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Amyloid and tau signatures of brain metabolic decline in preclinical Alzheimer's disease.

ABSTRACT: PURPOSE:We aimed to determine the amyloid (A?) and tau biomarker levels associated with imminent Alzheimer's disease (AD) - related metabolic decline in cognitively normal individuals. METHODS:A threshold analysis was performed in 120 cognitively normal elderly individuals by modelling 2-year declines in brain glucose metabolism measured with [18F]fluorodeoxyglucose ([18F]FDG) as a function of [18F]florbetapir A? positron emission tomography (PET) and cerebrospinal fluid phosphorylated tau biomarker thresholds. Additionally, using a novel voxel-wise analytical framework, we determined the sample sizes needed to test an estimated 25% drugeffect with 80% of power on changes in FDG uptake over 2 years at every brain voxel. RESULTS:The combination of [18F]florbetapir standardized uptake value ratios and phosphorylated-tau levels more than one standard deviation higher than their respective thresholds for biomarker abnormality was the best predictor of metabolic decline in individuals with preclinical AD. We also found that a clinical trial using these thresholds would require as few as 100 individuals to test a 25% drug effect on AD-related metabolic decline over 2 years. CONCLUSIONS:These results highlight the new concept that combined A? and tau thresholds can predict imminent neurodegeneration as an alternative framework with a high statistical power for testing the effect of disease-modifying therapies on [18F]FDG uptake decline over a typical 2-year clinical trial period in individuals with preclinical AD.

SUBMITTER: Pascoal TA

PROVIDER: S-EPMC5915512 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Amyloid and tau signatures of brain metabolic decline in preclinical Alzheimer's disease.

Pascoal Tharick A TA Mathotaarachchi Sulantha S Shin Monica M Park Ah Yeon AY Mohades Sara S Benedet Andrea L AL Kang Min Su MS Massarweh Gassan G Soucy Jean-Paul JP Gauthier Serge S Rosa-Neto Pedro P

European journal of nuclear medicine and molecular imaging 20180202 6

<h4>Purpose</h4>We aimed to determine the amyloid (Aβ) and tau biomarker levels associated with imminent Alzheimer's disease (AD) - related metabolic decline in cognitively normal individuals.<h4>Methods</h4>A threshold analysis was performed in 120 cognitively normal elderly individuals by modelling 2-year declines in brain glucose metabolism measured with [<sup>18</sup>F]fluorodeoxyglucose ([<sup>18</sup>F]FDG) as a function of [<sup>18</sup>F]florbetapir Aβ positron emission tomography (PET) ...[more]

PMID: 29396637

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Project description:Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.

Dataset Information

Amyloid and tau signatures of brain metabolic decline in preclinical Alzheimer's disease.

Publications

Amyloid and tau signatures of brain metabolic decline in preclinical Alzheimer's disease.

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