White matter hyperintensities ‘core feature’ in dementia, Alzheimer’s disease

Increased white matter hyperintensities occurred frequently among patients with behavioral-variant frontotemporal dementia and Alzheimer’s disease in a cross-sectional MRI study published in Neurology.

The study results suggested that white matter hyperintensities (WMH) “are partly independent of vascular pathology and associated with the neurodegenerative process,” according to the researchers.

“WMH are increasingly common with age and interpreted as reflecting small vessel disease. WMH volume is associated with risk for cognitive impairment and dementia, including AD,” Katharine Huynh, BPsych (Hons), of the School of Psychology and the Brain and Mind Center, both at the University of Sydney, and colleagues wrote. “In frontotemporal dementia (FTD), only a handful of cohort and case studies have been conducted, and only in genetic cases of FTD.”

Huynh and colleagues performed a cross-sectional brain MRI study using volumetric and voxel-wise analyses to examine the hypothesis that WMH in behavioral-variant FTD (bvFTD) and AD correlated with markers of disease, including severity, cortical atrophy and cognition. The study cohort comprised 129 patients, including 64 with bvFTD and 65 with AD, and 66 controls.

All patients underwent MRI as well as clinical and neuropsychological exams. The researchers performed genetic screening in 124 participants, including 54 individuals with bvFTD, 44 with AD and 26 controls, and had access to postmortem pathology in 18 cases, including 13 cases of bvFTD and 5 cases of AD. They observed no significant differences in age, sex, years of education and vascular risk across all groups, nor did they see differences in lifetime rates of hypertension, hypercholesterolemia, diabetes and smoking or disease duration. More patients with bvFTD had a strong family history of neurodegenerative disease compared with patients with AD and controls (P < .001).

Study findings showed that total WMH volumes were larger in patients with bvFTD compared with patients with AD and controls. Among patients with bvFTD, WMH volumes correlated with disease severity but not vascular risk. Analyses in bvFTD and AD demonstrated distinct spatial patterns of WMH “that mirrored characteristic patterns of cortical atrophy,” according to Huynh and colleagues.

Regional WMH load correlated with poorer cognitive performance in discrete cognitive domains, including attention and language, among others. Cognitive impairment related to WMH “were shared between syndromes,” according to the researchers, with additional correlations in language and visuospatial deficits observed in bvFTD.

Among patients with bvFTD, 13 of 59 screened demonstrated genetic abnormalities, including C9orf72 (n = 7), GRN (n = 4) and MAPT (n = 2). In AD, two of 44 patients screened displayed genetic mutations, one for PSEN1 and one for MAPT. The researchers found no genetic mutations among healthy controls whom they screened.

Most cases of bvFTD on autopsy (10/13; 76.9%) showed underlying frontotemporal lobar degeneration (FTLD) pathology, including FTLD-tau (n = 6) and FTLD-TDP (n = 4). Other pathologies included AD (2/13; 15.4%) and hippocampal sclerosis pathologies (1/13; 7.7%). The researchers confirmed underlying AD pathology in all cases of AD examined on autopsy (5/5).

“These findings have implications for interpreting the occurrence of WMH in bvFTD and AD,” Huynh and colleagues wrote. “WMH should be viewed as a core feature of bvFTD and AD that can contribute to cognitive deficits, not simply a marker of small vessel disease.”