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Development, validation and application of a new fornix template for studies of aging and preclinical Alzheimer's disease.

ABSTRACT: We developed a merged younger-older adult template of the fornix and demonstrated its utility for studies of aging and preclinical Alzheimer's disease (AD). In Experiment 1, probabilistic tractography was used to reconstruct the fornix in younger and older adults and successful streamlines were then averaged to create a merged template in standard space. The new template includes the majority of the fornix from the hippocampal formation to the subcallosal region and the thalamus/hypothalamus. In Experiment 2, the merged template was validated as an appropriate measure for studies of aging, with comparisons against manual tracing measures indicating identical spatial coverage in younger and older adult groups. In Experiment 3, the merged template was found to outperform age-specific templates in measures of sensitivity and specificity computed on diffusion tensor imaging data of an independent participant cohort. In Experiment 4, relevance to preclinical AD was demonstrated via associations between fractional anisotropy within the new fornix template and cerebrospinal fluid markers of AD pathology (A?₄₂ and the t-tau/A?₄₂ ratio) in a third independent cohort of cognitively normal older adults. Our new template provides an appropriate measure for use in future studies seeking to characterize microstructural alterations in the fornix associated with aging and preclinical AD.

SUBMITTER: Brown CA

PROVIDER: S-EPMC5137184 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Development, validation and application of a new fornix template for studies of aging and preclinical Alzheimer's disease.

Brown Christopher A CA Johnson Nathan F NF Anderson-Mooney Amelia J AJ Jicha Gregory A GA Shaw Leslie M LM Trojanowski John Q JQ Van Eldik Linda J LJ Schmitt Frederick A FA Smith Charles D CD Gold Brian T BT

NeuroImage. Clinical 20161125

We developed a merged younger-older adult template of the fornix and demonstrated its utility for studies of aging and preclinical Alzheimer's disease (AD). In Experiment 1, probabilistic tractography was used to reconstruct the fornix in younger and older adults and successful streamlines were then averaged to create a merged template in standard space. The new template includes the majority of the fornix from the hippocampal formation to the subcallosal region and the thalamus/hypothalamus. In ...[more]

PMID: 27942453

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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

Development, validation and application of a new fornix template for studies of aging and preclinical Alzheimer's disease.

Publications

Development, validation and application of a new fornix template for studies of aging and preclinical Alzheimer's disease.

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