White matter hyperintensities associate with pathological stages of neurodegenerative disease.

Abstract

AbstractBackgroundWhite matter hyper‐intensities (WMH) are observed on FLAIR MRI, increase with age and are more prominent in neurodegenerative diseases such as in Alzheimer’s disease (AD) and Parkinson’s disease (PD). The aim of this study was to assess the association between WMH and neuropathological staging of amyloid‐beta, neurofibrillary tangles (NFT) and α‐synuclein (α‐syn).MethodIn‐situ 3T‐MRI 3DT1‐weighted and 3D‐FLAIR data were collected for 77 clinically defined and pathologically‐confirmed brain donors; 31 AD, 21 PD and PD dementia (PDD), and 25 controls. WMH were segmented on FLAIR using an in‐house developed multiview convolutional neural network, followed by manual checking, and volume was obtained with FSL. Fifteen brain regions were dissected at autopsy, immunostained and evaluated for neuropathological diagnosis, including Thal amyloid phase, CAA type, and Braak stages for NFT and α‐syn. Group differences were assessed with linear models (corrected for age, gender, post‐mortem delay), and associations with Spearman and Pearson partial correlations.ResultCompared to controls, WMH load was higher in AD (p<0.001), specifically amnestic AD (p = 0.003) rather than non‐amnestic AD (p = 0.053), and higher in PD (p = 0.016), specifically non‐demented PD (p = 0.015) rather than PDD (p = 1.0). No difference in gender was observed (p = 0.38). Without the influence of pathology (in controls), WMH was associated with age (r = 0.49,p = 0.016).In the whole cohort, WMH was associated with Fazekas score (r = 0.67; p<0.001), normalized brain volume (NBV; r = ‐0.31,p = 0.007), gray matter volume (NGMV; r = ‐0.36,p = 0.002), Thal phase (r = 0.24,p0.034), Braak NFT stage (r = 0.33,p = 0.004), and Braak α‐syn stage (r = 0.27, p0.018).Across controls and AD, WMH associated with NBV (r = ‐0.39,p = 0.004), NGMV (r = ‐0.42,p = 0.002), left and right hippocampal volume (r = ‐0.36,p = 0.008 and r = ‐0.32,p = 0.022), Braak NFT (r = 0.41,p<0.001), Thal phase (r = 0.41,p = 0.002), and CAA (r = 0.34,p = 0.01). Amnestic and non‐amnestic AD showed similar results, except for CAA, which was associated with WMH in non‐amnestic AD only (r = 0.33,p = 0.04).Across controls and PD(D), WMH associated with Braak NFT stage (r = 0.39,p = 0.008) and Braak α‐syn stage (r = 0.60,p<0.001), but not with MRI outcome measures. In this respect PD and PDD showed different results; in PD WMH associated with NGMV (r = ‐0.37,p = 0.031), in PDD with left and right hippocampal volume (r = ‐0.44,p = 0.014 and r = ‐0.44,p = 0.015).ConclusionWMH associate with pathological stages of AD and PD(D), and contributes to MRI atrophy.