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FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease.

ABSTRACT: We report the first clinicopathological series of longitudinal FDG-PET scans in post-mortem (PM) verified cognitively normal elderly (NL) followed to the onset of Alzheimer's-type dementia (DAT), and in patients with mild DAT with progressive cognitive deterioration.Four NL subjects and three patients with mild DAT received longitudinal clinical, neuropsychological and dynamic FDG-PET examinations with arterial input functions. NL subjects were followed for 13 +/- 5 years, received FDG-PET examinations over 7 +/- 2 years, and autopsy 6 +/- 3 years after the last FDG-PET. Two NL declined to mild cognitive impairment (MCI), and two developed probable DAT before death. DAT patients were followed for 9 +/- 3 years, received FDG-PET examinations over 3 +/- 2 years, and autopsy 7 +/- 1 years after the last FDG-PET. Two DAT patients progressed to moderate-to-severe dementia and one developed vascular dementia.The two NL subjects who declined to DAT received a PM diagnosis of definite AD. Their FDG-PET scans indicated a progression of deficits in the cerebral metabolic rate for glucose (CMRglc) from the hippocampus to the parietotemporal and posterior cingulate cortices. One DAT patient showed AD with diffuse Lewy body disease (LBD) at PM, and her last in vivo PET was indicative of possible LBD for the presence of occipital as well as parietotemporal hypometabolism.Progressive CMRglc reductions on FDG-PET occur years in advance of clinical DAT symptoms in patients with pathologically verified disease. The FDG-PET profiles in life were consistent with the PM diagnosis.

SUBMITTER: Mosconi L

PROVIDER: S-EPMC2774795 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease.

Mosconi Lisa L Mistur Rachel R Switalski Remigiusz R Tsui Wai Hon WH Glodzik Lidia L Li Yi Y Pirraglia Elizabeth E De Santi Susan S Reisberg Barry B Wisniewski Thomas T de Leon Mony J MJ

European journal of nuclear medicine and molecular imaging 20090114 5

<h4>Purpose</h4>We report the first clinicopathological series of longitudinal FDG-PET scans in post-mortem (PM) verified cognitively normal elderly (NL) followed to the onset of Alzheimer's-type dementia (DAT), and in patients with mild DAT with progressive cognitive deterioration.<h4>Methods</h4>Four NL subjects and three patients with mild DAT received longitudinal clinical, neuropsychological and dynamic FDG-PET examinations with arterial input functions. NL subjects were followed for 13 +/- ...[more]

PMID: 19142633

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Project description:Background: Several studies have linked type 2 diabetes (T2D) to an increased risk of developing Alzheimer's disease (AD). This has led to an interest in using antidiabetic treatments for the prevention of AD. However, the underlying mechanisms explaining the relationship between T2D and AD have not been completely elucidated. Objective: Our objective was to examine cerebral 18F-fluorodeoxyglucose (FDG) uptake during normal aging and in AD patients in regions associated with diabetes genetic risk factor expression to highlight which genes may serve as potential targets for pharmaceutical intervention. Methods: We calculated regional glucose metabolism differences in units of standardized uptake values (SUVR) for 386 cognitively healthy adults and 335 clinically probable AD patients. We then proceeded to extract gene-expression data from the publicly available Allen Human Brain Atlas (HBA) database. We used the nearest genes to 46 AD- and T2D-associated SNPs previously identified in the literature, and mapped their expression to the same 34 cortical regions in which we calculated SUVRs. SNPs with a donor consistency of 0.40 or greater were selected for further analysis. We evaluated the associations between SUVR and gene-expression across the brain. Results: Of the 46 risk-factor genes, 15 were found to be significantly correlated with FDG-PET brain metabolism in healthy adults and probable AD patients after correction for multiple comparisons. Using multiple regression, we found that five genes explained a total of 72.5% of the SUVR variance across the healthy adult group regions, while four genes explained a total of 79.3% of the SUVR variance across the probable AD group regions. There were significant differences in whole-brain SUVR as a function of allele frequencies for two genes. Conclusions: These results highlight the association between risk factor genes for T2D and regional glucose metabolism during both normal aging and in probable AD. Highlighted genes were associated with mitochondrial stability, vascular maintenance, and glucose intolerance. Pharmacological intervention of these pathways has the potential to improve glucose metabolism during normal again as well as in AD patients.

Project description:BackgroundA Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer's disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose-positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points.MethodsThis was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model.ResultsFifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P < 0.025), anterior cingulate (P < 0.041), and striatal (P < 0.023) regions. Clinical measures showed benefit in quality of life (P < 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group.DiscussionThese outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response.

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FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease.

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FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease.

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