The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment

Abstract

Introduction: It is unclear whether white matter hyperintensities (WMHs), magnetic resonance imaging markers of small-vessel cerebrovascular disease, promote neurodegeneration and associated clinical decline in Alzheimer's disease (AD), or simply co-occur with recognized pathogenic processes.

Methods: In 169 patients with mild cognitive impairment, followed for 3 years, we examined the association of (1) baseline regional WMH and cerebral spinal fluid-derived t-tau (total tau) with entorhinal cortex atrophy rates, as a marker of AD-related neurodegeneration, and conversion to AD; and (2) baseline regional WMH with change in t-tau level.

Results: In participants with low baseline t-tau, higher regional WMH volumes were associated with faster entorhinal cortex atrophy. Higher parietal WMH volume predicted conversion to AD in those with high t-tau. Higher parietal and occipital WMH volumes predicted increasing t-tau.

Discussion: WMHs affect AD clinical and pathologic processes both directly and interacting with tau.

Keywords: Alzheimer's disease; CSF tau; Mild cognitive impairment; White matter hyperintensities.

Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Rate of atrophy of entorhinal cortex volume stratified by total CSF t-tau level (Low t-tau top panel, High t-tau bottom panel) as a function of parietal white matter hyperintensity (WMH) volume dichotomized by mean log WMH value (for visualization purposes). Entorhinal cortex atrophy was particularly precipitous among individuals with low baseline CSF t-tau. Error bars are 95% confidence intervals.

Figure 2

Cox regression survival analysis: time to event (conversion from MCI to AD status) as a function of parietal white matter hyperintensity (WMH) volume and t-tau. Compared with participants with low t-tau, those with high t-tau had a 25% increase in the risk of incident AD for every 1 cm3 increase in parietal lobe WMH. High and low t-tau groups are defined by cut score of 93 mg/ml, according to previous studies in ADNI [36]. High and low parietal lobe WMH groups are defined by the mean log parietal lobe WMH volume for graphical purposes only.

Figure 3

Rate of change of CSF total-tau (t-tau) level over 36-months stratified by mean log parietal lobe white matter hyperintensity (WMH) volume (for descriptive purposes). Individuals with higher baseline parietal lobe WMH had more rapid increase in CSF t-tau than those with lower amounts of parietal lobe WMH. Error bars are 95% confidence intervals.

Figure 4

Conceptual model linking WMH to clinical progression in AD. Current pathogenic models of the disease emphasize the precipitating role of Aβ, which leads to tau pathology, resulting in regional atrophy, cognitive decline, and conversion to dementia. Results from this study suggest that regional WMH affect tau directly (a), affect markers of disease progression (i.e., regional atrophy and clinical progression) directly (b), and modify the effect of tau on disease progression (c). Whether or how regional WMH and Aβ interact needs to be elucidated (e).