Amyloid-β associated cortical thinning in clinically normal elderly

Abstract

Objective: Both amyloid-β (Aβ) deposition and brain atrophy are associated with Alzheimer's disease (AD) and the disease process likely begins many years before symptoms appear. We sought to determine whether clinically normal (CN) older individuals with Aβ deposition revealed by positron emission tomography (PET) imaging using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume reductions in a pattern similar to that seen in AD.

Methods: A total of 119 older individuals (87 CN subjects and 32 patients with mild AD) underwent PiB PET and high-resolution structural magnetic resonance imaging (MRI). Regression models were used to relate PiB retention to cortical thickness and hippocampal volume.

Results: We found that PiB retention in CN subjects was (1) age-related and (2) associated with cortical thickness reductions, particularly in parietal and posterior cingulate regions extending into the precuneus, in a pattern similar to that observed in mild AD. Hippocampal volume reduction was variably related to Aβ deposition.

Interpretation: We conclude that Aβ deposition is associated with a pattern of cortical thickness reduction consistent with AD prior to the development of cognitive impairment.

FIGURE 1

Aβ-associated reduction in cortical thickness in CN subjects and AD patients. Regression coefficients expressing reduction in thickness at each vertex per unit increase in PCC DVR controlling for age (bottom row), and corresponding statistical significance as p value (top row) in CN or AD groups (left or right column, respectively). Only clusters of 3000 or more contiguous vertices with regression coefficients exceeding 0.12mm/DVR are shown on the bottom row of surfaces.

FIGURE 2

Aβ-associated hippocampal volume and regional thickness changes in CN and AD groups. Regression coefficients expressing change in hippocampal volume or regional average thickness per unit increase in PCC DVR controlling for age (age and gender for hippocampal volume), and corresponding 95% confidence intervals and statistical significances (right).

FIGURE 3

Modeling of PCC thickness as a function of PiB retention in CN and AD groups. Least squares fit (solid curve) of thickness-PiB functional relationship based on sigmoid time courses, with the maximum rate of thickness decline later in time than the maximum rate of PiB increase; compare solid (thickness) and dotted (PiB) sigmoids (inset graph). Dashed curves correspond to shorter time lags, long-dashed curves correspond to one-half the best-fit time lag, and short-dashed curves correspond to no lag. The inset shows the underlying sigmoid time courses for PiB (dotted) and thickness at the 2 time lags. As the time lag between thickness and PiB increases, the curvature of the thickness-PiB curve increases. Binding potential (which is equal to DVR − 1) was used as the PiB measure in the modeling since we assumed that PiB BP asymptotes to zero prior to disease onset.