Selective disruption of the cerebral neocortex in Alzheimer's disease

Abstract

Background: Alzheimer's disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown.

Methodology/principal findings: In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aβ levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals.

Conclusions/significance: Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia.

Figure 1. Three-dimensional representations of the 8 ROIs examined in the current study (only right hemisphere is shown).

All of the ROIs visible in the lateral (top) and medial (bottom) views of the gray matter surface.

Figure 2. General linear model analyses demonstrating the prediction of longitudinal hippocampal atrophy (over one year) using baseline cortical thickness for the amyloid positive (top panel) and p-tau positive individuals (bottom panel).

All results are corrected for multiple comparisons by method of Monte Carlo simulation and shown on the gray matter surface (only right hemisphere). The color scale illustrates the magnitude of effect with blue indicating areas of strongest prediction strength.

Figure 3. Bar plots illustrating mean cortical thickness, standardized to Z scores, for the 8 neocortical ROIs amongst the amyloid positive (Aβ+), amyloid negative (Aβ−), p-tau positive (Pτ+), and p-tau negative (Pτ−) older individuals.

Error bars indicate 1 standard error of the mean.