Prediction of progression to dementia in patients with mild cognitive impairment combining FDG-PET imaging with apolipoprotein E genotyping

Abstracts: Identification of Risk Factors / 1 (Suppl 1) (2005) in women, estrogen levels increase the risk for Alzheimer disease in older men. From this study, it is not recommended to increase testosterone levels through androgen replacement therapy in healthy men to reduce risk for dementia. P-073

PREDICTION OF PROGRESSION TO DEMENTIA IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT COMBINING FDG-PET IMAGING WITH APOLIPOPROTEIN E GENOTYPING

Timo Grimmer1, Alexander Drzezga1, Matthias Riemenschneider1, Nicola Lautenschlager2, Satoshi Minoshima3, Hans Foerstl1, Alexander Kurz1; 1Technische Universitaet Muenchen, Munich, Germany; 2University of Western Australia, Perth, Australia; 3 University of Washington, Seattle, WA, USA Background: Etiology and prognosis of mild cognitive impairment (MCI) are heterogeneous. Progression to dementia is frequently associated with Alzheimer’s disease (AD) pathology. Prediction of outcome is difficult on clinical grounds. Objective(s): To determine the predictive value of neurobiological markers of AD (FDG-PET and apoE genotype) for the progression from MCI to dementia. Methods: Patients with (MCI) defined by Mayo Clinic criteria were consecutively recruited in our memory clinic. All patients underwent F18-FDG-PET imaging and apoE genotyping. PET data was analyzed by an established observer-independent method. The pattern of metabolic impairment was evaluated by an experienced clinician. Significant hypometabolism in temporal, parietal or posterior cingulate areas were rated as consistent with AD. Patients were re-examined to determine the individual outcome, i. e. progression to dementia. Positive and negative predictive value (PPV and NPV) for apoE genotype and FDG PET alone and in combination were calculated. Results: 30 patients (14 female, 16 male) were included (baseline: age 70 ⫹/- 8 years; MMSE 27.2 ⫾ 1.7). 17 (57%) were apoE e4 carriers. FDG-PET was consistent with AD in 13 patients (43%). All patients were followed-up after 16 ⫾ 2 months. 12 patients (40%) had deteriorated to dementia. Of 17 apoE e4 carriers, 9 progressed to dementia. The PPV and NPV of the genetic marker were 53 % and 77 %, respectively. Of 13 patients with AD-typical PET, 11 were found to be demented at re-examination. The PPV and NPV of the imaging marker were 85 % and 94 %. respectively. All 8 patients who carried the e4 allele and had AD-typical PET findings were diagnosed with dementia at follow-up. On the other hand, all 8 patients who lacked both markers were still diagnosed with MCI. The combination of the apoE e4 allele and a PET scan suggestive of AD achieved a PPV and NPV of 100 %. Conclusions: ApoE genotyping and FDG-PET imaging both contribute to establishing the individual prognosis in patients with MCI. When used in combination these markers achieve very high positive and negative predictive values. These findings require confirmation in larger and less selected patient populations. P-074

THE PRIMARY PATHOGENETIC ROLE OF VASCULAR CONTAINS VASOACTIVE SUBSTANCES, HYPOPERFUSION, MITOCHONDRIA FAILURE AND OXIDATIVE STRESS IN AGING AND ALZHEIMER DISEASE

Gjumrakch Aliev1, George Perry1, Jiankang Liu2, Mark A. Smith1, Shu G. Chen1, Bruce N. Ames3, Jack C. de la Torre1; 1Case Western Reserve University, Cleveland, OH, USA; 2Children Hospital Oakland Research Institute, Oakland, CA, USA; 3Children Hospital Oakland Research Institute, Oakland, CA, USA Background: It is controversial whether vascular abnormalities participate as pathogenic factors during the development and maturation of agedassociated diseases that trigger mild cognitive impairment (MCI) and eventual conversion to AD. Objective: We studied the cellular and subcellular features of vascular lesions including vascular content, vasoactive substances immunoreactivity and mitochondria in brain vascular wall cells and in hippocampal neurons from human AD and animal models that

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mimic AD or MCI. Methods: In situ hybridization, using mitochondrial DNA (mtDNA) probes for human wild type, 5kb deleted and mouse mtDNA, was performed in conjunction with immunocytochemistry using antibodies against AbPP, 8-hydroxyguanosine (8OHG), all three isoforms of NOS and cytochrome c oxidase (COX). Conclusions: We found a higher degree of amyloid deposition in the vessels with more severe lesions which are immunopositive staining for AbPP and iNOS and possessed large, lipid-laden vacuoles in the cytoplasm of endothelial cells. Significantly more mitochondrial abnormalities were seen in microvessels, where lesions occurred, in human AD specimens, YAC, ApoE4 and C57B6/SJL Tg (⫹) mice, 2 vessels occluded aged rats and old aged rats without selective mitochondrial antioxidants (Lipoic Acid and ALCAIR) treatment. In situ hybridization, using wild type and chimera (recognizing mtDNA with the 5 kB deletion) mtDNA probes, revealed positive signals in the damaged mitochondria from the vascular endothelium and in perivascular cells of lesioned microvessels in human AD, YAC, ApoE4 and C57B6/SJL Tg (⫹) mouse and rats subjected to the long term CBH occlusion tissues. This damage was proximal to regions of large amyloid deposition. These mtDNA deletions were associated with increased amounts of immunoreactive AbPP, 8OHG and COX but not eNOS in the same cellular and subcellular compartments. The mtDNA deletion and expression of oxidative stress markers in vascular wall cells of these brains indicates that energy deficiency and oxidative stress, in AD, selectively affects the brain vascular tree and whole populations of vulnerable neurons. Future studies that examine the importance of mitochondrial pathophysiology in different cellular compartments may provide important insight not only into neurodegenerative and/or cerebrovascular disease pathobiology but may provide treatment targets of these conditions. P-075

LONGITUDINAL STUDY OF MODERATE ALCOHOL CONSUMPTION AND RISK OF DEMENTIA IN AN ELDERLY COMMUNITY BASED SAMPLE

Carol A. Derby, Charles B. Hall, Mindy J. Katz, Aaron J. Levalley, Richard B. Lipton; Albert Einstein College of Medicine, Bronx, NY, USA Background: Data from prospective studies regarding the relationship of alcohol consumption to cognitive impairment have been inconsistent. Although high levels of alcohol appear to increase dementia risk, whether light to moderate drinking is protective remains unclear. Objective: To examine the relation of moderate alcohol consumption to risk of incident dementia using long term follow-up data from the population-based Bronx Aging Study (BAS) sample. Methods: Between 1980-1983, the BAS enrolled 488 subjects aged 70-85 years who were free of dementia. These analyses include 441 subjects with complete information on alcohol use and covariates (64% female, median age 78.7 years, median follow-up 5 years, maximum 20 years). Detailed clinical and neuropsychological evaluations were completed every 12-18 months. Dementia diagnosis was assigned at case conferences using DSM-IV criteria. Medical history and demographics were by self-report on an interviewer administered questionnaire. To ascertain alcohol consumption, the interviewer recorded the weekly frequency and number of drinks consumed at a time for beer, wine and liquor. Grams of alcohol/day were calculated by applying the number of alcohol grams in a standard serving of each beverage to reported number of beverages. Alcohol use was categorized as none (N⫽183), low (1 to 30 grams/day; N⫽12), approximately corresponding to 2 drinks/day. Proportional hazard models were constructed with incident dementia as the outcome, category of alcohol grams/day was the independent variable, and with models adjusted for age, gender, education, religion, current smoking, and history of stroke, myocardial infarction, or diabetes. Conclusions: Using non-drinkers as the reference group, the adjusted hazard ratio (HR) for dementia for moderate alcohol use was 0.37 (95% CI 0.14--1.0, p⫽0.05. Low alcohol consumption (⬍ 1 drink/day) was not associated with dementia risk (HR 0.925, 95% CI 0.61-1.39, p⫽0.7). The high consumption group was small, and the HR for dementia was non-significant. Results from this community residing cohort confirm previous studies