Increased regional white matter hyperintensity volume in objectively‐defined subtle cognitive decline and mild cognitive impairment

Abstract

Background White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, less is known about the extent and pattern of WMH in pre‐MCI stages, such as among those with objectively‐defined subtle cognitive decline (Obj‐SCD). Therefore, we aimed to examine regional WMH volume in Obj‐SCD versus those who were cognitively normal (CN) and MCI. Method Six hundred twenty‐one Alzheimer’s Disease Neuroimaging Initiative participants (182 CN; 96 Obj‐SCD; 343 MCI) underwent neuropsychological testing and MRI exams. Cerebrospinal fluid (CSF) data were available for ∼50% of the sample. MCI was classified using Jak/Bondi criteria and Obj‐SCD was classified using criteria proposed by Thomas et al. (2018, 2020). ANCOVA models were used to compare cognitive groups on regional WMHs adjusting for age, sex, and apolipoprotein E (APOE) ɛ4 status. We also ran analyses stratified by CSF phosphorylated tau (p‐tau)/amyloid‐β (Aβ) ratio positivity versus negativity. Result Compared to the CN group, those with Obj‐SCD had greater frontal (p=.036) and temporal WMH (p=.034) with a trend toward greater occipital WMH (p=.052). Those with MCI had greater frontal, temporal, parietal, and occipital WMH (p’s <.01). No significant differences in WMH volume were observed between Obj‐SCD and MCI (p’s >.05). Among p‐tau/Aβ negative individuals, those with Obj‐SCD showed a trend toward greater temporal WMH (p=.053) compared to CN individuals. In addition, the p‐tau/Aβ negative MCI participants showed significantly higher frontal (p=.001), temporal (p=.004), and parietal (p=.027) WMH relative to the CN group. Among p‐tau/Aβ positive individuals, there were no significant group differences in WMH volume. Conclusion Regional WMH vary across cognitive groups. Compared to the CN group, the Obj‐SCD group showed higher temporal and frontal WMH whereas the MCI group showed more widespread WMH increases affecting all lobes, which is in line with their greater cognitive impairment. Notably, these findings do not appear to be driven by p‐tau/Aβ positive individuals. Findings add to growing evidence of associations between Obj‐SCD and imaging biomarkers, providing support for utility of our criteria to capture very subtle cognitive changes.