White matter hyperintensities and regional tau‐PET signal independently contribute to cognitive deficits in symptomatic patients on the Alzheimer’s disease continuum

Abstract

AbstractBackgroundWe examined the associations of white matter hyperintensities (WMH), amyloid‐PET, and tau‐PET with multi‐domain cognitive performance in symptomatic patients on the Alzheimer’s disease (AD) continuum.Method119 amyloid‐PET‐positive patients diagnosed with MCI or AD dementia underwent 3‐Tesla structural MRI, 18F‐flortaucipir (tau)‐PET,11C‐PIB (amyloid)‐PET, and neuropsychological assessment. Standardized uptake value ratio (SUVR) flortaucipir‐ and PIB‐PET images were created using tracer‐specific reference regions and warped to template space. Patients were split based on availability of FLAIR‐MRI (Figure 1). The exploratory sample (n=50; no FLAIR) was used to run voxelwise models to identify regions where flortaucipir‐ and PIB‐PET were associated with episodic memory, executive, language, semantic memory, and visuospatial composite scores. In the validation sample (n=69), WMH were segmented from FLAIR and T1‐MRIs using a two‐step supervised algorithm. Linear regression models assessed the independent contributions of global WMH volume (corrected for intracranial volume and log‐transformed) and cognitive domain‐specific regional PET‐SUVR (derived in the exploratory sample) to each cognitive domain.ResultThe two samples had comparable demographics and clinical characteristics, with relatively young age (mean ∼65.5) and moderate impairment (mean MMSE ∼ 22, Table 1). In the exploratory sample, cognitive scores were associated with regional flortaucipir‐SUVR patterns (Figure 2); PIB‐SUVR was not robustly associated with cognition. In the validation sample, global WMH volume was inversely correlated with global PIB‐SUVR (r=‐.25, p=.04) but not global cortical flortaucipir‐SUVR (r=‐.18, p=.15). Older age predicted lower cortical flortaucipir‐SUVR (r=‐.70, p<.001) and greater WMH volume (r=.46, p<.001). Female sex was specifically associated with greater cortical flortaucipir‐SUVR (d=0.64, p=.01; psdsps ConclusionIn patients at the early clinical stages of AD, tau‐PET and global WMH volume were not associated with each other, but independently contributed to cognitive impairment. These findings emphasize the clinical relevance of cerebrovascular injury in the context of AD pathology, even in younger patients.