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Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline.

ABSTRACT: The amyloid hypothesis suggests that beta-amyloid (A?) deposition leads to alterations in neural function and ultimately to cognitive decline in Alzheimer's disease. However, factors that underlie A? deposition are incompletely understood. One proposed model suggests that synaptic activity leads to increased A? deposition. More specifically, hyperactivity in the hippocampus may be detrimental and could be one factor that drives A? deposition. To test this model, we examined the relationship between hippocampal activity during a memory task using fMRI and subsequent longitudinal change in A? using PIB-PET imaging in cognitively normal older adults. We found that greater hippocampal activation at baseline was associated with increased A? accumulation. Furthermore, increasing A? accumulation mediated the influence of hippocampal activation on declining memory performance, demonstrating a crucial role of A? in linking hippocampal activation and memory. These findings support a model linking increased hippocampal activation to subsequent A? deposition and cognitive decline.

SUBMITTER: Leal SL

PROVIDER: S-EPMC5325620 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline.

Leal Stephanie L SL Landau Susan M SM Bell Rachel K RK Jagust William J WJ

eLife 20170208

The amyloid hypothesis suggests that beta-amyloid (Aβ) deposition leads to alterations in neural function and ultimately to cognitive decline in Alzheimer's disease. However, factors that underlie Aβ deposition are incompletely understood. One proposed model suggests that synaptic activity leads to increased Aβ deposition. More specifically, hyperactivity in the hippocampus may be detrimental and could be one factor that drives Aβ deposition. To test this model, we examined the relationship betw ...[more]

PMID: 28177283

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Project description:Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by β-amyloid (Aβ) accumulation in and around the cerebral blood vessels and capillaries and is highly comorbid with Alzheimer's disease (AD). Familial forms of CAA result from mutations within the Aβ domain of the amyloid β precursor protein (AβPP). Numerous transgenic mouse models have been generated around expression of human AβPP mutants and used to study cerebral amyloid pathologies. While behavioral deficits have been observed in many AβPP transgenic mouse lines, relative to rats, mice are limited in behavioral expression within specific cognitive domains. Recently, we generated a novel rat model, rTg-DI, which expresses Dutch/Iowa familial CAA Aβ in brain, develops progressive and robust accumulation of cerebral microvascular fibrillar Aβ beginning at 3 months, and mimics many pathological features of the human disease. The novel rTg-DI model provides a unique opportunity to evaluate the severity and forms of cognitive deficits that develop over the emergence and progression of CAA pathology. Here, we present an in-depth, longitudinal study aimed to complete a comprehensive assessment detailing phenotypic disease expression through extensive and sophisticated operant testing. Cohorts of rTg-DI and wild-type (WT) rats underwent operant testing from 6 to 12 months of age. Non-operant behavior was assessed prior to operant training at 4 months and after completion of training at 12 months. By 6 months, rTg-DI animals demonstrated speed-accuracy tradeoffs that later manifested across multiple operant tasks. rTg-DI animals also demonstrated delayed reaction times beginning at 7 months. Although non-operant assessments at 4 and 12 months indicated comparable mobility and balance, rTg-DI showed evidence of slowed environmental interaction. Overall, this suggests a form of sensorimotor slowing is the likely core functional impairment in rTg-DI rats and reflects similar deficits observed in human CAA.

Dataset Information

Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline.

Publications

Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline.

Similar Datasets

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