replacement therapy. Because progestin-related side effects are among the main reasons for discontinuation of hormone replacement therapy, the selection of a formulation that contains the same well-tolerated progestin as in the woman's oral contraceptive can be particularly important to successful use of hormone replacement therapy. Currently in the United States continuous combined hormone replacement therapy is available in 3 formulations and 1 continuous estrogen/intermittent progestin formulation. Although direct comparative trials are lacking, available data suggest that the new, continuous 17beta-estradiol/intermittent norgestimate hormone replacement therapy formulation may offer advantages over regimens that contain older progestins with metabolic disadvantages.

Mattson, M. P., S. L. Chan, et al. (2001). "Presenilin mutations and calcium signaling defects in the nervous and immune systems." Bioessays 23(8): 733-44.
Presenilin-1 (PS1) is thought to regulate cell differentiation and survival by modulating the Notch signaling pathway. Mutations in PS1 have been shown to cause early-onset inherited forms of Alzheimer's disease (AD) by a gain-of-function mechanism that alters proteolytic processing of the amyloid precursor protein (APP) resulting in increased production of neurotoxic forms of amyloid beta-peptide. The present article considers a second pathogenic mode of action of PS1 mutations, a defect in cellular calcium signaling characterized by overfilling of endoplasmic reticulum (ER) calcium stores and altered capacitive calcium entry; this abnormality may impair synaptic plasticity and sensitize neurons to apoptosis and excitotoxicity. The calcium signaling defect has also been documented in lymphocytes, suggesting a contribution of immune dysfunction to the pathogenesis of AD. A better understanding of the calcium signaling defect resulting from PS1 mutations may lead to the development of novel preventative and therapeutic strategies for disorders of the nervous and immune systems.

Mattson, M. P., D. S. Gary, et al. (2001). "Perturbed endoplasmic reticulum function, synaptic apoptosis and the pathogenesis of Alzheimer's disease." Biochem Soc Symp(67): 151-62.
Endoplasmic reticulum (ER) appears to be a focal point for alterations that result in neuronal dysfunction and death in Alzheimer's disease (AD). Aberrant proteolytic processing and/or trafficking of the beta-amyloid precursor protein (APP) in ER may promote neuronal degeneration by increasing the levels of the neurotoxic forms of beta-amyloid (A beta) and by decreasing the levels of the neuroprotective secreted form of APP (sAPP alpha). Some cases of AD are caused by mutations in the genes encoding presenilin 1 (PS1). When expressed in cultured neuronal cells and transgenic mice, PS1 mutations cause abnormalities in ER calcium homoeostasis, enhancing the calcium responses to stimuli that activate IP3- and ryanodine-sensitive ER calcium pools. Two major consequences of this disrupted ER calcium regulation are altered proteolytic processing of APP and increased vulnerability of neurons to apoptosis and excitotoxicity. The impact of PS1 mutations and aberrant APP processing is particularly great in synaptic terminals. Perturbed synaptic calcium homoeostasis promotes activation of apoptotic cascades involving production of Par-4 (prostate apoptosis response-4), mitochondrial dysfunction and caspase activation. A beta 42 (the 42-amino-acid form of A beta) induces membrane lipid peroxidation in synapses and dendrites resulting in impairment of membrane ion-motive ATPases and glucose and glutamate transporters. This disrupts synaptic ion and energy homoeostasis thereby promoting synaptic degeneration. In contrast, sAPP alpha activates signalling pathways that protect synapses against excitotoxicity and apoptosis. In the more common sporadic forms of AD, the initiating causes of the neurodegenerative cascade are less well defined, but probably involve increased levels of oxidative stress and impaired energy metabolism. Such alterations have been shown to disrupt neuronal calcium homoeostasis in experimental models, and may therefore feed into the same neurodegenerative cascade initiated by mutations in presenilins and APP. Perturbed synaptic ER calcium homoeostasis and consequent alterations in APP processing appear to be pivotal events in both sporadic and familial forms of AD.

Mattson, M. P., W. Duan, et al. (2001). "Neurodegenerative disorders and ischemic brain diseases." Apoptosis 6(1-2): 69-81.
Degeneration and death of neurons is the fundamental process responsible for the clinical manifestations of many different neurological disorders of aging, incuding Alzheimer's disease, Parkinson's disease and stroke. The death of neurons in such disorders involves apoptotic biochemical cascades involving upstream effectors (Par-4, p53 and pro-apoptotic Bcl-2 family members), mitochondrial alterations and caspase activation. Both genetic and environmental factors, and the aging process itself, contribute to intiation of such neuronal apoptosis. For example, mutations in the amyloid precursor protein and presenilin genes can cause Alzheimer's disease, while head injury is a risk factor for both Alzheimer's and Parkinson's diseases. At the cellular level, neuronal apoptosis in neurodegenerative disorders may be triggered by oxidative stress, metabolic compromise and disruption of calcium homeostasis. Neuroprotective (antiapoptotic) signaling pathways involving neurotrophic factors, cytokines and "conditioning responses" can counteract the effects of aging and genetic predisposition in experimental models of neurodegenerative disorders. A better understanding of the molecular underpinnings of neuronal death is leading directly to novel preventative and therapeutic approaches to neurodegenerative disorders.

Mattson, M. P. and S. Camandola (2001). "NF-kappaB in neuronal plasticity and neurodegenerative disorders." J Clin Invest 107(3): 247-54.

McDaid, D. (2001). "Estimating the costs of informal care for people with Alzheimer's disease: methodological and practical challenges." Int J Geriatr Psychiatry 16(4): 400-5.
Although Alzheimer's disease and related disorders may have a heavy impact on informal caregivers, estimates of informal care costs have been neglected and when included in cost of illness studies, valuations have been highly variable. Although these variations are in part due to differences in samples and the difficulty in measuring caregiving time, this illustrates the need to standardise the methodology not only for valuing formal, but also informal care costs. Methods used for valuing informal care are identified, together with theoretical and practical challenges in measurement. In particular the measurement of time and it's associated satisfaction or utility is complex and valuations of time need to consider aspects of the caregiving experience which influence the marginal valuation of the time spent caring. More empirical work is required to elicit information on both the positive and negative satisfaction associated with caregiving and to incorporate this into valuations of the costs related to informal care.

McDowell, I. (2001). "Alzheimer's disease: insights from epidemiology." Aging (Milano) 13(3): 143-62.
While a complete understanding of the pathogenesis of Alzheimer's disease (AD) remains elusive, many conclusions can be drawn from the numerous epidemiological studies undertaken to date. Prevalence and incidence estimates show consistency, following a roughly exponential pattern with a doubling of both parameters roughly every five years after age 65. Roughly 7% of the population aged 65 and over has AD. The clinical course of the disease is reasonably well established and mortality rates rise with increasing levels of cognitive deficit. Four risk factors for AD are firmly established: increasing age, the presence of the apolipoproteinE-epsilon4 allele, familial aggregation of cases, and Down's syndrome. Numerous other associations have been shown in some studies, but not in others. For example, women generally appear at higher risk than men, as do people with lower levels of education; depression is probably prodromal; head injury is an established risk factor, and may interact with the apoE gene; several occupational exposures appear hazardous, and exposure to aluminum in the water supply confers excess risk. Hypertension and other vascular symptoms appear to predispose to AD, which is now seen as nosologically closer to vascular dementia than was previously believed. Several apparently protective factors have been identified, although preventive trials based on these have so far shown minimal effectiveness. The use of non-steroidal anti-inflammatory drugs to treat arthritis is associated with a reduced risk of AD, as is estrogen use by post-menopausal women. Physical activity appears beneficial, as does a diet with high levels of vitamins B6, B12 and folate. while red wine in moderate quantities appears protective. This review concludes with a discussion of the strengths and limitations of current epidemiological methods for studying Alzheimer's disease.

McEwen, B. S. (2001). "Invited review: Estrogens effects on the brain: multiple sites and molecular mechanisms." J Appl Physiol 91(6): 2785-801.
Besides their well-established actions on reproductive functions, estrogens exert a variety of actions on many regions of the nervous system that influence higher cognitive function, pain mechanisms, fine motor skills, mood, and susceptibility to seizures; they also appear to have neuroprotective actions in relation to stroke damage and Alzheimer's disease. Estrogen actions are now recognized to occur via two different intracellular estrogen receptors, ER-alpha and ER-beta, that reside in the cell nuclei of some nerve cells, as well as by some less well-characterized mechanisms. In the hippocampus, such nerve cells are sparse in number and yet appear to exert a powerful influence on synapse formation by neurons that do not have high levels of nuclear estrogen receptors. However, we also find nonnuclear estrogen receptors outside of the cell nuclei in dendrites, presynaptic terminals, and glial cells, where estrogen receptors may couple to second messenger systems to regulate a variety of cellular events and signal to the nuclear via transcriptional regulators such as CREB. Sex differences exist in many of the actions of estrogens in the brain, and the process of sexual differentiation appears to affect many brain regions outside of the traditional brain areas involved in reproductive functions. Finally, the aging brain is responsive to actions of estrogens, which have neuroprotective effects both in vivo and in vitro. However, in an animal model, the actions of estrogens on the hippocampus appear to be somewhat attenuated with age. In the future, estrogen actions over puberty and in pregnancy and lactation should be further explored and should be studied in both the hypothalamus and the extrahypothalamic regions.

McGeer, P. L. and E. G. McGeer (2001). "Inflammation, autotoxicity and Alzheimer disease." Neurobiol Aging 22(6): 799-809.
Neuroinflammation is a central feature of Alzheimer disease (AD). It involves an innate immune reaction of sufficient intensity that self attack on neurons occurs. This phenomenon is best described as autotoxicity to distinguish it from classical autoimmunity which involves cloning of peripheral lymphocytes. Many compounds have been identified in AD brain which are known to promote and sustain inflammatory responses. They include beta-amyloid protein; the pentraxins C-reactive protein and amyloid P; complement proteins; the inflammatory cytokines interleukin-1, interleukin-6 and tumor necrosis factor-alpha; the protease inhibitors alpha-2-macroglobulin and alpha-1-antichymotrypsin; and the prostaglandin generating cyclooxygenases COX-1 and COX-2. Orally effective agents which can counteract the influence of these inflammatory stimulators should be effective in treating AD. Epidemiological evidence, coupled with results from pilot clinical trials, suggest there is great promise for traditional COX-1 inhibiting NSAIDs. Inhibitors of mediators closer to the core processes might offer even greater therapeutic promise. Some theoretical opportunities are suggested, based on intervention in the action of the above mentioned mediators.

McGeer, P. L. and E. G. McGeer (2001). "Polymorphisms in inflammatory genes and the risk of Alzheimer disease." Arch Neurol 58(11): 1790-2.
The concept of inflammation as a major factor in Alzheimer disease (AD) has heretofore been based on postmortem findings of autodestructive changes associated with the lesions coupled with epidemiological evidence of a protective effect of anti-inflammatory agents. Now there is evidence that the risk of AD is substantially influenced by a total of 10 polymorphisms in the inflammatory agents interleukin 1alpha, interleukin 1beta, interleukin 6, tumor necrosis factor alpha, alpha(2)-macroglobulin, and alpha(1)-antichymotrypsin. The polymorphisms are all common ones in the general population, so there is a strong likelihood that any given individual will inherit 1 or more of the high-risk alleles. The overall chances of an individual developing AD might be profoundly affected by a "susceptibility profile" reflecting the combined influence of inheriting multiple high-risk alleles. Since some of the polymorphisms in question have already been linked to peripheral inflammatory disorders, such as juvenile rheumatoid arthritis, myasthenia gravis, and periodontitis, associations between AD and several chronic degenerative diseases may eventually be demonstrated. Such information could lead to strategies for therapeutic intervention in the early stages of such disorders.

McGuire, S. E. and R. L. Davis (2001). "Presenilin-1 and memories of the forebrain." Neuron 32(5): 763-5.
In this issue of Neuron, report that forebrain-specific Presenilin-1 conditional knockout mice show defects in enrichment-induced neurogenesis in the dentate gyrus. This defect in neurogenesis is associated with enhanced fear memory of contextual cues when animals are subjected to enrichment between training and testing. The authors suggest that neurogenesis in the adult dentate gyrus may serve to clear out old memory traces from the hippocampus, thus leaving the hippocampus available for new memory processing.

McKenna, D. J., K. Jones, et al. (2001). "Efficacy, safety, and use of ginkgo biloba in clinical and preclinical applications." Altern Ther Health Med 7(5): 70-86, 88-90.
Ginkgo biloba is a dioecious tree with a history of use in traditional Chinese medicine. Although the seeds are most commonly employed in traditional Chinese medicine, in recent years standardized extracts of the leaves have been widely sold as a phytomedicine in Europe and as a dietary supplement in the United States. The primary active constituents of the leaves include flavonoid glycosides and unique diterpenes known as ginkgolides; the latter are potent inhibitors of platelet activating factor. Clinical studies have shown that ginkgo extracts exhibit therapeutic activity in a variety of disorders including Alzheimer's disease, failing memory, age-related dementias, poor cerebral and ocular blood flow, congestive symptoms of premenstrual syndrome, and the prevention of altitude sickness. Due in part to its potent antioxidant properties and ability to enhance peripheral and cerebral circulation, ginkgo's primary application lies in the treatment of cerebrovascular dysfunctions and peripheral vascular disorders.

Meda, L., P. Baron, et al. (2001). "Glial activation in Alzheimer's disease: the role of Abeta and its associated proteins." Neurobiol Aging 22(6): 885-93.
A common feature of Alzheimer's disease (AD) pathology is the abundance of reactive astrocytes and activated microglia in close proximity to neuritic plaques containing amyloid-beta protein (Abeta). The relationship between glial activation and neurodegeneration remains unclear, although several cytokines and inflammatory mediators produced by activated glia have the potential to initiate or exacerbate the progression of neuropathology. Assuming that glial activation plays a central role in the development and progression of AD, a prominent feature is to understand which stimuli drive this activation in senile plaques and to define their effects in vitro. There is a growing body of evidence to suggest that deposition of Abeta and expression of its associated molecules represent important trigger factors in glial activation leading to an inflammatory reaction in the brain. Thus, unraveling the mechanisms by which these proteins exert their effect on glial cells may provide significant insight into the pathophysiology of AD, and may lead to the identification of new strategies for AD treatment.

Mega, M. S. (2001). "Differential diagnosis of dementia: clinical examination and laboratory assessment." Clin Cornerstone 3(4): 1-14.
Recent breakthroughs in putative disease-modifying interventions for Alzheimer's disease (AD) underscore the urgency of making the earliest possible diagnosis. In the absence of a convenient and reliable laboratory test for AD, the clinical assessment is still the cornerstone of the diagnostic approach. This article provides a basis for conducting an assessment within the realities of a busy clinical practice for patients complaining of cognitive decline. The assessment will enable the clinician to diagnose the earliest manifestation of AD.

Mercer, J. F. (2001). "The molecular basis of copper-transport diseases." Trends Mol Med 7(2): 64-9.
Copper (Cu) is a potentially toxic yet essential element. MENKES DISEASE, a copper deficiency disorder, and WILSON DISEASE, a copper toxicosis condition, are two human genetic disorders, caused by mutations of two closely related Cu-transporting ATPases. Both molecules efflux copper from cells. Quite diverse clinical phenotypes are produced by different mutations of these two Cu-transporting proteins. The understanding of copper homeostasis has become increasingly important in clinical medicine as the metal could be involved in the pathogenesis of some important neurological disorders such as Alzheimer's disease, motor neurone diseases and prion diseases.

Mesulam, M. M. (2001). "Primary progressive aphasia." Ann Neurol 49(4): 425-32.
Primary progressive aphasia (PPA) is a focal dementia characterized by an isolated and gradual dissolution of language function. The disease starts with word-finding disturbances (anomia) and frequently proceeds to impair the grammatical structure (syntax) and comprehension (semantics) of language. The speech output in PPA can be fluent or nonfluent. Memory, visual processing, and personality remain relatively well-preserved until the advanced stages and help to distiguish PPA from frontal lobe dementia and the typical forms of Alzheimer's disease. The term "semantic dementia" was originally introduced to designate a different group of patients with a combination of verbal and visual processing deficits. In practice, however, this diagnosis is also being used in a variant sense to denote a subtype of PPA with fluent speech and impaired comprehension, even in the absence of visual processing deficits. Insofar as the diagnosis of semantic dementia can have these two different meanings, it is important to specify whether it is being used in the original sense or to denote a subtype of PPA. Structural and physiological neuroimaging confirms the selective predilection of PPA for the left hemisphere, especially for its language-related cortices. A few patients with PPA display the neuropathological markers of Alzheimer's disease, but in an unusual distribution. The majority of the autopsies in PPA have shown either Pick's disease or lobar atrophy without distinctive histopathology. The suggestion has been made that PPA and frontal lobe dementia constitute phenotypical variations of a unitary disease process within the "Pick-lobar atrophy" spectrum. Recent advances in chromosome 17-linked dementias justify a rigorous search for tau polymorphisms and tauopathy in sporadic PPA. An informed approach to this syndrome will increase the effectiveness with which clinicians can address the unique challenges associated with the diagnosis and care of PPA.

Meyer, V. F. (2001). "The medicalization of menopause: critique and consequences." Int J Health Serv 31(4): 769-92.
Menopause is in the process of becoming medicalized. Midlife and older women are being told that natural menopause is actually a deficiency condition requiring replacement hormones to maintain health and increase longevity. The three major diseases that are being linked with the lower estrogen levels of midlife and older women are heart disease, osteoporosis and, most recently, Alzheimer's disease. Primary prevention of these diseases is the rationale used for urging healthy women to take long-term hormones. Although there have been many challenges to these links and warnings against the widespread use of hormones, they have been either ignored or trivialized. In this article, the author examines mortality and morbidity statistics across and within nations and over time, critiques the major arguments used to support the notion that menopause places women at an increased risk of disease and that exogenous hormones reduce this risk, and discusses the adverse consequences of defining all midlife and older women as hormonally deficient and in need of medical intervention.

Michel, J. P., D. Zekry, et al. (2001). "Economic considerations of Alzheimer's disease and related disorders." Aging (Milano) 13(3): 255-60.
Economic analyses of geriatric syndromes are seldom performed. However, demographic and epidemiological imperatives have led to significant interest in the evaluation of AD-related costs. Over 300 papers devoted to economic considerations of Alzheimer's disease have been published in peer-reviewed journals, within the last five years. In these papers, the chosen perspective (costs to society or to specific payers) is important. Analytical methods are still evolving and remain complex. Unresolved methodological issues will need to be addressed to further our understanding of long-term economic consequences. At present, it is clear that diagnostic and drug costs are low compared to the major cost of institutionalization. Thus, directing efforts at early diagnosis and delaying nursing home placement are two key cost-containment interventions. In this respect, the need to support informal care should not be underestimated.

Miller, M. M., A. A. Monjan, et al. (2001). "Estrogen replacement therapy for the potential treatment or prevention of Alzheimer's disease." Ann N Y Acad Sci 949: 223-34.
Alzheimer's disease (AD) is an irreversible, progressive brain disorder that occurs gradually and results in memory loss, behavior and personality changes, and a decline in cognitive abilities. Although basic biological data suggest that estrogen may have neuroprotective and neuroenhancing functions, a number of studies have produced conflicting findings on the use of estrogen for maintaining cognitive function in older people. This review summarizes clinical studies that have examined the effects of estrogen in women with AD.

Miller, B. L. (2001). "Tau mutations--center tent or sideshow?" Arch Neurol 58(3): 351-2.

Minami, M. (2001). "[Cytokines and chemokines: mediators for intercellular communication in the brain]." Yakugaku Zasshi 121(12): 875-85.
The brain includes glial cells (astrocytes, microglia and oligodendrocytes) and endothelial cells in addition to neurons. Under some pathological conditions, it is invaded by leukocytes such as neutrophils, monocytes/macrophages and lymphocytes. Intercellular communication across these cell species is supposed to play crucial roles both in the brain functions and dysfunctions. However, the molecular basis of such intercellular communication remains unclear. We have studied the roles of cytokines and chemokines, which have been investigated as essential mediators in the immune and inflammatory systems, in intercellular communication across neurons, glial cells, endothelial cells and leukocytes. Messenger RNA expression of cytokines such as interleukin-1 beta was induced in brain microglia by i.p. injection of excitotoxin and neurostimulant, at least, partly via catecholaminergic systems. Messenger RNA of other cytokines such as leukemia inhibitory factor was induced in astrocytes. This cytokine specifically induced nociceptin mRNA in the cultured cortical neurons. Constitutive expression of some chemokines such as fractalkine and stromal cell derived factor-1 alpha was observed in the brain, suggesting that they play important roles in maintenance of brain homeostasis or determination of the patterning of neurons and/or glial cells in the developing and adult brains. Cytokines such as interleukin-1 beta and chemokines such as monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 alpha were produced in ischemic brain and implicated in ischemic brain injury. In addition to ischemia, cytokines, chemokines and their receptors have been shown to be involved in various neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and AIDS dementia syndrome. They are potential targets for therapeutic intervention for neurodegenerative diseases.

Mintzer, J. E. (2001). "Underlying mechanisms of psychosis and aggression in patients with Alzheimer's disease." J Clin Psychiatry 62 Suppl 21: 23-5.
It is well known that serotonergic function is related to aggression. Patients with Alzheimer's disease exhibit aggressive behavior, and alterations in their serotonergic function have been identified. Recent clinical trials involving new antipsychotic agents, such as risperidone, which has both serotonergic and dopaminergic activity, have demonstrated the efficacy and safety of these drugs in treating the psychosis and aggressive behavior associated with dementia.

Molloy, A. M. and J. M. Scott (2001). "Folates and prevention of disease." Public Health Nutr 4(2B): 601-9.
Research in the past decade has established that low or inadequate folate status may contribute to congenital malformations and the development of chronic disease in later life. Using an evidence based approach, there are clear guidelines for recommending folic acid supplementation or fortification in certain disease conditions but further proof of its efficacy is required in other circumstances. There is conclusive evidence that maternal periconceptional supplementation with folic acid prevents the majority of NTDs, probably by overcoming one or more genetically inherited metabolic blocks in folate dependent enzymes. Public health efforts to advise women to increase their folate intake have not been successful. As a result, the U.S. government passed legislation to have all flour fortified with folic acid. This intervention has had a dramatic effect on folate status in the U.S. To date, countries of the EU have not adopted mandatory fortification policies. The amino acid homocysteine is an essential intermediate in folate metabolism. Substantial evidence indicates that elevated plasma homocysteine is an independent risk factor for heart disease and stroke. Plasma homocysteine levels can be reduced by folic acid supplements. A food fortification policy would probably be an effective population strategy to reduce plasma homocysteine. However, many experts believe that this would be premature without first showing that such reduction would cause a decrease in the prevalence of cardiovascular disease. The contribution of folate to cancer risk is not well defined although there is reasonable evidence to implicate low folate status in the specific case of colorectal cancer. In particular, long-term folic acid supplementation may reduce risk of colorectal cancer substantially. Various mental disorders including Alzheimer's Disease have been associated with low folate status or elevated plasma homocysteine. While it is hard to determine if this is cause or effect, there is little doubt that if it were true then low dose folic acid intervention would be highly effective.

Morgan, C. and N. C. Inestrosa (2001). "Interactions of laminin with the amyloid beta peptide. Implications for Alzheimer's disease." Braz J Med Biol Res 34(5): 597-601.
Extensive neuronal cell loss is observed in Alzheimer's disease. Laminin immunoreactivity colocalizes with senile plaques, the characteristic extracellular histopathological lesions of Alzheimer brain, which consist of the amyloid beta (A(beta)) peptide polymerized into amyloid fibrils. These lesions have neurotoxic effects and have been proposed to be a main cause of neurodegeneration. In order to understand the pathological significance of the interaction between laminin and amyloid, we investigated the effect of laminin on amyloid structure and toxicity. We found that laminin interacts with the A(beta)1-40 peptide, blocking fibril formation and even inducing depolymerization of preformed fibrils. Protofilaments known to be intermediate species of A(beta) fibril formation were also detected as intermediate species of laminin-induced A(beta) fibril depolymerization. Moreover, laminin-amyloid interactions inhibited the toxic effects on rat primary hippocampal neurons. As a whole, our results indicate a putative anti-amyloidogenic role of laminin which may be of biological and therapeutic interest for controlling amyloidosis, such as those observed in cerebral angiopathy and Alzheimer's disease.

Mori, S. (2001). "[Apolipoprotein E4 and Alzheimer's disease]." Nippon Rinsho 59 Suppl 3: 812-7.

Morishima-Kawashima, M., T. C. Saido, et al. (2001). "[Alzheimer's disease and the proteins]." Tanpakushitsu Kakusan Koso 46(11 Suppl): 1798-804.

Morris, R. G. (2001). "Episodic-like memory in animals: psychological criteria, neural mechanisms and the value of episodic-like tasks to investigate animal models of neurodegenerative disease." Philos Trans R Soc Lond B Biol Sci 356(1413): 1453-65.
The question of whether any non-human species displays episodic memory is controversial. Associative accounts of animal learning recognize that behaviour can change in response to single events but this does not imply that animals need or are later able to recall representations of unique events at a different time and place. The lack of language is also relevant, being the usual medium for communicating about the world, but whether it is critical for the capacity to represent and recall events is a separate matter. One reason for suspecting that certain animals possess an episodic-like memory system is that a variety of learning and memory tasks have been developed that, even though they do not meet the strict criteria required for episodic memory, have an 'episodic-like' character. These include certain one-trial learning tasks, scene-specific discrimination learning, multiple reversal learning, delayed matching and non-matching tasks and, most recently, tasks demanding recollection of 'what, where and when' an event happened. Another reason is that the neuronal architecture of brain areas thought to be involved in episodic memory (including the hippocampal formation) are substantially similar in mammals and, arguably, all vertebrates. Third, our developing understanding of activity-dependent synaptic plasticity (which is a candidate neuronal mechanism for encoding memory traces) suggests that its expression reflects certain physiological characteristics that are ideal components of a neuronal episodic memory system. These include the apparently digital character of synaptic change at individual terminals and the variable persistence of potentiation accounted for by the synaptic tag hypothesis. A further value of studying episodic-like memory in animals is the opportunity it affords to model certain kinds of neurodegenerative disease that, in humans, affect episodic memory. An example is recent work on a transgenic mouse that over-expresses a mutation of human amyloid precursor protein (APP) that occurs in familial Alzheimer's disease, under the control of platelet derived (PD) growth factor promoter (the PDAPP mouse). A striking age- and amyloid plaque-related deficit is seen using a task in which the mice have to keep changing their memory representation of the world rather than learn a single fact.

Mrak, R. E. and W. S. Griffinbc (2001). "The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer's disease." Neurobiol Aging 22(6): 915-22.
Activated astrocytes, overexpressing the neurotrophic signaling molecule S100beta, are invariant components of the Abeta plaques of Alzheimer's disease. Even early, nonfibrillar amyloid deposits in Alzheimer's disease contain such astrocytes, and the numbers and degree of activation of these wax and wane with the subsequent neuritic pathology of plaque evolution. Astrocytic overexpression of S100B in the neuritic plaques of Alzheimer's disease correlates with the degree of neuritic pathology in Abeta plaques in this disease, suggesting a pathogenic role for S100B's neurotrophic properties in the evolution of these lesions. Astrocytic overexpression of S100B, in turn, is promoted by high levels of interleukin-1 (IL-1), originating from activated microglia that are also constant components of Abeta plaques in Alzheimer's disease. Similar patterns of astrocyte activation, S100B overexpression, microglial activation, and IL-1 overexpression are seen in conditions that confer risk for Alzheimer's disease (aging, head trauma, Down's syndrome), in conditions that predispose to accelerated appearance of Alzheimer-like neuropathologic changes (chronic epilepsy, HIV infection), and in animal models of Alzheimer's disease. These cells and molecules are an important components of a cytokine cycle of molecular and cellular cascades that may drive disease progression in Alzheimer's disease.

Mrak, R. E. and W. S. Griffin (2001). "Interleukin-1, neuroinflammation, and Alzheimer's disease." Neurobiol Aging 22(6): 903-8.
Interleukin-1 (IL-1)-1) is a pluripotent immunomodulatory cytokine that has an initiating role in cellular and humoral immunity in the periphery. Il-1 is overexpressed in Alzheimer brain, and this overexpression is directly related to plaque formation and progression, nonsensical growth of dystrophic neurites, and neuronal overexpression of acetylcholinesterase. IL-1 has a number of actions relevant to Alzheimer's disease, including excessive expression of neuronal Abeta precursor protein and other plaque-associated proteins, and induction of astrocyte activation and astrocytic overexpression of S100B. These latter events may be related to the overgrowth of dystrophic neurites in neuritic plaques, a necessary event for conversion of diffuse Abeta deposits into the neuritic amyloid plaques diagnostic of Alzheimer's disease. Four new genetic studies underscore the relevance of IL-1 to Alzheimer pathogenesis, showing that homozygosity of a specific polymorphism in the IL-1A gene at least triples Alzheimer risk, especially for an earlier age of onset and in combination with homozygosity for another polymorphism in the IL-1B gene.

Muller, W. E., C. Kirsch, et al. (2001). "Membrane-disordering effects of beta-amyloid peptides." Biochem Soc Trans 29(Pt 4): 617-23.
beta-Amyloid (Abeta) protein is the major constituent of senile plaques and cerebrovascular deposits characteristic of Alzheimer's disease (AD). The causal relationship between Abeta and AD-specific lesions like neurodegeneration and atrophy is still not known. The present article summarizes our studies indicating that rather low concentrations of Abeta significantly alter the fluidity of cell membranes and subcellular fractions from different tissues and different species including humans, as a possible initial step of its biological effects. Using different fluorescent probes our data show clearly that Abeta peptides specifically disturb the acyl-chain layer of cell membranes in a very distinct fashion. By contrast, membrane properties at the level of the polar heads of the phospholipid bilayer at the interface with membrane proteins are much less affected.

Muller, E. E. (2001). "[Steroids, cognitive processes and aging]." Recenti Prog Med 92(5): 362-72.
Adrenal steroids, besides acting on the pituitary and the hypothalamus to exert classical feedback activity, can also have endocrine and extra-endocrine actions at the level of sub-cortical areas, as the hippocampus and the amygdala, involved in cognition and effectiveness. Acting on the hippocampus, an area particularly equipped with specific receptor sites, adrenal steroids exert either a feedback inhibition on their own secretion or a morphological and functional age-related deterioration of this target area. Loss of hippocampal neurons and corticosteroid receptors with ageing endangers the feedback inhibitory action of the steroids, and induces an over-exposition of the hippocampus to their detrimental action, enhancing the vulnerability of the neuronal cells to metabolic stimuli (hypoxia, hypoglycemia). Hence, either in the physiological ageing of the brain as well as in age-related neurological diseases or psychiatric diseases, harboring a primary neuro-anatomical-functional alteration of the hippocampus, or when the hippocampus is over-exposed to adrenal steroids, a cohort of cognitive and behavioral alterations may be partly due to adrenal gland hyperfunction. Gonadal steroids exert effects on the CNS which go far beyond regulation of gonadotropin secretion and sexual function, though their action is opposite to that of adrenal steroids. Estrogens stimulate hippocampal synaptogenesis, enhance cholinergic neurotransmission, possess anti-oxidative and anti-amiloidogenic properties, dilate cerebral vessels and have platelet anti-aggregating activity. One is led to postulate that the dramatic decrease of estrogen secretion at menopause should increase the vulnerability of the CNS by the many factors contributing to neurodegeneration associated to brain ageing or Alzheimer disease.

Murer, M. G., Q. Yan, et al. (2001). "Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease." Prog Neurobiol 63(1): 71-124.
Brain-derived neurotrophic factor (BDNF) is a small dimeric protein, structurally related to nerve growth factor, which is abundantly and widely expressed in the adult mammalian brain. BDNF has been found to promote survival of all major neuronal types affected in Alzheimer's disease and Parkinson's disease, like hippocampal and neocortical neurons, cholinergic septal and basal forebrain neurons, and nigral dopaminergic neurons. In this article, we summarize recent work on the molecular and cellular biology of BDNF, including current ideas about its intracellular trafficking, regulated synthesis and release, and actions at the synaptic level, which have considerably expanded our conception of BDNF actions in the central nervous system. But our primary aim is to review the literature regarding BDNF distribution in the human brain, and the modifications of BDNF expression which occur in the brain of individuals with Alzheimer's disease and Parkinson's disease. Our knowledge concerning BDNF actions on the neuronal populations affected in these pathological states is also reviewed, with an aim at understanding its pathogenic and pathophysiological relevance.

Murre, J. M., K. S. Graham, et al. (2001). "Semantic dementia: relevance to connectionist models of long-term memory." Brain 124(Pt 4): 647-75.
Semantic dementia is a recently documented syndrome associated with non-Alzheimer degenerative pathology of the polar and inferolateral temporal neocortex, with relative sparing (at least in the early stages) of the hippocampal complex. Patients typically show a progressive deterioration in their semantic knowledge about people, objects, facts and the meanings of words. Yet, at least clinically, they seem to possess relatively preserved day-to-day (episodic) memory. Neuropsychological investigations of semantic dementia provide, therefore, a unique opportunity to investigate the organization of human long-term memory and, more specifically, to determine the relationship between semantic memory and other cognitive systems, such as episodic memory. In this review, we summarize recent empirical findings from patients with semantic dementia and discuss whether the neuropsychological phenomena of the disease are consistent with current cognitive and computational models of human long-term memory and amnesia. Six specific issues are addressed: (i) the relative preservation of category-level (superordinate) compared with fine-graded (subordinate) semantic knowledge as the disease progresses; (ii) the better recall of recent autobiographical and semantic memories compared with those in the distant past; (iii) the preservation of new learning, as measured by recognition memory, early in the disease; (iv) the interaction between autobiographical experience and semantic knowledge in the current, but not the distant, time-period; (v) increased long-term forgetting of newly learned material; and (vi) impaired implicit memory. It is concluded that recent findings from semantic dementia offer strong support for the view that memory consolidation in humans is dependent upon interactions between the hippocampal complex and neocortex. Furthermore, these investigations have provided computational modellers of human memory with a novel set of neuropsychological data to be simulated and tested.

Myers, A. J. and A. M. Goate (2001). "The genetics of late-onset Alzheimer's disease." Curr Opin Neurol 14(4): 433-40.
Of late-onset Alzheimer's disease patients 50% do not carry an apolipoprotein E epsilon 4 allele, indicating that there must be other genetic or environmental risk factors for the disease. During the past few years, both genetic linkage and candidate gene studies have been undertaken in order to identify novel genetic risk factors for late-onset Alzheimer's disease. Previous genome screens implicated a region of chromosome 12 that contains the genes that encode both alpha(2)-macroglobulin and the low-density lipoprotein receptor-related protein. However, candidate gene studies have produced mixed results with respect to both of these genes. New linkage studies now provide strong evidence for Alzheimer's disease susceptibility loci on chromosomes 9 and 10. The locus on chromosome 10 very probably modifies risk for Alzheimer's disease by modulating beta-amyloid-42 levels.

Nakamura, S., T. Takahashi, et al. (2001). "Nicotinic acetylcholine receptors and neurodegenerative disease." Alcohol 24(2): 79-81.
Nicotinic acetylcholine receptor (nAChR) in the central nervous system represents a new potential therapeutic target in neurodegenerative diseases, and this is driven by new findings in the molecular biology of nicotinic ion channel. Results of epidemiological studies have revealed that the incidence of Alzheimer's disease is lower among smokers compared with findings for nonsmokers, which seems to indicate that nicotine may influence cortical functions. We observed an increase in extracellular dopamine concentrations after administration of nicotine through a microdialysis tube. Nicotine might inhibit the uptake of dopamine through the nAChR, which could serve as a preventive factor against neurodegenerative diseases. We evaluated the ability of nicotine to protect neuronal cells from death by using the model system of serum- and nerve growth factor (NGF)-free cultures of PC12 cells. Serum and NGF deprivation induced rapid and massive death of these cells, which was inhibited by the addition of nicotine. These results suggest to us that nicotine may be involved in the protection of neuronal cells from death by means of nAChR. The effect of NGF and nicotine on the expression of nAChR subunits in PC12 cells was examined by using Northern blot analysis. Nerve growth factor increased the transcription of alpha5 and beta4 subunits, whereas nicotine increased mRNA level encoding alpha5 and beta2 subunits. These results suggest to us that NGF changes the expression of nAChR in a subtype-specific manner over the course of differentiation, and disproportionate subunit expressions might be related to the neuroprotective effect exerted by nicotine.

Nakamura, M. (2001). "[Alzheimer disease, familial]." Ryoikibetsu Shokogun Shirizu(33): 168-9.

Narula, J. and R. Baliga (2001). "What's in a name? Would that which we call death by any other name be less tragic?" Ann Thorac Surg 72(5): 1454-6.

Neumann, H. (2001). "Control of glial immune function by neurons." Glia 36(2): 191-9.
The immune status of the central nervous system (CNS) is strictly regulated. In the