Brain atrophy and white matter hyperintensities are independently associated with plasma neurofilament light chain in an Asian cohort of patients with mixed pathology

Abstract

AbstractBackgroundRecent studies on subjects with “pure” Alzheimer’s disease (AD) reported significant association between high blood neurofilament light chain (NfL) and AD‐related atrophy and poor cognition, but not with white matter hyperintensities (WMHs). In contrast, studies on non‐demented elderly with cerebral small vessel disease (CSVD) revealed a significant association between blood NfL and magnetic resonance imaging (MRI) markers of SVD including WMHs, lacunes and microbleeds. A major limitation of these studies is the lack of participants with mixed pathology to explore the potential independent and/or combined effects of brain atrophy, CSVD and amyloid burden (Aβ) on blood NfL.MethodThis study included 208 Singaporean participants of an ongoing longitudinal study, including non‐cognitively impaired controls (NCI; n=43), cognitively impaired no dementia (CIND; n=99), AD (n=44) and Vascular dementia (VaD; n=22). The presence of brain atrophy was defined by medial temporal atrophy scores ≥2. CSVD were determined by MRI markers. Brain Aβ was assessed by [11C]‐PiB PET SUVR. Plasma NfL (pNfL) was measured by Single molecule array (Simoa) immunoassay.ResultpNfL concentrations were significantly increased in AD and VaD. In the full cohort, stepwise regression including neuroimaging markers (brain atrophy, WMH, cerebral microbleeds, lacunes and brain Aβ), vascular risk factors (hypertension, hyperlipidemia, diabetes, smoking and APOE ε4 carriership) and demographics (age, gender, education) as independent variables showed that brain atrophy, WMH, age, gender and presence of diabetes to be independently associated with pNfL (all p<0.05). Further univariate general linear models (Fig 1) showed that in the presence of brain atrophy (N+WMH‐) or high WMH (N‐WMH+) alone, pNfL was significantly increased after controlling for age, gender and presence of diabetes (p≤0.007). There was a trend of further increase in pNfL in the presence of both brain atrophy and high WMH burden.ConclusionThe independent associations and potential combined effects of brain atrophy and WMH on pNfL, together with the high prevalence of SVD burden in the elderly, suggests that SVD needs to be considered when interpreting elevated pNfL in elderly patients.