White matter hyperintensities: relationship to amyloid and tau burden

Abstract

Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer's disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer's disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer's biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen's d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.

Keywords: cerebral amyloid angiopathy; cerebral microbleeds; tau burden; white matter hyperintensities.

Figure 1

Results of the voxel-wise multiple regression analyses and frequency maps. (A and B) Areas of positive associations between amyloid-PET SUVR and WMHs adjusted by age, sex, hypertension and tau meta-region of interest. (A) The sensitive mask, and (B) the specific mask. (C) The frequency of WMHs in the study sample, ranging from very infrequent (dark blue colours) to very frequent (green to red colours).

Figure 2

Log (WMH) plotted against log (tau-PET SUVR) in different lobes. There were no significant associations between the two variables after accounting for age, sex, amyloid load and hypertension.

Figure 3

Box plot of WMH in the sensitive and specific masks as a function of two or more lobar CMBs. y-axis is volume of WMH.