Philippe Desmarais1,2,3,4, Andrew F Gao5, Julia Keith5, Mario Masellis6,7,8,9,10, Krista Lanctôt3,11, Ekaterina Rogaeva4,12, Joel Ramirez2,3, Nathan Herrmann3,11, Donald T Stuss3,4, Sandra E Black2,3,4. 1. Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Room A4 42, Toronto, ON, M4N 3M5, Canada. 2. L.C. Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. 3. Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada. 4. Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada. 5. Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. 6. Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Room A4 42, Toronto, ON, M4N 3M5, Canada. mario.masellis@sunnybrook.ca. 7. L.C. Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. mario.masellis@sunnybrook.ca. 8. Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada. mario.masellis@sunnybrook.ca. 9. Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada. mario.masellis@sunnybrook.ca. 10. Institute of Medical Science, University of Toronto, Toronto, ON, Canada. mario.masellis@sunnybrook.ca. 11. Department of Psychiatry, University of Toronto, Toronto, ON, Canada. 12. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
Abstract
BACKGROUND: 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). METHODS: Autopsy-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. RESULTS: Burden 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. CONCLUSIONS: 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.
BACKGROUND: 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). METHODS: Autopsy-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. RESULTS: Burden 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. CONCLUSIONS: 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.
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