(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-re