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Abstracts

Alzheimer's Disease

ABSTRACTS

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Dietary fat intake and the risk of incident dementia in the Rotterdam Study.

Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM Department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam, The Netherlands.

Ann Neurol 1997 Nov;42(5):776-82

A high intake of saturated fat and cholesterol and a low intake of polyunsaturated fatty acids have been related to an increased risk of cardiovascular disease. Cardiovascular disease has been associated with dementia. We investigated the association between fat intake and incident dementia among participants, age 55 years or older, from the population-based prospective Rotterdam Study. Food intake of 5,386 nondemented participants was assessed at baseline with a semiquantitative food-frequency questionnaire. At baseline and after an average of 2.1 years of follow-up, we screened for dementia with a three-step protocol that included a clinical examination. The risk of dementia at follow-up (RR [95% CI]) was assessed with logistic regression. After adjustment for age, sex, education, and energy intake, high intakes of the following nutrients were associated with an increased risk of dementia: total fat (RR = 2.4 [1.1-5.2]), saturated fat (RR = 1.9 [0.9-4.0]), and cholesterol (RR = 1.7 [0.9-3.2]). Dementia with a vascular component was most strongly related to total fat and saturated fat. Fish consumption, an important source of n-3 polyunsaturated fatty acids, was inversely related to incident dementia (RR = 0.4 [0.2-0.91), and in particular to Alzheimer's disease (RR = 0.3 [0.1-0.9]). This study suggests that a high saturated fat and cholesterol intake increases the risk of dementia, whereas fish consumption may decrease this risk.

Cerebrospinal fluid biopterin is decreased in Alzheimer's disease.

Kay AD, Milstien S, Kaufman S, Creasey H, Haxby JV, Cutler NR, Rapoport SI.

Arch Neurol 1986 Oct;43(10):996-9

Tetrahydrobiopterin is the cofactor in the hydroxylation of phenylalanine, tyrosine, and tryptophan leading to the eventual synthesis of the monoaminergic neurotransmitters, dopamine, norepinephrine, and serotonin, respectively. Total biopterin (90% of which is in the tetrahydro form) was measured in cerebrospinal fluid (CSF) and plasma of 30 patients with Alzheimer's disease and of 19 healthy controls. Plasma and CSF biopterin concentrations were not significantly correlated, but the mean CSF biopterin concentration in patients with Alzheimer's disease was significantly less than in age-matched controls, 13.5 pmol/mL as compared with 18.9 pmol/mL. The CSF biopterin concentration was not correlated with ventricular volume, as estimated by quantitative computed tomography, nor with the severity of dementia, as measured by various cognitive tests. The results suggest that a central biopterin deficiency exists in Alzheimer's disease.

A review of nutrients and botanicals in the integrative management of cognitive dysfunction.

Kidd PM

Altern Med Rev 1999 Jun;4(3):144-61

Dementias and other severe cognitive dysfunction states pose a daunting challenge to existing medical management strategies. An integrative, early intervention approach seems warranted. Whereas, allopathic treatment options are highly limited, nutritional and botanical therapies are available which have proven degrees of efficacy and generally favorable benefit-to-risk profiles. This review covers five such therapies: phosphatidylserine (PS), acetyl-l-carnitine (ALC), vinpocetine, Ginkgo biloba extract (GbE), and Bacopa monniera (Bacopa). PS is a phospholipid enriched in the brain, validated through double-blind trials for improving memory, learning, concentration, word recall, and mood in middle-aged and elderly subjects with dementia or age-related cognitive decline. PS has an excellent benefit-to-risk profile. ALC is an energizer and metabolic cofactor which also benefits various cognitive functions in the middle-aged and elderly, but with a slightly less favorable benefit-to-risk profile. Vinpocetine, found in the lesser periwinkle Vinca minor, is an excellent vasodilator and cerebral metabolic enhancer with proven benefits for vascular-based cognitive dysfunction. Two meta-analyses of GbE demonstrate the best preparations offer limited benefits for vascular insufficiencies and even more limited benefits for Alzheimer's, while "commodity" GbE products offer little benefit, if any at all. GbE (and probably also vinpocetine) is incompatible with blood-thinning drugs. Bacopa is an Ayurvedic botanical with apparent anti-anxiety, anti-fatigue, and memory-strengthening effects. These five substances offer interesting contributions to a personalized approach for restoring cognitive function, perhaps eventually in conjunction with the judicious application of growth factors.

Decreased brain histamine-releasing factor protein in patients with Down syndrome and Alzheimer's disease.

Kim SH, Cairns N, Fountoulakisc M, Lubec G. Department of Pediatrics, University of Vienna, Waehringer Guertel 18, A-1090, Vienna, Austria.

Neurosci Lett 2001 Mar 2;300(1):41-4

Histamine-releasing factor (HRF) stimulates secretion of histamine that is widely distributed in brain and released as neurotransmitter. Several studies suggested that histaminergic deficits could contribute to the cognitive decline in Alzheimer's disease (AD). Based upon deranged histamine metabolism in brain of patients with AD and Down Syndrome (DS), we aimed to study HRF in brain of AD and DS. We used two-dimensional gel electrophoresis, matrix-assisted laser desorption ionization mass spectroscopy and specific software to quantify HRF. HRF was significantly reduced in temporal cortex, thalamus and caudate nucleus of DS and in temporal cortex of AD as compared to controls. This is the first report to show decreased HRF brain levels in DS and AD suggesting the explanation for the decreased cognitive function in neurodegenerative/dementing disorders.

Do raised brain aluminium levels in Alzheimer's dementia contribute to cholinergic neuronal deficits?

King RG.

Med Hypotheses 1984 Jul;14(3):301-6

Raised aluminium levels have been found in brains of patients with Alzheimer's dementia (1,2), a disease in which reductions have been reported in various parameters of presynaptic cholinergic nerve function, including choline uptake, acetylcholine synthesis and choline acetyltransferase activity (3). Aluminium has been found to inhibit choline transport by isolated rat brain nerve endings (4) and human erythrocytes (5), and also to cause an encephalopathy in rabbits with neurofibrillary tangles and reduced neuronal choline acetyltransferase activity (6). It is therefore hypothesised that raised brain aluminium levels in Alzheimer's dementia may contribute to the cholinergic neuronal deficits in this disease. If this is the case, then aluminium chelating agents may be of value in its treatment.

Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer's disease.

Kontush A, Mann U, Arlt S, Ujeyl A, Luhrs C, Muller-Thomsen T, Beisiegel U. Clinic of Internal Medicine, University Hospital Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

Free Radic Biol Med 2001 Aug 1;31(3):345-54

Because increased oxidation is an important feature of Alzheimer's disease (AD) and low concentrations of antioxidant vitamins C and E have been observed in cerebrospinal fluid (CSF) of AD patients, supplementation with these antioxidants might delay the development of AD. Major targets for oxidation in brain are lipids and lipoproteins. We studied whether supplementation with antioxidative vitamins E and C can increase their concentrations not only in plasma but also in CSF, and as a consequence decrease the susceptibility of lipoproteins to in vitro oxidation. Two groups, each consisting of 10 patients with AD, were for 1 month supplemented daily with either a combination of 400 IU vitamin E and 1000 mg vitamin C, or 400 IU vitamin E alone. We found that supplementation with vitamin E and C significantly increased the concentrations of both vitamins in plasma and CSF. Importantly, the abnormally low concentrations of vitamin C were returned to normal level following treatment. As a consequence, susceptibility of CSF and plasma lipoproteins to in vitro oxidation was significantly decreased. In contrast, the supplementation with vitamin E alone significantly increased its CSF and plasma concentrations, but was unable to decrease the lipoprotein oxidizability. These findings document a superiority of a combined vitamin E + C supplementation over a vitamin E supplementation alone in AD and provide a biochemical basis for its use.

Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties.

Kornhuber J, Weller M, Schoppmeyer K, Riederer P. Department of Psychiatry, University of Wurzburg, Federal Republic of Germany.

J Neural Transm Suppl 1994;43:91-104

The pharmacological inhibition of excitatory amino acid neurotransmission has evolved to be a major topic in neuropharmacology since enhanced synaptic action of glutamate and possibly other related neurotransmitters has been suggested to play a role both in acute neurological conditions such as ischemia and epilepsy and in chronic degenerative neurological diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. While antagonists at N-methyl-D-aspartate (NMDA) type glutamate receptors include psychotomimetic and neurotoxic agents such as phencyclidine and MK-801, the aminoadamantanes represent a class of drugs which may be largely free of such actions and which have already been used clinically as antiviral and antiparkinsonian agents. Multiple in vitro studies have recently delineated the neuroprotective properties of amantadine, and of its more potent congener, memantine, which appear to mediate neuroprotection via inhibition of NMDA receptor-dependent glutamate activity. Thus, neuroprotection targeting glutamate receptors does apparently not have to be associated with prominent psychotogenicity, and the development and evaluation of new neuroprotective drugs will have to performed in consideration both of the relative safety and of the good clinical effect of the already known and established aminoadamantanes.

Music therapy increases serum melatonin levels in patients with Alzheimer's disease.

Kumar AM, Tims F, Cruess DG, Mintzer MJ, Ironson G, Loewenstein D, Cattan R, Fernandez JB, Eisdorfer C, Kumar M. Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, FL 33101, USA. akumar@med.miami.edu

Altern Ther Health Med 1999 Nov;5(6):49-57

CONTEXT: Music therapy is known to have healing and relaxing effects. Although these effects appear to be mediated by release of neurotransmitters and neurohormones, the specific neurohormonal systems involved have not been fully investigated.

OBJECTIVE: To assess the effects of a music therapy intervention on concentrations of melatonin, norepinephrine, epinephrine, serotonin, and prolactin in the blood of a group of patients with Alzheimer's disease.

DESIGN: Blood samples were obtained before initiating the therapy, immediately at the end of 4 weeks of music therapy sessions, and at 6 weeks follow-up after cessation of the sessions.

SETTING: Miami Veterans Administration Medical Center, Miami, Fla.

PATIENTS: 20 male inpatients with Alzheimer's disease.

INTERVENTION: 30- to 40-minute morning sessions of music therapy 5 times per week for 4 weeks.

MAIN OUTCOME MEASURES: Changes in melatonin, norepinephrine, epinephrine, serotonin, and prolactin following music therapy.

RESULTS: Melatonin concentration in serum increased significantly after music therapy and was found to increase further at 6 weeks follow-up. A significant increase was found between baseline values and data recorded after the music therapy sessions as well as at 6 weeks follow-up. Norepinephrine and epinephrine levels increased significantly after 4 weeks of music therapy, but returned to pretherapy levels at 6 weeks follow-up. Serum concentration of prolactin and platelet serotonin levels remained unchanged after 4 weeks of music therapy and at 6 weeks follow-up.

CONCLUSION: Increased levels of melatonin following music therapy may have contributed to patients' relaxed and calm mood.

Low serum docosahexaenoic acid is a significant risk factor for Alzheimer's dementia.

Kyle DJ, Schaefer E, Patton G, Beiser A. Tufts University School of Medicine, Boston, Massachusetts 02118, USA.

Lipids 1999;34 Suppl:S245

No Abstract Available

Melatonin affects the metabolism of the beta-amyloid precursor protein in different cell types.

Lahiri DK Department of Psychiatry and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202, USA. dlahiri@iupui.edu

J Pineal Res 1999 Apr;26(3):137-46

Melatonin is released in mammals during the dark phase of the circadian cycle, and its production declines with age in animals and humans. Since supplemental administration of melatonin may be beneficial in delaying age-related degenerative conditions, it is necessary to study its effect on neuronal differentiation and the processing of key neuronal proteins, such as beta-amyloid precursor protein (beta APP) and synaptophysin. One of the important pathological hallmarks of Alzheimer's disease (AD) is the cerebrovascular deposition of amyloid plaques. The amyloid in senile plaques is mainly composed of the amyloid beta-peptide (A beta) of 39-43 amino acids derived from a larger beta APP. The proteolytic cleavage by 'alpha-secretase' generate soluble derivatives of beta APP (sAPP), lacking the cytoplasmic tail, transmembrane domain, and a small portion of the extracellular domain. Here levels of sAPP and beta APP were analyzed in cell lines of different origins by Western immunoblot of samples from conditioned media and cell lysates, respectively. Normal levels of secretion of sAPP into conditioned media were severely inhibited by treating different cell lines with a high dose of melatonin. In PC12 cells, levels of the fully matured beta APP forms of the post-Golgi compartment were more drastically decreased than the unglycosylated beta APP of the endoplasmic-reticulum (ER) forms. In other cell types, the unglycosylated ER-bound beta APP derivatives are predominant forms that were marginally affected by melatonin treatment. When the treatment of cells with melatonin was withdrawn, the normal level of secretion of sAPP was restored. Melatonin reduces the secretion of soluble A beta. Melatonin also inhibits the secretion of synaptophysin in PC12 cells. Taken together, these data suggest that melatonin probably affects the secretion of sAPP in the conditioned medium by interfering with its full maturation, and melatonin also affects the presysnaptic terminal marker.

Interactions between melatonin, reactive oxygen species, and nitric oxide.

Lahiri DK, Ghosh C. Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202-4887, USA. DLAHIRI@IUPUI.EDU

Ann N Y Acad Sci 1999;893:325-30

Accumulation of reactive oxygen species is critical for the neuropathology of Alzheimer's disease. Melatonin hormone, an antioxidant, could play a key role in aging and senescence. Nitric oxide, a biologically active unstable radical, is synthesized by nitric oxide synthase when converting L-arginine to L-citrulline. We have investigated whether the treatment of cultured cells with melatonin could possibly reduce the release of free radicals and other ROS. We assayed NO indirectly by measuring the level of its stable end products, nitrite/nitrate (NOx), using the Griess reagent. When the neuroblastoma cells such as N1E-115 were treated with a NO donor such as sodium nitroprusside (SNP), a significant level of NOx was detected in a time- and dose-dependent manner in the conditioned medium compared to the untreated cells or SNP-containing media. In neuroblastoma cells, the release of NOx as mediated by SNP was significantly inhibited by treatment with (i) carboxy-PTIO, a NO scavenger; (ii) SOD-1, superoxide dismutase; and (iii) melatonin. In these cells SNP-mediated NOx release was mediated by superoxide ions and/or free radicals that can be inhibited by melatonin. The ROS-scavenging function of melatonin along with its neuroprotective and neurodifferentiating role can be utilized for the prevention of neurodegenerative disorders such as AD.

A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group.

Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. New York Institute for Medical Research, Tarrytown 10591, USA. NYI@HZI.com

JAMA 1997 Oct 22-29;278(16):1327-32

CONTEXT: EGb 761 is a particular extract of Ginkgo biloba used in Europe to alleviate symptoms associated with numerous cognitive disorders. Its use in dementias is based on positive results from only a few controlled clinical trials, most of which did not include standard assessments of cognition and behavior.

OBJECTIVE: To assess the efficacy and safety of EGb in Alzheimer disease and multi-infarct dementia.

DESIGN: A 52-week, randomized double-blind, placebo-controlled, parallel-group, multicenter study.

PATIENTS: Mildly to severely demented outpatients with Alzheimer disease or multi-infarct dementia, without other significant medical conditions.

INTERVENTION: Patients assigned randomly to treatment with EGb (120 mg/d) or placebo. Safety, compliance, and drug dispensation were monitored every 3 months with complete outcome evaluation at 12, 26, and 52 weeks.

PRIMARY OUTCOME MEASURES: Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI), and Clinical Global Impression of Change (CGIC).

RESULTS: From 309 patients included in an intent-to-treat analysis, 202 provided evaluable data for the 52-week end point analysis. In the intent-to-treat analysis, the EGbgroup had an ADAS-Cog score 1.4 points better than the placebo group (P=.04) and a GERRI score 0.14 points better than the placebo group (P=.004). The same patterns were observed with the evaluable data set in which 27% of patients treated with EGb achieved at least a 4-point improvement on the ADAS-Cog, compared with 14% taking placebo (P=.005); on the GERRI, 37% were considered improved with EGb, compared with 23% taking placebo (P=.003). No difference was seen in the CGIC. Regarding the safety profile of EGb, no significant differences compared with placebo were observed in the number of patients reporting adverse events or in the incidence and severity of these events.

CONCLUSIONS: EGb was safe and appears capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year. Although modest, the changes induced by EGb were objectively measured by the ADAS-Cog and were of sufficient magnitude to be recognized by the caregivers in the GERRI.

A 26-week analysis of a double-blind, placebo-controlled trial of the ginkgo biloba extract EGb 761 in dementia.

Le Bars PL, Kieser M, Itil KZ Memory Centers of America Inc., New York, NY, USA. info@mcai.com

Dement Geriatr Cogn Disord 2000 Jul-Aug;11(4):230-7

This intent-to-treat (ITT) analysis was performed to provide a realistic image of the efficacy that could be expected after 26 weeks treatment with a 120-mg dose (40 mg t.i.d.) of EGb 761 (EGb). The data were collected during a 52-week, double-blind, placebo-controlled, fixed dose, parallel-group, multicenter study. Patients were mildly to severely impaired and diagnosed with uncomplicated Alzheimer's disease or multi-infarct dementia according to ICD-10 and DSM-III-R criteria. The primary outcome measures included the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI) and Clinical Global Impression of Change. From 309 patients included in the ITT analysis, 244 patients (76% for placebo and 73% for EGb) actually reached the 26th week visit. In comparison to the baseline values, the placebo group showed a statistically significant worsening in all domains of assessment, while the group receiving EGb was considered slightly improved on the cognitive assessment and the daily living and social behavior. Mean treatment differences favored EGb with 1.3 and 0.12 points, respectively, on the ADAS-Cog (p = 0.04) and the GERRI (p = 0.007). In the group receiving EGb, 26% of the patients achieved at least a 4-point improvement on the ADAS-Cog, compared to 17% with placebo (p = 0.04). On the GERRI, 30% of the EGb group improved and 17% worsened, while the placebo group showed an opposite trend with 37% of patients worsening for 25% improved (p = 0.006). Regarding safety, no differences between EGb and placebo were observed.

Hyperhomocysteinemia in dementia.

Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K, Widner B, Reibnegger G, Fuchs D. Department of Gerontology, Landesnervenklinik Wagner Jauregg, Linz, Austria.

J Neural Transm 2000;107(12):1469-74

Hyperhomocysteinemia is a strong risk factor for atherosclerotic vascular disease, and elevated serum homocysteine is correlated with vitamin B deficiency. In this pilot study, significantly elevated homocysteine levels were found in patients with Alzheimer's disease as well as in patients with vascular dementia, probably indicating similar pathophysiological pathways. We found significant correlations between low folic acid concentrations as well as high homocysteine concentrations and cognitive decline. Supplementation with folic acid may be an inexpensive way to reduce elevated homocysteine levels in demented patients.

Identification of cognitive impairment in the elderly: homocysteine is an early marker.

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

Dement Geriatr Cogn Disord 1999 Jan-Feb;10(1):12-20

In 336 consecutive patients attending a university-affiliated memory unit, clinical and psychological findings, neuroimaging and laboratory tests were analyzed. The patients were diagnosed with early Alzheimer's disease 3%, senile dementia (SDAT) 16%, vascular dementia (VAD) 20%, other dementias 9%, minor cognitive impairment (dysmentia) 32% and subjective symptoms only 21%. Increases in vascular risk factors, serum homocysteine, ApoE4 load and neuroimaging pathology were found in dementia but also in dysmentia and in patients with subjective symptoms only. The homocysteine levels correlated inversely with cognitive performance. The increases in serum homocysteine, which were pathological in VAD, Dysmentia and SDAT, may be indicative of a disturbed cerebral one-carbon metabolism and signal-accelerated development of cognitive disease.

Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease.

Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM. University of California Los Angeles, Departments of Medicine and Neurology, 90095, USA.

J Neurosci 2000 Aug 1;20(15):5709-14

The brain in Alzheimer's disease (AD) shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced risk for AD in patients using nonsteroidal anti-inflammatory drugs (NSAIDs), prompting further inquiries about how NSAIDs might influence the development of AD pathology and inflammation in the CNS. We tested the impact of chronic orally administered ibuprofen, the most commonly used NSAID, in a transgenic model of AD displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Transgene-positive (Tg+) and negative (Tg-) mice began receiving chow containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This treatment produced significant reductions in final interleukin-1beta and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of beta-amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble Abeta. Ibuprofen also decreased the numbers of ubiquitin-labeled dystrophic neurites and the percentage area per plaque of anti-phosphotyrosine-labeled microglia. Thus, the anti-inflammatory drug ibuprofen, which has been associated with reduced AD risk in human epidemiological studies, can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging.

Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, McDowell I. Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. Joan_Lindsay@hc-sc.gc.ca

Am J Epidemiol 2002 Sep 1;156(5):445-53

A prospective analysis of risk factors for Alzheimer's disease was a major objective of the Canadian Study of Health and Aging, a nationwide, population-based study. Of 6,434 eligible subjects aged 65 years or older in 1991, 4,615 were alive in 1996 and participated in the follow-up study. All participants were cognitively normal in 1991 when they completed a risk factor questionnaire. Their cognitive status was reassessed 5 years later by using a similar two-phase procedure, including a screening interview, followed by a clinical examination when indicated. The analysis included 194 Alzheimer's disease cases and 3,894 cognitively normal controls. Increasing age, fewer years of education, and the apolipoprotein E epsilon4 allele were significantly associated with increased risk of Alzheimer's disease. Use of nonsteroidal anti-inflammatory drugs, wine consumption, coffee consumption, and regular physical activity were associated with a reduced risk of Alzheimer's disease. No statistically significant association was found for family history of dementia, sex, history of depression, estrogen replacement therapy, head trauma, antiperspirant or antacid use, smoking, high blood pressure, heart disease, or stroke. The protective associations warrant further study. In particular, regular physical activity could be an important component of a preventive strategy against Alzheimer's disease and many other conditions.

A double-blind, placebo controlled trial of high-dose lecithin in Alzheimer's disease.

Little A, Levy R, Chuaqui-Kidd P, Hand D.

J Neurol Neurosurg Psychiatry 1985 Aug;48(8):736-42

The first long-term double-blind placebo controlled trial of high dose lecithin in senile dementia of the Alzheimer type is reported. Fifty one subjects were given 20-25 g/day of purified soya lecithin (containing 90% phosphatidyl plus lysophosphatidyl choline) for six months and followed up for at least a further six months. Plasma choline levels were monitored throughout the treatment period. There were no differences between the placebo group and the lecithin group but there was an improvement in a subgroup of relatively poor compliers. These were older and had intermediate levels of plasma choline. It is suggested that the effects of lecithin are complex but that there may be a "therapeutic window" for the effects of lecithin in the condition and that this may be more evident in older patients.

Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype.

Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF. Netherlands Institute for Brain Research, Amsterdam.

J Clin Endocrinol Metab 1999 Jan;84(1):323-7

Sleep disruption, nightly restlessness, sundowning, and other circadian disturbances are frequently seen in Alzheimer's disease (AD) patients. Changes in the suprachiasmatic nucleus and pineal gland are thought to be the biological basis for these behavioral disturbances. Melatonin is the main endocrine message for circadian rhythmicity from the pineal. To determine whether melatonin production was affected in AD, melatonin levels were determined in the cerebrospinal fluid (CSF) of 85 patients with AD (mean age, 75 +/- 1.1 yr) and in 82 age-matched controls (mean age, 76 +/- 1.4 yr). Ventricular postmortem CSF was collected from clinically and neuropathologically well defined AD patients and from control subjects without primary neurological or psychiatric disease. In old control subjects (>80 yr of age), CSF melatonin levels were half of those in control subjects of 41-80 yr of age [176 +/- 58 (n = 29) and 330 +/- 66 (n = 53) pg/mL, respectively; P = 0.016]. We did not find a diurnal rhythm in CSF melatonin levels in control subjects. In AD patients the CSF melatonin levels were only one fifth (55 +/- 7 pg/mL) of those in control subjects (273 +/- 47 pg/mL; P = 0.0001). There was no difference in the CSF melatonin levels between the presenile (42 +/- 11 pg/mL; n = 21) and the senile (59 +/- 8 pg/mL; n = 64; P = 0.35) AD patients. The melatonin level in AD patients expressing apolipoprotein E-epsilon3/4 (71 +/- 11 pg/mL) was significantly higher than that in patients expressing apolipoprotein E-epsilon4/4 (32 +/- 8 pg/ml; P = 0.02). In the AD patients no significant correlation was observed between age of onset or duration of AD and CSF melatonin levels. In the present study, a dramatic decrease in the CSF melatonin levels was found in old control subjects and even more so in AD patients. Whether supplementation of melatonin may indeed improve behavioral disturbances in AD patients should be investigated.

Efficacy and safety of nicotine on Alzheimer's disease patients.

Lopez-Arrieta JM, Rodriguez JL, Sanz F. Hospital de Cantoblanco, Consejeria de Sanidad, Carretera de Colmenar km 14.500, Madrid, Madrid, Spain, 28049. med013440@nacom.es

Cochrane Database Syst Rev 2001;(2):CD001749

BACKGROUND: Nicotine is a cholinergic agonist that also has a presynaptic effect in releasing acetylcholine. In animal model has been shown to reverse spatial memory deficits produced by lesions in the medial septal nucleus of rats, and in aged monkeys nicotine administration improves memory and alertness to visual stimuli. Observational studies have claimed a protective effect of smoking against Alzheimer's disease (AD), but recent studies have called this into question. Smoking is a risk factor for stroke and so, possibly, for vascular dementia. Because nicotine has adverse effects, it is important to conduct a systematic review to assess the clinical efficacy and safety of nicotine for patients with AD

OBJECTIVES: To evaluate the efficacy and safety of nicotine, administered in any way or form, for people with Alzheimer's disease.

SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 24 January 2001 using the term nicotine.

SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with nicotine patches or administration of nicotine intravenously or in any other way or form was administered for more than a day and compared with placebo for people with Alzheimer's disease.

DATA COLLECTION AND ANALYSIS: The one included trial did not present results suitable for inclusion in the review.

MAIN RESULTS: The poor quality of trials did not allow any synthesis of data across studies.

REVIEWER'S CONCLUSIONS: This review is not able to provide any evidence that nicotine is a useful treatment for Alzheimer's disease.

Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging.

Mackenzie IR, Munoz DG. Department of Pathology and Laboratory Medicine, Vancouver General Hospital, British Columbia, Canada.

Neurology 1998 Apr;50(4):986-90

Anti-inflammatory drugs have been suggested as a possible treatment for Alzheimer's disease (AD). The association of immune proteins and immune-competent microglial cells with senile plaques (SP) in both AD and normal aging suggests that these drugs may be able to modify the course of AD, either by interfering with SP formation or by suppressing the inflammation associated with SP. We compared postmortem brain tissue from elderly, nondemented, arthritic patients with a history of chronic nonsteroidal anti-inflammatory drug (NSAID) use (n = 32, aged 77 +/- 7 years) and nondemented control subjects with no history of arthritis or other condition that might promote the regular use of NSAIDs (n = 34, aged 77 +/- 6 years). In both the NSAID-treated group and control subjects, 59% of patients had some SP. There was no difference between the two groups in the mean number of plaques or in the number of specific SP subtypes (diffuse or neuritic). The degree of neurofibrillary pathology was also similar. Activated microglia were identified using CR3/43, an anti-MHC class II antibody. Both patient age and the presence of SP correlated positively with the number of CR3/43+ microglia (p < 0.02), whereas NSAID use was associated with less microglial activation (p < 0.01). Control patients with SP had almost three times the number of activated microglia as NSAID-treated patients with SP (11 versus 4 cells/mm2, p < 0.02). These results suggest that if NSAID use is effective in treating AD, the mechanism is more likely to be through the suppression of microglial activity than by inhibiting the formation of SP or neurofibrillary tangles.

Association between changes in adrenal secretion and cerebral morphometric correlates in normal aging and senile dementia.

Magri F, Terenzi F, Ricciardi T, Fioravanti M, Solerte SB, Stabile M, Balza G, Gandini C, Villa M, Ferrari E Department of Internal Medicine and Medical Therapy, Chair of Geriatrics, University of Pavia, Italy. ferrari@ipv36.unipv.it

Dement Geriatr Cogn Disord 2000 Mar-Apr;11(2):90-9

The circadian organization of adrenal secretion was studied in 23 healthy elderly subjects, 23 elderly demented patients and 10 healthy young subjects, in order to investigate the relationships between the hypothalamic-pituitary-adrenal axis and some cerebral morphometric parameters. The cerebral morphometric analysis was performed in some subjects of the three groups by MRI. A significant increase in cortisol levels during evening and nighttime was found in both groups of the aged subjects. In elderly subjects, particularly if demented, the mean serum dehydroepiandrosterone sulfate (DHEAs) levels throughout the 24-hour cycle were significantly lower than in young controls. A significant reduction of the hippocampal and temporal volume and an enlargement of the lateral ventricles were found in aged subjects, these changes being significantly related to subjects' age. Moreover, the hippocampal volume was positively correlated with the circadian mesor of DHEAs (i.e., the circadian rhythm adjusted mean) and with the cortisol nocturnal increase. Our data may suggest the existence of a link between the selective impairment of cortisol secretion and DHEAs levels, and the progression of hippocampal degeneration.

Molecular basis of the neurodegenerative disorders.

Martin JB. Harvard Medical School, Boston, MA 02115, USA. josephvmartin@hms.harvard.edu

N Engl J Med 1999 Jun 24;340(25):1970-80

No Abstract Available

The therapeutic potential for tryptophan and melatonin: possible roles in depression, sleep, Alzheimer's disease and abnormal aging.

Maurizi CP.

Med Hypotheses 1990 Mar;31(3):233-42

Evidence suggests that stress and/or a dietary lack of tryptophan may make deficiencies of serotonin and melatonin common. In addition, older animals and human beings have a reduced ability to synthesize melatonin. Disorders of melatonin levels and rhythms are suggested to be a cause of affective disease, abnormal sleep, Alzheimer's disease, and some age related disorders. If these ideas prove to be true, then preventive measures are possible.

Analogues, ageing and aberrant assimilation of vitamin B12 in Alzheimer's disease.

McCaddon A, Hudson P, Abrahamsson L, Olofsson H, Regland B. Gardden Road Surgery, Rhosllanerchrugog, Wrexham, North Wales, UK. Andrew@mccaddon.demon.co.uk

Dement Geriatr Cogn Disord 2001 Mar-Apr;12(2):133-7

Vitamin B12 assimilation might be disrupted in patients with Alzheimer's disease. We therefore measured B12 carrier protein saturation and inactive B12 'analogues' in patients compared with healthy elderly individuals in a prospective case-controlled survey. Twenty-three patients, aged 60 or over, with features compatible with DSM-IV criteria for primary degenerative dementia of the Alzheimer type were recruited together with 18 cognitively intact age-matched control subjects. Total vitamin B12 (active corrinoids), holo- and apo-haptocorrin and transcobalamin were measured in serum. B12 analogues (inactive corrinoids) were estimated from the difference between R-binder-determined corrinoids and an intrinsic factor based B12 assay. Alzheimer patients had significantly lower active corrinoid than control subjects and the analogue/corrinoid ratio was significantly higher in the Alzheimer group. The inter-relationship between age, analogues and transcobalamin polarised patients into two distinct groups. Two disparate mechanisms might exist for the development of cerebral B12 deficiency in Alzheimer's disease, although both imply a disruption of selective B12 assimilation and analogue elimination in such patients. Copyright 2001 S. Karger AG, Basel

Total serum homocysteine in senile dementia of Alzheimer type.

McCaddon A, Davies G, Hudson P, Tandy S, Cattell H Wrexham Maelor Hospital, North Wales, UK. andrew@mccaddon.demon.co.uk

Int J Geriatr Psychiatry 1998 Apr;13(4):235-9

OBJECTIVE: The main hypothesis was that subtle vitamin B12 deficiencies occur more commonly in senile dementia of Alzheimer type (SDAT) that in healthy elderly individuals, and may be revealed by elevated total serum homocysteine (tHcy). A subsidiary hypothesis was that such deficiencies would be nutritionally independent as determined by retinol binding protein (RBP).

DESIGN: A prospective case-controlled survey.

SETTING: A Welsh urban psychogeriatric assessment centre and local general practice.

PATIENTS: Thirty patients, aged 65 or over, seen consecutively in 1994 with features compatible with DSM-III-R criteria for primary degenerative dementia of Alzheimer type and 30 cognitively intact age-matched control subjects.

MEASURES: Diagnosis was assessed using the CAMDEX. Cognitive scores were evaluated with the CAMCOG scale for patients and MMSE scores for control subjects. THcy was measured using high performance liquid chromatography (HPLC), and RBP assayed by a radial immunodiffusion method.

RESULTS: Patients had a highly significant elevation of tHcy compared with control (p < 0.0001). Multiple regression highlighted the interrelated effects of tHcy and total serum cobalamin on cognitive scores. RBP did not differ between groups. Macrocytosis was absent, and neutrophil hypersegmentation uncommon, in hyperhomocysteinaemic patients.

CONCLUSIONS: SDAT patients have significantly elevated tHcy. This is independent of RBP determined nutritional status. 'Classical' haematological changes of cobalamin or folate deficiency are poor predictors of tHcy in these patients. Aberrant cobalamin tissue delivery appears to contribute to SDAT cognitive decline. Relative contributions of other tHcy determinants require further investigation.

Homocysteine and cognitive decline in healthy elderly.

McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C. University of Wales College of Medicine, Wrexham, LL14 2EN, Wales, UK. andrew@mccaddon.demon.co.uk

Dement Geriatr Cogn Disord 2001 Sep-Oct;12(5):309-13

Serum homocysteine is increased, and correlates inversely with cognitive scores, in Alzheimer's disease (AD), vascular dementia and "age-associated memory impairment". Elevated levels might signal accelerated cognitive decline, although this remains to be established. We therefore repeated Mini-Mental State Examinations, together with additional ADAS-Cog assessments, in 32 healthy elderly individuals to determine whether prior homocysteine levels predicted cognitive changes over a 5-year period. Homocysteine predicted follow-up cognitive scores and rate of decline in cognitive performance independently of age, sex, education, renal function, vitamin B status, smoking and hypertension (p < 0.001). Homocysteine predicted word recall (p = 0.01), orientation (p = 0.02) and constructional praxis scores (p < 0.0001). One subject, with the second highest initial homocysteine, had developed probable AD at follow-up. Fasting total serum homocysteine appears to be an independent predictor of cognitive decline in healthy elderly and exerts a maximal effect on spatial copying skills. Copyright 2001 S. Karger AG, Basel

Vascular nitric oxide, sex hormone replacement, and fish oil may help to prevent Alzheimer's disease by suppressing synthesis of acute-phase cytokines.

McCarty MF Nutrition 21/AMBI, San Diego, CA, USA.

Med Hypotheses 1999 Nov;53(5):369-74

The neurodegenerative plaques of Alzheimer's disease (AD) are characterized by a self-sustaining acute-phase reaction in which both interleukin-1 (IL-1) and interleukin-6 (IL-6) are up-regulated. The fact that IL-6 is detectable in early stage diffuse plaques encourages the speculation that the acute-phase process is crucial to the pathogenesis of AD. The epidemiological association of AD with estrogen deficiency, as well as with various disorders characterized by vascular endotheliopathy, suggest a protective role for vascular nitric oxide (NO). NO has an autocrine anti-inflammatory impact on endothelium, owing in part to antagonism of NF-kappaB activity; since induction of IL-6 is dependent on NF-kappaB, this may explain recent evidence that NO inhibits macrophage IL-6 production. It is reasonable to postulate that, analogously, cerebrovascular NO decreases IL-6 production in the brain. Vascular NO may also have direct europrotective activity. Estrogen, in addition to promoting vascular NO synthesis, can block IL-6 production by a more direct mechanism in cells expressing estrogen receptors; since such receptors have been reported in brain glia and astrocytes, estrogen has the potential to limit brain IL-1 activity. Testosterone likewise can inhibit IL-6 induction in androgen-responsive cells, which may include brain glia and astrocytes. Since fish oil and gamma linolenic acid (GLA) suppress IL-1 production by stimulated monocytes, they conceivably could exert this effect in the brain as well; the comparatively low prevalence of AD in elderly Japanese is intriguing in this regard. These considerations suggest that a healthy cerebrovascular endothelium, sex hormone activity, and dietary fish oil/GLA may slow or prevent AD onset by dampening acute-phase mechanisms in the brain.

Brain aluminum in aging and Alzheimer disease.

McDermott JR, Smith AI, Iqbal K, Wisniewski HM.

Neurology 1979 Jun;29(6):809-14

Aluminum was assayed by atomic absorption spectroscopy in 274 brain samples, and assayed in neurons isolated in bulk from the frontal cortex of patients with Alzheimer dementia and from age-matched patients with no neurologic disease. Brain aluminum concentration increased with age, from late middle age to old age. There were no statistically significant differences in brain aluminum concentration between the 10 patients with Alzheimer disease (mean, 2.7 microgram per gram dry weight of tissue; mean age, 81 years), and the 9 nonneurologic controls (mean, 2.5 microgram per gram; mean age, 73 years). In both groups, the hippocampus had the highest concentration of aluminum (5.6 microgram per gram), and the corpus callosum the lowest (1.5 microgram per gram).

Brain inflammation in Alzheimer disease and the therapeutic implications

McGeer E.G.; McGeer P.L. E.G. McGeer, Kinsmen Lab. of Neurol. Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T IZ3 Canada mcgeerpl@interchange.ubc.ca

Current Pharmaceutical Design ( CURR. PHARM. DES. ) (Netherlands) 1999, 5/10 (821-836)

Immunohistochemical studies suggested the existence of a chronic inflammatory condition in affected regions of the brain in Alzheimer disease (AD). Since inflammation can be damaging to host tissue, it was hypothesized that antiinflammatory drugs might inhibit both the onset and the progression of AD. This hypothesis is supported by a number of epidemiological studies suggesting that the prevalence of AD in persons is reduced by 40 - 50% in persons using antiinflammatory drugs. In one small pilot trial in early AD, the nonsteroidal antiinflammatory drug indomethacin appeared to halt the progressive memory loss. Immunohistochemical and molecular biological studies on immune system components in AD brain are revealing the complexities of the innate immune reaction. This very complexity may offer points of therapeutic intervention for new types of antiinflammatory agents. The complement system, microglia and cytokines are key components. This review summarizes the present state of knowledge on the immune system elements found in AD brain.

Risk for neuropathologically confirmed Alzheimer's disease and residual aluminum in municipal drinking water employing weighted residential histories.

McLachlan DR, Bergeron C, Smith JE, Boomer D, Rifat SL. Department of Physiology and Medicine, University of Toronto, ON, Canada.

Neurology 1996 Feb;46(2):401-5

We investigated a possible relation between aluminum concentration ([Al]) in public drinking water and Alzheimer's disease (AD), with AD cases and controls defined on the basis of strict neuropathologic criteria. Using the case/control odds ratio as an estimate of relative risk and [Al] > or = 100 microgram/L as the cutoff point, elevated risks for histopathologically verified AD were associated with higher [Al]. Comparing all AD cases with all non-AD controls, and using the [Al] of public drinking water at last residence before death as the measure of exposure, the estimated relative risk associated with [Al] > or = 100 microgram/L was 1.7 (95% CI: 1.2-2.5). Estimating aluminum exposure from a 10-year weighted residential history resulted in estimates of relative risk of 2.5 or greater. The public health implications of the observed relationship between [Al] in drinking water and AD prevalence in the population depend in large measure on population exposure characteristics. In Ontario, it is estimated that 19% of the population was exposed to residual [Al] greater than or equal to 100 microgram/L. Based on the estimated relative risk and the assumption of causality, this translates to an etiologic fraction of 0.23. Although the potential contributions of confounding and mitigating factors are not defined in this report, the merit of limiting residual aluminum in drinking water supplies deserves serious attention.

Subnormal serum vitamin B12 and behavioural and psychological symptoms in Alzheimer's disease.

Meins W, Muller-Thomsen T, Meier-Baumgartner HP Memory-Clinic, Department of Geriatric Medicine, Albertinen Hospital, Hamburg, Germany.

Int J Geriatr Psychiatry 2000 May;15(5):415-8

The objective of this study was to examine whether patients with Alzheimer's disease (AD) with subnormal vitamin B12 levels show more frequent behavioural and psychological symptoms of dementia (BPSD) than AD patients with normal vitamin B12 levels. The design was a prospective case-control study. The study took place at a memory-clinic of a department of geriatric medicine in a teaching hospital. There were seventy-three consecutive outpatients with probable AD, including 61 patients with normal and 12 patients with subnormal (<200 pg/ml) vitamin B12. BPSD were measured using the subscales disturbed behaviour and mood of the Nurses' Observation Scale for Geriatric Patients (NOSGER), the Cornell Scale for Depression and the four criteria for personality change in dementia from the International Classification of Diseases (ICD-10). Controlling for dementia duration and degree of severity of the cognitive deficits, there were significant inverse associations between vitamin B12 status and ICD-10 irritability (p=0.045) and NOSGER subscale disturbed behaviour (p=0.015). Low vitamin B12 serum levels are associated with BPSD in AD. Vitamin B12 could play a role in the pathogenesis of behavioural changes in AD.

Homocysteine and Alzheimer's disease.

Miller JW. University of California-Davis Medical Center, Department of Medical Pathology, Sacramento 95817, USA.

Nutr Rev 1999 Apr;57(4):126-9

In a recent case-control study of 164 patients with clinically diagnosed Alzheimer's disease (AD), including 76 patients with the AD diagnosis confirmed postmortem, mean total serum homocysteine concentration was found to be significantly higher than that of a control group of elderly individuals with no evidence of cognitive impairment. Because homocysteine is considered an independent risk factor for vascular disease, this finding is consistent with the emerging hypothesis that vascular disease is a contributing factor in the pathogenesis of AD.

Cholinergic deficits contribute to behavioral disturbance in patients with dementia.

Minger SL, Esiri MM, McDonald B, Keene J, Carter J, Hope T, Francis PT. Dementia Research Laboratory, Centre for Neuroscience Research, GKT School of Biomedical Sciences, King's College London, UK.

Neurology 2000 Nov 28;55(10):1460-7

BACKGROUND: Noncognitive behavioral changes such as depression, aggressive behavior, psychosis, and overactivity occur frequently in patients with dementia, in addition to cognitive impairment, and often determine the need for institutionalization. The biochemical basis of such changes is poorly understood. Clinical trial data indicate that cholinomimetics improve noncognitive behaviors. This study investigated the relationship between markers of the cholinergic and dopaminergic neurotransmitter systems and noncognitive behavioral symptoms assessed during the course of dementing illness.

METHOD: Brains from 46 patients with dementia (36 with AD and 10 with mixed or other dementias using Consortium to Establish a Registry for AD criteria) were examined together with 32 normal controls. The patients with dementia had been evaluated every 4 months, often over several years, for cognitive performance (Mini-Mental State Examination) and behavior (Present Behavioral Examination). Concentrations of dopamine (DA) and major metabolites, choline acetyltransferase activity (ChAT), and density (Bmax) of DA D1 receptors in frontal and temporal cortex were studied by radioligand binding protocols. None of the patients was receiving cholinomimetic drugs.

RESULTS: ChAT activity, but no other neurochemical markers, was reduced in AD compared with controls. Loss of ChAT activity correlated with cognitive impairment. Lowered ChAT activity also correlated with increasing overactivity in patients with dementia in both frontal and temporal cortex whereas ChAT:DA and ChAT:D1 ratios in temporal cortex correlated negatively with aggressive behavior.

CONCLUSIONS: Disturbance of the cholinergic system may underlie both cognitive and some noncognitive behavioral changes in dementia, providing a basis for rational therapy.

Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease.

Morris MC, Beckett LA, Scherr PA, Hebert LE, Bennett DA, Field TS, Evans DA. Rush Institute for Healthy Aging and Rush Alzheimer's Disease Center, Rush University, Chicago, Illinois, USA.

Alzheimer Dis Assoc Disord 1998 Sep;12(3):121-6

Oxidative stress may play a role in neurologic disease. The present study examined the relation between use of vitamin E and vitamin C and incident Alzheimer disease in a prospective study of 633 persons 65 years and older. A stratified random sample was selected from a disease-free population. At baseline, all vitamin supplements taken in the previous 2 weeks were identified by direct inspection. After an average follow-up period of 4.3 years, 91 of the sample participants with vitamin information met accepted criteria for the clinical diagnosis of Alzheimer disease. None of the 27 vitamin E supplement users had Alzheimer disease compared with 3.9 predicted based on the crude observed incidence among nonusers (p = 0.04) and 2.5 predicted based on age, sex, years of education, and length of follow-up interval (p = 0.23). None of the 23 vitamin C supplement users had Alzheimer disease compared with 3.3 predicted based on the crude observed incidence among nonusers (p = 0.10) and 3.2 predicted adjusted for age, sex, education, and follow-up interval (p = 0.04). There was no relation between Alzheimer disease and use of multivitamins. These data suggest that use of the higher-dose vitamin E and vitamin C supplements may lower the risk of Alzheimer disease.

Piracetam: novelty in a unique mode of action.

Muller WE, Eckert GP, Eckert A Department of Pharmacology, Biocenter University of Frankfurt, Germany.

Pharmacopsychiatry 1999 Mar;32 Suppl 1:2-9

Extensive research of the recent years has demonstrated that piracetam is effective in the treatment of cognitive decline in aging and dementia. It is usually much more active in situations of impaired brain function. Accordingly, its mechanism of action has been associated with neurochemical deficits of the aged brain relevant to cognitive dysfunctions. Since many of these neurochemical deficits depend on changes of membrane properties, including fluidity, it is of special importance that piracetam not only modifies membrane properties by interacting with the polar head moieties of the phospholipid bilayer, but also that this effect is more pronounced in membranes of aged as opposed to young animal and human brains, and that this mechanism also has specific relevance for brain membranes of Alzheimer's disease patients. Altering membrane properties might also be involved in vascular effects of piracetam such as improved erythrocyte deformability and normalization of hyperactive platelet aggregation. This novel mechanism of piracetam thus combines a rather non-specific physico-chemical mode of action with the pharmacological and clinical experience with this unique drug - effects are always much more pronounced when function is impaired.

Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide.

Munch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Muller R, Neumann A, Schinzel R, Cunningham AM. Theodor-Boveri-Institute (Biocenter), Wurzburg, Germany. muench@biozentrum.uni-wuerzburg.de

Biochim Biophys Acta 1997 Feb 27;1360(1):17-29

Nucleation-dependent polymerization of beta-amyloid peptide, the major component of plaques in patients with Alzheimer's disease, is significantly accelerated by crosslinking through Advanced Glycation End-products (AGEs) in vitro. During the polymerization process, both nucleus formation and aggregate growth are accelerated by AGE-mediated crosslinking. Formation of the AGE-crosslinked amyloid peptide aggregates could be attenuated by the AGE-inhibitors Tenilsetam, aminoguanidine and carnosine. These experimental data, and clinical studies, reporting a marked improvement in cognition and memory in Alzheimer's disease patients after Tenilsetam treatment, suggest that AGEs might play an important role in the etiology or progression of the disease. Thus AGE-inhibitors may generally become a promising drug class for the treatment of Alzheimer's disease.

Hippocampal perfusion and pituitary-adrenal axis in Alzheimer's disease.

Murialdo G, Nobili F, Rollero A, Gianelli MV, Copello F, Rodriguez G, Polleri A Department of Endocrinological and Metabolic Sciences, Epidemiology Service, University of Genova, Italy. disem@unige.it

Neuropsychobiology 2000;42(2):51-7

The hippocampus is involved in Alzheimer's disease (AD) and regulates the hypothalamus-pituitary-adrenal axis (HPAA). Enhanced cortisol secretion has been reported in AD. Increased cortisol levels affect hippocampal neuron survival and potentiate beta-amyloid toxicity. Conversely, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are believed to antagonize noxious glucocorticoid effects and exert a neuroprotective activity. The present study was aimed at investigating possible correlations between hippocampus perfusion - evaluated by SPECT - and HPAA function in AD. Fourteen patients with AD and 12 healthy age-matched controls were studied by (99m)Tc-HMPAO high-resolution brain SPECT. Plasma adrenocorticotropin, cortisol, and DHEAS levels were determined at 2.00, 8.00, 14.00, 20.00 h in all subjects and their mean values were computed. Cortisol/DHEAS ratios (C/Dr) were also calculated. Bilateral impairment of SPECT hippocampal perfusion was observed in AD patients as compared to controls. Mean cortisol levels were significantly increased and DHEAS titers were lowered in patients with AD, as compared with controls. C/Dr was also significantly higher in patients. Using a stepwise procedure for dependent SPECT variables, the variance of hippocampal perfusional data was accounted for by mean basal DHEAS levels. Moreover, hippocampal SPECT data correlated directly with mean DHEAS levels, and inversely with C/Dr. These data show a relationship between hippocampal perfusion and HPAA function in AD. Decreased DHEAS, rather than enhanced cortisol levels, appears to be correlated with changes of hippocampal perfusion in dementia.

Effects of co-dergocrine mesylate (Hydergine) in multi-infarct dementia as evaluated by positron emission tomography.

Nagasawa H, Kogure K, Kawashima K, Ido T, Itoh M, Hatazawa J Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.

Tohoku J Exp Med 1990 Nov;162(3):225-33

Three female patients aged from 74 to 79 with multi-infarct dementia were studied using positron emission tomography (PET) to assess the effect of co-dergocrine mesylate (Hydergine) on cerebral glucose metabolism. The cerebral glucose utilization (CMRGlc) of each patient was evaluated by PET scan using 2-deoxy-[18F]-2-fluoro-D-glucose (FDG). Following the first PET study, 0.04 mg/kg of co-dergocrine mesylate was injected intravenously with 250 ml saline solution, and then the second PET study was performed. The CMRGlc was determined from the images of the PET scan and the radioactivity of 18F in the plasma. After the administration of co-dergocrine mesylate, the value of CMRGlc increased significantly in the cerebral cortex (p less than 0.01 and p less than 0.05) and basal ganglia (p less than 0.05) compared with values before the administration, but no significant increase was found in the centrum semiovale. These results suggest that co-dergocrine mesylate stimulates glucose metabolism of neurons in the human brain.

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