Underlying histopathology features of white matter hyperintensities in vascular and neurodegenerative disorders: a systematic review

White matter hyperintensities (WMHs) are a hallmark of cerebral small vessel disease, commonly seen in cognitively normal older adults and patients with neurodegenerative disorders, and are thought to reflect varying degrees of tissue damage. Although FLAIR and T2-weighted MRI remain the best modalities for detecting WMHs, these lesions cannot be reliably distinguished macroscopically from normal appearing white matter, so standard neuropathology protocols do not specifically consider WMH regions unless MRI guidance is available. As a result, histopathological data on WMHs from gold-standard studies remain limited relative to their clinical prevalence. This review aimed to evaluate existing evidence linking MRI-defined WMHs to their underlying histopathology in postmortem brains from patients with various neurodegenerative disorders and aging controls. After a PubMed literature search and screening of abstracts and full texts, we included 45 articles: 10 on normal aging, 16 on Alzheimer's disease, 10 on vascular dementia, and 9 on related conditions. WMHs were histopathologically characterized by myelin loss (including spongiosis), axonal rarefaction, edema, dilated perivascular spaces, gliosis, arteriolosclerosis, and venous collagenosis, all indicative of underlying white matter pathology. The findings overall suggest that WMHs are pathologically heterogeneous, varying according to their anatomical location and distribution. Disease-specific differences in regional distribution, neuroinflammation, vascular pathology, and proteinopathy further contribute to their development and clinical significance, highlighting the need to consider both diagnosis and anatomical location when interpreting the pathological substrates of WMHs.