Association of white matter hyperintensities with sub‐threshold amyloid accumulation

Abstract

AbstractBackgroundPrevious studies investigating the relationship between amyloid‐β (Aβ) pathology and white matter lesions have led to inconsistent results. A potential explanation for these disparities is the cross‐sectional design of most of these studies, which might have increased the confounding effect of vascular pathology. Here, we used a longitudinal design to investigate whether white matter lesion burden is associated with faster rates of longitudinal Aβ accumulation among cognitively normal older adults without PET‐evidenced Aβ pathology.MethodOne hundred fifty‐nine cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who were Aβ‐negative at baseline were examined. All the participants had a T1 and FLAIR MRI scan at baseline, as well as baseline and at least one follow‐up [18F]florbetapir PET scans acquired in 2‐year intervals for up to 8 years. The Geometric Transfer Matrix method was used to correct for partial volume effects, including those coming from spill‐in counts from the white matter. A previously defined cortical summary region including frontal, parietal, cingulate, and temporal cortices was used to assess global amyloid burden. Standardized Uptake Value Ratios (SUVR) were computed using the cerebellar gray matter as reference region. The association between global and regional white matter hypertense (WMH) burden, and Aβ accumulation was assessed using linear mixed models adjusted by demographics and baseline SUVR.ResultPartial volume correction increased the measured annual rate of change of cortical SUVR (+2.4%) compared to non‐corrected data (+0.5%). There were no significant correlations between baseline WMH and baseline subthreshold cortical SUVR. In the longitudinal analysis, increased baseline cortical SUVR and increased baseline burden of global (p = 0.006), frontal (p = 0.006), and parietal WMH (p = 0.003) were associated with faster amyloid accumulation (Fig.1). WMH‐related Aβ accumulation occurred in parietal, frontal, and, to a lesser extent, cingulate cortices. These results remained unchanged after a sensitivity analysis excluding participants with the highest cortical SUVRs.ConclusionWe demonstrate that a specific spatial distribution of WMH is predictive of future Aβ accumulation among cognitively normal elderly without PET‐detectable Aβ pathology. These findings add to recent studies pointing to a direct relationship between WMH and Aβ pathology in early Alzheimer’s Disease.