Neuropathological Correlates of White Matter Hyperintensities in Cerebral Amyloid Angiopathy

Background White matter hyperintensities (WMHs) are frequently observed on magnetic resonance imaging (MRI) in patients with cerebral amyloid angiopathy (CAA). The neuropathological substrates that underlie WMHs in CAA are unclear, and it remains largely unexplored whether the different WMH distribution patterns associated with CAA (posterior confluent and subcortical multispot) reflect alternative pathophysiological mechanisms.Methods and Results We performed a combined in vivo MRI-ex vivo MRI-neuropathological study in patients with definite CAA. Formalin-fixed hemispheres from 19 patients with CAA, most of whom also had in vivo MRI available, underwent 3T MRI, followed by standard neuropathological examination of the hemispheres and targeted neuropathological assessment of WMH patterns. Ex vivo WMH volume was independently associated with CAA severity (P=0.046) but not with arteriolosclerosis (P=0.743). In targeted neuropathological examination, compared with normal-appearing white matter, posterior confluent WMHs were associated with activated microglia (P=0.043) and clasmatodendrosis (P=0.031), a form of astrocytic injury. Trends were found for an association with white matter rarefaction (P=0.074) and arteriolosclerosis (P=0.094). An exploratory descriptive analysis suggested that the histopathological correlates of WMH multispots were similar to those underlying posterior confluent WMHs.Conclusions This study confirmed that vascular amyloid beta severity in the cortex is significantly associated with WMH volume in patients with definite CAA. The histopathological substrates of both posterior confluent and WMH multispots were comparable, suggesting overlapping pathophysiological mechanisms, although these exploratory observations require confirmation in larger studies.