A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer’s Disease Neuropathology

Abstract

Background: White matter hyperintensities (WMH) on magnetic resonance imaging have been postulated to be a core feature of Alzheimer’s disease. Clinicopathological studies are needed to elucidate and confirm this possibility. Objective: This study examined: 1) the association between ante-mortem WMH and autopsy-confirmed Alzheimer’s disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH and ADNP. Methods: The sample included 82 participants from the National Alzheimer’s Coordinating Center’s Data Sets who had quantitated volume of WMH from ante-mortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. Results: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p=0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p=0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts and lacunes (p’s<0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP− participants (p’s<0.04). Conclusions: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer’s disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

White matter hyperintensities and neuropsychiatric symptoms in Alzheimer’s disease and mild cognitive impairment

“…SVD may even be involved early in the disease process by accelerating amyloid deposition in AD as a result of impaired perivascular drainage of amyloid- (Grimmer et al, 2012). Similarly, a recent study found that higher volume of ante-mortem WMH volume predicted greater odds of having autopsy-confirmed AD neuropathology, suggesting SVD may contribute to the severity and progression of AD (Alosco et al, 2018). They identified brain regions where lower GM DBM values were related to higher WMH load, indicating atrophy and CVD pathology may act synergistically in contributing to NPS in MCI and AD.…”

“…WMHs that result from small vessel disease (SVD) have been associated with vascular risk factors, like hypertension (Shim et al, 2015). WMH load has been associated with AD pathology (Alosco et al, 2018;Dadar et al, 2018), and a relationship between SVD and WMH lesions in AD has been reported in other studies (Shim et al, 2015). WMHs of presumed vascular origin have also been associated with NPS in various populations, including AD (Berlow et al, 2010;Dadar, Maranzano, et al, 2017).…”

Association between white matter lesions and cerebral Aβ burden

“…One study used biochemical analysis to show that WMLs are associated with demyelination and degenerative axonal loss, but not ischemic damage, in patients with AD [ 26 ]. Another autopsy study has reported that WMLs are associated with cerebrovascular neuropathology (amyloid angiopathy, microinfarcts, infarcts, lacunes), and tau pathology [ 27 ]. Although the etiology and pathophysiology of WMLs are not fully understood, recent studies have added to the increasing evidence that WMLs are important in the development of AD.…”

Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns

“…7,8 AD and cerebrovascular disease (CVD) share risk factors, 9 and although a definite pathomechanistic interaction is not identified, pertinent findings strongly support a vascular component in AD. 8,[10][11][12] Neuropathological studies have revealed that WMHs are of heterogeneous origin, including amyloid angiopathy, arteriolosclerosis, activated glia and axonal rarefaction, [13][14][15] and thus associated with both amyloid pathology and ischemia. Frontal WMHs were recently related to age and vascular risk.…”