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Alzheimer's Disease



The possible role of vitamin K deficiency in the pathogenesis of Alzheimer's disease and in augmenting brain damage associated with cardiovascular disease.

Allison AC. SurroMed Corporation, Mountain View, California 94043, USA.

Med Hypotheses 2001 Aug;57(2):151-5

The incidence of Alzheimer's disease (AD) increases with age and in carriers of the apolipoprotein E4 genotype. A relative deficiency of vitamin K, affecting the extrahepatic functions of the vitamin, is common in ageing men and women. The concentration of vitamin K is lower in the circulating blood of APOE4 carriers than in that of persons with other APOE genotypes. Evidence is accumulating that vitamin K has important functions in the brain, including the regulation of sulfotransferase activity and the activity of a growth factor/tyrosine kinase receptor (Gas 6/Axl). The hypothesis is now proposed that vitamin K deficiency contributes to the pathogenesis of AD and that vitamin K supplementation may have a beneficial effect in preventing or treating the disease. Vitamin K may also reduce neuronal damage associated with cardiovascular disease. Copyright 2001 Harcourt Publishers Ltd.

Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study.

Anthony JC, Breitner JC, Zandi PP, Meyer MR, Jurasova I, Norton MC, Stone SV Department of Mental Hygiene, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. janthony@jhu.edu

Neurology 2000 Jun 13;54(11):2066-71

OBJECTIVE: To test the hypothesis that nonsteroidal anti-inflammatory drugs (NSAIDs) and histamine H2 receptor antagonists (H2RAs) are associated with a decreased risk of AD in late life.

BACKGROUND: Sustained use of non-aspirin NSAIDs has been repeatedly associated with a reduced occurrence of AD. Similar effects with aspirin have been weaker. One prior study showed a strong association between use of H2RAs and reduced AD prevalence.

METHODS: In a population study of AD in Cache County, UT, we used a sequenced plan of sampling and case ascertainment to identify 201 cases of AD and 4425 participants with no indication of cognitive impairment. Independently, an interview and medicine chest inventory assessed use of several medicines including aspirin, non-aspirin NSAIDs, H2RAs, and three classes of "control" drugs not thought to be associated with AD. Follow-up questioning probed possible indications for use of these drugs.

RESULTS: Compared with cognitively intact individuals, the AD cases had significantly less reported current use of NSAIDs, aspirin, and H2RAs. Stronger associations appeared when subjects reported use of both NSAIDs and aspirin (no H2RAs), two different NSAIDs (no H2RAs), or two different H2RAs (with neither aspirin nor NSAIDs). There was little or no such association with use of the control medicines. Adjustment for usage indication did not influence these findings, and there was no appreciable variation with number of APOE epsilon4 alleles.

CONCLUSIONS: As predicted, use of NSAIDs and aspirin were specifically associated with reduced occurrence of AD. Notably, a previous observation of an inverse association of AD and use of H2RAs was also affirmed. Definitive evidence for a preventive action of these agents will require randomized prevention trials.

[A new interventional strategy for Alzheimer's disease by Japanese herbal medicine]. [Article in Japanese]

Arai H, Suzuki T, Sasaki H, Hanawa T, Toriizuka K, Yamada H Department of Geriatric Medicine, Tohoku University School of Medicine.

Nippon Ronen Igakkai Zasshi 2000 Mar;37(3):212-5

A Japanese herbal medicine termed "Kami-Umtan-To (KUT)" was first described in Japanese literature in 1626, KUT consists of 13 different herbs, and it has been used for a long time in the treatment of a variety of neuropsychiatric problems including neurosis and insomnia. Recently, Yabe et al. have demonstrated that KUT increased both choline acetyltransferase (ChAT) and nerve growth factor at the protein and mRNA levels in cultured rat brain cells. Moreover, the same research group has reported that KUT improved mean latency on passive avoidance test in both basal forbrain lesioned and aged rats. KUT significantly improved the survival rate, and increased the number of ChAT-positive neurons in aged rats. Here, we report a 12-month open clinical trial of KUT and combination of estrogen, vitamin E and NSAID to aim at slowing down the progression of Alzheimer's disease (AD). Twenty AD patients (MMSE score: 18.6 +/- 5.8) received extracts from original KUT herbs, and 7AD patients (MMSE score: 21.3 +/- 2.8) were placed on the combination therapy. Rate of cognitive decline as measured by change in MMSE score per year was significantly slower (p = 0.04, ANOVA) in the KUT group (1.4 points) and the combination group (0.4 points) as compared to 4.1 points in 32 control AD patients (MMSE score: 20.8 +/- 5.6) who received no medicines for AD. Any of CSF measures including tau. and A beta 1-42 did not differ significantly after KUT theraopy. The efficacy of the KUT therapy was most obvious at 3 months. Our results suggest that traditional Japanese herbal medicine(s) may serve a new interventional strategy for AD.

Non-familial Alzheimer's disease is mainly due to genetic factors.

Ashford JW, Mortimer JA. Departments of Psychiatry and Neurology, Sanders-Brown Center on Aging, University of Kentucky, Veterans Affairs Medical Center, Lexington, KY, USA.

J Alzheimers Dis 2002 Jun;4(3):169-77

This team takes the position that what is commonly referred to as non-familial Alzheimer's disease (AD) is predominantly due to genetic factors. Population-based studies suggest that genetic factors cause the majority of cases that begin after age 60. There are several lines of evidence supporting this position: - Data from the Nun Study suggest that the risk for AD is largely established by early adulthood, implying that later adult exposures likely play only a small role in causation. - Family studies show that first-degree blood relatives of persons with non-familial AD have a substantially increased risk of AD relative to controls. - Twin studies suggest that the heritability of AD exceeds 60%. - Environmental factors, such as socioeconomic status, education, and head injury, are strong risk factors for AD only in individuals with a genetic predisposition. - The APOE genotype is a powerful risk factor for AD and accounts for as much as 50%. - There are numerous other candidate genes with strong associations with AD that presumably explain the remaining population risk. This paper further reviews the mechanisms associated with AD causation for APOE and other candidate genes and implications for the development of prevention strategies.

Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease.

Bai DL, Tang XC, He XC. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031, China.

Curr Med Chem 2000 Mar;7(3):355-74

HupA is a potent, reversible and selective inhibitor of AChE with a rapid absorption and penetration into the brain in animal tests. It exhibits memory-enhancing activities in animal and clinical trials. Compared to tacrine and donepezil, HupA possesses a longer duration of action and higher therapeutic index, and the peripheral cholinergic side effects are minimal at therapeutic doses. This review article deals with a comprehensive survey of the progress in chemical and pharmacological studies of HupA including the isolation and structure elucidation, pharmacological actions, total synthesis, SAR studies and the future development of HupA. Recently, it has been reported that HupA could reduce neuronal cell death caused by glutamate. The dual bio-activities of HupA would further enhance its value and potentiality as the therapeutic agent for Alzheimer s disease.

Inositol treatment of Alzheimer's disease: a double blind, cross-over placebo controlled trial.

Barak Y, Levine J, Glasman A, Elizur A, Belmaker RH. Abarbanel Mental Health Center, Bat Yam, Israel.

Prog Neuropsychopharmacol Biol Psychiatry 1996 May;20(4):729-35

1. A double-blind controlled crossover trial of 6 gm of inositol daily vs glucose for one month each was carried out in 11 Alzheimer patients. 2. Overall CAMCOG scores showed a trend for greater improvement with inositol that was not significant. 3. Language and orientation improved significantly more on inositol than on placebo. There were no serious side effects. 4. Higher doses of inositol should be studied in Alzheimer's Disease for longer periods.

The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid.

Bastianetto S, Ramassamy C, Dore S, Christen Y, Poirier J, Quirion R Douglas Hospital Research Centre, Department of Psychiatry, McGill University, 6875 Bld LaSalle, Verdun, Quebec, Canada.

Eur J Neurosci 2000 Jun;12(6):1882-90

Substantial evidence suggests that the accumulation of beta-amyloid (Abeta)-derived peptides, and to a lesser extent free radicals, may contribute to the aetiology and/or progression of Alzheimer's disease (AD). Ginkgo biloba extract (EGb 761) is a well-defined plant extract containing two major groups of constituents, i.e. flavonoids and terpenoids. It is viewed as a polyvalent agent with a possible therapeutic use in the treatment of neurodegenerative diseases of multifactorial origin, e.g. AD. We have investigated here the potential effectiveness of EGb 761 against toxicity induced by (Abeta)-derived peptides (Abeta25-35, Abeta1-40 and Abeta1-42) on hippocampal primary cultured cells, this area being severely affected in AD. A co-treatment with EGb 761 concentration-dependently (10-100 microg/mL) protected hippocampal neurons against toxicity induced by Abeta fragments, with a maximal and complete protection at the highest concentration tested. Similar, albeit less potent protective effects were seen with the flavonoid fraction of the extract (CP 205), while the terpenes were ineffective. Most interestingly, EGb 761 (100 microg/mL) was even able to protect (up to 8 h) hippocampal cells from a pre-exposure to Abeta25-35 and Abeta1-40. EGb 761 was also able to both protect and rescue hippocampal cells from toxicity induced by H2O2 (50-150 microM), a major peroxide possibly involved in mediating Abeta toxicity. Moreover, EGb 761 (10-100 microg/mL), and to a lesser extent CP 205 (10-50 microg/mL), completely blocked Abeta-induced events, e.g. reactive oxygen species accumulation and apoptosis. These results suggest that the neuroprotective effects of EGb 761 are partly associated with its antioxidant properties and highlight its possible effectiveness in neurodegenerative diseases, e.g. AD via the inhibition of Abeta-induced toxicity and cell death.

Mitochondria, NO and neurodegeneration.

Beal MF Neurochemistry Laboratory, Neurology Service/WRN 408, Massachusetts General Hospital, Boston, USA.

Biochem Soc Symp 1999;66:43-54

A role for mitochondrial dysfunction in neurodegenerative disease is gaining increasing support. Mitochondrial dysfunction may be linked to neurodegenerative diseases through a variety of different pathways, including free-radical generation, impaired calcium buffering and the mitochondrial permeability transition. This can lead to both apoptotic and necrotic cell death. Recent evidence has shown that there is a mitochondrial defect in Friedreich's ataxia, which leads to increased mitochondrial iron content, that appears to be linked to increased free-radical generation. There is evidence that the point mutations in superoxide dismutase which are associated with amyotrophic lateral sclerosis may contribute to mitochondrial dysfunction. There is also evidence for bioenergetic defects in Huntington's disease. Studies of cybrid cell lines have implicated mitochondrial defects in both Parkinson's disease and Alzheimer's disease. If mitochondrial dysfunction plays a role in neurodegenerative diseases then therapeutic strategies such as coenzyme Q10 and creatine may be useful in attempting to slow the disease process.

Vitamin E protects neurons against oxidative cell death in vitro more effectively than 17-beta estradiol and induces the activity of the transcription factor NF-kappaB.

Behl C. Independent Research Group Neurodegeneration, Max Planck Institute of Psychiatry, Munich, Federal Republic of Germany. chris@mpipsykl.mpg.de

J Neural Transm 2000;107(4):393-407

Antioxidants can function as powerful protectants for neurons in vitro. Here, the neuroprotective activity of lipophilic free radical scavengers synthetic (+/-) alpha-tocopherol (synthetic vitamin E) and natural (+) alpha-tocopherol (natural vitamin E) against oxidative stress was investigated and compared to the neuroprotective effect of the female sex hormone estradiol. Employing mouse clonal hippocampal HT22 cells and rat cerebellar granule neurons, we found that both types of alpha-tocopherol exerted a higher neuroprotective antioxidant activity than 17-beta estradiol. At concentrations as low as 100 nM, synthetic (+/-) alpha-tocopherol and natural (+) alpha-tocopherol protected neurons effectively against the oxidative cell death caused by the Alzheimer's disease-associated amyloid beta protein, hydrogen peroxide, and the excitatory amino acid glutamate. Moreover, vitamin E induced the activity of the redox-sensitive transcription factor NF-kappaB, which is involved in the control of nerve cell survival and, therefore, may play also a role in vitamin E-induced neuroprotection. These results may have implications regarding the prevention and treatment of oxidative stress-related degenerative disorders such as Alzheimer's disease.

Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type.

Bergamasco B, Scarzella L, La Commare P. III Neurological Clinic, University of Turin, Italy.

Funct Neurol 1994 May-Jun;9(3):161-8

Alzheimer's disease (AD) is a central nervous system disorder characterized by the presence of neurofibrillary tangles, neuritic plaques and dystrophic neurones in susceptible areas of the brain. Few options for treatment of AD symptomatology are available. We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel trial consisting of a 90 day treatment period followed by a 30 day single blind placebo administration and by an optional long term period of treatment up to a year with idebenone in open fashion. Ninety two patients entered the study and nine of them dropped out before the first control. Treatment with idebenone was found effective on memory, attention, and orientation and in slowing down the natural progressive worsening of the disease. The most common side effects associated with this treatment were insomnia, gastralgia, nausea, and anxiety. However, all adverse effects were of mild intensity and did not require specific therapies.

The effect of chronic hydergine treatment on the plasticity of synaptic junctions in the dentate gyrus of aged rats.

Bertoni-Freddari C, Giuli C, Pieri C, Paci D, Amadio L, Ermini M, Dravid A

J Gerontol 1987 Sep;42(5):482-6

The number of synapses (Nv), the surface density of contact zones (Sv) as well as the average size (S) of E-PTA stained synapses in the supragranular layer of the dentate gyrus from adult (12 months), old (30 month), and Hydergine-treated old (30 months) rats were measured by using quantitative morphometric techniques. In old animals, Nv and Sv were significantly reduced, whereas S was significantly increased as compared with the values in adult rats. Hydergine (Codergocrine mesylate) treatment of old animals (3 mg/Kg/day for 4 weeks) influenced these three parameters, differentially. The Sv in aged animals receiving Hydergine, relative to that in untreated old rats, was significantly increased; the number and size of synapses in the treated old rats were significantly higher and smaller, respectively, than that in old controls. We interpret the present findings to indicate a modulating effect of Hydergine on the morphological plasticity of synaptic junctions in the dentate gyrus of aged rats.

Rivastigmine for Alzheimer's disease.

Birks J, Iakovidou V, Tsolaki M. Department of Geratology, University of Oxford, Oxford, UK, OX2 6HE. jacqueline.birks@geratology.ox.ac.uk

Cochrane Database Syst Rev 2000;(2):CD001191

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. One of the most successful therapeutic strategies for Alzheimer's disease has been the use of acetylcholinesterase inhibitors to enhance surviving cholinergic neurotransmission by inhibiting breakdown of released acetylcholine. The first generation acetylcholinesterase inhibitors, such as tacrine, revealed major limitations to use including hepatotoxicity. Several second generation acetylcholinesterase inhibitors have now been introduced, including rivastigmine, which are believed to have superior proprieties. The mode of action and metabolism of rivastigmine suggest that it is unlikely to interact significantly with other medications. This is of particular relevance in elderly AD patients, the majority of whom are likely to be receiving concomitant medication. Large multi-centre trials have been completed in the USA, Canada, Europe and South Africa. Rivastigmine has received EU approval for use in all member states. It has approval in 30 countries but not the US. It is currently under review by the Food and Drug Administration, who requested additional analyses in 1998.

OBJECTIVES: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of the Alzheimer's type.

SEARCH STRATEGY: The Cochrane Controlled Trials Register, the Dementia Group Register of Clinical Trials, other electronic databases and other sources of reports were searched using the terms ENA 713, EXELON, and rivastigmine in addition to the terms for controlled trials in dementia (see the Group's search strategy for full details).

SELECTION CRITERIA: All unconfounded, double-blind, randomised trials in which treatment with rivastigmine was administered for more than one day and compared to placebo for patients with dementia of the Alzheimer's type.

DATA COLLECTION AND ANALYSIS: Data were extracted by the reviewer (JSB) and entered into an appropriate meta-analysis. The data extracted were cross-checked by the second reviewer (VI). For each outcome measure, data were sought on every patient randomised. To allow an intention-to-treat analysis, the data were sought irrespective of compliance, whether or not the patient was subsequently deemed ineligible, or otherwise excluded from treatment or follow-up. If these data were not available, an analysis of data on patients who completed treatment was conducted.

MAIN RESULTS: There are seven included trials. There are no published reports for two large phase III trials, B304 and B351, although they were completed more than 3 years ago. These are part of the Novartis ADENA programme and comprise 1379 (49%) out of 2803 phase III patients. It is unclear how missing data are replaced in ITT analyses, as reports from the ADENA programme provide no description of the use of this method. This has a profound effect on the results: if the method is substantially the same as LOCF, the benefits of treatment inferred from the analyses described in the publications as ITT, may be exaggerated. The meta-analysis reveals benefits on cognitive function as measured by ADAS-Cog test scores for the higher dose of rivastigmine compared to placebo at 26 weeks and for the lower dose. An additional analysis of ADAS-Cog dichotomised into those showing less than 4 points improvement and those showing 4 or more points improvement at 26 weeks shows benefit for cognitive function for the higher dose of rivastigmine compared to placebo and not for the lower dose. Global clinical state, dichotomised, counting those showing no change or decline, against those showing improvement shows benefit due to lower dose rivastigmine compared to placebo at 26 weeks and not for the higher dose. One trial reported results at 18 weeks and there are no significant differences between higher dose rivastigmine and placebo. One trial reported results at 13 weeks, and there are no significant differences between the 4 or 6 mg/d rivastigmine group and p

Donepezil for mild and moderate Alzheimer's disease (Cochrane Review).

Birks JS, Melzer D, Beppu H Department of Clinical Geratology, University of Oxford, Oxford, UK, OX2 6HE. jacqueline.birks@geratology.ox.ac.uk

Cochrane Database Syst Rev 2000;4:CD001190

BACKGROUND: Alzheimer's disease is the most common cause of dementia in older people. One of the aims of therapy is to inhibit the breakdown of a chemical neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be done by a group of chemicals known as cholinesterase inhibitors. However, some (like tacrine) are associated with adverse effects such as hepatotoxicity, but E2020 (donepezil, Aricept) is thought to be more specific in its action, and safer.

OBJECTIVES: The objective of this review is to assess whether or not donepezil improves the well-being of patients with mild or moderate Alzheimer's disease.

SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group specialized register was searched using the terms 'donepezil', 'E2020' and 'Aricept'. Members of the Donepezil Study Group and Eisai Inc were contacted.

SELECTION CRITERIA: All unconfounded, double-blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with Alzheimer's disease.

DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer (JSB ), pooled where appropriate and possible, and the weighted mean differences or Peto odds ratios (95%CI) estimated. Where possible, intention-to-treat (ITT) data were used.

MAIN RESULTS: Eight trials are included, involving 2664 participants. The trials were of 12, 24 or 52 weeks duration in selected patients. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are not available. For cognition there is a statistically significant improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared to placebo (1.9 points on the ADAS-Cog scale, WMD 1.86, 95%CI -2.60 to -1.11; 2.9 points on the ADAS-Cog scale, WMD -2.91, 95% CI -3.65 to -2.16)and for 10mg/day donepezil compared to placebo at 52 weeks (1.7 MMSE points, 95% CI, -2.59 to -0.82). The results of three studies show some improvement in global clinical state (assessed by an independent clinician) in those treated with 5 and 10mg/day of donepezil compared with placebo at 12 and 24 weeks. The patients' own ratings of their Quality of Life showed no benefit of donepezil compared with placebo. There were significantly more withdrawals before the end of treatment from the 10mg/day (but not the 5mg/day) donepezil group compared with placebo which may have resulted in some overestimation of beneficial changes at 10mg/day A variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhoea and anorexia in the 10mg/day group compared with placebo and the 5mg/day group, but very few patients left a trial as a direct result of the intervention.

REVIEWER'S CONCLUSIONS: In selected patients with mild or moderate Alzheimer's disease treated for periods of 12, 24 or 52 weeks, donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers is unclear.

The cholinergic neuronal phenotype in Alzheimer's disease.

Blusztajn JK, Berse B Department of Pathology and Laboratory Medicine, Boston University School of Medicine, MA 02118, USA. jbluszta@bu.edu

Metab Brain Dis 2000 Mar;15(1):45-64

The synthesis, storage and release of acetylcholine (ACh) requires the expression of several specialized proteins, including choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT). The VAChT gene is located within the first intron of the ChAT gene. This unique genomic organization permits coordinated activation of expression of the two genes by extracellular factors. Much less is known about factors that reduce the expression of the cholinergic phenotype. A cholinergic deficit is one of the primary features of Alzheimer's disease (AD), and AD brains are characterized by amyloid deposits composed primarily of A beta peptides. Although A beta peptides are neurotoxic, part of the cholinergic deficit in AD could be attributed to the suppression of cholinergic markers in the absence of cell death. Indeed, we and others demonstrated that synthetic A beta peptides, at submicromolar concentrations that cause no cytotoxicity, reduce the expression of cholinergic markers in neuronal cells. Another feature of AD is abnormal phospholipid turnover, which might be related to the progressive accumulation of apolipoprotein E (apoE) within amyloid plaques, leading perhaps to the reduction of apoE content in the CSF of AD patients. ApoE is a component of very low density lipoproteins (VLDL). As a first step in investigating a potential neuroprotective function of apoE, we determined the effects of VLDL on ACh content in neuronal cells. We found that VLDL increases ACh levels, and that it can partially offset the anticholinergic actions of A beta peptides.

Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation end-products: comparison with aminoguanidine.

Booth AA, Khalifah RG, Hudson BG. Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City 66160-7421, USA.

Biochem Biophys Res Commun 1996 Mar 7;220(1):113-9

Nonenzymatic glycation of proteins by glucose leading to the formation of toxic and immunogenic advanced glycation end products (AGEs) may be a major contributor to the pathological manifestations of diabetes mellitus, aging, and, possibly, neurodegenerative diseases such as Alzheimer's. We tested the in vitro inhibition of antigenic AGE formation on bovine serum albumin, ribonuclease A, and human hemoglobin by various vitamin B1 and B6 derivatives. Among the inhibitors, pyridoxamine and thiamine pyrophosphate potently inhibited AGE formation and were more effective than aminoguanidine, suggesting that these two compounds may have novel therapeutic potential in preventing vascular complications of diabetes. An unexpected finding was that aminoguanidine inhibited the late kinetic stages of glycation much more weakly than the early phase.

In vitro kinetic studies of formation of antigenic advanced glycation end products (AGEs). Novel inhibition of post-Amadori glycation pathways

Booth A.A.; Khalifah R.G.; Todd P.; Hudson B.G. USA

Journal of Biological Chemistry (USA), 1997, 272/9 (5430-5437)

Nonenzymatic protein glycation (Maillard reaction) leads to heterogeneous, toxic, and antigenic advanced glycation end products ('AGEs') and reactive precursors that have been implicated in the pathogenesis of diabetes, Alzheimer's disease, and normal aging. In vitro inhibition studies of AGE formation in the presence of high sugar concentrations are difficult to interpret, since AGE-forming intermediates may oxidatively arise from free sugar or from Schiff base condensation products with protein amino groups, rather than from just their classical Amadori rearrangement products. We recently succeeded in isolating an Amadori intermediate in the reaction of ribonuclease A (RNase) with ribose (Khalifah, R. G., Todd, P., Booth, A. A., Yang, S. X., Mott, J. D., and Hudson, B. G. (1996) Biochemistry 35, 4645- 4654) for rapid studies of post-Amadori AGE formation in absence of free sugar or reversibly formed Schiff base precursors to Amadori products. This provides a new strategy for a better understanding of the mechanism of AGE inhibition by established inhibitors, such as aminoguanidine, and for searching for novel inhibitors specifically acting on post-Amadori pathways of AGE formation. Aminoguanidine shows little inhibition of post-Amadori AGE formation in RNase and bovine serum albumin, in contrast to its apparently effective inhibition of initial (although not late) stages of glycation in the presence of high concentrations of sugar. Of several derivatives of vitamins B1 and B6 recently studied for possible AGE inhibition in the presence of glucose (Booth, A. A., Khalifah, R. G., and Hudson, B. G. (1996) Biochem. Biophys. Res. Commun. 220, 113-119), pyridoxamine and, to a lesser extent, thiamine pyrophosphate proved to be novel and effective post-Amadori inhibitors that decrease the final levels of AGEs formed. Our mechanism- based approach to the study of AGE inhibition appears promising for the design and discovery of novel post-Amadori AGE inhibitors of therapeutic potential that may complement others, such as aminoguanidine, known to either prevent initial sugar attachment or to scavenge highly reactive dicarbonyl intermediates.

[Vitamin B12 deficiency in geriatrics]. [Article in German]

Bopp-Kistler I, Ruegger-Frey B, Grob D, Six P Klinik fur Geriatrie und Rehabilitation, Stadtspital Waid, Zurich. irene.bopp@waid.stzh.ch

Schweiz Rundsch Med Prax 1999 Nov 4;88(45):1867-75

Cobalamin deficiency increases with advancing age. The cut-off point of serum concentration should be raised, because many elderly people with "normal" serum vitamin B12 concentrations are metabolically deficient in cobalamin. The measurement of the metabolites homocysteine and/or methylmalonic acid is recommended. Cobalamin deficiency may result in a variety of atypical symptoms. Hematological changes typical of megaloblastic anemia are absent in a majority of patients with neuropsychiatric disorders. Generally underlying pernicious anemia is not the main cause of cobalamin deficiency in the elderly. Protein-bound cobalamin malabsorption due to atrophic gastritis with hypo- or achlorhydria is a common cause of cobalamin deficiency in elderly people. An important manifestation of cobalamin deficiency is cognitive impairment. Much controversy exists on the subject of the association of dementia of the Alzheimer type with cobalamin deficiency. In several studies dementia has been related to low serum cobalamin levels. Physicians should be liberal of cobalamin therapy. The window of opportunity for effective intervention may be as short as one year from the onset of medical symptoms. At last a compilation of recommendations is given.

S-adenosylmethionine levels in psychiatric and neurological disorders: a review.

Bottiglieri T, Hyland K. Metabolic Disease Center, Baylor Research Institute, Dallas, TX 75226.

Acta Neurol Scand Suppl 1994;154:19-26

INTRODUCTION--S-adenosylmethionine (SAMe) is an important methyl donor in over 35 methylation reactions involving DNA, proteins, phospholipids and catechol- and indole-amines.

MATERIAL AND METHODS--This article reviews the studies that have examined brain and blood levels of SAMe in several psychological, neurological and metabolic disorders.

RESULTS--Although studies have found no consistent changes in whole blood SAMe levels in psychiatric patients, other investigators have found low cerebrospinal fluid (CSF) SAMe levels in patients with neurological disorders such as Alzheimer's dementia, subacute combined degeneration of the spinal cord (SACD), and HIV-related neuropathies, as well as in patients with metabolic disorders such as 5, 10-CH2-H4 folate reductase deficiency.

CONCLUSION--Intravenous or oral administration of SAMe thus represents a possible treatment for these neurological and metabolic disorders.

Genetic and environmental risk factors for Alzheimer's disease in Israeli Arabs.

Bowirrat A, Friedland RP, Farrer L, Baldwin C, Korczyn A. Department of Neurology, Case Western Reserve University School of Medicine, Cleveland OH 44106, USA.

J Mol Neurosci 2002 Aug-Oct;19(1-2):239-45

OBJECTIVE: We studied the genetic and environmental risk factors and prevalence, and incidence of dementia of the Alzheimer type (DAT) among the elderly in an Arab community in Israel.

BACKGROUND: Epidemiological and genetic studies of dementia have rarely been reported in an Arab population.

METHODS: All persons aged 60 years or older who were residents of the rural area of Wadi Ara were examined for identification of DAT, vascular dementia (VaD) and conversion from age related cognitive decline (ARCD) to DAT using DSM-IV criteria and a semi-structured questionnaire for collection of demographic and medical data. ApoE genotype was also determined. Total plasma homocysteine (tHcy) was determined using HPLC with fluorescence detection. Vitamins B12 and plasma folate were determined using a commercial radioisotope dilution kit assay (ICN).

RESULTS: DAT was diagnosed in 20.5% of this population. Its prevalence increased steeply with age. Illiteracy was very common, and strongly associated with higher prevalence of DAT. The annual incidence of DAT among ARCD cases was 4.4%. Subjects with ARCD who developed DAT were older than ARCD subjects who did not develop dementia. Hypertension was significantly more common among converted patients than among non-converted. Illiteracy was insignificantly more common among those who developed DAT than among those who remained ARCD. Vascular dementia (VaD) constitutes about 22% of the total dementia population. We also confirm the association between VaD, illiteracy and hypertension. Smoking did not represent a risk factor for VaD. The survival rates among the three groups (healthy subjects, ARCD and DAT) was 80.5%, 58.8% and 55.5% respectively. Homocysteine levels were significantly higher than found in studies in Cleveland. Plasma B12 and plasma folate levels did not differ significantly between DAT patients and controls after adjusting for year of birth.

CONCLUSIONS: Our findings suggest that the Wadi Ara population is unique because of high prevalence rates of dementia. We found old age, female gender and lack of education to be risk factors for the development of DAT. The ApoE epsilon4 allele is relatively uncommon in this population and it cannot explain the high DAT prevalence. We also confirm the association between VaD, illiteracy and hypertension and older age and hypertension are risk factors for the transformation of ARCD to DAT.

Effect of melatonin in selected populations of sleep-disturbed patients.

Brusco LI, Fainstein I, Marquez M, Cardinali DP. Departamento de Fisiologia, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.

Biol Signals Recept 1999 Jan-Apr;8(1-2):126-31

In an open pilot study on the efficacy of melatonin in the treatment of sleep disorders, patients with sleep disturbances alone, patients with sleep disturbances and signs of depression and patients with sleep disorders and dementia received 3 mg melatonin p.o. for 21 days, at bed time. After 2-3 days of treatment, melatonin significantly augmented sleep quality and decreased the number of awakening episodes in patients with sleep disturbances associated or not with depression. Estimates of next-day alertness improved significantly only in patients with primary insomnia. Agitated behavior at night (sundowning) decreased significantly in dementia patients. In a second retrospective study, 14 Alzheimer's disease (AD) patients received 9 mg melatonin daily for 22-35 months. A significant improvement of sleep quality was found, while there were no significant differences between initial and final neuropsychological evaluation (Functional Assessment Tool for AD, Mini-Mental). The results indicate that melatonin can be useful to treat sleep disturbances in elderly insomniacs and AD patients.

Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer's disease.

Brusco LI, Marquez M, Cardinali DP. Departamento de Fisiologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina.

Neuroendocrinol Lett 2000;21(1):39-42

OBJECTIVES: A retrospective study on the efficacy of melatonin in treatment of sleep and cognitive disorders of Alzheimer's disease was conducted.

METHODS: Fourteen patients (8 females, 6 males), mean +/- S.D. age 72 +/- 9 years were included. All patients received 9 mg gelatin melatonin capsules p.o. daily at bedtime for 22 to 35 months. Overall quality of sleep was assessed from sleep logs filled in by the patients or their caretakers. Neuropsychological evaluation was performed by Functional Assessment Tool For Alzheimer's Disease (FAST), Mini-Mental, Alzheimer's Disease Assessment Scale (ADAS), and Mattis' and Blessed's scales. At diagnosis, all patients had cognitive and neuroimaging alterations (cortical and bitemporal atrophy) compatible with different evolutionary stages of the disease.

RESULTS: At the time of assessment, a significant improvement of sleep quality was found in all cases examined. There were no significant differences between initial and present evaluation in scores of FAST, Mini-Mental, and ADAS, and of Mattis' and Blessed's scales. Clinically, the patients exhibited lack of progression of the cognitive and behavioral signs of the disease during the time they received melatonin. Sundowning was no longer detectable in 12 patients and persisted, although attenuated, in 2 patients.

CONCLUSION. The results suggest that melatonin can be useful for treatment of Alzheimer's disease.

Evidence for forebrain cholinergic neuronal loss in congenital ornithine transcarbamylase deficiency.

Butterworth RF Neuroscience Research Unit, CHUM/Hopital Saint-Luc, Montreal, Quebec, Canada. butterwr@medclin.umontreal.ca

Metab Brain Dis 2000 Mar;15(1):83-91

Congenital ornithine transcarbamylase (OTC) deficiency in humans results in failure to thrive, hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals significant cerebral cortical atrophy, delayed myelination and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, studies reveal convincing evidence of a loss of forebrain cholinergic neurons in this condition. Evidence includes (i) reduced activities of the cholinergic nerve terminal enzyme choline acetyltransferase (ChAT), (ii) a 25% loss of ChAT immunostaining, (iii) reduced high affinity transport of [3H]choline by cortical synaptosomes and (iv) a selective reduction in densities of presynaptic muscarinic M2 binding sites, in spf mouse brain compared to controls. A partial correction of the cholinergic deficit was observed following treatment with acetyl-L-carnitine. Possible mechanisms responsible for cholinergic neuronal loss in congenital OTC deficiency include decreased synthesis of the ChAT substrate acetyl CoA, impaired cerebral energy metabolism and NMDA receptor-mediated excitotoxicity. Loss of forebrain cholinergic neurons is consistent with the severe cognitive impairment characteristic of congenital OTC deficiency.

Relationships between dehydroepiandrosterone sulfate (DHEAS) and cortisol (CRT) plasma levels and everyday memory in Alzheimer's disease patients compared to healthy controls.

Carlson LE, Sherwin BB, Chertkow HM Department of Psychology, McGill University, Montreal, Canada.

Horm Behav 1999 Jun;35(3):254-63

Fifty-two age-matched Alzheimer's disease (AD) patients (26 men, 26 women), mean age 76.2 years, were assessed with the Rivermead Behavioural Memory Test, a test of everyday memory, coincident with the measurement of plasma cortisol (CRT) and dehydroepiandrosterone sulfate (DHEAS) via radioimmunoassay. The AD patients were compared to a control group of age- and gender-matched healthy elderly men and women. No differences were found between the AD patients and the controls in DHEAS or CRT levels, or in the DHEAS/CRT ratio. There were no gender differences in DHEAS or CRT levels, or in the DHEAS/CRT ratio in subjects with AD. However, AD patients with higher levels of DHEAS scored better than those with lower levels on the subtests of Remembering a Name associated with a picture, Digit Span Total and Forward, and the Mini Mental Status Exam. AD patients with higher CRT levels performed worse on Delayed Route Recall than those with lower levels. These findings suggest that AD patients with higher endogenous levels of DHEAS may perform better on some memory tasks than those with lower levels, while AD patients with lower levels of CRT may perform better than those with higher CRT.

Alzheimer's disease: model behaviour.

Chapman PF.

Nature 2000 Dec 21-28;408(6815):915-6

No Abstract Available

Huperzine A, a novel promising acetylcholinesterase inhibitor.

Cheng DH; Ren H; Tang XC State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, P.R. China.

Neuroreport (ENGLAND) Dec 20 1996, 8 (1) p97-101

The effects of huperzine A on memory impairments induced byscopolamine were valuated using a radial maze task and inhibition of cholinesterase in vitro compared with the effects of E2020 and tacrine. Scopolamine (0.2 mg kg-1) significantly impaired spatial memory in rats. Huperzine A (0.1-0.4 mg kg-1, p.o.), E2020 (0.5-1.0 mg kg-1, p.o.) and tacrine (1.0-2.0 mg kg-1, p.o.) could reverse these scopolamine-induced memory deficits. The ratios of huperzine A, E2020 and tacrine for butyrylcholinesterase:acetylcholinesterase determined by a colourimetric method were 884.57, 489.05, and 0.80, respectively. The results demonstrated that huperzine A was the most selective acetylcholinterase inhibitor, and improved the working memory deficit induced by scopolamine significantly better than did E2020 or tacrine, suggesting it may be a promising agent for clinical therapy of cognitive impairment in patients with Alzheimer's Disease.

Oxidative stress and Alzheimer disease.

Christen Y Fondation Ipsen, 24 rue Erlanger, 75016 Paris, France. yves.christen@beaufour-ipsen.com.

Am J Clin Nutr 2000 Feb;71(2):621S-629S

Research in the field of molecular biology has helped to provide a better understanding of both the cascade of biochemical events that occurs with Alzheimer disease (AD) and the heterogeneous nature of the disease. One hypothesis that accounts for both the heterogeneous nature of AD and the fact that aging is the most obvious risk factor is that free radicals are involved. The probability of this involvement is supported by the fact that neurons are extremely sensitive to attacks by destructive free radicals. Furthermore, lesions are present in the brains of AD patients that are typically associated with attacks by free radicals (eg, damage to DNA, protein oxidation, lipid peroxidation, and advanced glycosylation end products), and metals (eg, iron, copper, zinc, and aluminum) are present that have catalytic activity that produce free radicals. beta-Amyloid is aggregated and produces more free radicals in the presence of free radicals; beta-amyloid toxicity is eliminated by free radical scavengers. Apolipoprotein E is subject to attacks by free radicals, and apolipoprotein E peroxidation has been correlated with AD. In contrast, apolipoprotein E can act as a free radical scavenger and this behavior is isoform dependent. AD has been linked to mitochondrial anomalies affecting cytochrome-c oxidase, and these anomalies may contribute to the abnormal production of free radicals. Finally, many free radical scavengers (eg, vitamin E, selegeline, and Ginkgo biloba extract EGb 761) have produced promising results in relation to AD, as has desferrioxamine-an iron-chelating agent-and antiinflammatory drugs and estrogens, which also have an antioxidant effect.

Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.

Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM Clinical Trial Service Unit, Nuffield Department of Clinical Medicine, Oxford, England.

Arch Neurol 1998 Nov;55(11):1449-55

BACKGROUND: Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD.

OBJECTIVE: To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. DESIGN: Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. SETTING: Referral population to a hospital clinic between July 1988 and April 1996.

MAIN OUTCOME MEASURES: Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. RESULTS: Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (< or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The orresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry.

CONCLUSIONS: Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.

Essential fatty acids in Alzheimer's disease.

Corrigan FM, Van Rhijn A, Horrobin DF. Argyll and Bute Hospital, Lochgilphead, Scotland.

Ann N Y Acad Sci 1991;640:250-2

Concentrations of essential fatty acids (EFAs) in plasma and red blood cell phospholipids were found to be abnormal in patients with Alzheimer's disease. A double-blind, placebo-controlled trial of treatment with EFAs plus appropriate antioxidants was carried out in 36 patients with Alzheimer's disease. After 20 weeks both the EFA and placebo groups had improved, but the degree of improvement was consistently greater in the EFA group.

Intramuscular desferrioxamine in patients with Alzheimer's disease.

Crapper McLachlan DR, Dalton AJ, Kruck TP, Bell MY, Smith WL, Kalow W, Andrews DF. Department of Physiology, University of Toronto, Ontario, Canada.

Lancet 1991 Jun 1;337(8753):1304-8

Although epidemiological and biochemical evidence suggests that aluminium may be associated with Alzheimer's disease (AD), there is no convincing proof of a causal link for aluminium in disease progression. We have completed a two year, single-blind study to investigate whether the progression of dementia could be slowed by the trivalent ion chelator, desferrioxamine. 48 patients with probable AD were randomly assigned to receive desferrioxamine (125 mg intramuscularly twice daily, 5 days per week, for 24 months), oral placebo (lecithin), or no treatment. No significant differences in baseline measures of intelligence, memory, or speech ability existed between groups. Activities of daily living were assessed and videorecorded at 6, 12, 18, and 24 month intervals. There were no differences in the rate of deterioration of patients receiving either placebo or no treatment. Desferrioxamine treatment led to significant reduction in the rate of decline of daily living skills as assessed by both group means (p = 0.03) and variances (p less than 0.04). The mean rate of decline was twice as rapid for the no-treatment group. Appetite (n = 4) and weight (n = 1) loss were the only reported side-effects. We conclude that sustained administration of desferrioxamine may slow the clinical progression of the dementia associated with AD.

Alzheimer's disease risk factors as related to cerebral blood flow: additional evidence.

Crawford JG. Indiana University School of Medicine, Terre Haute Centerfor Medical Education, 47890, USA. iccrawfo@scifac.indstate.edu

Med Hypotheses 1998 Jan;50(1):25-36

In a previous report, Alzheimer's disease risk factors, including alcohol abuse, depression, Down's syndrome, cerebral glucose metabolism defect, head trauma, old age, Parkinson's disease, sleep disturbance, and underactivity, were shown to have an association with reduced cerebral blood flow. In this report an attempt is made to strengthen a hypothesis that reduced cerebral blood flow may be a required cofactor in the cause of Alzheimer's disease with examples of additional putative risks, including aluminum, ApoE 4 alleles, estrogen deficiency, family history of dementia, low education-attainment, olfactory deficit, and underactivity coupled with gender, considered to have a relationship or potential relationship with reduced cerebral blood flow. Factors, believed to ameliorate Alzheimer's disease, associated with improved or stabilized cerebral blood flow are tabulated. A tentative cerebral blood flow nomogram is shown as a potential model to possibly help predict Alzheimer's disease susceptibility.

Alzheimer's disease risk factors as related to cerebral blood flow.

Crawford JG. Indiana University School of Medicine, Terre Haute Center for Medical Science, IN 47809, USA.

Med Hypotheses 1996 Apr;46(4):367-77

Inconsistencies within results of case-control studies on Alzheimer's disease risk factors led to a search of the literature for a potential cofactor. Reduced cerebral blood flow was selected and literature was surveyed for evidence of a cerebral blood flow linkage with the more than 40 putative risks. Alcohol abuse, depression, head trauma, underactivity, old age, sleep disturbance, glucose utilization, Down's syndrome, and Parkinson's disease are risk factors where an association with reduced cerebral blood flow is documented. Studies were cited showing that improved cerebral blood flow is associated with factors thought to be helpful in Alzheimer's disease, such as education or occupational attainment, exercise, headache, smoking, and arthritis/anti-inflammatory drugs to the extent that aspirin is used. Sugar consumption is identified as a potential risk factor with glucose management in Alzheimer's disease also shown to involve reduced cerebral blood flow. An hypothesis is developed showing how compromised regional cerebral blood flow could fit as a cofactor for genetic, autoimmune, and neurotoxic aspects of Alzheimer's disease.

Effects of phosphatidylserine in Alzheimer's disease

Crook T, Petrie W, Wells C, Massari DC Memory Assessment Clinics, Inc., Bethesda, MD 20814. USA

Psychopharmacol. Bull. (USA), 1992, 28/1 (61-66)

We studied 51 patients meeting clinical criteria for probable Alzheimer's disease (AD). Patients were treated for 12 weeks with a formulation of bovine cortex phosphatidylserine (BC-PS; 100 mg t.i.d.) or placebo, and those treated with the drug improved on several cognitive measures relative to those administered placebo. Differences between treatment groups were most apparent among patients with less severe cognitive impairment. Results suggest that phosphatidylserine may be a promising candidate for study in the early stages of AD.

Treatment of Alzheimer's disease.

Cummings JL. UCLA Alzheimer's Disease Center, UCLA School of Medicine, Los Angeles, California, USA.

Clin Cornerstone 2001;3(4):27-39

A growing consensus indicates that Alzheimer's disease (AD) results from an increase in the production or accumulation of beta-amyloid protein (A beta) leading to nerve cell death. Mechanisms by which A beta accumulation leads to neuronal death include oxidative damage and inflammation. This article discusses the management of AD patients with antioxidants, cholinesterase inhibitors, and psychotropic agents. Studies show that these agents can slow the progression of the disease, improve cognition, and reduce behavioral disturbances. A therapeutic alliance between physician and caregiver is an essential element in successfully managing the AD patient. The 3Rs--repeat, reassure, and redirect--can help caregivers reduce behavioral disturbances in patients with AD and limit the need for pharmacologic management.

Cerebromicrovascular pathology in Alzheimer's disease compared to normal aging.

de la Torre JC. Division of Neurosurgery, University of New Mexico School of Medicine, Albuquerque, USA.

Gerontology 1997;43(1-2):26-43

A growing amount of data using light and electron microscopy, immunocytochemistry, uptake of brain markers and metabolic studies suggest that the pathogenesis of Alzheimer's disease may be due to impaired vascular delivery of nutrients to the brain. The bulk of this evidence indicates that cerebral capillary transport of glucose, oxygen and other vital nutrients is dysfunctional in Alzheimer brains due to abnormal hemodynamic flow patterns caused by structural deformities of the capillaries. Clinical disorders which can worsen cerebral blood flow, such as head injury, coronary artery disease, cerebrovascular ischemia or the presence of apolipoprotein E4 allele will increase the risk of Alzheimer's dementia. By contrast, activities that increase cerebral blood flow during aging such as complex thinking patterns or the use of drugs to reduce vascular resistance, such as aspirin or NSAIDs, will reduce the risk or improve the status of Alzheimer's disease. The production of neuritic plaques and neurofibrillary tangles may develop from the hypometabolic abnormalities caused by the impaired cerebromicrovasculature in Alzheimer brains. Such metabolic and cerebral blood flow changes are considerably less significant in age-matched control subjects. The major physiological, pathological and cognitive changes reported for Alzheimer's disease appear to have a common denominator which is reflected by the physically distorted cerebromicrovessels and their inability to optimally deliver nutrients to the brain, a condition which ultimately disturbs neurono-glial homeostasis.

Alzheimer disease as a vascular disorder: nosological evidence.

de la Torre JC. Department of Neuropathology, University of California at San Diego, CA 92026, USA. jdelator@nctimes.net

Stroke 2002 Apr;33(4):1152-62

BACKGROUND: The main stumbling block in the clinical management and in the search for a cure of Alzheimer disease (AD) is that the cause of this disorder has remained uncertain until now.

SUMMARY OF REVIEW: Evidence that sporadic (nongenetic) AD is primarily a vascular rather than a neurodegenerative disorder is reviewed. This conclusion is based on the following evidence: (1) epidemiological studies showing that practically all risk factors for AD reported thus far have a vascular component that reduces cerebral perfusion; (2) risk factor association between AD and vascular dementia (VaD); (3) improvement of cerebral perfusion obtained from most pharmacotherapy used to reduce the symptoms or progression of AD; (4) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques to preclinically identify AD candidates; (5) presence of regional brain microvascular abnormalities before cognitive and neurodegenerative changes; (6) common overlap of clinical AD and VaD cognitive symptoms; (7) similarity of cerebrovascular lesions present in most AD and VaD patients; (8) presence of cerebral hypoperfusion preceding hypometabolism, cognitive decline, and neurodegeneration in AD; and (9) confirmation of the heterogeneous and multifactorial nature of AD, likely resulting from the diverse presence of vascular risk factors or indicators of vascular disease.

CONCLUSIONS: Since the value of scientific evidence generally revolves around probability and chance, it is concluded that the data presented here pose a powerful argument in support of the proposal that AD should be classified as a vascular disorder. According to elementary statistics, the probability or chance that all these findings are due to an indirect pathological effect or to coincidental circumstances related to the disease process of AD seems highly unlikely. The collective data presented in this review strongly support the concept that sporadic AD is a vascular disorder. It is recommended that current clinical management of patients, treatment targets, research designs, and disease prevention efforts need to be critically reassessed and placed in perspective in light of these important findings.

Impaired cerebromicrovascular perfusion. Summary of evidence in support of its causality in Alzheimer's disease.

de la Torre JC. Department of Neuroscience, University of California, San Diego, La Jolla, California 92093, USA. jdelator@nctimes.net

Ann N Y Acad Sci 2000;924:136-52

After nearly a century of inquiry, the cause of Alzheimer's disease (AD) remains to be found. In this review, basic and clinical evidence is presented that assembles and hypothetically explains most of the key pathologic events associated with the development of AD. These pathologic events are triggered in AD by impaired cerebral perfusion originating in the microvasculature that affects the optimal delivery of glucose and oxygen and results in an energy metabolic breakdown of brain cell biosynthetic and synaptic pathways. We propose that two factors must be present before cognitive dysfunction and neurodegeneration is expressed in the AD brain: (1) advanced aging, (2) presence of a condition that lowers cerebral perfusion, such as a vascular risk factor. The first factor introduces a normal but potentially menacing process that lowers cerebral blood flow in proportion to increased aging, while the second factor adds a crucial burden that further lowers brain perfusion and places vulnerable neurons in a state of metabolic compromise leading to a death pathway. These two factors will lead to a critically attained threshold of cerebral hypoperfusion (CATCH). CATCH is a self-sustaining and progressive circulatory insufficiency that will destabilize neurons, synapses, neurotransmission, and cognitive function, creating in its wake a neurodegenerative process characterized by the formation of senile plaques, neurofibrillary tangles, amyloid angiopathy, and, in some cases, Lewy bodies. Since any of a considerable number of vessel-related conditions must be present in the aging individual for cognition to be affected, CATCH supports the heterogeneic disease profile assumed to be characteristic of the AD syndrome. A brief discussion of target therapy based on the proposed pathogenesis of AD is also reviewed.

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