Abstract
BackgroundAlzheimer'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 FindingsIn this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aß 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/SignificanceCortical 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.
Highlights
Selective neurodegeneration of the cerebral cortex is a characteristic pathological feature of Alzheimer’s disease (AD)
Positron emission tomography (PET) studies examining fibrillar amyloid deposition with Pittsburgh Compound B (PiB) and MRI studies of functional and structural connectivity have observed a significant overlap in a number of neocortical regions that appear preferentially affected in the earliest stages of AD [8,9,10,11,12,13,14]
Though several studies have demonstrated a relationship between post-mortem neurofibrillary tangle (NFT) pathology and structural MRI measures of atrophy [15,16], few have examined in vivo the effect of tau burden on atrophy in heteromodal and limbic cortices
Summary
Selective neurodegeneration of the cerebral cortex is a characteristic pathological feature of Alzheimer’s disease (AD). Positron emission tomography (PET) studies examining fibrillar amyloid deposition with Pittsburgh Compound B (PiB) and MRI studies of functional and structural connectivity have observed a significant overlap in a number of neocortical regions that appear preferentially affected in the earliest stages of AD [8,9,10,11,12,13,14]. Taken collectively, these studies suggest that select heteromodal cortical regions are vulnerable to amyloid deposition and exhibit neuronal dysfunction early in the disease process. In this study, using significant reductions in cerebrospinal fluid (CSF) Aß levels as a surrogate for elevated intra-cranial amyloid plaques [27,28] and significant elevations in CSF phosphorylated tau levels as a surrogate for neocortical NFTs [29], we explored relationships between the presence of Alzheimer’s pathology, thickness of select neocortical regions and the volume of the hippocampus
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