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Abstracts

Alzheimer's Disease

ABSTRACTS

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Double-blind randomized controlled study of phosphatidylserine in senile demented patients.

Delwaide PJ, Gyselynck-Mambourg AM, Hurlet A, Ylieff M.

Acta Neurol Scand 1986 Feb;73(2):136-40

A double-blind randomized controlled study was conducted in 42 hospitalized demented patients to evaluate the therapeutical effect of phosphatidylserine (BS-PS). Half of the patients received 3 X 100 mg of this product, and the other half a placebo of the same appearance. After a wash-out period, prescription lasted for six weeks. To evaluate the patients, two distinct rating scales were used: the Crichton Scale and an original one (Peri Scale) designed in our geriatric unit (see Appendix). A circle crossing test was added. Out of the 35 patients who completed the trial, 18 had received placebo and 17 BC-PS. The results indicated a trend toward improvement in the BC-PS treated patients and an analysis of covariance showed a significant (p less than 0.05) treatment effect on the Peri Scale. The results at the end of the treatment period were compared with those obtained three weeks later. Here again there was a statistically significant difference in the Peri Scale results, indicating that modifications are drug-related. The behavioral improvement shown in this study is in agreement with experimental studies on aged animals.

Ginkgo biloba extract: mechanisms and clinical indications.

Diamond BJ, Shiflett SC, Feiwel N, Matheis RJ, Noskin O, Richards JA, Schoenberger NE Department of Research, Center for Research in Complementary and Alternative Medicine, Kessler Medical Rehabilitation Research and Education Corporation, West Orange, NJ 07052, USA.

Arch Phys Med Rehabil 2000 May;81(5):668-78

OBJECTIVE: Ginkgo biloba may have a role in treating impairments in memory, cognitive speed, activities of daily living (ADL), edema, inflammation, and free-radical toxicity associated with traumatic brain injury (TBI), Alzheimer's dementia, stroke, vasoocclusive disorders, and aging. The purpose of this review is to provide a synthesis of the mechanisms of action, clinical indications, and safety of Ginkgo biloba extract.

DATA SOURCES: Empirical studies, reviews, chapters, and conference proceedings were identified in the following databases: Medline, the Research Council for Complementary Medicine based on the British Library database, and Psychlnfo. Ginkgo biloba, EGb 761, Tanakan, Tebonin, Rokan, and LI 1370 were the principal index terms.

STUDY SELECTION AND DATA EXTRACTION: Controlled clinical studies with both positive and negative findings are included, in addition to animals studies illustrating mechanisms of activity.

DATA SYNTHESIS: Ginkgo has shown activity centrally and peripherally, affecting electrochemical, physiologic, neurologic, and vascular systems in animals and humans with few adverse side effects or drug interactions. Ginkgo shows promise in patients with dementia, normal aging, and cerebrovascular-related disorders. Clinical indications include memory, information processing, and ADL.

CONCLUSIONS: Ginkgo shows promise in treating some of the neurologic sequelae associated with Alzheimer's disease, TBI, stroke, normal aging, edema, tinnitus, and macular degeneration. Mechanisms of action may include antioxidant, neurotransmitter/receptor modulatory, and antiplatelet activating factor properties. While safe, caution is advised when recommending ginkgo to patients taking anticoagulants. Future studies should examine dose effects, component activity, mechanisms, and clinical applications.

Clinical profile of donepezil in the treatment of Alzheimer's disease.

Doody RS. Baylor College of Medicine, Department of Neurology and Alzheimer's Disease Research Center, Houston, Tex. 77030-3498, USA.

Gerontology 1999;45 Suppl 1:23-32

Although the underlying pathogenesis of Alzheimer's disease (AD) is not fully understood, one of its key features is the widespread loss of central cholinergic innervation, known to be fundamental for cognitive processes. This finding led to the hypothesis that pharmacological enhancement of acetylcholine (ACh) neurotransmission may alleviate the symptoms of AD. Currently, cholinergic therapy, particularly cholinesterase (ChE) inhibition, represents the most realistic approach to the symptomatic treatment of AD. Donepezil HCl, for example, is a piperidine-based, reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other ChE inhibitors and rationally designed for the symptomatic treatment of AD. It is highly selective for centrally acting AChE, with little or no affinity for butyrylcholinesterase, present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favourable pharmacokinetic, pharmacodynamic and safety profile with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. Furthermore, its long half-life supports a simple and convenient once-daily dosing regimen. Subsequent to encouraging phase II clinical trial results, two pivotal, randomized, double-blind phase III trials (of 15 and 30 weeks' duration) demonstrated highly significant improvements in cognition and global function in mild to moderately severe AD patients treated with either 5 or 10 mg/day donepezil compared with placebo. Adverse events in the phase II and III trials, primarily cholinergic in nature, were transient and generally mild in severity and resolved during continued donepezil administration. Thus, the donepezil clinical trials programme has shown that this drug is a clinically effective and well-tolerated, once-daily treatment for the symptoms of mild to moderately severe AD.

Therapeutic standards in Alzheimer disease.

Doody RS Baylor College of Medicine, Department of Neurology, Houston, Texas 77030, USA. rdoody@bcm.tmc.edu

Alzheimer Dis Assoc Disord 1999 Nov;13 Suppl 2:S20-6

Donepezil is an effective, well-tolerated, and easily administered symptomatic treatment for mild-to-moderate Alzheimer disease (AD). Data from Phase III clinical trials have demonstrated that donepezil improves cognition, global function, and activities of daily living. In addition, there were no clinically significant treatment-related effects on vital signs or laboratory values in any trial. Adverse events, when present, were generally mild in intensity, transient, and resolved during continued treatment with donepezil. This favorable safety profile, together with its reported clinical benefits established donepezil as one standard of AD therapy. Vitamin E is one of two anti-oxidant therapies that may help to slow the progression of AD over at least a two-year period. One large-scale clinical trial suggests that it has sufficient benefit and safety to join donepezil as a current standard of AD therapy.

Increased effectiveness of tacrine by deprenyl co-treatment in rats: EEG and behavioral evidence

Dringenberg HC, Laporte PP, Diavolitsis P Department of Psychology, Queen's University, Kingston, Ontario, Canada.

Neuroreport 2000 Nov 9;11(16):3513-6

The acetylcholinesterase inhibitor tacrine and the monoamine oxidase inhibitor deprenyl are considered useful pharmacotherapies for Alzheimer's disease (AD). We assessed whether co-administration of these two compounds increases their effectiveness against two measures of cholinergic-monoaminergic hypofunction in rats, cortical EEG slowing and impaired spatial performance. EEG slowing induced by cholinergic-monoaminergic blockade was reversed by both deprenyl (10 - 50 mg/kg) and tacrine (1 - 20 mg/kg), but co-treatment with a subthreshold dose of deprenyl plus tacrine was markedly more effective. Neither tacrine (5 mg/kg) nor deprenyl (10 mg/kg) alone reduced water maze deficits due to cholinergic-monoaminergic hypofunction, but co-treatment (using these doses) improved performance. Cholinergic-monoaminergic co-treatment may constitute a useful pharmacotherapy to correct physiological and behavioral dysfunction due to neurotransmitter deficiencies in AD.

Vitamin B12 deficiency in dementia and cognitive impairment: the effects of treatment on neuropsychological function.

Eastley R, Wilcock GK, Bucks RS. Avon and Western Wiltshire Mental Health Care NHS Trust, Southmead Hospital, Bristol, UK.

Int J Geriatr Psychiatry 2000 Mar;15(3):226-33

BACKGROUND: Vitamin B12 assay is part of the routine investigation of dementia, although few studies have investigated the effects of treatment on cognition. We examined the effects of B12 treatment on neuropsychological function and disease progression in patients presenting with dementia or cognitive impairment.

METHODS: From 1432 patients who were assessed at the Bristol Memory Disorders Clinic, 125 patients with low serum B12 were identified. Sixty-six patients presenting with dementia, and 22 with cognitive impairment were seen for a second assessment after treatment. Changes in neuropsychological test scores were compared with those of patients with normal serum B12, matched by age and diagnosis.

RESULTS: The majority of patients with low serum B12 had normal Hb and MCV values. We found no cases of reversible B12 deficiency dementia. The B12 treatment patients who presented with dementia showed no significant improvement, and no less deterioration, in their neuropsychological function than their matched group. However, a treatment effect was demonstrated among the patients presenting with cognitive impairment. These improved significantly compared to matched patients on the verbal fluency test (p<0.01).

CONCLUSION: All patients with cognitive impairment should be investigated for B12 deficiency. Vitamin B12 treatment may improve frontal lobe and language function in patients with cognitive impairment, but rarely reverses dementia. Copyright 2000 John Wiley & Sons, Ltd.

Piracetam reverses hippocampal membrane alterations in Alzheimer's disease.

Eckert GP, Cairns NJ, Muller WE Department of Pharmacology, Biocenter, University of Frankfurt, Federal Republic of Germany.

J Neural Transm 1999;106(7-8):757-61

The in vitro effects of piracetam treatment on the fluidity of membranes from the hippocampus of Alzheimer's Disease patients (AD) and non-demented controls were studied. Hippocampal membranes of AD patients showed a significant lower hydrocarbon core fluidity compared with membranes from elderly non-demented controls. Preincubation with piracetam enhanced the hydrocarbon core fluidity of hippocampal membranes from AD-patients as well as elderly controls in a concentration depending fashion, although the effect was more pronounced for the AD membranes. In the presence of piracetam, the difference of the membrane fluidity between AD and control membranes was not longer apparent.

Immunological mechanisms and the spectrum of psychiatric syndromes in Alzheimer's disease.

Eikelenboom P, Hoogendijk WJ, Jonker C, van Tilburg W. Graduate School Neuroscience, Amsterdam, The Netherlands

J Psychiatr Res 2002 Sep-Oct;36(5):269-80

Pathological, genetic and epidemiological studies support the opinion that inflammatory mechanisms are involved in the pathogenesis of Alzheimer's disease (AD). Recent pathological and neuroradiological (PET) data show that activation of microglia is an early pathogenic event that precedes the process of severe neuropil destruction in AD brains. In this paper we review the evidence that inflammatory mediators can play a pathogenic role in some behavioural disorders frequently encountered during the clinical course in AD patients. Motivational disturbances are the most striking of the depressive symptoms in AD and can be present in a preclinical stage of the disease. Experimental animal studies and clinical trials in humans have shown that cytokines can induce similar symptoms which were described as 'sickness behaviour' or 'depressive-like' state. Delirious states are frequently observed in more advanced stages of dementia. Delirium is generally considered the result of an imbalance in neurotransmitter systems with severe deficits of the cholinergic systems. Animal studies show that pro-inflammatory cytokines, such as interleukin-1, induce a reduced activity of the cholinergic system. In AD, the release of cytokines would exacerbate any already existing disturbances in the cholinergic neurotransmission. This could explain the susceptibility of demented patients to delirium provoked by a wide variety of trivial incidents that are accompanied by an acute phase response. The data reviewed in this paper suggest that it could be worthwhile employing a neuroimmunological approach to study at molecular level the pathogenesis of a broad spectrum of behavioural disturbances common in the clinical course of AD patients.

Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type . Engel RR, Satzger W, Gunther W, Kathmann N, Bove D, Gerke S, Munch U, Hippius H. Psychiatric Hospital, University of Munich, Germany.

Eur Neuropsychopharmacol 1992 Jun;2(2):149-55

Thirty-three patients with mild primary degenerative dementia according to DSM-III (MMS between 15 and 27) took part in a double-blind cross-over study of phosphatidylserine (Fidia, 300 mg/d) versus placebo. Both treatment phases lasted for 8 weeks with an 8 week washout phase in between and a 4 week washout phase before treatment phase one. Clinical global improvement ratings showed significantly more patients improving under BC-PS than under placebo during treatment phase one. The improvement carried over to the following wash-out and treatment phases. There were no significant improvements in GBS dementia rating scale, psychometric tests or P300-latency. 16-channel EEG mapping findings indicated that the patients initially showed higher power values in all frequency bands (except alpha), when compared to a younger, healthy control group. BC-PS reduced the higher power values compared to placebo, shifting EEG power more towards the normal level.

Selegiline in the treatment of Alzheimer's disease: a long-term randomized placebo-controlled trial. Czech and Slovak Senile Dementia of Alzheimer Type Study Group.

Filip V, Kolibas E Department of Psychiatry, Comenius University, Bratislava, Slovak Republic. pharmnet@comp.cz

J Psychiatry Neurosci 1999 May;24(3):234-43

OBJECTIVE: To evaluate the efficacy and adverse effects of the type B monoamine oxidase inhibitor selegiline (also known as I-deprenyl) in the treatment of Alzheimer's disease. DESIGN: Long-term, double-blind, placebo-controlled trial.

SETTING: Seven cities (1 or 2 nursing homes in each city) in the Czech and Slovak Republics. PATIENTS: A total of 173 nursing-home residents fulfilling the DSM-III criteria for mild to moderate Alzheimer's disease. INTERVENTIONS: Selegiline (10 mg per day) or placebo (both including 50 mg ascorbic acid) administered for 24 weeks.

OUTCOME MEASURES: Clinical Global Impressions scale and Nurses Observation Scale for Inpatient Evaluation at baseline and at weeks 6, 12 and 24; Clock Drawing Test at baseline and 24 weeks, results of which were evaluated as normal or pathologic, and quantitatively on a modified 6-point scale; Sternberg's Memory Scanning test at baseline and at weeks 6, 12 and 24; Mini Mental State Examination, and electroencephalogram at baseline and 24 weeks; Structured Adverse Effects Rating Scale; physical, laboratory, hematological and electrocardiographic examinations at baseline and weeks 12 and 24.

RESULTS: A total of 143 subjects completed enough of the trial to be entered in the analysis. Subjects were analyzed by 2 subgroups depending on whether they had a normal or pathologic result of the Clock Drawing Test. Analysis of variance showed significant improvement with selegiline versus placebo among those with a normal result of the Clock Drawing Test on the Mini Mental Status Examination (total score and orientation-place subscale) and among those with a pathologic result of the Clock Drawing Test of Sternberg's Memory Scanning test (for both speed and accuracy), on the Clinical Global Impressions scale as well as in terms of the dominant frequency on electroencephalograms.

CONCLUSION: Selegiline has a long-term beneficial effect in Alzheimer's disease on memory modalities that reflect the function of the prefrontal areas of the brain, which are rich in dopamine receptors. The delayed appearance of differences between selegiline and placebo supports the notion that the mechanism of action is through neuronal rescue or neuroprotection. The differential response of patients with normal and pathologic results of the Clock Drawing Test may reflect the fact that the evaluation methods' sensitivity to change depends on the severity of dementia.

Treatment of Alzheimer's disease with short- and long-term oral THA and lecithin: a double-blind study.

Fitten LJ, Perryman KM, Gross PL, Fine H, Cummins J, Marshall C. VA Medical Center, Sepulveda, Calif 91343.

Am J Psychiatry 1990 Feb;147(2):239-42

Ten Alzheimer's disease patients underwent a trial of oral tetrahydroaminoacridine (THA) and lecithin. After 3 inpatient weeks there was no clear therapeutic effect. Three of six patients able to continue in long-term treatment showed measurable cognitive improvement, but only one displayed clinically obvious improvement.

Donepezil. Pharmacoeconomic implications of therapy.

Foster RH, Plosker GL Adis International Limited, Auckland, New Zealand. demail@adis.co.nz

Pharmacoeconomics 1999 Jul;16(1):99-114

Donepezil is a specific acetylcholinesterase inhibitor that can improve symptoms in patients with mild-to-moderate Alzheimer's disease; cognitive function is maintained above baseline levels for up to 1 year and normal decline of cognitive function is slowed. The ability of the patient to perform daily activities and neuropsychiatric symptoms may also be improved by donepezil, but data are limited. Donepezil is not expected to alter the underlying neurodegenerative process, and the response to the drug varies between individuals. In the absence of validated instruments to measure quality of life, it is not clear how donepezil affects this parameter. In a US survey of caregivers of patients with Alzheimer's disease who were being cared for at home at the start of the 6-month study period, treatment with donepezil did not increase overall direct medical costs. The acquisition cost of the drug was balanced by reduced institutionalisation costs. Economic analyses using Markov models from the US, UK and Canada suggest that donepezil initiated in the early stages of disease may be effectively cost neutral as a result of patients remaining in a nonsevere state of disease for a longer time.

Neuronal sparing and behavioral effects of the antiapoptotic drug, (-)deprenyl, following kainic acid administration.

Gelowitz DL, Paterson IA Department of Psychiatry, University of Cincinnati, OH 45267-0559, USA.

Pharmacol Biochem Behav 1999 Feb;62(2):255-62

(-)Deprenyl is an irreversible inhibitor of monoamine oxidase B (MAO-B) frequently used as an adjunct therapy in the treatment of Parkinson's Disease. Recent evidence, however, has found that deprenyl's metabolites are associated with an antiapoptotic action within certain neuronal populations. Interestingly, deprenyl's antiapoptotic actions appear not to depend upon the inhibition of MAO-B. Due to a paucity of information surrounding (-)deprenyl's ability to spare neurons in vivo, a series of studies was conducted to further investigate this phenomenon within an apoptotic neuronal death model: kainic acid induced excitotoxicity. Results indicated that (-)deprenyl increased hippocampal neuronal survival compared to saline-matched controls following kainic acid insult. Furthermore, it was discovered that (-)deprenyl treatment could be stopped 14 days following CNS insult by kainate, with evidence of neuronal sparing still present by day 28. In open-field locomotor activity testing of kainate-treated animals, those given subsequent (-)deprenyl treatment showed habituation curves similar to control subjects, while saline-treated animals did not. Given deprenyl's antiapoptotic actions, it is proposed that (-)deprenyl may be beneficial in the treatment of a variety of neurodegenerative diseases where evidence of apoptosis exists, such as Parkinson's and Alzheimer's Disease, by slowing the disease process itself.

The incidence of dementia and intake of animal products: preliminary findings from the Adventist Health Study.

Giem P, Beeson WL, Fraser GE Department of Preventive Medicine, School of Medicine, Loma Linda University, CA 92350.

Neuroepidemiology 1993;12(1):28-36

We investigated the relationship between animal product consumption and evidence of dementia in two cohort substudies. The first enrolled 272 California residents matched for age, sex, and zip code (1 vegan, 1 lacto-ovo-vegetarian, and 2 'heavy' meat eaters in each of 68 quartets). This design ensured a wide range of dietary exposure. The second included 2,984 unmatched subjects who resided within the Loma Linda, California area. All subjects were enrolled in the Adventist Health Study. The matched subjects who ate meat (including poultry and fish) were more than twice as likely to become demented as their vegetarian counterparts (relative risk 2.18, p = 0.065) and the discrepancy was further widened (relative risk 2.99, p = 0.048) when past meat consumption was taken into account. There was no significant difference in the incidence of dementia in the vegetarian versus meat-eating unmatched subjects. There was no obvious explanation for the difference between the two substudies, although the power of the unmatched sub-study to detect an effect of 'heavy' meat consumption was unexpectedly limited. There was a trend towards delayed onset of dementia in vegetarians in both substudies.

Abdominal omentum transfer and the nervous system.

Goldsmith HS.

Lancet 1985 Jun 29;1(8444):1514

No Abstracts Available

Brain vascularization by intact omentum.

Goldsmith HS, Chen WF, Duckett SW.

Arch Surg 1973 May;106(5):695-8

No Abstracts Available

Lipid angiogenic factor from omentum.

Goldsmith HS, Griffith AL, Kupferman A, Catsimpoolas N.

JAMA 1984 Oct 19;252(15):2034-6

Placing the omentum on the brain surface by surgical transposition or transplantation will result in the development of numerous neovascular connections between these two structures. This phenomenon occurs even in the absence of cerebral ischemia, which raised the question as to whether an angiogenic factor was causing the response. A lipid material obtained from the omentum contains a potent angiogenic factor extractable in a chloroform-methanol solvent mixture. Angiogenesis created by this material was observed in the rabbit cornea after only a single injection of the substance. The angiogenic material obtained from the omentum is abundant in supply. This important characteristic offers promise for the purification and identification of its structure, which should allow for extensive animal and clinical studies dealing with the development or inhibition of angiogenesis.

Vascularization of brain and spinal cord by intact omentum.

Goldsmith HS, Steward E.

Appl Neurophysiol 1984;47(1-2):57-61

No Abstracts Available

Vasoactive neurochemicals identified in omentum: a preliminary report.

Goldsmith HS, McIntosh T, Vezina RM, Colton T. Department of Surgery, Boston University School of Medicine.

Br J Neurosurg 1987;1(3):359-64

There has been increasing interest in biologic, immunologic, and chemical activity originating from omental tissue. Since clinical improvement has been observed in some patients very shortly after surgically transposing their omentum to the spinal cord or brain, the question arose as to whether neurochemicals might be present in omental tissue; a possible explanation for some of these neurological changes. This paper reports the presence of vasoactive neurochemicals in canine omental tissue. It remains unclear, however, whether the omentum produces or simply concentrates these and other neurochemicals.

Early diagnosis of cognitive impairment in the elderly with the focus on Alzheimer's disease.

Gottfries CG, Lehmann W, Regland B. Department of Psychiatry and Neurochemistry, Institute of Clinical Neuroscience, Goteborg University, Molndal, Sweden.

J Neural Transm 1998;105(8-9):773-86

In dementia disorders, it can be assumed that the pathological process in the brain has been present for a long time. It is therefore of importance to have a preclinical or an early clinical diagnosis. Obviously, vulnerability genes, such as ApoE-4, can be diagnosed preclinically. As we have no treatment to offer patients with genetic risk factors, genotyping for ApoE-4 is at present of no clinical use. Trained neuropsychologists have today access to sensitive tests which reveal cognitive impairment before the disturbances reach the level of dementia. Laboratory investigations of cerebrospinal fluid have so far yielded no great results. Tau protein appears to be the most sensitive marker, but it is unspecific. Chromogranin A separates early onset from late onset Alzheimer's disease and seems to be a marker for synaptic degeneration. Synaptotagmin was also found to be reduced in patients with early onset Alzheimer's disease. Still we do not know, however, whether these proteins are early markers for degenerative processes in the brain. Laboratory investigations of blood have not yielded markers of use in early or differential diagnosis of dementia disorders. In a study at our own institute, however, we found serum-homocysteine (S-HCY) to be an early and sensitive marker for cognitive impairment. In patients with dysmentia (mild cognitive impairment), no less than 39% had pathological S-HCY levels, indicating insufficient 1-carbon metabolism.

Nuclear factor-kappaB/Rel proteins: a point of convergence of signalling pathways relevant in neuronal function and dysfunction.

Grilli M, Memo M. Schering-Plough Research Institute, San Raffaele Science Park, Milan, Italy. mariagrazia.grilli@spcorp.com

Biochem Pharmacol 1999 Jan 1;57(1):1-7

Nuclear factor-kappaB (NF-kappaB)/Rel designates a family of transcription factors participating in the activation of a wide range of genes crucially involved in immune and inflammatory function. NF-kappaB/Rel proteins have been demonstrated recently in primary neurons and in several brain areas. Functional significance of these proteins is still not understood completely, but since certain subsets of neurons appear to contain constitutively active DNA-binding activity, it seems likely that they may participate in normal brain function. A growing body of evidence is accumulating for a specific activation of NF-kappaB/Rel proteins in the CNS, and in particular in neuronal cells, during neurodegenerative processes associated to etiologically unrelated conditions. Whether NF-kappaB activation is part of the neurodegenerative process or of protective mechanisms is a matter of debate. This issue will be reviewed here with particular attention to the available reports on the activity of NF-kappaB/Rel proteins in both experimental paradigms of neurodegeneration and post-mortem brain tissue of patients affected by various neurological diseases. We hypothesize that NF-kappaB/Rel proteins may represent the point of convergence of several signalling pathways relevant for initiating or accelerating the process of neuronal dysfunction and degeneration in many neurological diseases, including Parkinson's disease, Alzheimer's disease, CNS viral infections, and possibly others. If NF-kappaB/Rel proteins represent an integrating point of several pathways potentially contributing to neuronal degeneration, molecules that finely modulate their activity could represent a novel pharmacological approach to several neurological diseases.

Evidence that nerve growth factor influences recent memory through structural changes in septohippocampal cholinergic neurons.

Gustilo MC, Markowska AL, Breckler SJ, Fleischman CA, Price DL, Koliatsos VE Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

J Comp Neurol 1999 Mar 22;405(4):491-507

We compared, in 4- and 23-month-old Fischer-344 rats, the effects of nerve growth factor (NGF) on basal forebrain cholinergic neurons with behavioral performance in acetylcholine-dependent memory tasks (recent and reference memory). Noncholinergic monoamine markers in target fields of cholinergic neurons were also investigated. We found that NGF has contrasting effects on recent memory in the two age groups in causing improvement in aged rats and deterioration in young rats. In addition, NGF caused significant increase in the size of cholinergic perikarya in all sectors of the basal nucleus complex (BNC). Higher doses of NGF were required to produce hypertrophy in aged animals, a pattern consistent with a lower sensitivity to NGF of aged cholinergic neurons. Analysis of covariance showed that the behavioral effects of NGF were eliminated after covarying out the hypertrophy of cholinergic perikarya. Therefore, NGF causes hypertrophy of cholinergic perikarya regardless of age, and this neurobiological measure correlates with the effects of NGF on recent memory. Reference memory improved moderately only in old rats. This mild effect covaried with an increase in choline acetyltransferase activity in neocortex. Cortical terminal fields of noradrenergic and serotoninergic pathways were not affected by NGF. Taken together, our results indicate that NGF influences recent memory in an age- and transmitter-specific fashion. We postulate that the direct cause of the effects of NGF on memory is not perikaryal hypertrophy per se but rather an increased density of terminals, which always accompanies perikaryal hypertrophy. Although these results continue to support the use of NGF for the treatment of Alzheimer's disease, they raise questions regarding the therapeutic role of NGF for degeneration of BNC neurons occurring in young age.

Clinical aspects of nimodipine.

Grobe-Einsler R

Pharma Research Center, Wuppertal, Germany.

Clin Neuropharmacol 1993;16 Suppl 1:S39-45

This overview describes the result of the clinical development program in organic brain syndrome (impaired brain function in old age), where efficacy was proven in 11 double-blind, placebo-controlled studies. Another study within this development program showed nimodipine not only to be superior to placebo but also to hydergine. Furthermore, in a placebo-controlled clinical trial, nimodipine caused further improvement in performance compared to regular mental exercise at home. Due to the results in the organic brain syndrome program, registration was granted in 23 countries worldwide for this indication. In one clinical trial in the dementia development program, patients with dementia were carefully allocated either to primary degenerative dementia (PDD) or multi-infarct dementia (MID) stratum; nimodipine was shown to be superior to placebo independent of the etiology. Other clinical trials conducted in this indication supported the evidence for efficacy and showed that nimodipine-treated patients performed better than placebo patients. The safety profile of the drug is well established and substantiated by extensive postmarketing surveillance. In general, nimodipine was well tolerated, showing few adverse events. Finally, topics for future research are covered such as developing new instruments to assess more severe patients, expanding the patient collective to secondary dementias such as AIDS and Parkinson dementia, implementation of cost/utility elements in the development program, and the issue of nimodipine's potential role in the prevention of disease.

Vitamin E and Alzheimer disease: the basis for additional clinical trials.

Grundman M. Alzheimer's Disease Cooperative Study, 9500 Gilman Drive 0949, La Jolla, CA, 92093-0949, USA. mgrundman@ucsd.edu.

Am J Clin Nutr 2000 Feb;71(2):630S-636S

Many lines of evidence suggest that oxidative stress is important in the pathogenesis of Alzheimer disease. In particular, beta-amyloid, which is found abundantly in the brains of Alzheimer disease patients, is toxic in neuronal cell cultures through a mechanism involving free radicals. Vitamin E prevents the oxidative damage induced by beta-amyloid in cell culture and delays memory deficits in animal models. A placebo-controlled, clinical trial of vitamin E in patients with moderately advanced Alzheimer disease was conducted by the Alzheimer's Disease Cooperative Study. Subjects in the vitamin E group were treated with 2000 IU (1342 alpha-tocopherol equivalents) vitamin E/d. The results indicated that vitamin E may slow functional deterioration leading to nursing home placement. A new clinical trial is planned that will examine whether vitamin E can delay or prevent a clinical diagnosis of Alzheimer disease in elderly persons with mild cognitive impairment.

The effect of tetrahydrofolate on tetrahydrobiopterin metabolism.

Hamon CG, Blair JA, Barford PA.

J Ment Defic Res 1986 Jun;30 ( Pt 2):179-83

5-Methyltetrahydrofolate and vitamin B12 appear to be required for the biosynthesis of tetrahydrobiopterin. A deficiency of either could be sufficient to bring about neurological change which can be corrected by reversing the deficiency. Patients with senile dementia could possibly be benefited by the administration of 5-methyltetrahydrofolate.

Long-term effects of phosphatidylserine, pyritinol, and cognitive training in Alzheimer's disease. A neuropsychological, EEG, and PET investigation

Heiss WD, Kessler J, Mielke R, Szelies B, Herholz K Max-Planck-Institut fur neurologische Forschung.

Dementia 1994 Mar-Apr;5(2):88-98

70 patients with probable Alzheimer's disease were randomly allocated to four groups: 17 patients received only social support. 18 cognitive training twice a week, in 17 cognitive training was combined with pyritinol 2 x 600 mg/day and in 18 cognitive training was combined with phosphatidylserine 2 x 200 mg/day. Treatment duration was 6 months. Before and after treatment, the patients underwent neuropsychological testing as well as measurement of the regional cerebral metabolic rate for glucose using positron emission tomography and 18F-2-fluoro-2-deoxy-D-glucose. Before treatment the groups were comparable in respect to resting and activated glucose pattern achieved by a visual recognition task. Electrophysiological changes were assessed as EEG power, globally and in 4 frequency bands. This 6-month study in four groups of patients with Alzheimer's disease indicated that phosphatidylserine treatment has an effect on different measures of brain function. Since neuropsychological improvements were best documented after 8 and 16 weeks and faded towards the end of the treatment period, it must be concluded that this symptomatic therapy is mainly of short-term benefit and was overcome by the progressive pathological changes at the end of the treatment period.

JC virus infection and Alzheimer's disease: reappraisal of an in situ hybridization approach.

Heinonen O, Syrjanen S, Mantyjarvi R, Syrjanen K, Riekkinen P. Department of Neurology, University of Kuopio, Finland.

Ann Neurol 1992 Apr;31(4):439-41

To assess the validity of the recently reported data on frequent occurrence of latent JC virus (JCV) infections in the brains of patients with Alzheimer's disease, we used in situ hybridization with biotinylated whole genomic JCV probes and the streptavidin-biotinylated alkaline phosphatase method to examine brain sections of such patients. We did not find any signs of JCV either in the brains of the patients with Alzheimer's disease or in those of nondemented, elderly control patients. Non-specific staining of corpora amylacea-like bodies, however, was invariably detected with in situ hybridization using JCV probes.

Lecithin for dementia and cognitive impairment (Cochrane Review).

Higgins JP, Flicker L MRC Biostatistics Unit, Institute of Public Health, Robinson Way, Cambridge, Cambridgeshire, UK, CB2 2SR. julian.higgins@mrc-bsu.cam.ac.uk [Record supplied by publisher]

Cochrane Database Syst Rev 2000;4:CD001015

BACKGROUND: Alzheimer's disease sufferers have been found to have a lack of the enzyme responsible for converting choline into acetylcholine within the brain. Lecithin is a major dietary source of choline, so extra consumption may reduce the progression of dementia.

OBJECTIVES: To determine the efficacy of lecithin in the treatment of dementia or cognitive impairment.

SEARCH STRATEGY: The Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials has been searched, as have the electronic databases MEDLINE, EMBASE, Psychlit, ISI and Current Contents. Reference lists and relevant books have been examined.

SELECTION CRITERIA: All unconfounded, randomized trials comparing lecithin with placebo in a treatment period longer than one day, in patients with dementia of the Alzheimer type, vascular dementia, mixed vascular and Alzheimer's disease, unclassified or other dementia or unclassified cognitive impairment not fulfilling the criteria for dementia are eligible for inclusion.

DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers and cross-checked. Meta-analyses were performed when more than one trial provided data on a comparable outcome on sufficiently similar patients. Random effects analyses were performed whenever heterogeneity between results appeared to be present. Standardised mean difference were used due do the use of different scales and periods of treatment. Odds ratios for dichotomous data were pooled using the Mantel-Haenszel or DerSimonian and Laird methods.

MAIN RESULTS: Twelve randomized trials have been identified involving patients with Alzheimer's disease (265 patients), Parkinsonian dementia (21 patients) and subjective memory problems (90 patients). No trials reported any clear clinical benefit of lecithin for Alzheimer's disease or Parkinsonian dementia. Few trials contributed data to meta-analyses. The only statistically significant result was in favour of placebo for adverse events, based on one trial, which appears likely to be a spurious result. A dramatic result in favour of lecithin was obtained in a trial of subjects with subjective memory problems.

REVIEWER'S CONCLUSIONS: Evidence from randomized trials does not support the use of lecithin in the treatment of patients with dementia. A moderate effect cannot be ruled out, but results from the small trials to date do not indicate priority for a large randomized trial.

DHEA-S plasma levels and incidence of Alzheimer's disease.

Hillen T, Lun A, Reischies FM, Borchelt M, Steinhagen-Thiessen E, Schaub RT Department of Internal Medicine-Geriatrics, Medical Faculty, Humboldt University Berlin/Charite, Germany.

Biol Psychiatry 2000 Jan 15;47(2):161-3

BACKGROUND: Cross-sectional studies controlling for age and gender reported a relationship between Alzheimer's disease and low dehydroepiandrosterone sulphate (DHEA-S) plasma levels. Prospective data with sufficient control for confounding factors are lacking.

METHODS: A nested case-control study examined baseline DHEA-S in participants of the Berlin Aging Study. Cases (n = 14) developed dementia of the Alzheimer type within 3 years. Control group A (n = 14) was matched for gender, age, multimorbidity, and immobility. Control group B (n = 13) was matched for gender and age and comprised participants free from multimorbidity, immobility, multimedication, need of help, incontinence, visual impairment, hearing impairment, and depression.

RESULTS: The mean plasma DHEA-S concentration of case subjects was 1.02 0.61 mumol/L. Both control groups had higher mean DEHA-S levels, in control group A, it was 1.89 1.24 mumol/L (p = .012) and in control group B 1.70 1.38 mumol/L (p = .093).

CONCLUSIONS: This population-based prospective study supports the role of DHEA-S as a risk factor for Alzheimer's disease.

Carnosine, a protective, anti-ageing peptide?

Hipkiss AR. Molecular Biology and Biophysics Group, King's College London, Strand, UK.

Int J Biochem Cell Biol 1998 Aug;30(8):863-8

Carnosine (beta-alanyl-L-histidine) has protective functions additional to anti-oxidant and free-radical scavenging roles. It extends cultured human fibroblast life-span, kills transformed cells, protects cells against aldehydes and an amyloid peptide fragment and inhibits, in vitro, protein glycation (formation of cross-links, carbonyl groups and AGEs) and DNA/protein cross-linking. Carnosine is an aldehyde scavenger, a likely lipofuscin (age pigment) precursor and possible modulator of diabetic complications, atherosclerosis and Alzheimer's disease.

Pluripotent protective effects of carnosine, a naturally occurring dipeptide.

Hipkiss AR, Preston JE, Himsworth DT, Worthington VC, Keown M, Michaelis J, Lawrence J, Mateen A, Allende L, Eagles PA, Abbott NJ. Molecular Biology and Biophysics Group, King's College London, Strand, United Kingdom. alan.hipkiss@kcl.ac.uk

Ann N Y Acad Sci 1998 Nov 20;854:37-53

Carnosine is a naturally occurring dipeptide (beta-alanyl-L-histidine) found in brain, innervated tissues, and the lens at concentrations up to 20 mM in humans. In 1994 it was shown that carnosine could delay senescence of cultured human fibroblasts. Evidence will be presented to suggest that carnosine, in addition to antioxidant and oxygen free-radical scavenging activities, also reacts with deleterious aldehydes to protect susceptible macromolecules. Our studies show that, in vitro, carnosine inhibits nonenzymic glycosylation and cross-linking of proteins induced by reactive aldehydes (aldose and ketose sugars, certain triose glycolytic intermediates and malondialdehyde (MDA), a lipid peroxidation product). Additionally we show that carnosine inhibits formation of MDA-induced protein-associated advanced glycosylation end products (AGEs) and formation of DNA-protein cross-links induced by acetaldehyde and formaldehyde. At the cellular level 20 mM carnosine protected cultured human fibroblasts and lymphocytes, CHO cells, and cultured rat brain endothelial cells against the toxic effects of formaldehyde, acetaldehyde and MDA, and AGEs formed by a lysine/deoxyribose mixture. Interestingly, carnosine protected cultured rat brain endothelial cells against amyloid peptide toxicity. We propose that carnosine (which is remarkably nontoxic) or related structures should be explored for possible intervention in pathologies that involve deleterious aldehydes, for example, secondary diabetic complications, inflammatory phenomena, alcoholic liver disease, and possibly Alzheimer's disease.

Endogenous mechanisms of neuroprotection: role of zinc, copper, and carnosine.

Horning MS, Blakemore LJ, Trombley PQ. Biomedical Research Facility, Department of Biological Science, Florida State University, Tallahassee 32306-4340, USA. horning@neuro.fsu.edu

Brain Res 2000 Jan 3;852(1):56-61

Zinc and copper are endogenous transition metals that can be synaptically released during neuronal activity. Synaptically released zinc and copper probably function to modulate neuronal excitability under normal conditions. However, zinc and copper also can be neurotoxic, and it has been proposed that they may contribute to the neuropathology associated with a variety of conditions, such as Alzheimer's disease, stroke, and seizures. Recently, we demonstrated that carnosine, a dipeptide expressed in glial cells throughout the brain as well as in neuronal pathways of the visual and olfactory systems, can modulate the effects of zinc and copper on neuronal excitability. This result led us to hypothesize that carnosine may modulate the neurotoxic effects of zinc and copper as well. Our results demonstrate that carnosine can rescue neurons from zinc- and copper-mediated neurotoxicity and suggest that one function of carnosine may be as an endogenous neuroprotective agent.

Health benefits of docosahexaenoic acid.

Horrocks LA, Yeo YK Docosa Foods Ltd, 1275 Kinnear Road, Columbus, OH 43212-1155, USA,

Pharmacol Res 1999 Sep;40(3):211-25

Docosahexaenoic acid (DHA) is essential for the growth and functional development of the brain in infants. DHA is also required for maintenance of normal brain function in adults. The inclusion of plentiful DHA in the diet improves learning ability, whereas deficiencies of DHA are associated with deficits in learning. DHA is taken up by the brain in preference to other fatty acids. The turnover of DHA in the brain is very fast, more so than is generally realized. The visual acuity of healthy, full-term, formula-fed infants is increased when their formula includes DHA. During the last 50 years, many infants have been fed formula diets lacking DHA and other omega-3 fatty acids. DHA deficiencies are associated with foetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis, phenylketonuria, unipolar depression, aggressive hostility, and adrenoleukodystrophy. Decreases in DHA in the brain are associated with cognitive decline during aging and with onset of sporadic Alzheimer disease. The leading cause of death in western nations is cardiovascular disease. Epidemiological studies have shown a strong correlation between fish consumption and reduction in sudden death from myocardial infarction. The reduction is approximately 50% with 200 mg day(-1)of DHA from fish. DHA is the active component in fish. Not only does fish oil reduce triglycerides in the blood and decrease thrombosis, but it also prevents cardiac arrhythmias. The association of DHA deficiency with depression is the reason for the robust positive correlation between depression and myocardial infarction. Patients with cardiovascular disease or Type II diabetes are often advised to adopt a low-fat diet with a high proportion of carbohydrate. A study with women shows that this type of diet increases plasma triglycerides and the severity of Type II diabetes and coronary heart disease. DHA is present in fatty fish (salmon, tuna, mackerel) and mother's milk. DHA is present at low levels in meat and eggs, but is not usually present in infant formulas. EPA, another long-chain n-3 fatty acid, is also present in fatty fish. The shorter chain n-3 fatty acid, alpha-linolenic acid, is not converted very well to DHA in man. These longchain n-3 fatty acids (also known as omega-3 fatty acids) are now becoming available in some foods, especially infant formula and eggs in Europe and Japan. Fish oil decreases the proliferation of tumour cells, whereas arachidonic acid, a longchain n-6 fatty acid, increases their proliferation. These opposite effects are also seen with inflammation, particularly with rheumatoid arthritis, and with asthma. DHA has a positive effect on diseases such as hypertension, arthritis, atherosclerosis, depression, adult-onset diabetes mellitus, myocardial infarction, thrombosis, and some cancers. Copyright 1999 Academic Press.

High brain myo-inositol levels in the predementia phase of Alzheimer's disease in adults with Down's syndrome: a 1H MRS study.

Huang W, Alexander GE, Daly EM, Shetty HU, Krasuski JS, Rapoport SI, Schapiro MB Laboratory of Neurosciences, National Institute on Aging, Clinical Center, NIH, Bethesda, MD, USA. whuang@clio.rad.sunysb.edu

Am J Psychiatry 1999 Dec;156(12):1879-86

OBJECTIVE: An extra portion of chromosome 21 in Down's syndrome leads to a dementia in later life that is phenotypically similar to Alzheimer's disease. Down's syndrome therefore represents a model for studying preclinical stages of Alzheimer's disease. Markers that have been investigated in symptomatic Alzheimer's disease are myoinositol and N-acetyl-aspartate. The authors investigated whether abnormal brain levels of myo-inositol and other metabolites occur in the preclinical stages of Alzheimer's disease associated with Down's syndrome.

METHOD: The authors used 1H magnetic resonance spectroscopy (MRS) with external standards to measure absolute brain metabolite concentrations in 19 nondemented adults with Down's syndrome and 17 age- and sex-matched healthy comparison subjects.

RESULTS: Concentrations of myoinositol and choline-containing compounds were significantly higher in the occipital and parietal regions of the adults with Down's syndrome than in the comparison subjects. Within the Down's syndrome group, older subjects (42-62 years, N = 11) had higher myo-inositol levels than younger subjects (28-39 years, N = 8). Older subjects in both groups had lower N-acetylaspartate levels than the respective younger subjects, although this old-young difference was not greater in the Down's syndrome group.

CONCLUSIONS: The approximately 50% higher level of myo-inositol in Down's syndrome suggests a gene dose effect of the extra chromosome 21, where the human osmoregulatory sodium/myo-inositol cotransporter gene is located. The even higher myoinositol level in older adults with Down's syndrome extends to the predementia phase earlier findings of high myoinositol levels in symptomatic Alzheimer's disease.

Inflammatory mechanisms in Alzheimer's disease

Hull M.; Strauss S.; Berger M.; Volk B.; Bauer J. Department of Psychiatry, Freiburg University Medical School,D-79104 Freiburg Germany

European Archives of Psychiatry and Clinical Neuroscience (Germany) 1996, 246/3 (124-128)

In recent years many studies have indicated an involvement of inflammatory mechanisms in Alzheimer's disease (AD). Acute-phase proteins such as alpha1-antichymotrypsin and c-reactive protein, elements of the complement system, and activated microglial and astroglial cells are consistently found in brains of AD patients. Most importantly, also cytokines such as interleukin-6 (IL-6) have been detected in the cortices of AD patients, indicating a local activation of components of the unspecific inflammatory system. Up to now it has remained unclear whether inflammatory mechanisms represent a primary event or only an unspecific reaction to brain tissue damage. Therefore, we investigated whether IL-6 immunoreactivity could be found in plaques prior to the onset of neuritic changes, or whether the presence of this cytokine is restricted to later stages of plaque pathology. We confirmed our previous observation that IL-6 is detectable in a significant proportion of plaques in the brains of demented patients. In AD patients IL-6 was found in diffuse plaques in a significant higher ratio as would have been expected from a random distribution of IL-6 among all plaque types. This observation suggests that IL-6 may precede neuritic changes, and that immunological mechanism may be involved both in the transformation from diffuse to neuritic plaques in AD and in the development of dementia.

Herpes simplex virus type 1 in brain and risk of Alzheimer's disease.

Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Molecular Neurobiology Laboratory, Department of Optometry and Vision Sciences, UMIST, Manchester.

Lancet 1997 Jan 25;349(9047):241-4

BACKGROUND: The apolipoprotein E epsilon 4 (APOE-epsilon 4) allele is a risk factor for Alzheimer's disease (AD), but it is neither essential nor sufficient for development of the disease. Other factors-genetic or environmental-must therefore have a role. By means of a PCR we have detected herpes simplex virus type 1 (HSV1) in latent form in brains of elderly people with and without AD. We have postulated that limited reactivation of the virus causes more damage in AD patients than in elderly people without AD because of a difference in the hosts. We now report the APOE genotypes of AD patients and non-AD sufferers with and without HSV1 in brain.

METHODS: DNA was extracted from 84 samples of brain from 46 AD patients (39 temporal lobe, 39 frontal lobe, three hippocampus) and from 75 samples of brain from 44 non-AD elderly people (33 temporal lobe, 36 frontal lobe, six hippocampus). PCR amplification was used to detect HSV1 thymidine kinase gene and the host APOE gene.

FINDINGS: By multiple logistic regression, the APOE-epsilon 4 allele frequency was significantly higher in the patients positive for HSV1 in brain than in the HSV1-negative AD group, the HSV1-positive non-AD group, or the HSV1-negative non-AD group (52.8% vs 10.0%, 3.6%, and 6.3%, respectively). The odds ratio for APOE-epsilon 4 in the HSV1-positive AD group compared with HSV1-negative non-AD group was 16.8 (95% CI 3.61-77.8) and in the HSV1-negative AD group, 1.67 (0.21-13.4). We also compared APOE genotypes of 40 people who had recurrent cold sores and 33 non-sufferers; the APOE-epsilon 4 allele frequencies were 36% and 9%, respectively (p < 0.0001).

INTERPRETATION: These findings suggest that the combination of HSV1 in brain and carriage of an APOE-epsilon 4 allele is a strong risk factor for AD, whereas either of these features alone does not increase the risk of AD. The findings in people with cold sores support our hypothesis that APOE-epsilon 4 and HSV1 together are damaging in the nervous system.

Demonstration of CRP immunoreactivity in brains of Alzheimer's disease: Immunohistochemical study using formic acid pretreatment of tissue sections

Iwamoto N.; Nishiyama E.; Ohwada J.; Arai H. Department of Psychiatry, Juntendo University, School of Medicine, 2-1-1 Hongo,Bunkyo-ku, Tokyo 113 Japan

Neuroscience Letters (Ireland) 1994, 177/1-2 (23-26) C-reactive protein (CRP) is a well-known serum protein which increases during inflammation and deposits in destructed tissues. To establish whether CRP appears in brain of Alzheimer's disease (AD), we immunohistochemically investigated tissue sections which were pretreated with formic acid. Positive immunostainings by anti-CRP antibodies were clearly recognized in senile plaques (SP) in the pretreated tissue sections whereas very weak immunostainings in non-treated sections. These findings may suggest that the formation process of SP contains an acute phase of inflammatory state.

Evaluation of memantine for neuroprotection in dementia.

Jain KK. Jain PharmaBiotech, Blasiring 7, CH-4057 Basel, Switzerland. jain@pharmabiotech.ch.

Expert Opin Investig Drugs 2000 Jun;9(6):1397-406

Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. Memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer's disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer's disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US$1 billion mark in annual sales.

Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Alzheimer' s disease.

Jimenez-Jimenez FJ; de Bustos F; Molina JA; Benito-Leon J; Tallon-Barranco A; Gasalla T; Orti-Pareja M; Guillamon F; Rubio JC; Arenas J; Enriquez-de-Salamanca R. Department of Neurology, Hospital Universitario Principe de Asturias, Alcala de Henares, Spain.

J Neural Transm (Austria) 1997, 104 (6-7) p703-10

We compared CSF and serum levels, and the CST/serum ratio of alpha-tocopherol (vitamin E), measured by HPLC, in 44 apparently well-nourished patients with Alzheimer's disease (AD) and 37 matched controls. CSF and serum vitamin E levels were correlated, both in AD patients and in controls. The mean CSF and serum vitamin E levels were significantly lower in AD patients, and the CSF/serum ratio of AD patients did not differ significantly between the 2 study groups. CSF vitamin E levels did not correlate with age, age at onset, duration of the disease and score of the Minimental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that low CSF and serum vitamin E concentrations in AD patients could be related with a deficiency of dietary intake of vitamin E.

Serum levels of beta-carotene, alpha-carotene and vitamin A in patients with Alzheimer's disease.

Jimenez-Jimenez FJ, Molina JA, de Bustos F, Orti-Pareja M, Benito-Leon J, Tallon-Barranco A, Gasalla T, Porta J, Arenas J. Department of Neurology of Hospital 'Principe de Asturias', University of Alcala de Henares, Madrid, Spain.

Eur J Neurol 1999 Jul;6(4):495-7

To elucidate the possible role of carotenoids and vitamin A as risk factors for Alzheimer's disease (AD), we compared serum levels of beta-carotene and alpha-carotene, and vitamin A, measured by isocratic high performance liquid chromatography, of 38 AD patients and 42 controls. The serum levels of alpha-carotene did not differ significantly between AD patients and control groups. However, the serum levels of beta-carotene and vitamin A were significantly lower in the AD-patient group. These values did not correlate to age, age at onset or score on the MiniMental State Examination. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that low serum beta-carotene concentrations in AD patients could be related to a deficiency in dietary intake of this provitamin, although its possible relationship with risk for AD could not be excluded. Copyright 1999 Lippincott Williams & Wilkins

Effect of curcumin and capsaicin on arachidonic acid metabolism and lysosomal enzyme secretion by rat peritoneal macrophages

Joe B.; Lokesh B.R. B.R. Lokesh, Dept. of Biochemistry and Nutrition, Centr. Food Technol. Res. Institute, Mysore-570 013 India sambaiah@nicfos.ernet.in

Lipids (United States) 1997, 32/11 (1173-1180)

The inflammatory mediators secreted by macrophages play an-important role in autoimmune diseases. Spice components, such as curcumin from turmeric and capsaicin from red pepper, are shown to exhibit antiinflammatory properties. The influence of these spice components on arachidonic acid metabolism and secretion of lysosomal enzymes by macrophages was investigated. Rat peritoneal macrophages preincubated with 10 muM curcumin or capsaicin for 1 h inhibited the incorporation of arachidonic acid into membrane lipids by 82 and 76%: prostaglandin Einf 2 by 45 and 48%; leukotriene Binf 4 by 61 and 46%, and leukotriene Cinf 4 by 34 and 48%, respectively, but did not affect the release of arachidonic acid from macrophages stimulated by phorbol myristate acetate. However, the secretion of 6-keto PG F(1alpha) was enhanced by 40 and 29% from macrophages preincubated with 10 muM curcumin or capsaicin, respectively, as compared to those produced by control cells. Curcumin and capsaicin also inhibited the secretion of collagenase, elastase, and hyaluronidase to the maximum extent of 57, 61, 66%, and 46, 69, 67%, respectively. These results demonstrated that curcumin and capsaicin can control the release of inflammatory mediators such as eicosanoids and hydrolytic enzymes secreted by macrophages and thereby may exhibit antiinflammatory properties.

Is metabolic evidence for vitamin B-12 and folate deficiency more frequent in elderly patients with Alzheimer' s disease?

Joosten E; Lesaffre E; Riezler R; Ghekiere V; Dereymaeker L; Pelemans W; Dejaeger E Department of Pathophysiology, University Hospitals K. U. Leuven, Belgium.

J Gerontol A Biol Sci Med Sci (United States) Mar 1997, 52 (2) M76-9.

BACKGROUND: It is still unclear whether there is an association between Alzheimer's disease and vitamin B-12 or folate deficiency. This study was designed to investigate whether patients with Alzheimer's disease are particularly prone to metabolically significant cobalamin or folate deficiency as compared to nondemented hospitalized controls and healthy elderly controls living at home.

METHODS: Evaluation for the diagnosis of Alzheimer's disease, routine laboratory tests, serum folate and vitamin B-12, serum methylmalonic acid (MMA), total homocysteine (tHcy), and radiological tests was performed in 52 patients with Alzheimer's disease (AD), 50 nondemented hospitalized controls, and 49 healthy elderly subjects living at home.

RESULTS: Serum vitamin B-12 and folate levels are comparable between patients with AD, hospitalized control patients, and subjects living at home. Patients with AD have the highest serum MMA and tHcy levels. The MMA levels of patients with AD and hospitalized controls are not different, but the mean tHcy level is significantly higher in patients with AD as compared to nondemented patients or subjects living at home.

CONCLUSION: The interpretation of the vitamin B-12 and folate status in patients with AD depends largely on the methodology (i.e., serum vitamin vs metabolite levels) and the selection of the control group. Although patients with AD have the highest tHcy and MMA levels, metabolically significant vitamin B-12 and folate deficiency is also a substantial problem in nondemented elderly patients.

Alzheimer's disease: risk and protection.

Jorm AF. National Health and Medical Research Centre Psychiatric Epidemiology Research Centre, Australian National University, Canberra, ACT. Anthony.Jorm@anu.edu.au

Med J Aust 1997 Oct 20;167(8):443-6

Only four risk factors for Alzheimer's disease can be regarded as confirmed--old age, family history of dementia, apo-E genotype and Down syndrome. Other disputed risk factors with some supporting evidence include ethnic group, head trauma and aluminium in drinking water. Possible protection factors, such as anti-inflammatory drugs, oestrogen replacement therapy and a high education level, are of great interest because they suggest possible preventive action.

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