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The transitional association between ?-amyloid pathology and regional brain atrophy.

ABSTRACT: Alzheimer's disease (AD) is characterized by the accumulation of ?-amyloid (A?) associated with brain atrophy and cognitive decline. The functional form to model the association between A? and regional brain atrophy has not been well defined. To determine the relationship between A? and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) A? to identify subjects as A?+ and A?- with a trilinear spline model of CSF A?.One hundred and eighty-three subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSF A? and up to 4 years of longitudinal magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed using mixed-effects regression. Piecewise-linear splines were used to evaluate the nonlinear nature of the association between CSF A? and regional atrophy and to identify points of acceleration of atrophy with respect to A?. Several parameterizations of CSF A? were compared using likelihood ratio tests and the Akaike information criterion. Periods of acceleration of atrophy in which subjects transition from CSF A? negativity to CSF A? positivity were estimated from the spline models and tested for significance.Spline models resulted in better fits for many temporal and parietal regions compared with the dichotomous models. The trilinear model showed that periods of acceleration of atrophy varied greatly by region with early changes seen in the insula, amygdala, precuneus, hippocampus, and other temporal regions, occurring before the clinical threshold for CSF A? positivity.The use of piecewise-linear splines provides an improved model of the nonlinear association between CSF A? and regional atrophy in regions implicated in the progression of AD. The important biological finding of this work is that some brain regions show periods of accelerated volume loss well before the CSF A?42 threshold. This implies that signs of brain atrophy develop before the current conventional definition of "preclinical AD".

SUBMITTER: Insel PS

PROVIDER: S-EPMC4461550 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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The transitional association between β-amyloid pathology and regional brain atrophy.

Insel Philip S PS Mattsson Niklas N Donohue Michael C MC Mackin R Scott RS Aisen Paul S PS Jack Clifford R CR Shaw Leslie M LM Trojanowski John Q JQ Weiner Michael W MW

Alzheimer's & dementia : the journal of the Alzheimer's Association 20141209 10

<h4>Introduction</h4>Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) associated with brain atrophy and cognitive decline. The functional form to model the association between Aβ and regional brain atrophy has not been well defined. To determine the relationship between Aβ and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) Aβ to identify subjects as Aβ+ and Aβ- with a trilinear spline model of CSF Aβ.<h4>Methods</h4>O ...[more]

PMID: 25499535

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Project description:Failure of Alzheimer's disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer's disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

Dataset Information

The transitional association between ?-amyloid pathology and regional brain atrophy.

Publications

The transitional association between β-amyloid pathology and regional brain atrophy.

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