Abstract
BackgroundWe aimed to systematically describe the burden and distribution of white matter hyperintensities (WMH) and investigate correlations with neuropsychiatric symptoms in pathologically proven Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD).MethodsAutopsy-confirmed cases were identified from the Sunnybrook Dementia Study, including 15 cases of AD and 58 cases of FTLD (22 FTLD-TDP cases; 10 FTLD-Tau [Pick’s] cases; 11 FTLD-Tau Corticobasal Degeneration cases; and 15 FTLD-Tau Progressive Supranuclear Palsy cases). Healthy matched controls (n = 35) were included for comparison purposes. Data analyses included ANCOVA to compare the burden of WMH on antemortem brain MRI between groups, adjusted linear regression models to identify associations between WMH burden and neuropsychiatric symptoms, and image-guided pathology review of selected areas of WMH from each pathologic group.ResultsBurden and regional distribution of WMH differed significantly between neuropathological groups (F5,77 = 2.67, P’ = 0.029), with the FTLD-TDP group having the highest mean volume globally (8032 ± 8889 mm3) and in frontal regions (4897 ± 6163 mm3). The AD group had the highest mean volume in occipital regions (468 ± 420 mm3). Total score on the Neuropsychiatric Inventory correlated with bilateral frontal WMH volume (β = 0.330, P = 0.006), depression correlated with bilateral occipital WMH volume (β = 0.401, P < 0.001), and apathy correlated with bilateral frontal WMH volume (β = 0.311, P = 0.009), all corrected for the false discovery rate. Image-guided neuropathological assessment of selected cases with the highest burden of WMH in each pathologic group revealed presence of severe gliosis, myelin pallor, and axonal loss, but with no distinguishing features indicative of the underlying proteinopathy.ConclusionsThese findings suggest that WMH are associated with neuropsychiatric manifestations in AD and FTLD and that WMH burden and regional distribution in neurodegenerative disorders differ according to the underlying neuropathological processes.
Highlights
We aimed to systematically describe the burden and distribution of white matter hyperintensities (WMH) and investigate correlations with neuropsychiatric symptoms in pathologically proven Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD)
These findings suggest that WMH are associated with neuropsychiatric manifestations in AD and FTLD and that WMH burden and regional distribution in neurodegenerative disorders differ according to the underlying neuropathological processes
No significant differences were present except for, as expected, overall performance on the cognitive tests, on the MiniMental Status Examination (MMSE) and on the Dementia Rating Scale (DRS). These were significantly lower in the pathologic neurodegenerative disease groups compared to the healthy control group (F5,95 = 10.27, P < 0.0001, and F5,90 = 13.42, P < 0.0001, respectively), but did not differ significantly between pathologic neurodegenerative disease groups (F4,61 = 1.69, P = 0.112 and F4,56 = 0.59, P = 0.680 for the mean scores on the MMSE and DRS, respectively)
Summary
We aimed to systematically describe the burden and distribution of white matter hyperintensities (WMH) and investigate correlations with neuropsychiatric symptoms in pathologically proven Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Regional gray matter atrophy has been linked to the clinical expression of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) [1,2,3]. While regional gray matter atrophy represents an important biomarker for these disorders, these changes occur late in their respective pathological cascades and development of other imaging biomarkers is warranted. White matter hyperintensities (WMH) have been associated with cerebrovascular disease, vascular risk factors, and age, and to parallel global and regional cortical atrophy [6].
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