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Alzheimer's Disease



Congeners of N(alpha)-acetyl-L-cysteine but not aminoguanidine act as neuroprotectants from the lipid peroxidation product 4-hydroxy-2-nonenal.

Neely MD, Zimmerman L, Picklo MJ, Ou JJ, Morales CR, Montine KS, Amaranth V, Montine TJ. Departments of Pathology and Pharmacology, and the Center for Molecular Neurosciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Free Radic Biol Med 2000 Nov 15;29(10):1028-36

Increased generation of neurotoxic lipid peroxidation products is proposed to contribute to the pathogenesis of Alzheimer's disease (AD). Current antioxidant therapies are directed at limiting propagation of brain lipid peroxidation. Another approach would be to scavenge the reactive aldehyde products of lipid peroxidation. N(alpha)-acetyl-L-cysteine (NAC) and aminoguanidine (AG) react rapidly and irreversibly with 4-hydroxy-2-nonenal (HNE) in vitro, and both have been proposed as potential scavengers of HNE in biological systems. We have compared NAC, AG, and a series of congeners as scavengers of HNE and as neuroprotectants from HNE. Our results showed that while both NAC and AG had comparable chemical reactivity with HNE, only NAC and its congeners were able to block HNE-protein adduct formation in vitro and in neuronal cultures. Moreover, NAC and its congeners, but not AG, effectively protected brain mitochondrial respiration and neuronal microtubule structure from the toxic effects of HNE. We conclude that NAC and its congeners, but not AG, may act as neuroprotectants from HNE.

Could diet be one of the causal factors of Alzheimer's disease?

Newman PE.

Med Hypotheses 1992 Oct;39(2):123-6

Recent developments show that the brains of persons who have died from Alzheimer's Disease (AD) have a deficiency of Essential Fatty acids in one of the principal classes of phospholipids. It is hypothesized that faulty brain cell membranes resulting from this deficiency may allow passage of an enzyme into the bilayer membrane space which cuts beta amyloid precursor proteins attached to such cells at a critical intramembrane position releasing a complete sequence of beta amyloid protein into the extracellular space. Beta amyloid protein appears to be the principal active constituent of senile plaques thought to be a probable cause of brain damage resulting in AD. Treatment of persons suffering from AD with desferrioxamine, a trivalent ion chelator to remove aluminium has shown results in slowing the progression of this disease, implicating aluminium and/or other chelated substances in its etiology. Both EFA deficiency and aluminium build-up may be prevented by dietary precautions.

Alzheimer's disease revisited.

Newman PE. Paris, France.

Med Hypotheses 2000 May;54(5):774-6

In a previous paper, it was suggested that a relative deficiency of essential fatty acids might play a role in the etiology of sporadic or non-familial Alzheimer's disease. A recent article regarding dementia in the Rotterdam Study reinforces this suggestion. It is also hypothesized that this relative deficiency could facilitate passage of aluminum into the brain, aluminum being increasingly suggested as one of the possible pathogenic factors in AD. It is further suggested that hypomethylation caused by a deficiency of S-adenosylmethionine might also play a role in the etiology of this disease and perhaps even of Parkinson's disease. Copyright 2000 Harcourt Publishers Ltd.

Presynaptic nicotinic acetylcholine receptors as a functional target of nefiracetam in inducing a long-lasting facilitation of hippocampal neurotransmission.

Nishizaki T, Matsuoka T, Nomura T, Kondoh T, Watabe S, Shiotani T, Yoshii M Department of Physiology, Kobe University School of Medicine, Japan.

Alzheimer Dis Assoc Disord 2000;14 Suppl 1:S82-94

Nefiracetam (1-10 microM), a nootropic (or cognition-enhancing) agent, persistently potentiated currents through Torpedo acetylcholine (ACh) receptors expressed in Xenopus oocytes as a result of interacting with a protein kinase C pathway and the ensuing protein kinase C phosphorylation of the receptors. A similar effect was found in neuronal nicotinic ACh receptors (alpha4beta2 and alpha7). In contrast, the other nootropic agents such as piracetam and aniracetam had no potentiating action on the receptors. A sustained enhancement in the activity of nicotinic ACh receptors induced by nefiracetam caused a marked increase in the glutamate release, leading to a long-term potentiation-like facilitation of hippocampal synaptic transmissions. One of the consistent neuropathologic features of the Alzheimer brain is a loss of nicotinic ACh receptors. This fact, together with the results of our study, raises the possibility that the loss of nicotinic ACh receptors may be a key factor in the decline of cognitive function observed in Alzheimer disease and that agents targeting neuronal nicotinic ACh receptors like nefiracetam could, therefore, be of great therapeutic importance.

Oral administration of idebenone, a stimulator of NGF synthesis, recovers reduced NGF content in aged rat brain.

Nitta A, Hasegawa T, Nabeshima T. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Japan.

Neurosci Lett 1993 Dec 12;163(2):219-22

The relationship between nerve growth factor (NGF) and senile dementia of the Alzheimer type is of interest. We demonstrate here that the oral administration of idebenone, a stimulator of NGF synthesis in vitro, produced recovery of reduced NGF content in aged rat brain. Twenty-one-day successive administration of idebenone produced significant recovery of reduced NGF content in the frontal cortex and parietal cortex of aged rats. These results suggest that NGF content in the brain is low in aged rats and that oral administration of idebenone leads to a recovery of this reduction.

Oral administration of idebenone induces nerve growth factor in the brain and improves learning and memory in basal forebrain-lesioned rats.

Nitta A, Murakami Y, Furukawa Y, Kawatsura W, Hayashi K, Yamada K, Hasegawa T, Nabeshima T. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Japan.

Naunyn Schmiedebergs Arch Pharmacol 1994 Apr;349(4):401-7

Nerve growth factor plays an important role in the survival and maintenance of cholinergic neurons in the central neuronal system. In senile dementia of the Alzheimer type, learning and memory are impaired by the loss of neurons in the magnocellular cholinergic neuronal system. It is therefore, of interest to investigate the role of nerve growth factor in this degenerative disorder. Since nerve growth factor does not cross the blood-brain barrier and is easily metabolized by peptidases when administered peripherally, it can be used for medical treatment only when directly injected into the brain. We demonstrate here that the oral administration of idebenone, a potent in vitro nerve growth factors synthesis stimulator, induced an increase in nerve growth factor protein and mRNA, and in choline acetyltransferase activity, in basal forebrain lesioned rats, but not in intact rats. Idebenone also ameliorated the behavioral deficits in habituation, water maze, and passive avoidance tasks in these animals. These results suggest that idebenone stimulated nerve growth factor synthesis in vivo and ameliorates the behavioral deficits which were accompanied with the recovery of the reduced choline acetyltransferase activity in the basal forebrain-lesioned rats.

Hydergine for dementia.

Olin J, Schneider L, Novit A, Luczak S Keck School of Medicine, University of Southern California, 1975 Zonal Avenue, KAM-400, Los Angeles, CA, 90033, USA.

Cochrane Database Syst Rev 2000;(2):CD000359

BACKGROUND: Currently hydergine is used almost exclusively for treating patients with either dementia, or 'age-related' cognitive symptoms. Since the early eighties there have been over a dozen more clinical trials, yet hydergine's efficacy remains uncertain. Although previous reviews offer generally favorable support for hydergine's efficacy, they were, however, limited by a bias with respect to the particular clinical studies chosen (eg, the inclusion of case reports, and uncontrolled trials), and by authors' impressionistic assessments of results. Not surprisingly, there has been a lack of consensus among reviewers with regard to the efficacy of hydergine. In 1994, a meta-analysis was published by the present reviewers who reported that overall, hydergine was more effective than placebo. However they also observed that the statistical evidence for efficacy in 'possible or probable Alzheimer's disease' patients was so modest that one additional statistically non-significant trial would have reduced the results to non significance.

OBJECTIVES: Because of uncertainty surrounding the efficacy of hydergine, the goals of this overview were to assess its overall effect in patients with possible dementia, and to investigate potential moderators of an effect.

SEARCH STRATEGY: The Cochrane Dementia Group Register of Clinical Trials was searched using the terms 'hydergine', 'ergoloids,' 'ergoloid mesylates,' 'dihydroergocristine,' 'dihydroergocryptine,' 'dihydroergotoxine,' and 'dihydroergocornine. MEDLINE, EMBASE, and two proprietary databases were searched also. Published reviews were inspected for further sources.

SELECTION CRITERIA: Trials to be included must be randomized, double-blind, parallel-group, and unconfounded comparisons of hydergine with placebo for a treatment duration of greater than 1 week in subjects with dementia or symptoms consistent with dementia.

DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers, pooled where appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used. Outcomes of interest included clinical global impressions of change and comprehensive rating scales. Potential moderating variables of a treatment effect included: inpatient/outpatient status, trial duration, age, sex, medication dose, publication year, and diagnostic grouping.

MAIN RESULTS: There were a total of nineteen trials that met inclusion criteria and that had data sufficient for analysis. Thirteen trials reported sufficient information to use a global rating of improvement and nine trials provided information on a comprehensive rating scale. Three trials provided both outcome measures. It was not possible to use many of the published results in a combined analysis owing to the lack of sufficient data to perform statistical analyses. For the twelve trials that used global ratings, there was a significant effect favoring hydergine (OR 3.78, 95%CI, 2.72-5.27). For the nine trials that used comprehensive ratings, there was a significant mean difference favoring hydergine (WMD 0.96, 95%CI, 0. 54-1.37). Hydergine was well tolerated in these trials, with 78% of randomized subjects available for data analyses. Greater effect sizes on global ratings were associated with younger age, and possibly higher dose, although most of the subgroup analyses were statistically insignificant.

REVIEWER'S CONCLUSIONS: As in an earlier systematic review, we found hydergine to show significant treatment effects when assessed by either global ratings or comprehensive rating scales (based here on a smaller set of trials than in the earlier published systematic review because trials were required to have data that could conform with MetaView, the Cochrane Collaboration statistics software). The small number of trials available for analysis, however, limited the ability of subgroup analyses to identify statistically significant modera

[Analysis of dietary factors in Alzheimer's disease: clinical use of nutritional intervention for prevention and treatment of dementia] [Article in Japanese]

Otsuka M. Department of Neurology, Jichi Medical School, Omiya Medical Center.

Nippon Ronen Igakkai Zasshi 2000 Dec;37(12):970-3

To determine dietary factors involved in the pathological process of Alzheimer's disease (AD), we analyzed food consumption and intake of nutrients using Self-administered Diet History Questionnaire (DHQ) developed for Japanese. Sixty four AD patients and 80 age-matched healthy subjects were enrolled in this study. AD was diagnosed according to the criteria of DSM-IV. Dietary behaviors of AD patients was markedly deviated from those of age-matched healthy elderly. AD patients disliked fish and green-yellow vegetables and took more meats than controls. Energy-adjusted analysis of nutrients revealed that AD patients took less vitamin C and carotene. Most conspicuously, AD patients took significantly smaller amount of n-3 polyunsaturated fatty acid (PUFA) reflecting low consumption of fish, and their n-6/n-3 ratio was significantly increased. These habits started from 3 months to 44 years before the onset of dementia, suggesting these dietary abnormalities are not merely the consequence of dementia. Rather, it implies that AD might be a life style-related disease such as coronary heart disease, western style diet-associated cancer and hyperallergy. To see if cognitive function was improved by correcting the n-6/n-3 ratio, we prescribed eicossapentaenoic acid (EPA), one type of n-3 PUFA, for AD patients. Cognitive function was evaluated using MMSE. Administration of EPA (900 mg/day) improved MMSE significantly with maximal effects at 3 months and the effects lasted 6 months. However, the score of MMSE decreased after 6 months. The present study showed that nutritional intervention is useful for the prevention of AD, and also for the therapy of dementia, though it has some limitation.

Estrogen deficiency and risk of Alzheimer's disease in women.

Paganini-Hill A, Henderson VW. Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles 90031.

Am J Epidemiol 1994 Aug 1;140(3):256-61

The authors explored the possibility that estrogen loss associated with menopause may contribute to the development of Alzheimer's disease by using a case-control study nested within a prospective cohort study. The Leisure World Cohort includes 8,877 female residents of Leisure World Laguna Hills, a retirement community in southern California, who were first mailed a health survey in 1981. From the 2,529 female cohort members who died between 1981 and 1992, the authors identified 138 with Alzheimer's disease or other dementia diagnoses likely to represent Alzheimer's disease (senile dementia, dementia, or senility) mentioned on the death certificate. Four controls were individually matched by birth date (+/- 1 year) and death date (+1 year) to each case. The risk of Alzheimer's disease and related dementia was less in estrogen users relative to nonusers (odds ratio = 0.69, 95 percent confidence interval 0.46-1.03). The risk decreased significantly with increasing estrogen dose and with increasing duration of estrogen use. Risk was also associated with variables related to endogenous estrogen levels; it increased with increasing age at menarche and (although not statistically significant) decreased with increasing weight. This study suggests that the increased incidence of Alzheimer's disease in older women may be due to estrogen deficiency and that estrogen replacement therapy may be useful for preventing or delaying the onset of this dementia.

Estrogen replacement therapy and risk of Alzheimer disease.

Paganini-Hill A, Henderson VW. Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, USA.

Arch Intern Med 1996 Oct 28;156(19):2213-7

BACKGROUND: With Alzheimer disease emerging as a major public health problem, the identification of factors that might prevent this disease are important. Estrogen loss associated with menopause may contribute to the development of Alzheimer disease.

OBJECTIVE: To evaluate the effects of different estrogen preparations, varying dosages of estrogen, and duration of estrogen replacement therapy on the risk of Alzheimer disease in postmenopausal women.

STUDY DESIGN AND METHODS: A case-control study nested within a prospective cohort study of residents of Leisure World Laguna Hills, a retirement community in Southern California. The cohort comprised 8877 women who were first mailed a health survey in 1981. Of the 3760 female cohort members who died between 1981 and 1995, 248 women with Alzheimer disease or other dementia diagnoses likely to represent Alzheimer disease (senile dementia, dementia, or senility) mentioned on the death certificate were identified. Five controls were individually matched to each case according to year of death and year of birth (+/- 1 year).

RESULTS: The risk of Alzheimer disease and related dementia was significantly reduced in estrogen users compared with nonusers (odds ratio, 0.65; 95% confidence interval, 0.49-0.88). The risk was reduced for both oral and nonoral (i.e., injections and/or creams) routes of administration. The risk decreased significantly with both increasing dosages (P = .01) and increasing duration (P = .01) of oral therapy with conjugated equine estrogen, the most commonly used estrogen preparation. Within each dose category, the risk decreased with increasing duration of therapy, with the lowest observed risk in long-term users who received high doses (odds ratio, 0.48; 95% confidence interval, 0.19-1.17).

CONCLUSION: This study suggests that estrogen replacement therapy may be useful for preventing or delaying the onset of Alzheimer disease in postmenopausal women.

Alzheimer beta protein mediated oxidative damage of mitochondrial DNA: prevention by melatonin.

Pappolla MA, Chyan YJ, Poeggeler B, Bozner P, Ghiso J, LeDoux SP, Wilson GL. University of South Alabama Medical Center, Department of Pathology and Neurology, Mobile 36617, USA.

J Pineal Res 1999 Nov;27(4):226-9

Most contemporary progress in Alzheimer's disease (AD) stems from the study of a 42 43 amino acid peptide. called the amyloid beta protein (Abeta), as the main neuropathologic marker of the disorder. It has been demonstrated that Abeta has neurotoxic properties and that such effects are mediated by free-radicals. Exposure of neuronal cells to Abeta results in a spectrum of oxidative lesions that are profoundly harmful to neuronal homeostasis. We had previously shown that Abeta25-35 induces oxidative damage to mitochondrial DNA (mtDNA) and that this modality of injury is prevented by melatonin. Because Abeta25 35 does not occur in AD and because the mode of toxicity by Abeta25-35 may be different from that of Abeta1-42 (the physiologically relevant form of Abeta), we extended our initial observations to determine whether oxidative damage to mtDNA could also be induced by Abeta1-42 and whether this type of injury is prevented by melatonin. Exposure of human neuroblastoma cells to Abeta1-42 resulted in marked oxidative damage to mtDNA as determined by a quantitative polymerase chain reaction method. Addition of melatonin to cell cultures along with Abeta completely prevented the damage. This study supports previous findings with Abeta25-35, including a causative role for Abeta in the mitochondrial oxidative lesions present in AD brains. Most important, the data confirms the neuroprotective role of melatonin in Abeta-mediated oxidative injury. Because melatonin also inhibits amyloid aggregation, lacks toxicity, and efficiently crosses the blood-brain barrier, this hormone appears superior to other available antioxidants as a candidate for pharmacologic intervention in AD.

A concise synthetic pathway for trans-metanicotine analogues.

Park H, Jang J, Sin KS. College of Pharmacy, Kangwon National University, Chunchon, Korea.

Arch Pharm Res 2000 Jun;23(3):202-5

A convenient pathway for synthesis of trans-metanicotine analogues was developed. trans-Metanicotine, a subtype (alpha4beta2)-selective ligand for neuronal nicotinic acetylcholine receptor, is under clinical phase for Alzheimer's disease. Zn-mediated allylation of allyl bromide and acetaldehyde followed by Heck reaction with 3-bromopyridine gave 5-pyridin-3-yl-pent-4-en-3-ol (2). Tosylation of 5-pyridin-3-yl-pent-4-en-3-ol followed by substitution reaction with methylamine in sealed tube gave methyl-(1-methyl-4-pyridin-3-yl-but-3-enyl)-amine (4) in good yields. Thus, trans-metanicotine analogues modified at the alpha-position of the methylamino group with various functional groups can be obtained in 4 steps.

Acetylcholine in mind: a neurotransmitter correlate of consciousness?

Perry E, Walker M, Grace J, Perry R. MRC Neurochemical Pathology Unit, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, UK NE4 6BE.

Trends Neurosci 1999 Jun;22(6):273-80

The cholinergic system is one of the most important modulatory neurotransmitter systems in the brain and controls activities that depend on selective attention, which are an essential component of conscious awareness. Psychopharmacological and pathological evidence supports the concept of a 'cholinergic component' of conscious awareness. Drugs that antagonize muscarinic receptors induce hallucinations and reduce the level of consciousness, while the nicotinic receptor is implicated as being involved in the mechanism of action of general (inhalational) anaesthetics. In degenerative diseases of the brain, alterations in consciousness are associated with regional deficits in the cholinergic system. In Alzheimer's disease (AD), there is a loss of explicit (more than implicit) memory and hypoactivity of cholinergic projections to the hippocampus and cortex, while the visual hallucinations experienced by subjects with Dementia with Lewy bodies (DLB) are associated with reductions in neocortical ACh-related activity. In Parkinson's disease, the additional loss of pedunculopontine cholinergic neurones, which control REM (rapid eye movement) sleep or dreaming, is likely to contribute to REM abnormalities, which also occur in DLB. Widespread basal-forebrain and rostral brainstem cholinergic pathways, which include converging projections to the thalamus, appear to be located strategically for generating and integrating conscious awareness. Alleviation of a range of cognitive and non-cognitive symptoms by drugs that modulate the cholinergic system, which are being developed for the treatment of AD and related disorders, could be caused by changes in consciousness.

Effects of physostigmine and lecithin on memory in Alzheimer disease.

Peters BH, Levin HS.

Ann Neurol 1979 Sep;6(3):219-21

Because there is evidence that central cholinergic mechanisms are depleted in dementia, we studied the effects of central cholinergic augmentation on the memory of 5 patients with Alzheimer disease. Patients received placebo, lecithin, physostigmine, or lecithin plus physostigmine in a double-blind study using titrated doses of the acetylcholinesterase inhibitor physostigmine. Memory was evaluated with alternate forms of the selective reminding procedure. Compared with lecithin alone, the combination of physostigmine and lecithin consistently enhanced memory storage and retrieval; physostigmine without lecithin produced no memory facilitation. The strategy of combining a cholinergic agonist and precursor holds promise, although a larger clinical trial is needed.

Medicinal plants and Alzheimer's disease: from ethnobotany to phytotherapy.

Perry EK, Pickering AT, Wang WW, Houghton PJ, Perry NS Medical Research Council, Newcastle General Hospital, Newcastle upon Tyne.

J Pharm Pharmacol 1999 May;51(5):527-34

The use of complementary medicines, such as plant extracts, in dementia therapy varies according to the different cultural traditions. In orthodox Western medicine, contrasting with that in China and the Far East for example, pharmacological properties of traditional cognitive- or memory-enhancing plants have not been widely investigated in the context of current models of Alzheimer's disease. An exception is Gingko biloba in which the gingkolides have antioxidant, neuroprotective and cholinergic activities relevant to Alzheimer's disease mechanisms. The therapeutic efficacy of Ginkgo extracts in Alzheimer's disease in placebo controlled clinical trials is reportedly similar to currently prescribed drugs such as tacrine or donepezil and, importantly, undesirable side effects of Gingko are minimal. Old European reference books, such as those on medicinal herbs, document a variety of other plants such as Salvia officinalis (sage) and Melissa officinalis (balm) with memory-improving properties, and cholinergic activities have recently been identified in extracts of these plants. Precedents for modern discovery of clinically relevant pharmacological activity in plants with long-established medicinal use include, for example, the interaction of alkaloid opioids in Papaver somniferum (opium poppy) with endogenous opiate receptors in the brain. With recent major advances in understanding the neurobiology of Alzheimer's disease, and as yet limited efficacy of so-called rationally designed therapies, it may be timely to re-explore historical archives for new directions in drug development. This article considers not only the value of an integrative traditional and modern scientific approach to developing new treatments for dementia, but also in the understanding of disease mechanisms. Long before the current biologically-based hypothesis of cholinergic derangement in Alzheimer' s disease emerged, plants now known to contain cholinergic antagonists were recorded for their amnesia- and dementia-inducing properties.

Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression.

Pettegrew JW, Levine J, McClure RJ Department of Psychiatry, School of Medicine, University of Pittsburgh, PA 15213, USA.

Mol Psychiatry 2000 Nov;5(6):616-32

Acetyl-L-carnitine (ALCAR) contains carnitine and acetyl moieties, both of which have neurobiological properties. Carnitine is important in the beta-oxidation of fatty acids and the acetyl moiety can be used to maintain acetyl-CoA levels. Other reported neurobiological effects of ALCAR include modulation of: (1) brain energy and phospholipid metabolism; (2) cellular macromolecules, including neurotrophic factors and neurohormones; (3) synaptic morphology; and (4) synaptic transmission of multiple neurotransmitters. Potential molecular mechanisms of ALCAR activity include: (1) acetylation of -NH2 and -OH functional groups in amino acids and N terminal amino acids in peptides and proteins resulting in modification of their structure, dynamics, function and turnover; and (2) acting as a molecular chaperone to larger molecules resulting in a change in the structure, molecular dynamics, and function of the larger molecule. ALCAR is reported in double-blind controlled studies to have beneficial effects in major depressive disorders and Alzheimer's disease (AD), both of which are highly prevalent in the geriatric population.

In-vivo glutathione elevation protects against hydroxyl free radical-induced protein oxidation in rat brain.

Pocernich CB, La Fontaine M, Butterfield DA. Department of Chemistry, University of Kentucky, Lexington 40506, USA.

Neurochem Int 2000 Mar;36(3):185-91

Glutathione deficiency has been associated with a number of neurodegenerative diseases including Lou Gehrig's disease, Parkinson's disease, and HIV. A crucial role for glutathione is as a free radical scavenger. Alzheimer's disease (AD) brain is characterized by oxidative stress, manifested by protein oxidation, lipid oxidation, oxidized glutathione, and decreased activity of glutathione S-transferase, among others. Reasoning that elevated levels of endogenous glutathione would offer protection against free radical-induced oxidative stress, rodents were given in vivo injections of N-acetylcysteine (NAC), a known precursor of glutathione, to study the vulnerability of isolated synaptosomal membranes treated with Fe2+/H2O2, a known hydroxyl free radical producer. Protein carbonyls, a marker of protein oxidation, were measured. NAC significantly increased endogenous glutathione levels in cortical synaptosome cytosol (P < 0.01). As reported previously, protein carbonyl levels of the Fe2+/H2O2-treated synaptosomes were significantly higher compared to that of non-treated controls (P < 0.01), consistent with increased oxidative stress. In contrast, protein carbonyl levels in Fe2+/H2O2-treated synaptosomes isolated from NAC-injected animals were not significantly different from saline-injected non-treated controls, demonstrating protection against hydroxyl radical induced oxidative stress. These results are consistent with the notion that methods to increase endogenous glutathione levels in neurodegenerative diseases associated with oxidative stress, including AD, may be promising.

Cognitive deficit induced by acute tryptophan depletion in patients with Alzheimer's disease.

Porter RJ, Lunn BS, Walker LL, Gray JM, Ballard CG, O'Brien JT. Academic Department of Psychiatry, University of Newcastle upon Tyne, England.

Am J Psychiatry 2000 Apr;157(4):638-40

OBJECTIVE: The study assessed the effects on global cognitive function and mood of a reduction of brain serotonin by means of acute tryptophan depletion in 16 patients with dementia of the Alzheimer type and in 16 cognitively intact comparison subjects.

METHOD: In a double-blind, crossover design, subjects received a tryptophan-free amino acid drink to induce acute tryptophan depletion and, on a separate occasion, a placebo drink containing a balanced mixture of amino acids. On each occasion, ratings of depressed mood were made at baseline and 4 and 7 hours later, and the Modified Mini-Mental State was administered at baseline and 4 hours later.

RESULTS: Patients with dementia of the Alzheimer type had a significantly lower mean score on the Modified Mini-Mental State after acute tryptophan depletion than after receiving placebo. The comparison group showed no difference in mean score on the Modified Mini-Mental State after acute tryptophan depletion and after receiving placebo. No significant changes in mood were found in either group.

CONCLUSIONS: Acute tryptophan depletion significantly impaired cognitive function in patients with dementia of the Alzheimer type. Compromised serotonergic function, in combination with cholinergic deficit, may make an important contribution to cognitive decline in dementia of the Alzheimer type.

Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine.

Preston JE, Hipkiss AR, Himsworth DT, Romero IA, Abbott JN. Institute of Gerontology, King's College London, UK.

Neurosci Lett 1998 Feb 13;242(2):105-8

The effect of a truncated form of the neurotoxin beta-amyloid peptide (A beta25-35) on rat brain vascular endothelial cells (RBE4 cells) was studied in cell culture. Toxic effects of the peptide were seen at 200 microg/ml A beta using a mitochondrial dehydrogenase activity (MTT) reduction assay, lactate dehydrogenase release and glucose consumption. Cell damage could be prevented completely at 200 microg/ml A beta and partially at 300 microg/ml A beta, by the dipeptide carnosine. Carnosine is a naturally occurring dipeptide found at high levels in brain tissue and innervated muscle of mammals including humans. Agents which share properties similar to carnosine, such as beta-alanine, homocarnosine, the anti-glycating agent aminoguanidine, and the antioxidant superoxide dismutase (SOD), also partially rescued cells, although not as effectively as carnosine. We postulate that the mechanism of carnosine protection lies in its anti-glycating and antioxidant activities, both of which are implicated in neuronal and endothelial cell damage during Alzheimer's disease. Carnosine may therefore be a useful therapeutic agent.

An overview of carbohydrate-protein interactions with specific reference to myosin and ageing.

Ramamurthy B, H]o]ok P, Larsson L. Noll Physiological Research Center, The Pennsylvania State University, University Park, PA 16802, USA.

Acta Physiol Scand 1999 Dec;167(4):327-9

Non-enzymatic glycosylation (glycation), a post-translational modification of proteins, results from the reaction of proteins with reducing sugars. Glycation is implicated in various pathologies like diabetes, Alzheimer's disease and it has been suggested to play an important role in the ageing process. Research on protein glycation has primarily studied extracellular proteins such as albumin, haemoglobin and collagen. However, there is increasing evidence that intracellular proteins may also be affected by glycation, and glycation of myosin is reported to decrease myosin ATPase activity. Glycated adducts are detected by various techniques such as chromatography, electrophoresis, fluorescence and immunochemistry. Inhibition or removal of these adducts has been achieved by chemical compounds such as aminoguanidine (amG), beta-mercaptoethanol (bME) and N-phenacylthiazolium bromide (PTB). In the present pilot study, using a novel in vitro motility assay, we have observed an attenuation in the motility speed of actin (approximately 13%) on myosin extracted from single muscle fibre segments after 15-min glucose incubation. Addition of bME to the incubation medium maintained actin motility speed.

Education, occupation, and prevalence of dementia: findings from the Conselice study.

Ravaglia G, Forti P, Maioli F, Sacchetti L, Mariani E, Nativio V, Talerico T, Vettori C, Macini PL. Department of Internal Medicine, Cardioangiology, and Hepatology, University Hospital S. Orsola-Malpighi, Bologna, Italy.

Dement Geriatr Cogn Disord 2002;14(2):90-100

Information about the epidemiology of dementia in Italy is still limited, although this cognitive disorder represents a serious public health concern. We estimated the prevalence of dementia and dementia subtypes in the elderly population of a Northern Italian municipality, Conselice, in the Emilia Romagna region (n = 1,016 subjects aged 65-97 years). The associations of dementia with two modifiable risk factors, education and occupation, were also evaluated. Overall dementia prevalence was 5.9% (95% confidence interval 4.3-7.8), exponentially increased with age, and was higher among women. Of the dementia cases, 50% were Alzheimer's disease (AD), but an unusually high prevalence (45%) was found for vascular dementia (VD). After adjustment for age and gender, education but not occupation was associated with both AD and VD. This association could not be explained by occupation, life habits, and previous history of hypertension or cardiovascular disease. Copyright 2002 S. Karger AG, Basel

The role of the polymorphic genes apolipoprotein E and methylene- tetrahydrofolate reductase in the development of dementia of the Alzheimer type.

Regland B, Blennow K, Germgard T, Koch-Schmidt AC, Gottfries CG. Institute of Clinical Neuroscience, Goteborg University, Goteborg, Sweden.

Dement Geriatr Cogn Disord 1999 Jul-Aug;10(4):245-51

The gene for apolipoprotein E (APOE) is polymorphic, and its variant APOE4 is a major risk factor for the development of Alzheimer-type dementia (AD). Another risk factor for AD appears to be negative cobalamin balance, which is very common in elderly people. Cobalamin and folate are interdependent and essential components of the one-carbon metabolism. Another important component is methylenetetrahydrofolate reductase (MTHFR), the gene for which is also polymorphic. Thermolabile MTHFR (tMTHFR), a gene variant that reduces the activity of its enzyme, is common in the general population. In the present study, 75% of 140 AD patients had at least one APOE4 allele. The numbers of APOE4 and tMTHFR alleles correlated significantly with the serum folate levels, however, in opposite directions. The significance of this was augmented by an inverse correlation between APOE4 and tMTHFR. Thus, not only MTHFR but also APOE appears to be related to the one-carbon metabolism, suggesting that APOE4 and insufficient one-carbon metabolism may be synergistic risk factors for AD.

Melatonin as a pharmacological agent against neuronal loss in experimental models of Huntington's disease, Alzheimer's disease and parkinsonism.

Reiter RJ, Cabrera J, Sainz RM, Mayo JC, Manchester LC, Tan DX. Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio 78229-3900, USA.

Ann N Y Acad Sci 1999;890:471-85

This review summarizes the experimental findings related to the neuroprotective role of melatonin. In particular, it focuses on research directed at models of Huntington's disease, Alzheimer's disease and Parkinsonism. Melatonin has been shown to be highly effective in reducing oxidative damage in the central nervous system; this efficacy derives from its ability to directly scavenge a number of free radicals and to function as an indirect antioxidant. In particular, melatonin detoxifies the highly toxic hydroxyl radical as well as the peroxyl radical, peroxynitrite anion, nitric oxide, and singlet oxygen, all of which can damage macromolecules in brain cells. Additionally, melatonin stimulates a variety of antioxidative enzymes including superoxide dismutase, glutathione peroxidase and glutathione reductase. One additional advantage melatonin has in reducing oxidative damage in the central nervous system is the ease with which to crosses the blood-brain barrier. This combination of actions makes melatonin a highly effective pharmacological agent against free radical damage. The role of physiological levels of melatonin in forestalling oxidative damage in the brain is currently being tested.

Nutritional status of free-living Alzheimer's patients.

Renvall MJ, Spindler AA, Ramsdell JW, Paskvan M. Department of Medicine, University of California Medical Center, San Diego 92103-1990.

Am J Med Sci 1989 Jul;298(1):20-7

Self-reported, dietary intake and biochemical estimates of thiamine, riboflavin, folate, vitamin B-12, protein, and iron were compared in 22, free-living elders by individuals who had senile dementia of the Alzheimer's type (SDAT) and in 41 who were cognitively normal (CN). The two groups did not differ significantly in their intake of these nutrients or the number of deficiency states for intake (less than 67% RDA). Low serum transketolase (thiamin; p less than 0.055), red blood cell (RBC) folate (p less than 0.06), and serum vitamin B-12 (p less than 0.05) levels occurred more often in SDAT patients than in CN subjects. Individuals in both groups who used multivitamin supplements had significantly higher biochemical values for thiamine (p less than 0.03), riboflavin (p less than 0.01), and vitamin B-12 (p less than 0.003) than nonsupplement users. Because of the differences in vitamin B-12 and RBC folate levels between groups, a retrospective analysis was performed on a larger group of subjects drawn from a geriatric assessment clinic. Patients with SDAT had significantly lower serum vitamin B-12 (p less than 0.01) and lower RBC folate (p less than 0.03) values than CN subjects. Which mean values for vitamin B-12 and RBC folate were grouped by degree of impairment in SDAT subjects, vitamin B-12 was significantly lower in mildly and moderately impaired subjects than in those with normal cognition. Mean values for both nutrients did not differ significantly between severely impaired and CN subjects. There was a significant quadratic relationship between cognitive impairment and biochemical values for vitamin B-12.(ABSTRACT TRUNCATED AT 250 WORDS)

Low plasma vitamin C in Alzheimer patients despite an adequate diet.

Riviere S, Birlouez-Aragon I, Nourhashemi F, Vellas B. Hopital La Grave-Casselar, Toulouse, France.

Int J Geriatr Psychiatry 1998 Nov;13(11):749-54

OBJECTIVE: To compare the vitamin C and E plasma levels in patients with Alzheimer's disease (AD) and to assess the vitamin C intake and nutritional status.

DESIGN: Case-control study. Four groups of sex- and age-matched subjects were compared: severe AD and moderate AD, in patients with moderate AD and controls.

SETTING: Community and hospitalized patients in the region of Toulouse, France.

PARTICIPANTS: Patients with dementia who fulfilled criteria for Alzheimer's disease: severe Alzheimer group (N = 20), Mini-Mental State Examination (MMSE) score range 0-9; moderate Alzheimer group (N = 24), MMSE 10-23; hospitalized Alzheimer group (N = 9), MMSE 10-23. Control group (N = 19), MMSE 24-30.

MEASURES: Plasma vitamin E and C were quantified by HPLC-fluorescence. Consumption of raw and cooked fruit and vegetables was evaluated in order to determine the mean vitamin C intakes. Mini Nutritional Assessment (MNA) and plasma albumin were used to measure nutritional status.

RESULTS: Institutionalized and community subjects were analysed separately. MNA scores were normal in home-living Alzheimer subjects with moderate dementia and significantly lower in those with severe disease, despite normal plasma albumin levels. In the home-living Alzheimer subjects, vitamin C plasma levels decreased in proportion to the severity of the cognitive impairment despite similar vitamin C intakes, whereas vitamin E remained stable. The hospitalized Alzheimer subjects had lower MNA scores and albumin levels but normal vitamin C intakes, but their plasma vitamin C was lower than that of community-living subjects. Institutionalized Alzheimer subjects had significantly lower MNA scores but normal vitamin C and albumin levels and vitamin C intakes compared with community-dwelling subjects of similar degree of cognitive impairment.

CONCLUSION: Plasma vitamin C is lower in AD in proportion to the degree of cognitive impairment and is not explained by lower vitamin C intake. These results support the hypothesis that oxygen-free radicals may cause damage.

[Cholinergic hypothesis and Alzheimer's disease: the place of donepezil (Aricept)]. [Article in French]

Robert PH, Gokalsing E, Bertogliati C Centre Memoire, Clinique Universitaire de Psychiatrie, Pavillon J, Hopital Pasteur, Nice.

Encephale 1999 Nov;25 Spec No 5:23-7; discussion 28-9

This presentation has two objectives: 1) presenting the relationships between the clinical symptoms of Alzheimer's disease and cholinergic deficiency, 2) presenting the results obtained with Aricept (proprietary name of donepezil hydrochloride), one of the most recent drugs developed in the context of the cholinergic hypothesis. One of the earliest pathological events in Alzheimer's disease consists in the degeneration of cholinergic neurons in the subcortical regions and, more particularly, in Meynert's nucleus basalis which projects, in a topographically organized manner, to the cortical regions and hippocampus. Some of those regions less affected by the degenerative process nonetheless retain active post-junctional receptors. The disappearance of cholinergic neurons from the nucleus basalis induces disactivation of the cortical and limbic cells and is responsible for the clinical symptoms, such as attention, memory and behavioral disorders. The marketing authorization application for Aricept is based on various studies designed to enable preliminary dose determination and assess efficacy and safety. The first large-scale study designed to evaluate the efficacy of Aricept administered at a daily dosage of 5 to 10 mg was conducted over 14 weeks. The results show a significant improvement in cognitive function in the treatment groups, compared to the placebo groups. The difference emerged after 3 weeks of treatment, lasted throughout the 12 weeks of the study and was still very marked 3 weeks post-treatment discontinuation. The results of a second study conducted over 30 weeks were similar to the foregoing results. Compared to placebo, Aricept at a daily dosage of 5 to 10 mg induces a significant improvement in cognitive function and overall function. At week 24, the patients still showed performances that were superior to their baseline performances. In parallel with its cognitive effects, Aricept was also shown to improve the activities of everyday life and alleviate the distress of caregivers directly confronted with the behavioral disorders of patients suffering from Alzheimer's disease.

A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer ' s disease. The Alzheimer' s Disease Cooperative Study

Sano M; Ernesto C; Thomas RG; Klauber MR; Schafer K; Grundman M; Woodbury P; Growdon J; Cotman CW; Pfeiffer E; Schneider LS; Thal LJ Department of Neurology, Columbia University College of Physicians and Surgeons, New York, USA.

N Engl J Med (United States) Apr 24 1997, 336 (17) p1216-22

BACKGROUND: There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer's disease.

METHODS: We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimer's disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3).

RESULTS: Despite random assignment, the baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups, and this riable was highly predictive of the primary outcome (P<0.001). In the unadjusted analyses, there was no statistically significant difference in the outcomes among the four groups. In analyses that included the base-line score on the Mini-Mental State Examination as a covariate, there were significant delays in the time to the primary outcome for the patients treated with selegiline (median time, 655 days; P=0.012), alpha-tocopherol (670 days, P=0.001) or combination therapy (585 days, P=0.049), as compared with the placebo group (440 days).

CONCLUSIONS: In patients with moderately severe impairment from Alzheimer's disease, treatment with selegiline or alpha-tocopherol slows the progression of disease.

Tyrosine hydroxylase, tryptophan hydroxylase, biopterin, and neopterin in the brains of normal controls and patients with senile dementia of Alzheimer type.

Sawada M, Hirata Y, Arai H, Iizuka R, Nagatsu T.

J Neurochem 1987 Mar;48(3):760-4

The activities of tyrosine hydroxylase and tryptophan hydroxylase, and the concentrations of the biopterin cofactor and the precursor neopterin were measured in 14 regions of postmortem brains from four histologically verified patients of senile dementia of the Alzheimer type (SDAT) and eight histologically normal controls. Neopterin concentrations were measured in the human brain for the first time. The activities of tyrosine hydroxylase and tryptophan hydroxylase in the brains of patients with SDAT were significantly reduced in the substantia nigra and in the lateral segment of the globus pallidus, locus ceruleus, and substantia nigra, respectively. The concentrations of total biopterin in the brains of patients with SDAT were significantly reduced in the putamen and substantia nigra, but the total neopterin concentrations did not change significantly. These results suggest that the reduction in biogenic amines in SDAT might be related to reductions in biosynthetic enzymes associated with biogenic amines, due to destruction of monoaminergic neurons.

Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti-inflammatory drug: implication in Alzheimer's disease.

Scali C, Prosperi C, Vannucchi MG, Pepeu G, Casamenti F Department of Pharmacology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy.

Eur J Neurosci 2000 Jun;12(6):1900-12

Brain inflammatory processes underlie the pathogenesis of Alzheimer's disease, and nonsteroidal anti-inflammatory drugs have a protective effect in the disease. The aim of this study was to characterize in vivo in the rat brain the inflammatory reaction in response to excitotoxic insult and to investigate the efficacy of nimesulide treatment. Quisqualic acid was injected into the right nucleus basalis of rats. The excitotoxin induced cholinergic degeneration, an intense glial reaction and the production of inflammatory mediators. Three hours after injection, a five-fold elevation in the concentration of interleukin-1beta in the injected area was observed. This elevation was reduced by 50% by nimesulide (10 mg/kg, i.m.) pretreatment. Electron microscope examination and immunocytochemical staining revealed an intense activation of microglia and astrocytes at both 24 h and 7 days after injection. Cyclooxygenase-2-immunoreactivity was induced in the blood vessels of the injected hemisphere in perivascular microglial and endothelial cells 24 h after injection. Seven days postinjection, a cyclooxygenase-2-positive signal was induced in the parenchymal microglia and large amounts of prostaglandin-E2 were measured in the injected area. Twenty-four hours and 7 days after injection, many inducible nitric oxide synthase-positive cells and a high level of nitrite were detected at the injection site. Seven days of nimesulide (10 mg/kg/day, i.m.) treatment strongly attenuated the microglial reaction, reduced the number of inducible nitric oxide synthase-positive cells and completely abolished the increase in prostaglandin-E2 formation. These data provide valuable support in vivo for the potential efficacy of cyclooxygenase-2 inhibitors in Alzheimer's disease therapy.

Alzheimer's disease after remote head injury: an incidence study.

Schofield PW, Tang M, Marder K, Bell K, Dooneief G, Chun M, Sano M, Stern Y, Mayeux R. Gertrude H Sergievsky Center, Columbia University, New York City 10032, USA.

J Neurol Neurosurg Psychiatry 1997 Feb;62(2):119-24

OBJECTIVE: To evaluate a history of remote head injury as a risk factor for subsequent dementia due to Alzheimer's disease.

METHODS: 271 participants of a community based longitudinal study of aging in north Manhattan without evidence of significant cognitive impairment were interrogated for a history of head injury on two occasions at entry into the study. The examining physician sought a history of head injury with loss of conciousness. Independently, a risk factor interviewer inquired about a history of head injury with loss of consiousness or amnesia, the duration of any loss of consiousness, and the date of the head injury. Patients were followed up with standardised annual evaluations for up to five years to determine the first occurrence of dementia.

RESULTS: Over the course of the study incident dementia due to probable or possible Alzheimer's disease was diagnosed in 39 patients. Cox proportional hazards modelling showed that a history of head injury with loss of consiousness reported to the physician was associated with earlier onset of dementia due to Alzheimer's disease (relative risk (RR) = 4.1, 95% confidence interval (95% CI) 1.3-12.7). head injury with loss of consiousness or amnesia reported to the risk factor interviewer was not significantly associated with earlier onset of Alzheimer's disease overall (RR 2.0, 95% CI 0.7-6.2), but those who reported loss of consiousness exceeding five minutes were at significantly increased risk (RR 11.2, 95% CI 2.3-59.8). Incident Alzheimer's disease was significantly associated with head injury which occurred within the preceding 30 years (RR 5.4, 95% CI 1.5-19.5).

CONCLUSION: The results of this cohort study are consistent with the findings of several case-control studies suggesting that head injury may be a risk factor for Alzheimer's disease.

Phenolic antioxidants attenuate neuronal cell death following uptake of oxidized low-density lipoprotein.

Schroeter H, Williams RJ, Matin R, Iversen L, Rice-Evans CA. Wolfson Centre for Age-Related Diseases, Guy's, King's, and St. Thomas's School of Biomedical Sciences, King's College, Guy's Campus, London, England.

Free Radic Biol Med 2000 Dec 15;29(12):1222-33

Oxidative stress is implicated in neuronal loss associated with neurodegeneration such as in Parkinson's disease, Alzheimer's disease and age-related cognitive decline. Recent reports indicate that the consumption of flavonoid-rich fruits partly reverses the age-related neuronal and cognitive decline. In this study, cultured striatal neurons were exposed to oxidized lipids in the form of low-density lipoprotein (oxLDL) as a model for the induction of oxidative injury, and the abilities of phenolic antioxidants, flavonoids and hydroxycinnamic acid derivatives, to attenuate this neuronal damage were examined. OxLDL was demonstrated to enter neuronal cells and to be capable of eliciting neurotoxicity in a dose- and time-dependent manner, inducing DNA fragmentation and cell lysis. Flavonoids exert protective effects, which appear to be related to specific structural characteristics, particularly relevant being those defining their reduction potentials and partition coefficients. In summary, these data suggest a possible role for flavonoids in reducing neurodegeneration associated with chronic disorders in which oxidative stress is implicated.

CSF-folate levels are decreased in late-onset AD patients.

Serot JM, Christmann D, Dubost T, Bene MC, Faure GC. Laboratoire d'Immunologie, GRIP, JE DRED 251, Faculte de Medecine, UHP, Nancy, France.

J Neural Transm 2001;108(1):93-9

Folates are involved in the cerebral metabolism of cobalamine, methionine, L-tyrosine and acetylcholine. Remarkably CSF-folate levels are 3 to 4 times higher than blood-folate levels. To reach the brain, folates are actively transported by choroid plexus (CP) as well as vitamins B6, B12, C and E. Epithelial atrophy having been reported in aging and in Alzheimer's disease (AD), we measured the CSF folate-levels of 126 patients, including 30 AD consecutive patients to evaluate whether CP functions of folate-transport were impaired. CSF-folate concentrations did not vary with age (10.47 +/- 1.93ng/ml between 20 and 60 years; 9.96 +/- 2.01 ng/ml in elderly control patients older than 60 years of age, p > 0.05) while late-onset AD patients had significantly lower CSF-folate levels (8.26 +/- 1.82 ng/ml, p < 0.001). These data support a specific alteration of CP transport function in AD patients.

Chronic (-) deprenyl administration alters dendritic morphology of layer III pyramidal neurons in the prefrontal cortex of adult Bonnett monkeys.

Shankaranarayana Rao BS, Lakshmana MK, Meti BL, Raju TR Department of Neurophysiology, National Institute of Mental Health and Neurosciences, P.B. #2900, Hosur Road, Bangalore 560 029, India.

Brain Res 1999 Mar 6;821(1):218-23

Chronic (-) deprenyl (0.2 mg/kg, b.wt; for 25 days) treatment induced alterations in the dendritic morphology of prefrontal cortical neurons in adult Bonnett monkeys were evaluated in the present study. The branching points and intersections in apical and basal dendrites were studied up to a distance of 400 and 200 micrometers, respectively, in Golgi impregnated layer III pyramidal neurons of the prefrontal cortex. Our results revealed a significant (p<0.001) increase in the number of branching points and intersections in both apical and basal dendrites in (-) deprenyl treated monkeys compared to controls. Such an enriched dendritic arborization in prefrontal cortical neurons may be responsible for the enhancement of cognitive functions in Alzheimer disease patients following (-) deprenyl treatment.

The pathogenesis of Alzheimer's disease.

Small GW. Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, and the Veterans Affairs Medical Center, USA.

J Clin Psychiatry 1998;59 Suppl 9:7-14

Despite consensus on clinical and neuropathologic definitions of Alzheimer's disease, limited information is available on its causes and pathogenesis. Current data suggest interactions among the various possible biological and environmental influences that result in a common pathway leading to the disease. Biological influences include genetic mutations causing the disease phenotype and polymorphisms contributing to disease risk. Alterations in immune or inflammatory responses may also represent biological influences. Various environmental influences that may interact with endogenous biological factors include education, traumatic injury, oxidative stress, drugs, and hormone replacement. The author describes some recent findings that suggest possible pathogenic mechanisms, which may eventually have important treatment implications.

Should the guidelines for monitoring serum cholesterol levels in the elderly be re-evaluated?

Sparks DL, Connor DJ, Browne P, Sabbagh MN; AD Cholesterol-Lowering Treatment Trial Team. Laboratory of Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ 85351, USA.

J Mol Neurosci 2002 Aug-Oct;19(1-2):209-12

Elevated circulating cholesterol can have profound effects on the health of an individual. Such excess cholesterol can promote coronary artery disease, production and accumulation of beta-amyloid in the brain, and possibly Alzheimer's disease (AD). In a clinical trial evaluating the benefit of a cholesterol-lowering drug in the treatment of AD, mean cholesterol levels at baseline among individuals participating in the trial were found to be relatively high. Based on this observation we suggest that cholesterol levels should be actively monitored in the elderly, as many individuals with AD are over 65 years of age and therefore excluded by currently accepted guidelines.

Influence of education and occupation on the incidence of Alzheimer's disease.

Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R. Department of Neurology, Columbia University College of Physicians and Surgeons, Gertrude H. Sergievsky Center, New York, NY 10032.

JAMA 1994 Apr 6;271(13):1004-10

OBJECTIVE--Several cross-sectional studies have found an association between Alzheimer's disease (AD) and limited educational experience. It has been difficult to establish whether educational experience is a risk factor for AD because educational attainment can influence performance on diagnostic tests. This study was designed to determine whether limited educational level and occupational attainment are risk factors for incident dementia.

DESIGN--Cohort incidence study.

SETTING--General community.

PARTICIPANTS-A total of 593 nondemented individuals aged 60 years or older who were listed in a registry of individuals at risk for dementia in North Manhattan, NY, were identified and followed up.

INTERVENTIONS--We reexamined subjects 1 to 4 years later with the identical standardized neurological and neuropsychological measures.

MAIN OUTCOME MEASURES-Incident dementia.

RESULTS--We used Cox proportional hazards models, adjusting for age and gender, to estimate the relative risk (RR) of incident dementia associated with low educational and occupational attainment. Of the 593 subjects, 106 became demented; all but five of these met research criteria for AD. The risk of dementia was increased in subjects with either low education (RR, 2.02; 95% confidence interval [Cl], 1.33 to 3.06) or low lifetime occupational attainment (RR, 2.25; 95% Cl, 1.32 to 3.84). Risk was greatest for subjects with both low education and low life-time occupational attainment (RR, 2.87; 95% Cl, 1.32 to 3.84).

CONCLUSIONS--The data suggest that increased educational and occupational attainment may reduce the risk of incident AD, either by decreasing ease of clinical detection of AD or by imparting a reserve that delays the onset of clinical manifestations.

Risk of Alzheimer's disease and duration of NSAID use.

Stewart WF, Kawas C, Corrada M, Metter EJ Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA.

Neurology 1997 Mar;48(3):626-32

In a longitudinal study of 1,686 participants in the Baltimore Longitudinal Study of Aging, we examined whether the risk of Alzheimer's disease (AD) was reduced among reported users of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). In addition, we examined use of acetaminophen, a pain-relief medication with little or no anti-inflammatory activity, to assess the specificity of the association between AD risk and self-reported medications. Information on use of medications was collected during each biennial examination between 1980 and 1995. The relative risk (RR) for AD decreased with increasing duration of NSAID use. Among those with 2 or more years of reported NSAID use, the RR was 0.40 (95% confidence interval [CI]: 0.19-0.84) compared with 0.65 (95% CI: 0.33-1.29) for those with less than 2 years of NSAID use. The overall RR for AD among aspirin users was 0.74 (95% CI: 0.46-1.18), and no trend of decreasing risk of AD was observed with increasing duration of aspirin use. No association was found between AD risk and use of acetaminophen (RR = 1.35; 95% CI: 0.79-2.30), and there was no trend of decreasing risk with increasing duration of use. These findings are consistent with evidence from cross-sectional studies indicating protection against AD risk among NSAID users and with evidence suggesting that one stage of the pathophysiology leading to AD is characterized by an inflammatory process.

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