[ Index ] [ Page Up ]

(205 References)

(2002). "Vinpocetine. Monograph." Altern Med Rev 7(3): 240-3.

(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            This chapter reviews 73 published and unpublished research reports of interventions for family members caring for an elder with dementia by nurse researchers and researchers from other disciplines.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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 dementia with the Lewy body variant of AD. These benefits may reflect the inhibition of both AChE and BuChE, as demonstrated by significant correlations between cognitive improvements and cholinesterase inhibition in rivastigmine-treated patients with AD. Rivastigmine shows a clear dose-response relationship, and physicians should aim to maintain patients on doses of 6 mg/day or higher, to a maximum of 12 mg/day. As with all cholinesterase inhibitors, rapid forced dose escalation may increase the incidence of typical cholinergic side-effects, resulting in lower maintenance doses. In a chronic disease such as AD, there is time to implement slow dose escalation and higher final maintenance doses. If used appropriately, the benefits of rivastigmine seen in clinical practice may prove to be even greater than those reported in clinical trials.

Bullock, R. (2002). "New drugs for Alzheimer's disease and other dementias." Br J Psychiatry 180: 135-9.

            BACKGROUND: Alzheimer's disease management involves symptomatic drug treatments passed by the National Institute for Clinical Excellence. Disease modification is now the goal. AIMS: To review current and developmental drugs for Alzheimer's disease, their usage, and the clinical context of known facts and proposed specific models. METHOD: A brief evidence-based review was made, using literature where available, or evidence from consensus groups where it was absent. RESULTS: There is good evidence to support the use of cholinesterase inhibitors, and perhaps vitamin E. Oestrogen and anti-inflammatory agents show possibility, but there is not enough evidence to support routine use. CONCLUSIONS: Symptomatic treatments exist for Alzheimer's disease. Observational studies and increasing knowledge of brain biology are leading towards further treatment options. Old age psychiatrists have valuable treatments they now have to learn to use.

Burgener, S. C. and P. Twigg (2002). "Interventions for persons with irreversible dementia." Annu Rev Nurs Res 20: 89-124.

            This chapter provides an overview and critique of the theoretical and research literature by nurse researchers and researchers in other disciplines regarding interventions for persons with dementia (PWD). Reports were included if published in English between 1990 and 2000 and if a descriptive, correlational, longitudinal, or intervention design was used. Case studies and narrative descriptions were not included. No specific age criteria for study participants were applied; however, PWD are generally over age 55. The theoretical literature and various disease stages were reviewed, including clinical and behavioral indicators for disease progression. Using a variety of approaches to survey the extant literature (review of computer databases, contacts with experts in the field, ancestry method, and manual searches of key gerontology journals), over 1,200 citations were initially reviewed, allowing for approximately 375 publications undergoing thorough analysis with 157 research publications being included in this synthesis. Key findings include the identification of well-supported cognitive-behavioral interventions to enhance cognitive functioning and memory, and to relieve depression in the early disease stages; multiple environmental and behavioral approaches for improvement in functioning, maintenance of activities, and alleviation of behavioral symptoms in the middle disease stages; and behavioral, interactive, and staff support and education interventions for adequate nutritional intake, urinary incontinence, and management of problematic vocalizations and other behavioral symptoms in the later disease stages. Recommendations for future studies include the need for development of operational definitions of behavioral symptoms, inclusion of the perspective of PWD, evaluation of long-term outcomes, adequate sample size, community rather than institutional-based studies, and increased intervention testing at various stages of the disease.

Burggren, A. C. and S. Y. Bookheimer (2002). "Structural and functional neuroimaging in Alzheimer's disease: an update." Curr Top Med Chem 2(4): 385-93.

            The field of neuroimaging has made several recent advances understanding Alzheimer's disease, a debilitating disease which affects approximately 4 million people in the United States [1]. Despite recent therapeutic advances, available treatments at present are aimed primarily at slowing progression of the disease rather than halting it completely or reversing its progression. Early detection of the disease has, therefore, been a major focus of a variety of neuroimaging techniques, including Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI), and structural MRI. Recently, these techniques have also been found to be useful in monitoring cognitive and pathological progression of the disease, as well as monitoring response to clinical intervention treatment. A methodology review will be included here as well as a critical evaluation of the advantages and disadvantages of the various techniques.

Bush, A. I. and R. E. Tanzi (2002). "The galvanization of beta-amyloid in Alzheimer's disease." Proc Natl Acad Sci U S A 99(11): 7317-9.

Campbell, A. (2002). "The potential role of aluminium in Alzheimer's disease." Nephrol Dial Transplant 17 Suppl 2: 17-20.

            Aluminium is a trivalent cation that does not undergo redox changes. It has, nonetheless, been implicated in a variety of neurological disorders that have been associated with an increase in the formation of reactive oxygen species (ROS). The exact mechanism of aluminium toxicity is not known. However, accumulating evidence suggests that the metal can potentiate oxidative and inflammatory events, leading to tissue damage. A review of the epidemiological and clinical evidence linking aluminium to Alzheimer's disease (AD) is presented. The article discusses the role of aluminium in two mechanisms that have been linked to neurodegenerative disorders, including AD. Studies are summarized that describe how aluminium can potentiate iron-induced oxidative events. Involvement of aluminium in inflammatory responses, mediated by interleukins and other inflammatory cytokines, is also discussed. Although a direct relationship between aluminium and AD has not been clearly demonstrated, a detailed mechanistic basis for the hypothesis that aluminium may exacerbate events associated with AD is clearly emerging. The results discussed here have broad implications for the role played by aluminium and other metals in neurodegenerative diseases, and suggest that long-term exposure to supra-physiological amounts these metals should be avoided.

Cardinali, D. P., L. I. Brusco, et al. (2002). "The use of melatonin in Alzheimer's disease." Neuroendocrinol Lett 23 Suppl 1: 20-3.

            About 45% of Alzheimer's disease (AD) patients have disruptions in their sleep and sundowning agitation. Since melatonin secretion is greatly inhibited in AD patients we have used melatonin to treat sleep disorders in AD patients since 1995. In a first study [21] we reported, in 7 out of 10 dementia patients treated with melatonin (3 mg p.o. at bed time), a decreased sundowning. In a second study [22] we examined 14 AD patients who received 9 mg melatonin daily for 22 to 35 months, observing a significant improvement of sleep quality with stabilization of behavioral and cognitive parameters. In a third study [23] we reported two monozygotic twins with AD and similar cognitive impairment, one of them receiving 6 mg melatonin at bedtime daily for 3 years. Melatonin treatment improved sleep quality and suppressed sundowning. We now report the effect of melatonin (4-month-long treatment with 6 mg/day) in 45 AD patients with sleep disturbances. Melatonin improved sleep and suppressed sundowning, an effect seen regardless of the concomitant medication employed to treat cognitive or behavioral signs of AD. Melatonin treatment seems to constitute a selection therapy to ameliorate sundowning and to slow evolution of cognitive impairment in AD patients.

Chassagne, P., L. Druesne, et al. (2002). "[Advances in geriatrics]." Rev Med Interne 23(3): 220-4.

Chiu, E. (2002). "Alzheimer disease. Current treatment options." Aust Fam Physician 31(4): 323-6.

            BACKGROUND: In the past Alzheimer disease (AD) has been presented to elderly people and their families as a very frightening condition, based on media representation of the worst possible case scenarios. OBJECTIVE: The current status of pharmacological and psychosocial Intervention in Alzheimer disease is reviewed from the recent literature. DISCUSSION: In the last decade, the picture of AD has turned to one of hope and optimism as a result of advances in developing pharmacological and psychological management.

Cholerton, B., C. E. Gleason, et al. (2002). "Estrogen and Alzheimer's disease: the story so far." Drugs Aging 19(6): 405-27.

            The ovarian hormone estrogen has long been used to treat the physical symptoms of menopause and to aid in the prevention of osteoporosis in postmenopausal women. Cumulative evidence from basic science and clinical research suggests that estrogen also plays a significant neuromodulatory and neuroprotective role. The numerous estrogenic effects in the brain include the modulation of synaptogenesis, increased cerebral blood flow, mediation of important neurotransmitters and hormones, protection against apoptosis, anti-inflammatory actions, and antioxidant properties. These multiple actions in the central nervous system support estrogen as a potential treatment for the cognitive decline associated with Alzheimer's disease (AD), the most common form of dementia. Evidence from epidemiological studies supports enhanced cognitive function in women with AD taking estrogen replacement therapy (ERT) as well as a reduced risk for developing AD in healthy women receiving ERT. Additional clinical evidence suggests that estrogen may modulate specific cognitive functions such as working memory and verbal learning and memory. However, results from more recent controlled trials have not consistently shown a beneficial effect of estrogen on the cognitive function of women with AD. Future research should focus on examining the influence of multiple potential mediators of ERT including the route of estrogen administration, form of estrogen (conjugated estrogens vs estradiol), duration of treatment, opposed versus unopposed estrogen and the use of estrogen analogues. Further, sensitive neuropsychological measures may provide more detailed information concerning the specific effects of estrogen on cognitive function. These important issues must be addressed in order to establish the role of estrogen for the prevention and treatment of AD in women.

Christen, Y. (2002). "[Proteins and mutations: a new vision (molecular) of neurodegenerative diseases]." J Soc Biol 196(1): 85-94.

            Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.

Cohen, G. D. (2002). "Alzheimer's disease. Managing behavioral problems in patients with progressive dementia." Geriatrics 57(2): 53-4.

Collie, A. and P. Maruff (2002). "An analysis of systems of classifying mild cognitive impairment in older people." Aust N Z J Psychiatry 36(1): 133-40.

            OBJECTIVE: Over the past two decades, a number of systems have been developed for the classification of cognitive and behavioural abnormalities in older people, in order that individuals at high risk of developing neurodegenerative disease, particularly Alzheimer's disease, may be identified well before the disease manifests clinically. This article critically examines the inclusion and exclusion criteria of a number of such classification systems, to determine the effect that variations in criterion may have on clinical, behavioural and neuroimaging outcomes reported from older people with mild cognitive impairment. METHOD: Qualitative review of the literature describing systems of classifying mild cognitive impairment, and outcomes from clinical, behavioural, neuroimaging and genetic studies of older people with mild cognitive impairment. RESULTS: The exclusion and inclusion criteria for these classification systems vary markedly, as do the design of studies upon which the validity of these systems has been assessed. Minor changes to individual exclusion/inclusion criterion may result in substantial changes to estimates of the prevalence and clinical outcome of mild cognitive impairment, while inadequate experimental design may act to confound the interpretation of results. CONCLUSIONS: As a result of these factors, accurate and consistent estimates of the outcome of mild cognitive impairments in otherwise healthy older people are yet to be obtained. On the basis of this analysis of the literature, optimal criteria via which accurate classifications of mild cognitive impairment can be made in future are proposed.

Colton, C. A., C. M. Brown, et al. (2002). "Apolipoprotein-E allele-specific regulation of nitric oxide production." Ann N Y Acad Sci 962: 212-25.

            Cognitive decline and dementia are key features of Alzheimer's disease (AD) that result from failure of neuronal function. Affected neurons demonstrate indices of nitrosative stress resulting from changes in nitric oxide (NO) mediated redox balance. Neurofibrillary tangles, a characteristic neuropathologic feature of AD, and dysfunctional neurons frequently display 3-nitrotyrosine or other markers of nitrosative stress and immunoreactive nitric oxide synthase (NOS), suggesting that NOS-containing neurons are affected in AD. Our previous studies showed that apolipoprotein E treatment of macrophages increased NO production. Using transgenic mouse models expressing human apoE2, apoE3, or apoE4 protein isoforms and no mouse apoE, we now report an isoform specific difference in microglial NO production. Mice expressing the apoE4 protein isoform have a greater NO production than mice expressing the apoE3 protein isoform. The supply of arginine, the sole substrate for NOS, is dependent on cationic amino acid transporters (CATs) that also demonstrate a similar pattern of apoE isoform dependency. Although arginine transport is greater in APOE4 microglia, this effect is not limited to tissue macrophages. Cortical neurons in primary culture from APOE4 transgenic mice exhibit a similar increase in arginine uptake over neurons cultured from APOE3 mice. The inappropriate levels of arginine transport and of NO in the presence of the APOE4 compared to the APOE3 gene and its products are likely to have significant impact in the CNS.

Combarros, O., A. Alvarez-Arcaya, et al. (2002). "Candidate gene association studies in sporadic Alzheimer's disease." Dement Geriatr Cogn Disord 14(1): 41-54.

            The genetics of Alzheimer's disease (AD) is complex. Three genes (amyloid precursor protein, presenilin 1 and presenilin 2) have been described in the relatively rare, early-onset, autosomal dominant familial form of AD. In the common, non-familial (sporadic) late-onset AD, the major known genetic risk factor is the epsilon4 allele of the apolipoprotein E (APOE) gene. However, at least half of the people who develop AD do not carry this allele, and not all people who do carry this allele develop AD even if they live to an old age. Therefore, approximately 30 other candidate genes involving a protein in a critical pathway in the pathogenesis of disease (principally interaction with amyloid-beta, oxidative stress and inflammation/apoptosis) have been considered as risk factors for sporadic AD. Then these genes have been sequenced in search of genetic variability or polymorphisms, and each putative polymorphism has been reported to alter the risk of AD either directly or by an interaction with the APOE epsilon4 allele. However, positive-association studies with these candidate genes have not been consistently confirmed.

Compton, J., T. van Amelsvoort, et al. (2002). "Mood, cognition and Alzheimer's disease." Best Pract Res Clin Obstet Gynaecol 16(3): 357-70.

            There is good evidence for sex differences in brain disease, and that oestrogen modulates brain development and ageing. For example, females are significantly more likely to suffer from Alzheimer's disease, depression and late-onset psychosis than are men. Moreover, hormone replacement therapy may reduce the rate of cognitive decline in post-menopausal women and reduce their risk of developing Alzheimer's disease (as compared to post-menopausal women who do not take hormone replacement therapy). The neurobiological basis of these differences in brain disease and ageing was unknown until relatively recently. In this chapter we discuss results of studies demonstrating that sex steroids (i) are crucial for development and ageing of brain regions affected in Alzheimer's disease; (ii) interact with neuronal networks and chemical systems at many different levels in brain, and (iii) affect mood and cognitive function in elderly women without Alzheimer's disease. The current literature supports the hypothesis that sex steroids can modulate brain ageing and provides a number of potential neurobiological explanations for the cognitive effects of hormone replacement therapy. There is only limited evidence that hormone replacement therapy is effective in women already suffering from Alzheimer's disease. Nonetheless, recent work may lead to new prevention strategies for age-related cognitive decline and brain diseases such as Alzheimer's disease.

Cox, P. A. and O. W. Sacks (2002). "Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam." Neurology 58(6): 956-9.

            The Chamorro people of Guam have been afflicted with a complex of neurodegenerative diseases (now known as ALS-PDC) with similarities to ALS, AD, and PD at a far higher rate than other populations throughout the world. Chamorro consumption of flying foxes may have generated sufficiently high cumulative doses of plant neurotoxins to result in ALS-PDC neuropathologies, since the flying foxes forage on neurotoxic cycad seeds.

Cummings, J. L., J. C. Frank, et al. (2002). "Guidelines for managing Alzheimer's disease: Part II. Treatment." Am Fam Physician 65(12): 2525-34.

            Once the clinical diagnosis of Alzheimer's disease has been made, a treatment plan must be developed. This plan should include cholinesterase inhibitor therapy to temporarily improve cognition or slow the rate of cognitive decline, management of comorbid conditions, treatment of behavioral symptoms and mood disorders, provision of support and resources for patient and caregiver, and compliance with state-mandated reporting requirements for driving impairment and elder abuse. The primary caregiver can be a valuable ally in communication, management of care, and implementation of the care plan. Patient symptoms and care needs change as Alzheimer's disease progresses. In the early stage of the disease, the family physician should discuss realistic expectations for drug therapy, solicit patient and family preferences on future care choices, and assist with advance planning for future care challenges. In the middle stage, the patient may exhibit behavioral symptoms that upset the caregiver and are difficult to manage. When the patient is in the advanced stage of Alzheimer's disease, the caregiver may need support to provide for activities of daily living, help in making a difficult placement decision, and guidance in considering terminal care options. Throughout the course of the disease, routine use of community resources allows care to be provided by a network of professionals, many of whom will be specialists in Alzheimer's disease.

Cummings, J. L., J. C. Frank, et al. (2002). "Guidelines for managing Alzheimer's disease: part I. Assessment." Am Fam Physician 65(11): 2263-72.

            Family physicians play a key role in assessing and managing patients with Alzheimer's disease and in linking the families of these patients to supportive services within the community. As part of comprehensive management, the family physician may be responsible for coordinating assessments of patient function, cognition, comorbid medical conditions, disorders of mood and emotion, and caregiver status. Suggestions for easily administered and scored assessment tools are provided, and practical tips are given for supporting primary caregivers, thereby increasing efficiency and quality of care for patients with Alzheimer's disease.

Cummings, J. L. and G. Cole (2002). "Alzheimer disease." Jama 287(18): 2335-8.

Dartigues, J. F., C. Helmer, et al. (2002). "[Alzheimer's disease: a public health problem: yes, but a priority?]." Rev Neurol (Paris) 158(3): 311-5.

            Alzheimer's Disease is a major Public Health problem for many reasons. First, it is a frequent disease since, in France, the prevalence was estimated at about 400.000 cases, and the annual incidence at 100.000 cases. The frequency of the disease increases, in particular due to the ageing of the population. This disease has major consequences on the life of the patient and his/her caretaker. The cost of the disease is important, estimated at about 50 milliards of French francs. Pharmaceutical treatment and other interventions are possible in particular to delay the nursing home placement. On the other hand, this disease is often ignored, under-diagnosed, underestimated and exposed to inequality in resorting to care. In summary, Alzheimer's Disease (AD) has all the criteria required for a major public health problem. In spite of this observation, AD is not yet considered as a priority for health authorities, although attitudes are changing.

Das, U. N. (2002). "Estrogen, statins, and polyunsaturated fatty acids: similarities in their actions and benefits-is there a common link?" Nutrition 18(2): 178-88.

            OBJECTIVES: To investigate whether there is any common link between estrogen, statins, and polyunsaturated fatty acids (PUFAs), which have similar actions and benefits. METHODS: To critically review the literature pertaining to the actions of estrogen, statins, and various PUFAs. RESULTS: Estrogen, statins, and PUFAs enhance nitric oxide synthesis, suppress the production of proinflammatory cytokines such as tumor necrosis factor(alpha), interleukin-1, interleukin-2, and interleukin-6, show antioxidant-like and antiatherosclerotic properties, have neuroprotective actions, and by themselves or their products inhibit tumor cell proliferation and improve osteoporosis. Estrogen, statins, and PUFAs not only have similar actions but also appear to interact with each other. For instance, the binding of estrogen to its receptor on the cell membrane may be determined by its lipid content, statins and PUFAs inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, statins influence the metabolism of PUFAs, and PUFA deficiency enhances 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Statins and PUFAs inhibit tumor cell proliferation, suppress ras activity, and may prevent neurodegeneration and improve cognitive functions such as learning and memory. This suggests that PUFAs might be mediators of the actions of statins. Estrogen boosts cognitive performance in women after menopause and may protect against Alzheimer's disease. CONCLUSIONS: The common link between estrogen, statins, and PUFAs may be nitric oxide. Hence, a combination(s) of estrogen or its derivatives, statins, and various PUFAs may form a novel approach in the management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, osteoporosis, cancer, neurodegenerative conditions, and to improve memory.

de Figueiredo, J. M. (2002). "Methodological aspects of comparative research in the epidemiology of Alzheimer disease." Am J Geriatr Psychiatry 10(4): 373-85.

            In recent years, major advances have been made in the investigation of the incidence and prevalence of Alzheimer disease in diverse social and cultural settings. Examples of issues being addressed are the methods used to estimate incidence and prevalence, the procedures for data collection and its harmonization, the definitions of numerator (cases) and denominator (population at risk), and the modeling of cognitive decline. This type of research will eventually lead to a better understanding of how protective and modifiable risk factors interact with the genotype to produce this disease.

de la Monte, S. M. and J. R. Wands (2002). "The AD7c-ntp neuronal thread protein biomarker for detecting Alzheimer's disease." Front Biosci 7: d989-96.

            Dementia in Alzheimer's disease (AD) is ultimately due to cell loss mediated by several mechanisms including, apoptosis, impaired mitochondrial function, and possibly necrosis. A second major neuroanatomic correlate of dementia is aberrant cortical neuritic sprouting with abundant proliferation of dystrophic neurites. Early in vivo detection of AD will require non-invasive assays of highly sensitive and relatively specific biomarkers that reflect these fundamental abnormalities in cellular function. The AD-associated neuronal thread protein (AD7c-NTP) gene encodes an approximately 41 kD membrane-spanning phosphoprotein that causes apoptosis and neuritic sprouting in transfected neuronal cells. The AD7c-NTP gene is over-expressed in AD beginning early in the course of disease. In the brain, increased AD7c-NTP immunoreactivity is associated with phospho-tau-immunoreactive cytoskeletal lesions, but not with amyloid-? accumulations. The levels of AD7c-NTP in postmortem brain tissue correlate with the levels measured in paired ventricular fluid samples, suggesting that the protein is secreted or released by dying cells into cerebrospinal fluid (CSF). In this regard, elevated levels of AD7c-NTP can be detected in both CSF and urine of patients with early or moderately severe AD, and the CSF and urinary levels of AD7c-NTP correlate with the severity of dementia. The newest configuration of the AD7c-NTP assay, termed "7c Gold", has greater than 90% sensitivity and specificity for detecting early AD. The aggregate results from a number of studies suggest that AD7c-NTP is an excellent biomarker that could be helpful in the routine clinical evaluation of elderly patients at risk for AD.

de la Torre, J. C. (2002). "Alzheimer disease as a vascular disorder: nosological evidence." Stroke 33(4): 1152-62.

            BACKGROUND: The main stumbling block in the clinical management and in the search for a cure of Alzheimer disease (AD) is that the cause of this disorder has remained uncertain until now. SUMMARY OF REVIEW: Evidence that sporadic (nongenetic) AD is primarily a vascular rather than a neurodegenerative disorder is reviewed. This conclusion is based on the following evidence: (1) epidemiological studies showing that practically all risk factors for AD reported thus far have a vascular component that reduces cerebral perfusion; (2) risk factor association between AD and vascular dementia (VaD); (3) improvement of cerebral perfusion obtained from most pharmacotherapy used to reduce the symptoms or progression of AD; (4) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques to preclinically identify AD candidates; (5) presence of regional brain microvascular abnormalities before cognitive and neurodegenerative changes; (6) common overlap of clinical AD and VaD cognitive symptoms; (7) similarity of cerebrovascular lesions present in most AD and VaD patients; (8) presence of cerebral hypoperfusion preceding hypometabolism, cognitive decline, and neurodegeneration in AD; and (9) confirmation of the heterogeneous and multifactorial nature of AD, likely resulting from the diverse presence of vascular risk factors or indicators of vascular disease. CONCLUSIONS: Since the value of scientific evidence generally revolves around probability and chance, it is concluded that the data presented here pose a powerful argument in support of the proposal that AD should be classified as a vascular disorder. According to elementary statistics, the probability or chance that all these findings are due to an indirect pathological effect or to coincidental circumstances related to the disease process of AD seems highly unlikely. The collective data presented in this review strongly support the concept that sporadic AD is a vascular disorder. It is recommended that current clinical management of patients, treatment targets, research designs, and disease prevention efforts need to be critically reassessed and placed in perspective in light of these important findings.

de Silva, R. and M. Farrer (2002). "Tau neurotoxicity without the lesions: a fly challenges a tangled web." Trends Neurosci 25(7): 327-9.

            Models of neurodegenerative disorders are challenging the classical defining role of tangles in neurotoxicity. In flies, tau overexpression is sufficient to cause neuronal death without the formation of fibrillar aggregates. This parallels observations in models of polyglutamine disorders and suggests that aggregated protein might not be the toxic species responsible for neuronal dysfunction and cell death.

Diehl, J. and A. Kurz (2002). "[Treatment of Alzheimer's disease. The status quo]." Med Monatsschr Pharm 25(1): 8-12.

Dobie, D. J. (2002). "Depression, dementia, and pseudodementia." Semin Clin Neuropsychiatry 7(3): 170-86.

Dominguez, D. I. and B. De Strooper (2002). "Novel therapeutic strategies provide the real test for the amyloid hypothesis of Alzheimer's disease." Trends Pharmacol Sci 23(7): 324-30.

            The amyloid and tangle cascade hypothesis is the dominant explanation for the pathogenesis of Alzheimer's disease (AD). A complete knowledge of the metabolic pathways leading to beta-amyloid (A beta) production and clearance in vivo and of the pathological events that lead to fibril formation and deposition into plaques is crucial for the development of an 'anti-amyloid' therapeutic strategy. Important advances in this respect have been achieved recently, revealing new candidate drug targets. Among the most promising potential treatments are beta- and gamma-secretase inhibitors, A beta vaccination, Cu-Zn chelators, cholesterol-lowering drugs and non-steroidal anti-inflammatory drugs. Now, the major question is whether these drugs will work in the clinic.

Eldar-Finkelman, H. (2002). "Glycogen synthase kinase 3: an emerging therapeutic target." Trends Mol Med 8(3): 126-32.

            Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that has recently emerged as a key target in drug discovery. It has been implicated in multiple cellular processes and linked with the pathogenesis of several diseases. GSK-3 inhibitors might prove useful as therapeutic compounds in the treatment of conditions associated with elevated levels of enzyme activity, such as type 2 diabetes and Alzheimer's disease. The pro-apoptotic feature of GSK-3 activity suggests a potential role for its inhibitors in protection against neuronal cell death, and in the treatment of traumatic head injury and stroke. Finally, selective inhibitors of GSK-3 could mimic the action of mood stabilizers such as lithium and valproic acid and be used in the treatment of bipolar mood disorders.

Emre, M. (2002). "Switching cholinesterase inhibitors in patients with Alzheimer's disease." Int J Clin Pract Suppl(127): 64-72.

            Despite recognition that cholinesterase inhibitors can provide clinical benefits for patients with Alzheimer's disease (AD), the average durations of treatment and beneficial effects are not optimal in all cases. This may be due to disappointing efficacy or poor tolerability of the initial treatment, as well as secondary efficacy failure or adverse effects emerging during the maintenance phase. In such cases, pharmacological differences between available cholinesterase inhibitors provide a good rationale to switch to another drug in the same class. The pharmacological properties of rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase, and donepezil and galantamine, two AChE-selective inhibitors, are reviewed. Rivastigmine is reported to show brain- and brain region-selectivity. Donepezil appeared to be more selective for central than peripheral enzymes in rats. Galantamine and donepezil have also been shown to exert nicotinic receptor allosteric modulation in vitro, while rivastigmine has been shown to increase binding of acetylcholine to nicotinic receptors in the AD brain. Donepezil and galantamine are metabolised by the hepatic CYP450 system, whereas rivastigmine is metabolised by its target enzymes. Several switching studies indicated that a substantial proportion of patients who fail to benefit from treatment with donepezil could draw benefits after being switched to rivastigmine. An immediate switch from donepezil to rivastigmine was reported to be well tolerated and was not associated with cholinergic side effects. A post hoc analysis of a 5-month trial with galantamine showed that patients had similar efficacy outcomes, whether or not they had received prior anticholinesterase therapy, suggesting that a previous failure to respond to another cholinesterase inhibitor did not predict response to galantamine. On the basis of available data it is suggested that patients not tolerating or not responding to one particular cholinesterase inhibitor may still draw benefits upon switching to another.

Engedal, K. (2002). "[Diagnosis and treatment of dementia]." Tidsskr Nor Laegeforen 122(5): 520-4.

            BACKGROUND: Dementia is one of the most common conditions in the elderly. In Norway the total prevalence is about 60,000. MATERIAL AND METHODS: The paper is based on the author's clinical experience and a review of the literature. RESULTS: No biological marker exists for Alzheimer's disease and other dementias. The diagnostic work-up thus consists of a comprehensive clinical neuropsychological, physical and psychiatric examination. Imaging of the brain could be useful in the differential diagnostic work-up. In mild cases and cases of suspected dementia, the work-up is carried out in specialist health care. Moderate and severe cases are assessed on primary care. There is currently no cure for dementia disorders, although acetylcholinesterase inhibitors may prove effective for Alzheimer's disease and Lewy body dementia. Behavioural and psychiatric symptoms can be pharmacologically treated. INTERPRETATION: A careful diagnostic work-up must be carried out to diagnose dementia. Symptomatic treatment is available and should be initiated.

Farcnik, K. and M. S. Persyko (2002). "Assessment, measures and approaches to easing caregiver burden in Alzheimer's disease." Drugs Aging 19(3): 203-15.

            The reduction of caregiver burden for those caring for patients with Alzheimer's disease (AD) is especially important given the prevalence of AD as populations age. This paper reviews the complex nature of caregiver burden, how it is measured, and possible interventions that may affect caregiver burden. Caregiver characteristics as well as symptoms exhibited by patients contribute to burden. A number of specific quantitative measures which have been developed to better evaluate caregiver burden are discussed. Such measures are also useful in measuring the impact of interventions on caregiver burden. Pharmacological treatment of patients with AD through the use of acetylcholinesterase inhibitors has positively affected cognition, activities of daily living, and behavioural problems. These benefits significantly reduce caregiver burden. The same is true for psychosocial interventions for the caregiver. It has been suggested that combining both approaches should be utilised for optimal management. Our knowledge of caregiver burden has greatly increased over the past two decades with clear benefits for both patients and caregivers. However, many aspects still clearly require further research. Given the significance of caregiver burden, various aspects have been extensively studied including contributing and protective factors, quantitative assessment, and pharmacological and psychosocial intervention. It is important for clinicians to be aware of this knowledge so that they can effectively incorporate it into their treatment plans for those affected by AD.

Farlow, M. R. (2002). "Do cholinesterase inhibitors slow progression of Alzheimer's disease?" Int J Clin Pract Suppl(127): 37-44.

            In the absence of a cure for Alzheimer's disease (AD), treatment has focused on therapy to provide symptomatic benefits and to slow progression of the disease, so that patients can maintain their independence for as long as possible. New research suggests that rivastigmine, a potent, pseudo-irreversible inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase that shows preferential selectivity for the G1 form of AChE, may provide symptomatic and disease progression slowing effects. The drug's pharmacological properties may help to slow the conversion of diffuse, benign amyloid plaques to neuritic plaques associated with clinical dementia. In 'delayed-start' paradigms--open-label extensions of placebo-controlled studies involving mild to moderate AD patients--the treatment effects of rivastigmine on cognitive and non-cognitive outcomes at 52 weeks were even greater than those observed at 26 weeks, and patients who received rivastigmine for the entire 52 weeks had better outcomes than those who received rivastigmine only for the latter 26 weeks (having received placebo for the first 26 weeks during the placebo-controlled phase). These treatment effects were even more robust in patients with moderately severe disease, indicating that the sustained long-term benefits of rivastigmine apply across the continuum of disease severity. The results seen in those patients with mild and moderately severe AD suggest that the progression of AD was being slowed in treated patients and that a disease-modifying effect may have been taking place. The effects of rivastigmine on cognition remain clinically relevant for at least 2 years, with benefits over projected placebo increasing over time. The long-term benefits of rivastigmine have also been reported in behavioural domains of patients with mild to moderate AD for 104 weeks and in patients with the Lewy body variant of AD for 96 weeks. Rivastigmine may slow AD progression, allowing patients to maintain autonomy for longer.

Farlow, M. R. (2002). "Cholinesterase inhibitors: relating pharmacological properties to clinical profiles: Introduction." Int J Clin Pract Suppl(127): 1-5.

Felber, S. R. (2002). "Magnetic resonance in the differential diagnosis of dementia." J Neural Transm 109(7-8): 1045-51.

            Magnetic resonance became an important tool for the differential diagnosis of dementia. Magnetic resonance imaging is the preferred method to exclude treatable entities accompanied by dementing symptoms. New techniques including diffusion and perfusion magnetic resonance imaging are helpful for the differentiation between vascular dementia and degenerative disorders. Magnetic Resonance spectroscopy evolves as a tool for the diagnosis of different forms of degenerative dementia. Multimodal magnetic resonance holds promise to diagnose Alzheimer's disease at early clinical stages and to monitor the progression of the disease.

Ferris, S. H. (2002). "Clinical trials in AD: are current formats and outcome measures adequate?" Alzheimer Dis Assoc Disord 16 Suppl 1: S13-7.

            Great strides have been made in the measurement of outcomes and treatment efficacy in clinical trials of Alzheimer disease (AD) drugs during the past 25 years. Several sensitive, reliable, and valid clinical outcome measures have been developed. The methodology, trial design, and outcome measures for demonstrating symptomatic benefits of an AD drug are now established. However, a greater challenge lies ahead. Major advances in fundamental knowledge about the pathophysiology of the disease and in animal models have transformed the focus of current efforts to developing and testing therapies that may actually slow disease progression, delay the onset of symptoms, and even ultimately prevent the disease. The long-duration trials that will likely be necessary to demonstrate an effect on disease progression will be costly and difficult. Proof-of-concept trials and subsequent long-term trials could gain power and efficiency from use of biologic markers of underlying disease severity, but currently available biologic markers are not ideal. A major barrier to such trials is their size and cost. One approach to reducing the cost would be to recruit "enriched" samples of subjects who are at greater risk of developing AD during the trial than the general, elderly population. The major effort required to screen and recruit large numbers of subjects for such trials also contributes to the cost. Probably the biggest problem currently is the enormous effort and cost of conducting periodic clinical evaluations to determine if subjects have declined or developed dementia. Research to develop more efficient assessment methods is clearly needed. Data acquisition over the Internet is potentially efficient and attractive and may become practical as Internet accessibility increases.

Fillit, H. M., A. W. O'Connell, et al. (2002). "Barriers to drug discovery and development for Alzheimer disease." Alzheimer Dis Assoc Disord 16 Suppl 1: S1-8.

            Alzheimer disease (AD) is a neurodegenerative condition leading to progressive, irreversible loss of cognitive and behavioral function. Despite considerable investments in neuroscience research, only four drugs, all cholinesterase inhibitors, have been approved for the symptomatic management of AD in the United States. Although basically safe and modestly effective, these drugs are far from ideal, being neither universally efficacious nor disease modifying. AD exacts a considerable toll in direct medical costs, quality of life, and caregiver burden for persons and society. In addition to the obvious clinical benefit, therapeutic agents for AD and related dementias represent a considerable market opportunity for the pharmaceutical and biotechnology industries. There are currently 8-10 million AD sufferers in the seven major pharmaceutical markets. The market will grow rapidly in coming decades, as the developed world experiences an enormous increase in its elderly population. Given the great need for new therapeutic agents to manage and prevent AD, the Institute for the Study of Aging and the Fidelity Foundation organized a workshop, "Barriers to the Discovery and Development of Drugs for Alzheimer's Disease," to examine ways to expedite drug discovery and development. The identified barriers and potential solutions will be discussed here and in the accompanying articles in more detail.

Findeis, M. A. (2002). "Peptide inhibitors of beta amyloid aggregation." Curr Top Med Chem 2(4): 417-23.

            Amyloid beta peptide (Abeta) is implicated in the pathogenesis of Alzheimer s disease (AD), particularly as oligomers or polymers that are correlated with Abeta cellular toxicity. Inhibition of the formation of toxic forms of Abeta has therefore emerged as one approach to the treatment of AD. This article reviews efforts to adapt the structure of Abeta to the design and testing of peptide-based inhibitors of Abeta polymerization of interest as potential AD therapeutics.

Firbank, M. J., R. M. Harrison, et al. (2002). "A comprehensive review of proton magnetic resonance spectroscopy studies in dementia and Parkinson's disease." Dement Geriatr Cogn Disord 14(2): 64-76.

            We reviewed the literature of proton magnetic resonance spectroscopy (MRS) in dementia and Parkinson's disease (PD) and quantitatively compared the reported values of the markers N-acetyl aspartate (NAA), choline, and myo-Inositol between control and disease groups. We analysed a total of 27 reports in dementia. Combining the quantitative data from these showed a relative decrease of 15% in NAA level in the temporal lobe tissue in patients with Alzheimer's disease (AD) compared with controls. The rest of the brain showed a seemingly uniform 10% decrease in NAA levels in AD compared with controls. myo-Inositol was raised by about 15%, again uniformly throughout the brain, but there was no evidence for changed levels of choline. We found 15 reports of MRS in PD, which show a small decrease (5%) in the NAA level in the lentiform nucleus compared with controls. In progressive supranuclear palsy (PSP), there is a greater decrease in NAA levels in the frontal region and the lentiform nucleus. This may aid in the diagnosis of PSP. Further research is needed to determine spectroscopic changes in other dementias, to monitor how markers change with disease progression and to establish clinical utility.

Freo, U., G. Pizzolato, et al. (2002). "A short review of cognitive and functional neuroimaging studies of cholinergic drugs: implications for therapeutic potentials." J Neural Transm 109(5-6): 857-70.

            In the last 20 years a cholinergic dysfunction has been the major working hypothesis for the pharmacology of memory disorders. Cholinergic antagonists and lesions impair and different classes of cholinomimetics (i.e. acetylcholine precursors, cholinergic agonists and acetylcholinesterase inhibitors) enhance attention and memory in experiment animals, healthy human subjects and Alzheimer disease patients. In addition, acetylcholinesterase inhibitors improve different cognitive (i.e. visuospatial and verbal) functions in a variety of unrelated disorders such as dementia with Lewy bodies, Parkinson disease, multiple sclerosis, schizoaffective disorders, iatrogenic memory loss, traumatic brain injury, hyperactivity attention disorder and, as we recently reported, vascular dementia and mild cognitive impairment. In animals, different cholinomimetics dose-dependently increased regional cerebral metabolic rates for glucose (rCMRglc) and regional blood flow (rCBF), two indices of neuronal function, more markedly in subcortical regions (i.e. thalamus, hippocampus and visual system nuclei). In both healthy human subjects and Alzheimer disease patients acetylcholinesterase inhibitors increased rCMRglc and rCBF in subcortical and cortical brain regions at rest but attenuated rCBF increases during cognitive performances. Hence, acetylcholinesterase inhibitors may enhance cognition and rCMRglc by acting primarily on subcortical regions that are involved in attentional (i.e. thalamus) and memory (i.e. hippocampus) processes; such an effect probably is not specific for Alzheimer disease and can be beneficial in patients suffering from a wide array of neuropsychiatric disorders.

Friedlander, A. H. (2002). "The physiology, medical management and oral implications of menopause." J Am Dent Assoc 133(1): 73-81.

            BACKGROUND: Approximately 36 million women in the United States are in the postmenopausal phase of life. The vast majority of these women experienced spontaneous cessation of menses between the ages of 47 and 55 years when the production of estrogen decreased because of an inadequate number of functioning follicles within their ovaries. Fewer women entered menopause after surgical removal of both ovaries. This procedure usually is performed prophylactically to prevent ovarian cancer in conjunction with a hysterectomy, which is required to treat abnormal bleeding, endometriosis or pelvic inflammatory disease. The physiological changes associated with spontaneous or surgical menopause cause some women to experience uncomfortable symptoms such as hot flashes, night sweats and vaginal dryness. In addition, estrogen deprivation arising from menopause in association with age-related factors disproportionately increases the risk of developing cardiovascular disease (that is, myocardial infarct, stroke), osteoporosis, Alzheimer's disease and oral disease. Hormone replacement therapy, or HRT (estrogen or estrogen and progestin), often is prescribed on a short-term basis to alleviate the uncomfortable symptoms associated with estrogen deficiency and on a long-term basis to prevent some of the chronic illnesses common to postmenopausal women. CONCLUSIONS: Dentists who treat women entering menopause need to consider the stressful phase of life their patients are experiencing. Clinical findings of postmenopausal problems on dental examination may include a paucity of saliva, increased dental caries, dysesthesia, taste alterations, atrophic gingivitis, periodontitis and osteoporotic jaws unsuitable for conventional prosthetic devices or dental implants. Panoramic dental radiographs may reveal calcified carotid artery atheromas. CLINICAL IMPLICATIONS: Dentists have an opportunity to refer women who are not under the care of a gynecologist for an evaluation to determine the appropriateness of HRT for its systemic and oral health benefits.

Frolich, L. (2002). "The cholinergic pathology in Alzheimer's disease--discrepancies between clinical experience and pathophysiological findings." J Neural Transm 109(7-8): 1003-13.

            The cholinergic hypothesis of Alzheimer's disease (AD) states 1. that cholinergic neurons in the basal forebrain are severely affected in the course of disease, detectable both histopathologically by a loss of neurons and neurochemically, by a loss of marker enzymes for acetylcholine synthesis and degradation, and 2. that the resulting cerebral cholinergic deficit leads to memory loss and other cognitive and non-cognitive symptoms, which are characteristic for the illness. This hypothesis was mainly based on studies, which had been conducted on brains of patients with advanced dementia. Nevertheless, it has served as the rationale for the development of drugs, i.e. acetylcholine-esterase inhibitors (AChE-I), which have shown consistent, but modest clinical efficacy against cognitive decline and behavioural symptoms of dementia for a limited period of time. These drugs are presently regarded the standard treatment of dementia in Alzheimer's disease. Now, due to a more sensitive and reliable clinical diagnosis, neurobiological investigations can be performed on early stages of disease, when the changes detected presumably are more relevant for the pathogenesis. New studies on the pathophysiology of the cholinergic system in AD suggest 1. that the cholinergic deficit occurs only late in the disease, 2. that at the earliest stages there even is an upregulation of cholinergic activity in the brain, and 3. that an increased activity of AChE may develop under therapy with AChE-I's. These data show that there is a plasticity of the central cholinergic system in AD and that the positive clinical effects of AChE-I are to be weighted against possible detrimental effects on a pathophysiological level. These data challenge the cholinergic hypothesis in its present form, e.g. should stimulate studies on the underlying process, which leads the cholinergic system to increase its activity in patients in the early stage of AD and may have clinical consequences regarding cholinergic drug therapy.

Fukatsu, R., M. Fujii, et al. (2002). "[Psychiatric symptoms and pathological processes in patients with Alzheimer's disease--special reference to dissection analysis of the visual-spatial world]." Seishin Shinkeigaku Zasshi 104(2): 139-43.

Gareri, P., P. De Fazio, et al. (2002). "Neuropharmacology of depression in aging and age-related diseases." Ageing Res Rev 1(1): 113-34.

            Depression in the elderly is nowadays a predominant health care problem, mainly due to the progressive aging of the population. It results from psychosocial stress, polypathology, as well as some biochemical changes which occur in the aged brain and can lead to cognitive impairments, increased symptoms from medical illness, higher utilization of health care services and increased rates of suicide and non-suicide mortality. Depression may be also caused by a various number of drugs currently administered; this is remarkable especially in elderly people, where polypathology is often associated with polypharmacotherapy. However, the pathogenesis of geriatric depression is not well understood; major depression may arise from dysfunction of the limbic-hypothalamic-pituitary-adrenal axis. Some clinical observations also suggest that striato-frontal dysfunction is associated with late life depression. A number of hypotheses have been made, focusing that mood disturbances are probably linked to a disturbed central metabolism of monoamines 5-hydroxytryptamine, noradrenaline and dopamine; however most of this knowledge is derived from animal models. Parkinson's and Alzheimer's diseases are age-related diseases associated to decreased activity or brain lesions in the orbital frontal cortex and basal ganglia. These observations lead to the hypothesis that the dysfunction of one or more of the cortical basal ganglia-thalamic neuronal loops are involved in the pathophysiology of primary and secondary depression. This dysfunction may be mediated by decreased serotonin release and probably, also by reduction in serotonin receptors. Development of novel approaches such as dynamic brain imaging methods, together with indirect knowledge coming from the effects of new antidepressants, will increase the understanding of neurochemistry of depression in old age.

Gauthier, S. (2002). "Advances in the pharmacotherapy of Alzheimer's disease." Cmaj 166(5): 616-23.

Geldmacher, D. S. (2002). "Cost-effective recognition and diagnosis of dementia." Semin Neurol 22(1): 63-70.

            Alzheimer's disease (AD) has the potential to become the most overwhelming public health concern of this century due to increasing life expectancy and growth in the aging population. As a result, primary care physicians and neurologists will be seeing a greater number of elderly patients in their practice and will subsequently be expected to both identify and initiate treatment in those individuals who may display signs of dementia and related neurologic conditions. There is good evidence that AD is underrecognized or undercoded in primary care settings. Underrecognition is an important problem in this population because early treatment and counseling have been shown to provide benefits to both patients and caregivers. As their patient population ages, physicians need to learn to recognize the early symptoms of AD and make a diagnosis in order to provide cost-effective therapies.

Gibson, G. E. and H. M. Huang (2002). "Oxidative processes in the brain and non-neuronal tissues as biomarkers of Alzheimer's disease." Front Biosci 7: d1007-15.

            Diminished metabolism and excessive oxidative stress occur in the brains of patients with Alzheimer's Disease (AD). These abnormalities in oxidative processes occur in the brain in early stages of AD, which suggests that the deficits are not just secondary to the neuro-degeneration. Alterations in oxidative processes also occur in early stages of AD in non-neuronal tissues including fluids (e.g., cerebrospinal fluid, plasma and urine), cell like particles (e.g., red blood cells and platelets) and cells (e.g., lymphocytes). AD-related abnormalities also persist in cultured cells such as fibroblasts, which indicates that the AD-related changes are not secondary to pathology, and reflect inherent properties of AD cells. These measures of abnormalities in oxidative processes in peripheral cells from AD patients have the potential to be useful as diagnostic markers, as indicators of the progression of the disease, as a tool to develop therapeutic approaches and as monitors of therapeutic efficacy. The peripheral cells are also useful for discovering mechanisms that underlie the multiple changes in cell signaling pathways that accompany AD. Several experimental approaches suggest that oxidative stress is a convergence factor that leads to many other AD-related changes. This review focuses on the considerable recent progress in the quest for markers of metabolism/oxidative stress in peripheral tissues from AD patients, and on experiments to test their pathophysiological importance.

Gnjec, A., J. A. Fonte, et al. (2002). "Transition metal chelator therapy--a potential treatment for Alzheimer's disease?" Front Biosci 7: d1016-23.

            A defining feature of Alzheimer's disease (AD) pathology is the presence of amyloid beta known as A-beta (Abeta) within neuritic plaques of the hippocampus and neocortex of the brain. While early in vitro studies suggested that Abeta could itself be toxic to neuronal cells, recent studies have indicated that this peptide has both neurotoxic and neuroprotective properties that are modulated by the binding of transition metal ions. Transition metal ion binding was shown to modulate Abeta solubility as well as its hydrogen peroxide production, thereby providing explanations for both its trophic and toxic properties. These findings lead to the suggestion that interference with this interaction may reverse the neurotoxic properties of Abeta. More recently, in vivo and in vitro studies into the effects of transition metal chelator treatments on Abeta solubilisation and neurological function have been published. Such studies have yielded promising results, however the potential side effects of many such metal chelators may prove too great for clinical use. It is widely agreed that the ideal chelator for such interdiction would act only on those transition metals that complex with Abeta, and only at metal ion binding sites that contribute to Abeta aggregation and reactive oxygen species generation. The efficacy of metal chelators in reducing Abeta load in transgenic mouse brains demonstrates that this approach has considerable merit as a research tool and as a stimulus to develop second generation agents that can selectively prevent transition metals from binding to the Abeta peptide itself without perturbing the action of other important metal requiring biomolecules in the brain.

Grace, J. and D. Cahn-Weiner (2002). "Behavioral issues in Alzheimer's disease." Med Health R I 85(7): 213-5.

Greicius, M. D., M. D. Geschwind, et al. (2002). "Presenile dementia syndromes: an update on taxonomy and diagnosis." J Neurol Neurosurg Psychiatry 72(6): 691-700.

            The four major degenerative dementias that often begin in presenescence: are reviewed. These are Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, and Creutzfeldt-Jakob disease. Their epidemiological, genetic, and clinical features are reviewed, and controversies in taxonomy arising from recent discoveries described. Particular attention is given to the pathological role of protein aggregation, which appears to be a factor in each disease.

Griffin, W. S. and R. E. Mrak (2002). "Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease." J Leukoc Biol 72(2): 233-8.

            Interleukin-1 (IL-1), a key molecule in systemic immune responses in health and disease, has analogous roles in the brain where it may contribute to neuronal degeneration. Numerous findings suggest that this is the case. For example, IL-1 overexpression in the brain of Alzheimer patients relates directly to the development and progression of the cardinal neuropathological changes of Alzheimer's disease, i.e., the genesis and accumulation of beta-amyloid (Abeta) plaques and the formation and accumulation of neurofibrillary tangles in neurons, both of which contribute to neuronal dysfunction and demise. Several genetic studies show that inheritance of a specific IL-1A gene polymorphism increases risk for development of Alzheimer's disease by as much as sixfold. Moreover, this increased risk is associated with earlier age of onset of the disease. Homozygosity for this polymorphism in combination with another in the IL-1B gene further increases risk.

Hake, A. M. (2002). "The treatment of Alzheimer's disease: the approach from a clinical specialist in the trenches." Semin Neurol 22(1): 71-4.

            Alzheimer's disease (AD) is the most common form of dementia, and its incidence increases with age. Treatment with cholinesterase inhibitor drugs is currently the standard of care. Several other medications and nonpharmacologic therapies are also available for the treatment of cognitive decline and other symptoms of AD. This article reviews the current recommendations for the treatment of Alzheimer's disease.

Hardy, J. and D. J. Selkoe (2002). "The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics." Science 297(5580): 353-6.

            It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta