Alzheimer's Disease Reviews: 2002
(573 References)
(2002). "Vinpocetine. Monograph." Altern Med Rev 7(3): 240-3.
(2002). "Nefiracetam. DM 9384, DZL 221, Translon." Drugs R D 3(3): 212-6.
(2002). "Seeking security for wandering Alzheimer patients." Johns Hopkins Med Lett Health After 50 14(2): 6-7.
(2002). "Understanding changes in cholinergic function: implications for treating dementia." J Clin Psychiatry 63(3): 259-69.
(2002). "Rimonabant. SR 141716, SR 141716a." Drugs R D 3(1): 65-6.
(2002). "Highlights from the annual scientific assembly: managing the stages of Alzheimer's disease--new management options." South Med J 95(1): 102-6.
Acton, G. J. and M. A. Winter (2002). "Interventions for family members caring for an elder with dementia." Annu Rev Nurs Res 20: 149-79.
This chapter reviews 73 published and unpublished research reports of interventions for family members caring for an elder with dementia by nurse researchers and researchers from other disciplines. Reports were identified through searches of MEDLINE, CINAHL, Social Science Index, PsycINFO, ERIC, Social Work Abstracts, American Association of Retired Persons database, CRISP index of the National Institutes of Health, Cochrane Center database, and Dissertation Abstracts using the following search terms: caregiver, caregiving, dementia, Alzheimer's, intervention study, evaluation study, experimental, and quasi-experimental design. Additional keywords were used to narrow or expand the search as necessary. All nursing research was included in the review and nonnursing research was included if published between 1991 and 2001. Studies were included if they used a design that included a treatment and control group or a one-group, pretest-posttest design (ex post facto designs were included if they used a comparison group). Key findings show that approximately 32% of the study outcomes (e.g., burden, depression, knowledge) were changed after intervention in the desired direction. In addition, several problematic issues were identified including small, diverse samples; lack of intervention specificity; diversity in the length, duration, and intensity of the intervention strategies; and problematic outcome measures.
Aguilar-Gaytan, R. and J. Mas-Oliva (2002). "[The scavenger receptor and its importance in amyloid processes]." Gac Med Mex 138(5): 445-60.
The scavenger receptor (SRA or RPA) belongs to a wide family of receptor proteins. The classification is based on sequence homologies and structural similarities; nevertheless, it has been useful to group them on the basis of ligand specificity. The SRA was first identified as a receptor for modified low-density lipoproteins, where such modification permits to regulate the uptake of modified LDL by macrophages leading to a massive cholesterol accumulation. Moreover, SRA facilitates the clearance by phagocytic cells of microbial pathogens and senescent cells. SRA is a transmembrane glycoprotein that exists as a trimer comprised of a cystein-linker dimer and a non-covalently bound monomer. SRA has an a-helical coiled coil domain, which is essential for both trimer formation and acid-dependent ligand dissociation. It also contains a collagenous domain, essential for ligand binding. The majority of these ligands are polyanionic molecules, such as the A beta-peptide, important in the development of Alzheimer's disease. Present findings including our own consider that binding of these peptides to SRA activates an inflammatory response with the production of oxidative stress.
Aisen, P. S. (2002). "Anti-inflammatory agents in Alzheimer's disease." Curr Neurol Neurosci Rep 2(5): 405-9.
Epidemiologic studies have raised expectations that existing anti-inflammatory drugs may be useful in slowing the progression of Alzheimer's disease (AD). However, the first large-scale studies of anti-inflammatory drug treatment regimens have been negative. These disappointing results, along with new evidence from cell culture and animal model systems, suggest that the inflammatory hypothesis must be refined. Generalizations about inflammation and anti-inflammatory drugs have not been useful in developing treatment strategies for AD. But new studies suggest that specific anti-inflammatory drugs may have beneficial effects mediated by unexpected mechanisms. Continued exploration of the neuroprotective potential of specific antirheumatic therapies, as well as consideration of treatment duration and subject selection, will improve the outlook for successful development of one or more of these drugs in the prevention or treatment of AD.
Aisen, P. S. (2002). "Evaluation of selective COX-2 inhibitors for the treatment of Alzheimer's disease." J Pain Symptom Manage 23(4 Suppl): S35-40.
Alzheimer's disease (AD) is a worldwide problem that affects 5 million people in the United States alone. Until the approval of tacrine in the mid-1990s, there was no effective therapy for the cognitive symptoms of AD. Although cholinergic therapy provides modest but significant symptomatic relief, the development of effective disease-modifying therapy is essential. It has been demonstrated that a number of inflammatory processes are active in the brain of patients with AD, and therefore it is believed that an anti-inflammatory regimen may offer some degree of neuroprotection. Several studies have indicated that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with delayed onset and/or slowed cognitive decline in AD. Although not currently approved for this condition, recent findings have demonstrated that cyclooxygenase (COX)-2 is of primary importance in the inflammatory response and may have a role in neurodegeneration. Therefore, selective COX-2 inhibitors (coxibs) may have an advantage over traditional NSAIDs as potential therapeutic agents in AD. The Alzheimer's Disease Cooperative Study (ADCS) is conducting an ongoing multicenter, double-blind, placebo-controlled trial to determine whether rofecoxib, a coxib, or naproxen, a nonselective NSAID, will slow the rate of cognitive and clinical decline in AD. This study, along with other clinical studies currently under way, will determine the utility of selective and nonselective COX inhibitors for the prevention and treatment of AD.
Albers, D. S. and M. F. Beal (2002). "Mitochondrial dysfunction in progressive supranuclear palsy." Neurochem Int 40(6): 559-64.
A progressive impairment of mitochondrial function has been suggested to play a critical role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. Mitochondrial dysfunction can lead to number of deleterious consequences including impaired calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition pore and secondary excitotoxicity. Progressive supranuclear palsy (PSP) is a rare neurological disorder characterized by the appearance of supranuclear gaze palsy and extrapyramidal symptoms [Arch. Neurol. 10 (1964) 333]. Although the etiological basis of PSP is unknown, compelling evidence from spectroscopy studies in PSP patients, biochemical studies in post-mortem PSP brain tissue and PSP cybrids has emerged that supports a contributory role of bio-energetic defects in the pathogenesis of PSP.
Albert, M. S. (2002). "Memory decline: the boundary between aging and age-related disease." Ann Neurol 51(3): 282-4.
Albert, S. M., M. H. Tabert, et al. (2002). "The impact of mild cognitive impairment on functional abilities in the elderly." Curr Psychiatry Rep 4(1): 64-8.
Mild cognitive impairment (MCI) covers a spectrum of cognitive impairment, bordered by normal cognitive performance on one end and frank dementia on the other. How wide the net for MCI is cast will affect the prevalence and severity of its functional consequences. Many studies suggest that MCI is an early stage of Alzheimer's disease. Therefore, investigation of the functional impact of MCI offers an important opportunity to examine the quality-of-life impact of a prodromal stage of Alzheimer's disease. In this review, the authors examine the nosology of the condition, the subjective experience of having an MCI diagnosis, and cross- sectional and prospective studies that have examined the topic.
Alexopoulos, G. S., S. Borson, et al. (2002). "Assessment of late life depression." Biol Psychiatry 52(3): 164-74.
This article focuses on diagnostic and nosologic challenges intrinsic to geriatric depression, including characteristics interfering with symptom and syndrome ascertainment, the impact of medical and cognitive disorders, the usefulness of screening instruments, and barriers imposed by treatment settings. The article also identifies gaps in existing knowledge and outlines a research agenda. Nosologic characterization of depressives syndromes contributed by specific medical disorders may lead to effective strategies for prevention and treatment of depression. Studies need to examine whether treatment of depression can improve the outcome of medical illnesses requiring active patient involvement in treatment. Considering disability a distinct aspect of health status may add an important dimension to the assessment of depression and result in complementary interventions aimed at depression and disability concurrently. The provisional criteria for depression of Alzheimer's disease, if validated, may facilitate treatment research. Studies need to characterize cognitive dysfunctions associated with later development of dementia or poor treatment response in patients with depression. Care managers working together with primary care physicians can improve the recognition and treatment of depressed elderly patients by obtaining the training in using validated instruments and treatment algorithms.
Aliev, G., M. A. Smith, et al. (2002). "The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer's disease." Brain Pathol 12(1): 21-35.
Alzheimer's disease (AD) and stroke are two leading causes of age-associated dementia. A rapidly growing body of evidence indicates that increased oxidative stress from reactive oxygen radicals is associated with the aging process and age-related degenerative disorders such as atherosclerosis, ischemia/reperfusion, arthritis, stroke, and neurodegenerative diseases. New evidence has also indicated that vascular lesions are a key factor in the development of AD. This idea is based on a positive correlation between AD and cardiovascular and cerebrovascular diseases such as arterio- and atherosclerosis and ischemia/reperfusion injury. In this review we consider recent evidence supporting the existence of an intimate relationship between oxidative stress and vascular lesions in the pathobiology of AD. We also consider the opportunities for therapeutic interventions based on the molecular pathways involved with these causal relationships.
Almeida, O. P., G. K. Hulse, et al. (2002). "Smoking as a risk factor for Alzheimer's disease: contrasting evidence from a systematic review of case-control and cohort studies." Addiction 97(1): 15-28.
AIMS: To investigate the risk of Alzheimer's disease (AD) associated with smoking. DESIGN: Meta-analyses of case-control and cohort studies. Data source: Index Medicus-Medline (1966-April 2000) and PsycINFO (1984-April 2000) databases were systematically consulted for the retrieval of references. This search was supplemented by manual search of relevant references quoted by other studies and reviews. STUDY SELECTION: Irrelevant abstracts and articles were identified by one of the authors. These papers were retrieved and examined by at least two of the authors, who initially assessed them for the relevance of the exposure (smoking), outcome (AD) and study-design (case-control or cohort study). DATA EXTRACTION: Two reviewers rated independently the quality of selected papers. Whenever possible, raw data were extracted and the crude odds ratio (OR) calculated using the Cornfield method. The pooled risk ratios were estimated using a fixed-effects model. FINDINGS: Twenty-one case-control studies reported data on 5323 subjects. The estimated pooled odds ratio (OR) was 0.74 [95% confidence interval (CI) = 0.66-0.84]. In another analysis incorporating ORs adjusted for confounding variables (such as age, sex, schooling and alcohol use), the pooled odds ratio was 0.82 (95% CI = 0.70-0.97). Finally, in a analysis that included only the four case-control studies that used matched design the pooled odds ratio was 0.82 (95% CI = 0.53-1.27). Eight cohort studies reported data on 43 885 people at risk-the overall relative risk (RR) of AD among ever smokers was 1.10 (95% CI = 0.94-1.29). Restricting the analysis to the two cohort studies that described the number of subjects who were smokers at baseline and later developed AD produced a RR of 1.99 (95% CI = 1.33-2.98). CONCLUSIONS: Case-control and cohort studies produce conflicting results as to the direction of the association between smoking and AD. Survival bias and other methodological problems associated with case-control studies may partly explain this difference. Access to information collected by ongoing follow-up studies may contribute to clarify the role of smoking in AD. If new results confirm that smoking is associated with increased risk of AD, then smoking prevention and cessation should become public health priorities in the fight against dementia.
Alperovitch, A., P. Amouyel, et al. (2002). "[Epidemiological studies on aging in France: from the PAQUID study to the Three-City study]." C R Biol 325(6): 665-72.
Follow-up of cohorts recruited in general population with active screening and diagnosis of incident cases, is the most appropriate epidemiological design for studying incidence and risk factors of Alzheimer disease and other types of dementia. In France, people considered in the PAQUID study, then in the EVA study, have been the first cohorts on dementia. They have prepared the way for the Three-City (3C) study, conducted in Bordeaux, Dijon and Montpellier. About 9500 persons aged 65 years and over have been recruited in these three cities and will be followed-up during four years. The main objective of the 3C study is to investigate the relation between vascular risk and neurodegenerative diseases. The 3C study will provide essential data for defining strategies for dementia prevention. To measure the impact of the strategies on the incidence of dementia and the social burden of this disease will be an important public health objective in the near future.
Altstiel, L. D. (2002). "Barriers to Alzheimer disease drug discovery and development in the biotechnology industry." Alzheimer Dis Assoc Disord 16 Suppl 1: S29-32.
The major barrier to Alzheimer disease (AD) drug discovery and development in the biotechnology industry is scale. Most biotechnology companies do not have the personnel or expertise to carry a drug from the bench to the market. Much effort in the industry has been directed toward the elucidation of molecular mechanisms of AD and the identification of new targets. Advances in biotechnology have generated new insights into disease mechanisms, increased the number of lead compounds, and accelerated biologic screening. The majority of costs associated with drug development are in clinical testing and development activities, many of which are driven by regulatory issues. For most biotechnology companies, the costs of such trials and the infrastructure necessary to support them are prohibitive. Another significant barrier is the definition of therapeutic benefit for AD drugs; Food and Drug Administration (FDA) precedent has established that a drug must show superiority to placebo on a performance-based test of cognition and a measure of global clinical function. This restrictive definition is biased toward drugs that enhance performance on memory-based tests. Newer AD drugs are targeted toward slowing disease progression; however, there is currently no accepted definition of what constitutes efficacy in disease progression. Despite these obstacles, the biotechnology industry has much to offer AD drug discovery and development. Biotechnology firms have already developed essential technology for AD drug development and will continue to do so. Biotechnology companies can move more quickly; of course, the trick is to move quickly in the right direction. Speed may offset some of the problems associated with lack of scale. Additionally, biotechnology companies can afford to address markets that may be too restricted for larger pharmaceutical companies. This advantage will have increasing importance, as therapies are developed to address subtypes of AD.
Alvarez, G., J. R. Munoz-Montano, et al. (2002). "Regulation of tau phosphorylation and protection against beta-amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer's disease." Bipolar Disord 4(3): 153-65.
Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of the beta-amyloid peptide and the hyperphosphorylation of the tau protein, among other features. The most widely accepted hypothesis on the etiopathogenesis of this disease proposes that the aggregates of the beta-amyloid peptide are the main triggers of tau hyperphosphorylation and the subsequent degeneration of affected neurons. In support of this view, fibrillar aggregates of synthetic beta-amyloid peptide induce tau hyperphosphorylation and cell death in cultured neurons. We have previously reported that lithium inhibits tau hyperphosphorylation and also significantly protects cultured neurons from cell death triggered by beta-amyloid peptide. As lithium is a relatively specific inhibitor of glycogen synthase kinase-3 (in comparison with other protein kinases), and other studies also point to a relevant role of this enzyme, we favor the view that glycogen synthase kinase-3 is a crucial element in the pathogenesis of Alzheimer's disease. In our opinion, the possibility of using lithium, or other inhibitors of glycogen synthase kinase-3, in experimental trials aimed to ameliorate neurodegeneration in Alzheimer's disease should be considered.
Ames, B. N., I. Elson-Schwab, et al. (2002). "High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms." Am J Clin Nutr 75(4): 616-58.
As many as one-third of mutations in a gene result in the corresponding enzyme having an increased Michaelis constant, or K(m), (decreased binding affinity) for a coenzyme, resulting in a lower rate of reaction. About 50 human genetic dis-eases due to defective enzymes can be remedied or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme, which at least partially restores enzymatic activity. Several single-nucleotide polymorphisms, in which the variant amino acid reduces coenzyme binding and thus enzymatic activity, are likely to be remediable by raising cellular concentrations of the cofactor through high-dose vitamin therapy. Some examples include the alanine-to-valine substitution at codon 222 (Ala222-->Val) [DNA: C-to-T substitution at nucleo-tide 677 (677C-->T)] in methylenetetrahydrofolate reductase (NADPH) and the cofactor FAD (in relation to cardiovascular disease, migraines, and rages), the Pro187-->Ser (DNA: 609C-->T) mutation in NAD(P):quinone oxidoreductase 1 [NAD(P)H dehy-drogenase (quinone)] and FAD (in relation to cancer), the Ala44-->Gly (DNA: 131C-->G) mutation in glucose-6-phosphate 1-dehydrogenase and NADP (in relation to favism and hemolytic anemia), and the Glu487-->Lys mutation (present in one-half of Asians) in aldehyde dehydrogenase (NAD + ) and NAD (in relation to alcohol intolerance, Alzheimer disease, and cancer).
Anand, R. (2002). "Barriers to Alzheimer disease drug discovery and drug development in the pharmaceutical industry." Alzheimer Dis Assoc Disord 16 Suppl 1: S33-9.
The drug development process in the pharmaceutical industry has evolved from separate programs, specific for each country, into one coordinated, global development scheme. As a result, such a development program must meet regulatory requirements for all countries in which approval for the new drug will be sought. Barriers to Alzheimer disease (AD) drug discovery and development in the pharmaceutical industry can be categorized as (1) regulatory, (2) logistical, and (3) drug development issues. Some of the regulatory barriers could be overcome by international harmonization of guidelines for the development of antidementia drugs. The logistical issues can be reduced through international collaboration in the conduct of clinical studies, and the developmental issues can be addressed by using an expedited drug development plan that not only can reduce the time but also the resources required to develop the drug.
Anderson, D. H., R. F. Mullins, et al. (2002). "A role for local inflammation in the formation of drusen in the aging eye." Am J Ophthalmol 134(3): 411-31.
PURPOSE: The accumulation of numerous or confluent drusen, especially in the macula, is a significant risk factor for the development of age-related macular degeneration (AMD). Identifying the origin and molecular composition of these deposits, therefore, has been an important, yet elusive, objective for many decades. Recently, a more complete profile of the molecular composition of drusen has emerged. DESIGN: In this focused review, we discuss these new findings and their implications for the pathogenic events that give rise to drusen and AMD. METHODS: Tissue specimens from one or both eyes of more than 400 human donors were examined by light, confocal or electron microscopy, in conjunction with antibodies to specific drusen-associated proteins, to help characterize the transitional events in drusen biogenesis. Quantification of messenger RNA from the retinal pigment epithelium (RPE)/choroid of donor eyes was used to determine if local ocular sources for drusen-associated molecules exist. RESULTS: The results indicate that cellular remnants and debris derived from degenerate RPE cells become sequestered between the RPE basal lamina and Bruch's membrane. We propose that this cellular debris constitutes a chronic inflammatory stimulus, and a potential "nucleation" site for drusen formation. The entrapped cellular debris then becomes the target of encapsulation by a variety of inflammatory mediators, some of which are contributed by the RPE and, perhaps, other local cell types; and some of which are extravasated from the choroidal circulation. CONCLUSIONS: The results support a role for local inflammation in drusen biogenesis, and suggest that it is analogous to the process that occurs in other age-related diseases, such as Alzheimer's disease and atherosclerosis, where accumulation of extracellular plaques and deposits elicits a local chronic inflammatory response that exacerbates the effects of primary pathogenic stimuli.
Anderton, B. H. (2002). "Ageing of the brain." Mech Ageing Dev 123(7): 811-7.
The brains of individuals who are cognitively normal show age-related changes that include an overall reduction in the brain volume and weight and enlargement of the brain ventricles. These changes are partly the result of nerve cell loss but accurate estimates of neuronal loss are notoriously difficult to make. There is loss of synapses and dendritic pruning in the aged brain but in selected areas rather than globally. Neurofibrillary tangles and senile plaques are the neuropathological hallmark of Alzheimer's disease in which they are more abundant and widespread than in the brains of intellectually intact elderly people. Alzheimer's disease has, therefore, been regarded as accelerated brain ageing, however, since there is a strong genetic contribution to developing the disease it implies that it may not be the inevitable, even if frequent, consequence of old age. The interplay between genetic and environmental factors probably determines the degree of pathological brain ageing and whether or not individuals develop dementia.
Araki, H., K. Suemaru, et al. (2002). "Neuronal nicotinic receptor and psychiatric disorders: functional and behavioral effects of nicotine." Jpn J Pharmacol 88(2): 133-8.
Both retrospective and prospective clinical studies have demonstrated positive associations of smoking with psychiatric disorders such as schizophrenia, depression and anxiety. Neuronal nicotinic acetylcholine receptors (nAChR) belong to a family of ligand-gated ion channels that are widely distributed in the brain. The pre-synaptically located nAChR, which are composed of alpha3 or alpha4 subunits in combination with beta2 subunit on axon terminals, modulate the multiple transmission release. Several studies indicated which individual nicotinic receptor subtype is responsible for mediating each of the behavioral effects of nicotine. A reduced number of alpha7 nicotinic receptor subtypes in the hippocampus were reported in schizophrenic patients. In addition, it was assumed that nicotine provided useful therapeutic treatment for a variety of cognitive impairments including those found in Alzheimer's disease, schizophrenia and attention deficit hyperactive disorder. Both alpha7 and alpha4beta2 nicotinic receptors in the hippocampus are involved in these phenomena. In the genetic depressive rats, nicotine showed antidepressant-like effects in forced swim models of depression, suggesting the involvement of alpha4beta2 nicotinic receptor in this phenomenon. Thus, it appears likely that pre-synaptic nAChR on monoaminergic fibers are composed of alpha3 or alpha4 subunits in combination with the beta2 subunit, and these subunit compositions mediate dopaminergic and noradrenergic release, and glutamate is mainly controlled by the alpha7 subunit. All these findings suggest that nicotine and other nicotinic drugs warrant further study for possible clinical prescription to psychiatric disorders.
Arendt, T. (2002). "Dysregulation of neuronal differentiation and cell cycle control in Alzheimer's disease." J Neural Transm Suppl(62): 77-85.
Degeneration in Alzheimer's disease primarily occurs in those neurons that in the adult brain retain, a high degree of structural plasticity and, is associated with the activation of mitogenic signaling and cell cycle activation. Brain areas affected by neurofibrillary degeneration in Alzheimer's disease are structures involved in the regulation of "higher brain functions" that become increasingly predominant as the evolutionary process of encephalization progresses. The functions these areas subserve require a life-long adaptive reorganization of neuronal connectivity. With the increasing need during evolution to organize brain structures of increasing complexity, these processes of dynamic stabilization and de-stabilization become more and more important but might also provide the basis for an increasing rate of failure. The hypothesis is put forward that it is the labile state of differentiation of a subset of neurons in the adult brain that allows for ongoing morphoregulatory processes after development is completed but at the same time renders these neurons particularly vulnerable. Interferring with neuronal differentiation control might, thus, be a potential strategy to prevent neurodegeneration in Alzheimer's disease and related disorders.
Arlt, S., U. Beisiegel, et al. (2002). "Lipid peroxidation in neurodegeneration: new insights into Alzheimer's disease." Curr Opin Lipidol 13(3): 289-94.
Imbalances of oxidative homeostasis and lipid peroxidation have been revealed as important factors involved in neurodegenerative disorders such as Alzheimer's disease. The brains of patients with Alzheimer's disease contain increased levels of lipid-peroxidation products such as 4-hydroxy-2-nonenal or acrolein, and enhanced lipid peroxidation can also be detected in cerebrospinal fluid and plasma from such patients. Recent research revealed that the interplay of transition metals, amyloid-beta peptide and lipid peroxidation might be responsible for increased oxidative stress and cell damage in this disease. In particular, the contrasting roles of amyloid-beta peptide, as a possible transition metal-chelating antioxidant for lipoproteins and a pro-oxidant when aggregated in brain tissue, has been the focus of discussion recently. In this context, lipid peroxidation has to be seen as an important part of the pathophysiological cascade in Alzheimer's disease, and its measurement in body fluids might serve as a therapy control for Alzheimer's disease and other neurodegenerative diseases.
Arroyo, G., M. Aldea, et al. (2002). "[Nicotinic Receptor, galantamine and Alzheimer disease]." Rev Neurol 34(11): 1057-65.
Population aging has increased and will drastically increase the prevalence of Alzheimer disease. The disease develops inexorably towards a syndrome of marked cognitive impairment, accompanied of emotional alterations and profound changes of personality. The patient loses its autonomy, and requires special attention of caregivers; this leads to a decrease of the quality of life, not only of the patient but also of its caregivers and family. The reduction of the number of functional nicotinic receptors in brain keeps pace with neurological symptoms and the severity of the disease (cholinergic theory of Alzheimer disease). There is a pleyade of data and observations reinforcing the idea that improving cholinergic neurotransmission is an investment in memory. Up to now, although with limited success, this improvement has been achieved only with the reversible inhibitors of acetylcholinesterase tacrine, rivastigmine and donepezil, available in the clinic since a few years. The last approved has been galantamine that in spite of being a modest inhibitor of acetylcholinesterase, improves memory (ADAS cog test) and slows down cognitive impairment of Alzheimer patients. To explain this therapeutic effect, a second mechanism of action for galantamine has been suggested, the positive allosteric modulation of presynaptic nicotinic receptors, that will favour the release of acetylcholine and other neurotransmitters involved in memory formation. Furthermore, galantamine possesses neuroprotectant antiapoptotic effects, according to recent data from our laboratory. These effects provide new ideas and therapeutic targets that might help to find novel and efficacious treatments for patients suffering Alzheimer disease.
Arsland, D. (2002). "[Dementia with Lewy bodies]." Tidsskr Nor Laegeforen 122(5): 525-9.
BACKGROUND: Some 10%-15% of patients with dementia are diagnosed as dementia with Lewy bodies (DLB), a disorder characterised by the presence of Lewy bodies in the brainstem and cortex. MATERIAL AND METHODS: Review of pathology, clinical symptoms, pharmacological and nonpharmacological treatment, based on the literature and on personal experience. RESULTS: Neurochemical findings are marked cortical reduction of acetylcholine and nigrostriatal dopamine deficiency. Key features of the clinical syndrome are dementia, fluctuating consciousness, visual hallucinations and parkinsonism. There are pathological and clinical overlaps between DLB and Alzheimer's disease on the one hand, and between DLB and Parkinson's disease on the other; the relationship between these diseases awaits further elucidation. Clinical consensus criteria for DLB have been published and shown to have high sensitivity and specificity. Fluctuating consciousness may be difficult to detect, but diagnostic instruments exist that may help in the evaluation. Drug treatment of DLB is difficult. Cholinesterase inhibitors have been shown to improve cognition and psychiatric symptoms. Atypical antipsychotics may improve psychosis, but some patients develop severe sensitivity reactions. The effect of antiparkinson agents is unknown.
Askanas, V. and W. K. Engel (2002). "Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms." Curr Opin Neurol 15(5): 525-31.
PURPOSE OF REVIEW: Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion body myopathies are progressive muscle diseases that lead to severe disability. We discuss recent advances in illuminating their pathogenic mechanism(s). RECENT FINDINGS: We emphasize how different etiologies might lead to the strikingly similar pathology and possibly similar pathogenic cascade. Our basic hypothesis is that over-expression of amyloid-beta precursor protein within aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. On the basis of our research, several processes seem to be important in relation to the still speculative pathogenesis: (a) increased transcription and accumulation of amyloid-beta precursor protein, and accumulation of its proteolytic fragment Abeta; (b) accumulations of phosphorylated tau and other Alzheimer-related proteins; (c) accumulation of cholesterol and low-density lipoprotein receptors, the cholesterol accumulation possibly due to its abnormal trafficking; (d) oxidative stress; and (e) a milieu of muscle cellular aging in which these changes occur. We discuss unfolded and/or misfolded proteins as a possible mechanism in formation of the inclusion bodies and their consequences. The remarkable pathologic similarities between s-IBM muscle and Alzheimer disease brain are discussed. SUMMARY: Unfolding knowledge of the various pathogenetic aspects of the s-IBMs and hereditary inclusion body myopathies may lead to new therapeutic avenues.
Askanas, V. and W. K. Engel (2002). "Newest pathogenetic considerations in inclusion-body myositis: possible role of amyloid-beta, cholesterol, relation to aging and to Alzheimer's disease." Curr Rheumatol Rep 4(5): 427-33.
This report summarizes clinical features and diagnostic criteria, and the newest advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis. On the basis of the authors' research, several processes seem to be important in relation to the still-speculative pathogenesis: increased transcription and accumulation of amyloid-b precursor protein and accumulation of its proteolytic fragment amyloid-b; abnormal accumulation of components related to lipid metabolism (eg, low-density lipoprotein receptors and cholesterol; accumulation of cholesterol is possibly caused by its abnormal trafficking); oxidative stress; accumulations of other Alzheimer-related proteins including phosphorylated tau; a milieu of muscle cellular aging in which these changes occur. The authors' basic hypothesis is that overexpression of amyloid-b precursor protein within the aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. The remarkable pathologic similarities between inclusion-body myositis muscle and Alzheimer's disease brain are discussed.
Assal, F. and J. L. Cummings (2002). "Neuropsychiatric symptoms in the dementias." Curr Opin Neurol 15(4): 445-50.
PURPOSE OF REVIEW: Neuropsychiatric, or non-cognitive symptoms are increasingly recognized as manifestations of dementias. RECENT FINDINGS: In Alzheimer's disease, recent advances have included the identification of behavioral profiles, differentiation of apathy and depression, characterization of risk factors for psychosis and its links to agitation and aggression, and an analysis of depressive symptoms in the absence of major depression. Functional neuroimaging data mainly supported the role of the anterior cingulate in apathy. The orbitofrontal and anterior cingulate tangle burden were associated with agitation, and increased orbitofrontal and mid-temporal muscarinic M2 receptors with psychosis and hallucinations. Selected genetic polymorphisms of dopamine and serotonin receptors or transporters were linked with aggression, hallucinations or psychosis. When compared with other dementias, individuals with frontotemporal dementia disclosed, as expected, different behaviors and particularly aberrant social behavior. The frequency of delusions and visual hallucinations was increased in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies, suggesting common mechanisms such as Lewy body pathology and cholinergic deficiency. The latter was supported by an improvement of these symptoms by cholinesterase inhibitors. SUMMARY: Future research directions include both clinical and basic neuroscience investigations. The detection of early neuropsychiatric symptoms might be a marker for dementia, and the possible existence of a mild neuropsychiatric impairment syndrome should be explored. More longitudinal studies with pathological confirmation will facilitate correlations with neuropsychiatric symptoms. Functional neuroimaging and behavioral neurogenetics will permit in-vivo correlations and consequently help patient management and care.
Atwood, C. S., G. M. Bishop, et al. (2002). "Amyloid-beta: a vascular sealant that protects against hemorrhage?" J Neurosci Res 70(3): 356.
Atwood, C. S., S. R. Robinson, et al. (2002). "Amyloid-beta: redox-metal chelator and antioxidant." J Alzheimers Dis 4(3): 203-14.
Avila, J., F. Lim, et al. (2002). "Tau function and dysfunction in neurons: its role in neurodegenerative disorders." Mol Neurobiol 25(3): 213-31.
Alzheimer's disease (AD) is the most usual neurodegenerative disorder leading to dementia in the aged human population. It is characterized by the presence of two main brain pathological hallmarks: senile plaques and neurofibrillary tangles (NFTs). NFTs are composed of fibrillar polymers of the abnormally phosphorylated cytoskeletal protein tau.
Bacskai, B. J., W. E. Klunk, et al. (2002). "Imaging amyloid-beta deposits in vivo." J Cereb Blood Flow Metab 22(9): 1035-41.
Alzheimer disease (AD) is an illness that can only be diagnosed with certainty with postmortem examination of brain tissue. Tissue samples from afflicted patients show neuronal loss, neurofibrillary tangles (NFTs), and amyloid-beta plaques. An imaging technique that permitted in vivo detection of NFTs or amyloid-beta plaques would be extremely valuable. For example, chronic imaging of senile plaques would provide a readout of the efficacy of experimental therapeutics aimed at removing these neuropathologic lesions. This review discusses the available techniques for imaging amyloid-beta deposits in the intact brain, including magnetic resonance imaging, positron emission tomography, single photon emission computed tomography, and multiphoton microscopy. A variety of agents that target amyloid-beta deposits specifically have been developed using one or several of these imaging modalities. The difficulty in developing these tools lies in the need for the agents to cross the blood-brain barrier while recognizing amyloid-beta with high sensitivity and specificity. This review describes the progress in developing reagents suitable for in vivo imaging of senile plaques.
Bahr, B. A. and J. Bendiske (2002). "The neuropathogenic contributions of lysosomal dysfunction." J Neurochem 83(3): 481-9.
Multiple lines of evidence implicate lysosomes in a variety of pathogenic events that produce neurodegeneration. Genetic mutations that cause specific enzyme deficiencies account for more than 40 lysosomal storage disorders. These mostly pre-adult diseases are associated with abnormal brain development and mental retardation. Such disorders are characterized by intracellular deposition and protein aggregation, events also found in age-related neurodegenerative diseases including (i) Alzheimer's disease and related tauopathies (ii) Lewy body disorders and synucleinopathies such as Parkinson's disease, and (iii) Huntington's disease and other polyglutamine expansion disorders. Of particular interest for this review is evidence that alterations to the lysosomal system contribute to protein deposits associated with different types of age-related neurodegeneration. Lysosomes are in fact highly susceptible to free radical oxidative stress in the aging brain, leading to the gradual loss of their processing capacity over the lifespan of an individual. Several studies point to this lysosomal disturbance as being involved in amyloidogenic processing, formation of paired helical filaments, and the aggregation of alpha-synuclein and mutant huntingtin proteins. Most notably, experimentally induced lysosomal dysfunction, both in vitro and in vivo, recapitulates important pathological features of age-related diseases including the link between protein deposition and synaptic loss.
Ball, L. J. and S. J. Birge (2002). "Prevention of brain aging and dementia." Clin Geriatr Med 18(3): 485-503.
The brain is subjected to multiple factors that result in damage to its cellular constituents, the neuron and supporting cells, and the neural networks that form the bases of cognitive ability. Like other systems, the brain has remarkable capacity to repair that damage and to adapt or compensate for the loss of neurons and the disruption of the neural architecture. Brain aging and dementia can be conceptualized as a balance between neuronal injury and repair. This balance can be affected not only by genetic and age-related factors but also by multiple environmental factors. The latter includes many factors, including education, nutrition, exercise, socialization, and stress. As individuals, we have the potential to modify these factors through lifestyle choices. Advances in neuroscience have led to the development of pharmacologic agents that can ameliorate the effects of even genetic (e.g., statins and antihypertensive agents) and age-related (e.g., antioxidants and estrogen replacement) factors. By altering the balance between neuronal injury and repair, we can delay the expression and progression of the neurodegenerative processes of brain aging, AD, and related dementias.
Ballard, C. G. (2002). "Advances in the treatment of Alzheimer's disease: benefits of dual cholinesterase inhibition." Eur Neurol 47(1): 64-70.
Cholinesterase inhibitors have produced the best evidence of clinical efficacy for treating patients with Alzheimer's disease (AD). Many of these drugs selectively inhibit acetylcholinesterase (AChE), but agents that also target butyrylcholinesterase (BuChE) may provide added benefits. As AD progresses, ACh regulation may become increasingly dependent on BuChE and dual inhibitors may provide more sustained efficacy than AChE-selective agents. Dual inhibition may also help to slow the formation of amyloidogenic compounds, providing an important disease-modifying mechanism. Rivastigmine is a dual inhibitor that has demonstrated benefits across the spectrum of AD severity and across the cognitive, functional and behavioural domains of AD. It is a priority for future clinical trials to determine whether agents with dual inhibition properties have greater clinical efficacy.
Bamberger, M. E. and G. E. Landreth (2002). "Inflammation, apoptosis, and Alzheimer's disease." Neuroscientist 8(3): 276-83.
The pathophysiology of Alzheimer's disease (AD) involves the deposition of amyloid in the brain and the extensive loss of neurons. The mechanisms subserving neuronal death in the disease remain unclear, although it has been postulated that this is due to apoptosis. There is compelling evidence that inflammatory processes play a role in disease progression and pathology. Amyloid plaque deposition is accompanied by the association of microglia with the senile plaque, and this interaction stimulates these cells to undergo phenotypic activation and the subsequent elaboration of proinflammatory and neurotoxic products. This review focuses on the mechanisms by which neurons are lost in AD and the role microglial proinflammatory products play in neuronal death.
Barril, X., S. G. Kalko, et al. (2002). "Rational design of reversible acetylcholinesterase inhibitors." Mini Rev Med Chem 2(1): 27-36.
A large amount of structural information on AChE and AChE-inhibitor complexes is currently available. Based on that, molecular modeling studies can be intensively used to gain insight into the mechanism of action of the enzyme and the molecular determinants that modulate the potency of inhibitors. In turn, this knowledge can be exploited to design new compounds leading to more effective cholinergic strategies. This manuscript reviews recent developments in the design of reversible acetylcholinesterase inhibitors.
Bazan, N. G., R. Palacios-Pelaez, et al. (2002). "Hypoxia signaling to genes: significance in Alzheimer's disease." Mol Neurobiol 26(2-3): 283-98.
Aberrations in neural signaling, converging to and diverging from oxidative metabolism and blood supply, contribute to the initiation and maintenance of inflammatory responses, neuronal degeneration, and age-related cognitive decline in Alzheimer's disease (AD). Hypoxia/ischemia triggers phospholipase A2, leading to the accumulation of free arachidonic and docosahexaenoic acids (AA, DHA), as well as that of lysophospholipids. Some of these bioactive lipid messengers in turn give rise to several downstream lipid messengers, such as platelet-activating factor (PAF) and ecosanoids (prostaglandins and leukotrienes). Eicosanoid synthesis is highly regulated in hypoxia and in reperfusion subsequent to ischemia. As one of the consequences, mitochondrial function is disrupted and reactive oxygen species (ROS) both contribute to the expansion of cellular inflammatory responses and reduce the expression of genes required to maintain synaptic structure and function. On the other hand, pro-inflammatory genes are up-regulated. One of these, the inducible cyclooxygenase-2 (COX-2), along with oxygen-starved mitochondria, comprise the major sources of ROS in the brain during hypoxia, ischemia, and reperfusion. One outcome is a sustained metabolic stress that drives progressive dysfunction, apoptosis and/or necrosis, and brain cell death. How hypoxia modulates oxygen-sensitive gene expression is not well understood. Pro-inflammatory gene families that contribute to neurodegeneration are transiently activated in part by the heterodimeric oxygen-sensitive DNA-binding proteins nuclear factor for kappa B (NF-kappaB) and hypoxia-inducible factor-alpha (HIF-1alpha). Here the authors summarize current studies supporting the hypothesis that synaptically-derived lipid messengers play significant roles in ischemic stroke and that hypoxia is an important contributor to the onset and progression of AD neurodegeneration.
Beal, M. F. (2002). "Oxidatively modified proteins in aging and disease." Free Radic Biol Med 32(9): 797-803.
There is a large body of evidence implicating oxidative damage in the pathogenesis of both normal aging and neurodegenerative diseases. Oxidative damage to proteins has been well established. Although there are a large number of potential oxidative modifications only a few have been systematically studied. The most frequently studied marker of oxidative damage to proteins is protein carbonyl groups. 3-Nitrotyrosine is thought to be a relatively specific marker of oxidative damage mediated by peroxynitrite. Increased concentrations of both protein carbonyls and 3-nitrotyrosine have been documented in both normal aging as well as in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). These findings help to provide a rationale for trials of antioxidants in neurodegenerative diseases.
Beblo, T. (2002). "[Relevance of neuropsychological studies of depression in the elderly]." Z Gerontol Geriatr 35(2): 111-7.
Neuropsychological deficits are a common feature of depressive disorders. In the systems ICD 10 and DSM IV neuropsychological deficits constitute a relevant diagnostic criterion. Deficits in executive functions, attention and memory are documented. Primarily, mental flexibility seems to be impaired. The relation between neuropsychological deficits and depression is moderated by the patient's age. In the elderly, depression is more often accompanied by neuropsychological deficits. Clinically, the relevance of neuropsychological testing in depression has different aspects. Neuropsychological testing is the prerequisite for neuropsychological therapy when patients exhibit residual cognitive symptoms, and for professional and social rehabilitation. The neuropsychological outcome provides important information for the therapy process, and for predicting therapy success. In addition, neuropsychological testing can influence the choice of medication and psychotherapy. Neuropsychological data can also help to differ depression from dementia, an important problem in elder psychiatric and neurological patients. For this purpose a comprehensive neuropsychological test-battery that covers different neuropsychological domains needs to be employed. Furthermore, the analysis of the patients behavior and errors during testing provides essential information. However, in many cases a neuropsychological re-test and the analysis of the course of neuropsychological deficits is needed to differ depression from dementia.
Behl, C. and B. Moosmann (2002). "Antioxidant neuroprotection in Alzheimer's disease as preventive and therapeutic approach." Free Radic Biol Med 33(2): 182-91.
Various neurodegenerative disorders and syndromes are associated with oxidative stress. The deleterious consequences of excessive oxidations and the pathophysiological role of reactive oxygen species (ROS) have been intensively studied in Alzheimer's disease (AD). Neuronal cell dysfunction and oxidative cell death caused by the AD-associated amyloid beta protein may causally contribute to the pathogenesis of AD. Antioxidants that prevent the detrimental consequences of ROS are consequently considered to be a promising approach to neuroprotection. While there is ample experimental evidence demonstrating neuroprotective activities of antioxidants in vitro, the clinical evidence that antioxidant compounds act as protective drugs is still relatively scarce. Nevertheless, antioxidants constitute a major part of the panel of clinical and experimental drugs that are currently considered for AD prevention and therapy. Here, focus is put mainly on phenolic antioxidant structures that belong to the class of direct antioxidants. Experimental and clinical evidence for the neuroprotective potential of alpha-tocopherol (vitamin E) and 17beta-estradiol (estrogen) is shortly summarized and an outlook is given on possible novel antioxidant lead structures with improved pharmacological features.
Behl, C. and B. Moosmann (2002). "Oxidative nerve cell death in Alzheimer's disease and stroke: antioxidants as neuroprotective compounds." Biol Chem 383(3-4): 521-36.
Many neurodegenerative disorders and syndromes are associated with an excessive generation of reactive oxygen species (ROS) and oxidative stress. The pathways to nerve cell death induced by diverse potential neurotoxins such as peptides, excitatory amino acids, cytokines or synthetic drugs commonly share oxidative downstream processes, which can cause either an acute oxidative destruction or activate secondary events leading to apoptosis. The pathophysiological role of ROS has been intensively studied in in vitro and in vivo models of chronic neurodegenerative diseases such as Alzheimer's disease (AD) and of syndromes associated with rapid nerve cell loss as occuring in stroke. In AD, oxidative neuronal cell dysfunction and cell death caused by protofibrils and aggregates of the AD-associated amyloid beta protein (Abeta) may causally contribute to pathogenesis and progression. ROS and reactive nitrogen species also take part in the complex cascade of events and the detrimental effects occuring during ischemia and reperfusion in stroke. Direct antioxidants such as chain-breaking free radical scavengers can prevent oxidative nerve cell death. Although there is ample experimental evidence demonstrating neuroprotective activities of direct antioxidants in vitro, the clinical evidence for antioxidant compounds to act as protective drugs is relatively scarce. Here, the neuroprotective potential of antioxidant phenolic structures including alpha-tocopherol (vitamin E) and 17beta-estradiol (estrogen) in vitro is summarized. In addition, the antioxidant and cytoprotective activities of lipophilic tyrosine- and tryptophan-containing structures are discussed. Finally, an outlook is given on the neuroprotective potential of aromatic amines and imines, which may comprise novel lead structures for antioxidant drug design.
Bendheim, P. E., B. Poeggeler, et al. (2002). "Development of indole-3-propionic acid (OXIGON) for Alzheimer's disease." J Mol Neurosci 19(1-2): 213-7.
The accumulation of amyloid-beta and concomitant oxidative stress are major pathogenic events in Alzheimer's disease. Indole-3-propionic acid (IPA, OXIGON) is a potent anti-oxidant devoid of pro-oxidant activity. IPA has been demonstrated to be an inhibitor of beta-amyloid fibril formation and to be a potent neuroprotectant against a variety of oxidotoxins. This review will summarize the known properties of IPA and outline the rationale behind its selection as a potential disease-modifying therapy for Alzheimer's disease.
Bernhardt, T., A. Seidler, et al. (2002). "[The effect of psychosocial factors on risk of dementia]." Fortschr Neurol Psychiatr 70(6): 283-8.
In the etiology of dementia several genetic and various environmental factors are assumed to interact. Most epidemiological studies on risk factors have focused on "constitutional" factors like age, sex, birth order, dementia in the family and "life style" factors like smoking and alcohol consumption. Only few studies have investigated the role of psychosocial factors at work and during leisure time on the risk to develop dementia. Our paper gives a systematic review of all published results of controlled studies about psychosocial risk factors. A positive association has been observed between dementia and living alone, having no close social ties, not participating in social and leisure activities, and never having married. Recent studies have found that Alzheimer's disease in particular is negatively associated with diversity of activities and intensity of intellectual activities and positively associated with psychosocial inactivity, unproductive working style, living with a dominant spouse and with physical inactivity.
Berrino, F. (2002). "[Western diet and Alzheimer's disease]." Epidemiol Prev 26(3): 107-15.
Alzheimer Disease, characterised by a global impairment of cognitive functions, is more and more common in Western societies, both because of longer life expectancy and, probably, because of increasing incidence. Several hints suggest that this degenerative disease is linked to western diet, characterised by excessive dietary intake of sugar, refined carbohydrates (with high glycaemic index), and animal product (with high content of saturated fats), and decreased intake of unrefined seeds--cereals, legumes, and oleaginous seeds--and other vegetables (with high content of fibres, vitamins, polyphenols and other antioxidant substances, phytoestrogens) and, in several populations, of sea food (rich in n-3 fatty acids). It has been hypothesised, in fact, that AD, may be promoted by insulin resistance, decreased endothelial production of nitric oxide, free radical excess, inflammatory metabolites, homocysteine, and oestrogen deficiency. AD, therefore, could theoretically be prevented (or delayed) by relatively simple dietary measures aimed at increasing insulin sensitivity (trough reduction of refined sugars and saturated fats from meat and dairy products), the ratio between n-3 and n-6 fatty acids (e.g. from fish and respectively seed oils), antioxidant vitamins, folic acid, vitamin B6, phytoestrogens (vegetables, whole cereals, and legumes, including soy products), vitamin B12 (bivalve molluscs, liver), and Cr, K, Mg, and Si salts. This comprehensive improvement of diet would fit with all the mechanistic hypotheses cited above. Several studies, on the contrary, are presently exploring monofactorial preventive strategies with specific vitamin supplementation or hormonal drugs, without, however, appreciable results.
Bishop, G. M., S. R. Robinson, et al. (2002). "Iron: a pathological mediator of Alzheimer disease?" Dev Neurosci 24(2-3): 184-7.
Brains from patients with Alzheimer disease (AD) show a disruption in the metabolism of iron, such that there is an accumulation of iron in senile plaques, and an altered distribution of iron transport and storage proteins. One of the earliest events in AD is the generation of oxidative stress, which may be related to the generation of free radicals by the excess iron that is observed in the disease. Iron has also been shown to mediate the in vitro toxicity of amyloid-beta peptide, and the presence of iron in most in vitro systems could underlie the toxicity that is normally attributed to amyloid-beta in these studies. In contrast, several recent studies have suggested that amyloid-beta may decrease oxidative stress and decrease the toxicity of iron. Continued examination of the complex interactions that occur between iron and amyloid-beta may assist in the elucidation of the mechanisms that underlie the neurodegeneration that leads to dementia in AD.
Blackwell, J. (2002). "Alzheimer's disease management." J Am Acad Nurse Pract 14(8): 338-40.
Blass, J. P., G. E. Gibson, et al. (2002). "The role of the metabolic lesion in Alzheimer's disease." J Alzheimers Dis 4(3): 225-32.
This paper discusses the hypothesis that the cerebrometabolic deficiency in Alzheimer's disease(AD) is the proximate cause of the clinical disability. Several sets of observations support this hypothesis. (1) Impaired brain metabolism essentially always occurs in clinically significant AD, and the degree of clinical disability is proportional to the degree of metabolic impairment. The earliest, mildest changes in brain metabolism occur even before the onset of measurable cognitive impairment or atrophy. This observation disproves the now outdated assumption that the decreased metabolism is simply a consequence of decreased mental function or of atrophy. One of the important mechanisms reducing brain metabolism in AD appears to be damage to key mitochondrial components. Another appears to relate to inappropriate responses to insulin, i.e. to diabetes of the brain. (2) Inducing impairments of brain metabolism causes changes in mentation that mimic the clinical disabilities in AD, in both humans and experimental animals. (3) Preliminary results from several units suggest that treatment directed at the impairment of brain metabolism can improve neuropsychological functions in AD patients. The hypothesis presented here in no way negates the importance of other mechanisms in AD, such as amyloid accumulation, vascular compromise, and free radical action. However, those other abnormalities including amyloidosis can occur in people whose mentation is still clinically unimpaired. In contrast, once significant decrease in the rate of brain metabolism occurs, mentation becomes defective.
Bliwise, D. L. (2002). "Sleep apnea, APOE4 and Alzheimer's disease 20 years and counting?" J Psychosom Res 53(1): 539-46.
Alzheimer's disease (AD) is acknowledged to be at least partially genetic, and one of the key genotypic markers for this condition is the APOE4 allele. Links between sleep apnea and AD have long been suspected because of mental impairment seen in some sleep apnea patients and possible evidence suggesting higher rates of sleep apnea in some dementia patients. The recent demonstration of an association between the APOE4 genotype and sleep apnea has rekindled further interest in this topic, particularly because sleep apnea is characterized by multiple genetic vulnerabilities. We review here evidence related to associations between sleep apnea and dementia, the role of APOE4 as a likely marker for cerebrovascular disease, and discuss treatment considerations relevant to sleep apnea as a potentially reversible cause of dementia.
Blobel, C. P. (2002). "Functional and biochemical characterization of ADAMs and their predicted role in protein ectodomain shedding." Inflamm Res 51(2): 83-4.
Proteolysis on the cell surface and in the extracellular matrix is essential for normal cellular functions during development and in the adult, but it may also have undesirable consequences by promoting diseases such as cancer, arthritis, and Alzheimer's disease. A particularly interesting function of proteolysis on the cell surface is to release ectodomains of membrane proteins from the plasma membrane. This process, which is referred to as protein ectodomain shedding, affects a variety of proteins with important roles in development and in disease, including cytokines, growth factors, receptors, adhesion proteins and other proteins such as the amyloid precursor protein. In principle, protein ectodomain shedding can dramatically change the properties of a substrate protein. For example, membrane anchored growth factors such as transforming growth factor-alpha (TGF-alpha) are only able to activate their receptor, the epidermal growth factor receptor (EGFR), after they are shed from the plasma membrane. Inhibitor studies have implicated zinc-dependent metalloproteases in protein ectodomain shedding, and in particular a family of metalloproteases termed ADAMs (a disintegrin and metalloprotease). The main focus of my lab is to understand the role of different ADAMs in protein ectodomain shedding, and to learn about the functional consequences of protein ectodomain shedding for individual substrates.
Blount, P. J., C. D. Nguyen, et al. (2002). "Clinical use of cholinomimetic agents: a review." J Head Trauma Rehabil 17(4): 314-21.
BACKGROUND: There are many agents in clinical use that manipulate central nervous system levels of epinephrine, dopamine, and serotonin. However, development of pharmacological options to manipulate central acetylcholine systems has lagged behind because of poor penetration of the blood-brain barrier and significant peripheral nervous system side effects. Newer agents have demonstrated some efficacy in the management of behavioral and cognitive side effects in Alzheimer's disease, and preliminary data in traumatic brain injury suggest acetylcholine esterase inhibitors may play a significant role in the treatment of this patient population as well. CONCLUSIONS: In this article, the basic neuroanatomy and pharmacology of the central acetylcholine system are reviewed, along with agents currently available for clinical use.
Bodemer, W. and F. J. Kaup (2002). "[Basic research on BSE transmission to people]." Dtsch Tierarztl Wochenschr 109(8): 338-41.
Prion diseases of animal and man belong to neurological diseases with amyloidal deposition of the respective proteins. As to prion disease, the cellular prionprotein is in its abnormal isoform(s) an essential component of prionprotein aggregates found in affected tissue. In contrast to all neurodegenerative diseases like Morbus Alzheimer or Huntington's disease, prion diseases are transmissible. Therefore, prion diseases were designated Transmissible Spongiform Encephalopathies (TSE). The diseases are well known since decades. Scrapie was first described around 1750, a BSE case was reported in the 1850, most likely a misdiagnosis, and in 1920/1930 the human Creutzfeldt-Jakob disease (CJD) had been described. Transmission of CJD i.e. Kuru had been suspected in the early 1950s and erronously classified as slow virus disease. The CJD transmission posed a problem to humans when transplants from CJD cases were used for treatment. Fortunately, these iatrogenic transmissions remained limited. But with the advent of BSE and appearance of variant CJD cases in the UK and some places in Europe scientists suspected that transmission from cattle to man could have happened. From animal models we know of successful transmission via several routes. Species barriers do not completely prevent transmission. Rather transmission barriers might exist controlling individual susceptibility against prions. Modes of transmission, susceptibility for transmission, identification of receptor molecules as well as molecular mechanisms of the transmission process are intensely investigated. Current knowledge let us to assume that inapparent stages of prion infection pretend a (not existing) species barrier. This inapparent infection preceeds overt disease and, thus, most re-search focuses on the development of highly sensitive assay systems for detection of minute amounts of pathological prionprotein in suspected cases. Inapparence also should warn us to underestimate BSE or human vCJD cases; at present, 124 in Europe and one probable case in Hongkong (7 March 2002). Whether BSE had spread to other parts of the world by animal nutrition components or meat can neither be excluded nor confirmed at this time. New data on transmission and consequences of BSE for the human population are summarized in this review.
Boller, F., M. Verny, et al. (2002). "Clinical features and assessment of severe dementia. A review." Eur J Neurol 9(2): 125-36.
Sound understanding of the dementia syndrome requires adequate acquaintance with its entire spectrum, from the lightest to the most advanced stages. Most studies of dementia deal with light to moderate stages of the condition, while relatively little attention has been paid to its most severe stages. This review presents a clinical description of patients with severe dementia and of the tests currently available to evaluate their cognitive, behavioural, and functional status. Available instruments such as the Hierarchic Dementia Scale or the Severe Impairment Battery now allow quantification of the cognitive and behavioural status of patients with severe dementia. Experience with severe dementia shows that, far from being in a "vegetative state", as is commonly thought, late-stage patients are in fact quite different from one another and in most cases continue to have an interaction with their environment. This ability to better define the characteristics of patients with severe dementia provides the basis for correlations between clinical data and data derived from neuroimaging, neurochemistry, or neuropathology. It also sets the stage for possible therapeutic trials involving these patients.
Bolton, J. L. (2002). "Quinoids, quinoid radicals, and phenoxyl radicals formed from estrogens and antiestrogens." Toxicology 177(1): 55-65.
Estrogens have a variety of beneficial effects in vivo including protection against osteoporosis, coronary heart disease, Alzheimer's disease, and stroke. Similarly, antiestrogens have been shown to be effective both in treating breast cancer as well as preventing this disease. Despite the health benefits of these drugs adverse side effects have been reported including increased risk for developing certain hormone dependent cancers. Although an estrogenic mechanism likely contributes to mechanism of estrogen/antiestrogen carcinogenesis there is substantial evidence to suggest that metabolism to reactive intermediates is also involved. Both estrogens and antiestrogens can be metabolized to phenoxyl radicals, o-quinones, and semiquinone radicals, all of which could cause damage in cells either through alkylation or oxidation of cellular macromolecules including DNA. In contrast, there are several reports that estrogens and antiestrogens can act as antioxidants which could protect cells against free radical mediated damage and contribute to the beneficial effects of these compounds discussed above. The focus of this review is the role of quinoids, quinoid radicals, and phenoxyl radicals in the biological effects of estrogens and antiestrogens.
Bonelli, R. M., A. Aschoff, et al. (2002). "Cerebrospinal fluid tissue transglutaminase in vascular dementia." J Neurol Sci 203-204: 207-9.
The enzyme tissue transglutaminase (tTG), an indicator of acute cell death, is found in brains of Alzheimer's and Huntington's disease patients. tTG, as a specific marker for apoptosis, may therefore be a powerful biochemical marker of the acute degenerating process in vivo and may be useful in discrimination between vascular dementia (VaD) and Alzheimer's disease (AD). It may serve as completion of CSF analysis in diagnosis of dementing disorders and be a simple way of assessing the efficacy of possible new anti-apoptotic drugs.
Bonnefoy, M., J. Drai, et al. (2002). "[Antioxidants to slow aging, facts and perspectives]." Presse Med 31(25): 1174-84.
FREE RADICALS AND THE THEORY OF AGING: Severe oxidative stress progressively leads to cell dysfunction and ultimately cell death. Oxidative stress is defined as an imbalance between pro-oxidants and/or free radicals on the one hand, and anti-oxidizing systems on the other. The oxygen required for living may indirectly be responsible for negative effects; these deleterious effects are due to the production of free radicals, which are toxic for the cells (superoxide anions, hydroxyl radicals, peroxyl radicals, hydrogen peroxide, hydroperoxides and peroxinitrite anions). Free radical attacks are responsible for cell damage and the targeted cells are represented by the cell membranes, which are particularly rich in unsaturated fatty acids, sensitive to oxidation reactions; DNA is also the target of severe attacks by these reactive oxygen species (ROS). THE DEFENCE SYSTEMS: These are represented by the enzymes and free radical captors. The latter are readily oxidizable composites. The free radical captor or neutralization systems of these ROS use a collection of mechanisms, vitamins (E and C), enzymes [superoxide dismutase (SOD), glutathion peroxidase (GPx) and others], and glutathion reductase (GSH), capable of neutralizing peroxinitrite. The efficacy of this system is dependent on the genome for the enzymatic defence systems, and on nutrition for the vitamins. Some strategies aimed at reducing oxidative stress-related alterations have been performed in animals. However, only a few can be used and are efficient in humans, such as avoidance of unfavourable environmental conditions (radiation, dietary carcinogens, smoking...) and antioxidant dietary supplementation. DIETARY SUPPLEMENTATION: Epidemiological data suggest that antioxidants may have a beneficial effect on many age-related diseases: atherosclerosis, cancer, some neurodegenerative and ocular diseases. However, the widespread use of supplements is hampered by several factors: the lack of prospective and controlled studies; insufficient knowledge on the pro-oxidant, oxidant and ant-oxidant properties of the various supplements; growing evidence that free radicals are not only by-products, but also play an important role in cell signal transduction, apoptosis and infection control. RECOMMENDATIONS: Although current data indicate that antioxidants cannot prolong maximal life span, the beneficial impact of antioxidants on various age-related degenerative diseases may forecast an improvement in life span and enhance quality of life. The current lack of sufficient data does not permit the systematic recommendation of anti-oxidants. Nevertheless, antioxidant-rich diets with fruit and vegetables should be recommended.
Bonner, L. T. and E. R. Peskind (2002). "Pharmacologic treatments of dementia." Med Clin North Am 86(3): 657-74.
The management of dementia patients encompasses pharmacologic, behavioral, and psychosocial intervention strategies. Before pharmacologic intervention is instituted, it is important that sources of excess disability and comorbidity be eliminated or reduced. Identification of comorbid medical and psychiatric conditions, such as depression and delirium, should be identified and appropriately treated. Providing caregivers with education, support, and practical advice is a critical component of the management of the demented patient. The current standard of care for pharmacologic management of the cognitive and functional disabilities of AD consists of the combination of a cholinesterase inhibitor and high-dose vitamin E. This standard is based on the results of large-scale, double-blind, placebo-controlled trials. Cholinesterase inhibitors are the only FDA-approved pharmacologic treatments for AD. Cholinesterase inhibitors have been shown to be effective in the treatment of the cognitive, behavioral, and functional deficits of AD. Large-scale placebo-controlled trials of tacrine, donepezil, rivastigmine, and galantamine have demonstrated moderate benefits in patients with mild to moderate AD. Donepezil, rivastigmine, and galantamine are the first-line choices in the treatment of AD because of their lack of hepatotoxicity, ease of administration, few significant drug-drug interactions, and mild to moderate side effects. There are few contraindications to the use of cholinesterase inhibitors. Known hypersensitivity to a specific drug or its derivatives is the only true contraindication. Cautious administration of cholinesterase inhibitors is advised in patients who have a previous history of allergy or adverse reactions to prior cholinesterase inhibitors, severe liver disease, preexisting bradycardia, peptic ulcer disease, current alcoholism, asthma, or chronic obstructive pulmonary disease. Nausea, vomiting, diarrhea, and anorexia are the most common side effects of cholinesterase inhibitors. These gastrointestinal side effects can be minimized by gradual dose increases, administration with food, adequate hydration, and judicious use of an antiemetic. Vitamin E has been demonstrated to slow the progression of AD in several small and one large placebo-controlled trials. Because of its low cost and safety, it is recommended in addition to a cholinesterase inhibitor for the treatment of AD. There are no FDA-approved treatments for DLB and VaD. One small placebo-controlled trial demonstrated that rivastigmine may be effective in the treatment of DLB. More large-scale placebo-controlled trials are needed to confirm the results of this study. Treatment of VaD focuses on the control, identification, and management of cerebrovascular disease and vascular risk factors. Although there are no peer-reviewed reports on the efficacy of cholinesterase inhibitors for VaD or mixed AD/VaD, early reports suggest that these agents may also be effective for mixed AD/VaD. The indications for the use of cholinesterase inhibitor drugs are eventually likely to broaden to include DLB, mixed AD/VaD, and AD in its more advanced stages.
Borroni, B., N. Akkawi, et al. (2002). "Microvascular damage and platelet abnormalities in early Alzheimer's disease." J Neurol Sci 203-204: 189-93.
Accumulating evidence from epidemiological and clinical studies suggests that vascular risk factors may be involved in Alzheimer disease (AD). Although the precise contribution of vascular disturbances to the pathogenesis of AD is still unclear, various biochemical and neuropathological data strengthen the view that cerebrovascular deficiencies such as reduced blood supply to the brain and disrupted microvascular integrity in brain parenchyma play a direct or intermediate role in the chain of events ending with a dementia syndrome. The present review focuses on platelet abnormalities and hemostatic alterations in AD. In particular, data from our group, along with current literature, are discussed with regard to the evidence of platelets amyloid precursor protein (APP) processing disturbances in early AD as well as to the recent observations of increased serum levels of thrombomodulin and sE-selectin, which are sensitive markers of endothelial dysfunction. These findings strongly indicate that platelet dysfunction and microvasculature deficiencies occur rather early during the course of AD, thus suggesting a further link between AD-related processes and vascular disorders.
Bosworth, H. B. and I. C. Siegler (2002). "Terminal change in cognitive function: an updated review of longitudinal studies." Exp Aging Res 28(3): 299-315.
We provide an update to Siegler's (1975) review of the terminal change literature. Articles identified through MEDLINE, CANCERLIT, PUBMED, and PSYCINFO from 1975 to 2000 were examined. Lower levels of cognitive function are related to increased risk of mortality; however, the relationship between rate of cognitive change and mortality is less clear. Although there has been an increase in the number of studies since our last review, prior studies have been limited by a lack of medical data, consideration of dementia, small sample sizes, and poor cognitive measures. The emphasis on Alzheimer's disease and the growth of epidemiology of aging in the past 25 years have provided well-characterized population studies with serial cognitive measures that provide an opportunity to test the theory of terminal change.
Bottini, N., E. Bottini, et al. (2002). "Low-molecular-weight protein tyrosine phosphatase and human disease: in search of biochemical mechanisms." Arch Immunol Ther Exp (Warsz) 50(2): 95-104.
A major challenge in the post-genomic era is to identify the physiological functions of genes and elucidate the molecular basis for human disease. Genetic polymorphisms offer a convenient avenue for these efforts by providing evidence for the involvement of a given gene in human pathophysiology. Here we review the current evidence linking the low-molecular-weight protein tyrosine phosphatase (LMPTP) to several common diseases, including allergy, asthma, obesity, myocardial hypertrophy, and Alzheimer's disease. Based on the known effects of the genetic polymorphisms on the alternative mRNA splicing and enzyme levels of LMPTP, we discuss the possible molecular mechanisms of LMPTP involvement in these diseases.
Bower, F. L., C. S. McCullough, et al. (2002). "Synthesis of research findings regarding Alzheimer's disease: part IV, Education of family and staff caregivers." Online J Knowl Synth Nurs 9: 6.
The purpose of this synthesis of research findings regarding education of family and staff caregivers of people with Alzheimer's disease (AD) is to provide knowledge about what has been tried and what has been successful in terms of education for both family and staff caregivers. This article provides research findings concerning family and staff education, content of these educational programs, and impact of education on staff and family. The implications of research for practice of nurses are also presented. The article concludes with comments about the nature of research so far and what needs to be accomplished in the future.
Bower, F. L., C. S. McCullough, et al. (2002). "Synthesis of research findings regarding Alzheimer's disease: part III, Caregiver burden and care settings." Online J Knowl Synth Nurs 9: 5.
While Alzheimer s disease (AD) is devastating for those who acquire it, AD can be equally devastating for the caregiver, whether that person is a professional or a family member. This article contains synthesized knowledge about the effects of AD on caregivers and the attempts that have been made to create special care units, residential living facilities, and group living arrangements to meet the unique needs of AD patients and their caregivers. While the research regarding caregivers of AD patients and the attempts to provide alternatives to institutionalization are not extensive, the findings presented here have proved to be very useful as a basis for clinical practice and future research.
Bower, F. L., C. S. McCullough, et al. (2002). "Synthesis of research findings regarding the care of people with Alzheimer's disease--Part II." Online J Knowl Synth Nurs 9: 4.
The purpose of this review is to present knowledge about the treatment of Alzheimer's disease (AD). Synthesized research findings about the pharmacological and nonpharmacological interventions used with patients who have Alzheimer's disease are presented and are followed by a discussion regarding the actions nurses can initiate to enhance functioning and delay institutionalization. While there is a great deal of interest and study of AD treatment, the research is variable and often with small populations. Even so, the results of these studies are promising, as they provide information about the ways AD symptoms can be controlled by medication and other means.
Bower, F. L., C. S. McCullough, et al. (2002). "Synthesis of research findings regarding assessment/diagnosis of Alzheimer's disease--Part I." Online J Knowl Synth Nurs 9: 3.
Alzheimer's disease (AD) is predicted to strike 14 million Americans by 2050. To date, the only accurate way to diagnose this devastating disease is at autopsy, so the importance of ruling out other diseases and instituting a plan of care for early symptoms is vital. The purpose of this review is to synthesize the knowledge about the assessment and diagnosis of Alzheimer's disease so clinicians can understand what is needed to differentiate AD from other diseases/conditions.
Bowers, W. J. and H. J. Federoff (2002). "Amyloid immunotherapy-engendered CNS inflammation." Neurobiol Aging 23(5): 675-6; discussion 683-4.
Bowler, J. V. (2002). "The concept of vascular cognitive impairment." J Neurol Sci 203-204: 11-5.
Vascular dementia (VaD) is increasingly recognised to reflect an outmoded concept in that it identifies cases too late for preventive therapy to have an opportunity to prevent the development of dementia and uses a cognitive paradigm inappropriately based on Alzheimer's disease. A replacement is urgently required and a new concept, that of vascular cognitive impairment (VCI), has been proposed to meet this need. It is imperative that criteria for VCI are developed on the basis of knowledge and data rather than supposition and assumption, as was the case for VaD. This review details the state of knowledge that we have now reached concerning the fundamental points of severity and cognitive paradigm and also covers a number of other imaging-related essential points embracing atrophy, leukoaraiosis, infarct volume and infarct location. Finally, the increasingly important concept of mixed dementia (co-existent Alzheimer's disease and VCI) is discussed.
Brendza, R. P., K. R. Bales, et al. (2002). "Role of apoE/Abeta interactions in Alzheimer's disease: insights from transgenic mouse models." Mol Psychiatry 7(2): 132-5.
Brodaty, H. and A. Green (2002). "Who cares for the carer? The often forgotten patient." Aust Fam Physician 31(9): 833-6.
BACKGROUND: Dementia not only affects the patient but also those nearest the patient most notably the carer. It is known that caring for a patient with dementia can adversely affect one's psychological, physical, social and financial health. OBJECTIVE: To highlight the needs of the carer of a patient with dementia and suggest means by which general practitioners may provide the necessary support for these carers. DISCUSSION: The GP has a key role in providing support to the carer of the patient with dementia. General practitioners and carers can work as partners in the long term management of dementia thereby reducing the adverse health effects on the carer.
Bronge, L. (2002). "Magnetic resonance imaging in dementia. A study of brain white matter changes." Acta Radiol Suppl(428): 1-32.
Non-specific white matter changes (WMC) in the brain are common findings in the elderly population. Although they are frequently seen in non-demented persons, WMC seem to be more common in demented patients. The significance of these changes, as well as their pathophysiological background, is incompletely understood. The aim of this thesis was to study different aspects of WMC using MR imaging (MRI) and to investigate the clinical significance of such changes in subjects with mild cognitive impairment or dementia. In study I post-mortem MRI of the brain was compared to corresponding neuropathology slices. WMC were quantified and found to be more extensive on neuropathology. The areas that appeared normal on MRI but not on histopathology represented only minor changes with increased distance between the myelinated fibres but with preserved axonal network and glial cell density. Study II evaluated the blood-brain barrier (BBB) integrity to investigate if an increased permeability could be shown in WMC. A contrast-enhanced MRI technique was used to detect small degrees of enhancement. No general increase in BBB could be detected in the WMC areas. In study III the relation between WMC and apolipoprotein E (APOE) genotype was explored in patients with Alzheimer's disease (AD). Results showed that AD patients, who were homozygous for the APOE epsilon 4 allele had more WMC than patients with other genotypes. This was most significant for changes in the deep white matter. Results also indicated that in AD patients carrying the epsilon 4 allele, WMC are not age-related phenomena, but might be related to the aetiology of the disease. Study IV aimed to investigate if WMC in a specific brain region affect cognitive functions related to that area. Periventricular WMC in the left frontal lobe predicted a decrease in initial word fluency, a test though to reflect left frontal lobe functioning. This indicates that WMC might have specific effects in different brain regions. In study V we evaluated the prognostic significance of WMC in patients with memory impairment, regarding the rate of further global cognitive decline. There was no difference in outcome between patients having extensive WMC and a matched control group, during 2-4 years of follow up, and assessed by the "Mini-Mental State Examination". In conclusion, this work has shown and characterised pathological changes in the white matter not visible on conventional MRI. We have also shown that there is no major general increase in BBB permeability in areas of WMC. In addition, homozygosity with regard to the APOE epsilon 4 gene allele implies an increased extent of WMC in AD patients. In AD patients carrying this gene allele, WMC are not merely age-related phenomena, but might be related to the aetiology of the disease. We also claim that WMC in a specific location might impair cognitive functions that rely on those specific pathways. In contrast, WMC do not seem to have any prognostic value in predicting the rate of global cognitive decline in patients at a memory clinic.
Brown, P. (2002). "Drug therapy in human and experimental transmissible spongiform encephalopathy." Neurology 58(12): 1720-5.
During the past 30 years, over 60 different chemical compounds have been used to treat experimental animals infected with transmissible spongiform encephalopathies (TSE), including a wide variety of anti-infectious agents, immunomodulating drugs, and chemicals interacting with the lympho-reticular system. Some compounds achieved a prolongation of the incubation period, but this effect decreased or disappeared when they were administered at or near the onset of symptomatic disease. Recent in vitro and tissue culture studies support earlier speculation about the importance of a chemical structure containing both water-soluble and lipid-soluble components, evidently as a means of interaction with the misfolded membrane-bound 'prion' protein. A number of compounds shown to eliminate the protein (or infectivity) in TSE-infected tissue cultures are the subject of ongoing studies in animals, and are under consideration for human drug trials. As with other recalcitrant infections, combinations of drugs with different modes of action are likely to be necessary for any effective therapy. Also, very recent work in developing antibodies that can neutralize in vitro infection (and, in conjunction with genetic engineering, in vivo infection) has renewed interest in the strategies of both active and passive immunization.
Bruce-Keller, A. J. and S. Estus (2002). "Concern over the amyloid vaccine: amyloid heterogeneity and Fc receptor signaling." Neurobiol Aging 23(5): 667-70; discussion 683-4.
Bucciarelli, L. G., T. Wendt, et al. (2002). "RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease." Cell Mol Life Sci 59(7): 1117-28.
Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation end-products, amyloid beta peptide and the family of beta sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered.
Buckwalter, M., J. P. Pepper, et al. (2002). "Molecular and functional dissection of TGF-beta1-induced cerebrovascular abnormalities in transgenic mice." Ann N Y Acad Sci 977: 87-95.
Cerebrovascular abnormalities, such as reduced blood flow, microvascular fibrosis, and cerebrovascular amyloid angiopathy, are prominent in Alzheimer's disease (AD). However, their etiology is poorly understood and it is unclear whether cerebrovascular changes contribute to functional impairments in the absence of neurodegeneration. In humans with AD, transforming growth factor-beta1 (TGF-beta1) mRNA levels in the midfrontal gyrus correlate positively with the relative degree of cerebrovascular amyloid deposition in that brain region, suggesting a possible role for TGF-beta1 in human cerebrovascular abnormalities. Transgenic mice overexpressing TGF-beta1 in astrocytes develop AD-like cerebrovascular abnormalities, including perivascular astrocytosis, microvascular basement membrane thickening, and accumulation of thioflavin S-positive amyloid in the absence of parenchymal degeneration. Mice overexpressing TGF-beta1 alone or in addition to human amyloid precursor protein (hAPP) show selective accumulation of human beta-amyloid (Abeta) in blood vessels and develop cerebral hemorrhages in old age. In 9-month-old TGF-beta1 transgenic mice, cerebral blood flow (CBF) in the limbic system was significantly less than in nontransgenic littermate controls. Aged TGF-beta1 mice also showed overall reduced cerebral glucose uptake (CGU) as a measure of brain activity. Thus, chronic overproduction of TGF-beta1 in the brain results in structural and functional impairments reminiscent of those in AD cases with amyloid angiopathy.
Buee, L., M. Hamdane, et al. (2002). "[Tau story: from frontotemporal dementia to other tauopathies]." J Soc Biol 196(1): 103-8.
Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, the recent discovery of tau gene mutations in fronto-temporal dementia with parkinsonism linked to chromosome 17 has reinforced the direct role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies. Conversely, recent data in myotonic dystrophy has demonstrated that indirect effect (CTG repeat expansion) leading to variations in tau alternative splicing also produce neurofibrillary degeneration.
Bullock, R. (2002). "The clinical benefits of rivastigmine may reflect its dual inhibitory mode of action: an hypothesis." Int J Clin Pract 56(3): 206-14.
Recent health technology assessments have given us the go-ahead to use cholinesterase inhibitors, which, in combination with community services, are currently the most appropriate treatment for patients with Alzheimer's disease (AD). Initial research focused upon acetylcholinesterase (AChE)-selective agents, but it is now thought that dual inhibitors of AChE and butyrylcholinesterase (BuChE) may provide more sustained efficacy over the course of AD and may help to slow disease progression. Rivastigmine is a potent inhibitor of AChE and BuChE and has demonstrated broad benefits across the severity of AD and across the cognitive, functional and behavioural domains of AD. In addition, rivastigmine has shown cognitive and behavioural benefits in patients with dementi