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