Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET

Abstract

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aβ) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aβ deposition ( 18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET)in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aβ and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aβ status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration.

Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease

“…Cognitive screening tests used for this study are previously described 30 and included processing speed and executive function (attention switching and working memory) measured with the Trail Making Test (TMT) parts A (TMT-A; N = 115) and B (TMT-B; N = 114), semantic fluency with animal naming ( N = 115), language with Boston Naming Test (BNT; N = 109), and global cognition with the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) ( N = 115). TMT scores were log-transformed to achieve a normal distribution.…”

“…The raw data of both cohorts were processed with the same imaging pipeline. 30 Standardized uptake value ratios (SUVR) were generated in the WMH and NAWM masks within the native T1w space and referenced to the whole cerebellum after removing T1-hypointense regions corresponding to cerebellar WM abnormalities with FreeSurfer. Previous work indicated the relevance of including WM in the reference region for AV45 quantification in dementia cohorts.…”

“…Both groups were matched for vascular risk factors including hypertension, pulse pressure, body mass index, sex, and smoking status. 30 All participants underwent 18 F-AV45 PET, 3 T MRI including 3D T1, FLAIR, and dMRI, and a neuropsychological assessment. MRI-PET and MRI-neuropsychology acquisitions were acquired in close proximity (54 AE 80 and 27 AE 78 days AE standard deviation, respectively).…”

Amyloid-PET of the white matter: relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease

“…Cognitive screening tests used for this study are previously described 27 and included processing speed and executive function (attention switching and working memory) measured with the Trail Making Test (TMT) parts A (TMT-A; N =115) and B (TMT-B; N =114), semantic fluency with animal naming ( N =115), language with Boston Naming Test (BNT; N =109), and global cognition with the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) ( N =115). TMT test scores were log-transformed to achieve a normal distribution.…”

“…Both groups were matched for vascular risk factors including hypertension, pulse pressure, body mass index, sex, and smoking status. 27 All participants underwent 18 F-AV45 PET, 3T MRI including 3D T1, FLAIR, and dMRI, and a neuropsychological assessment. MRI-PET and MRI-neuropsychology acquisitions were acquired in close proximity (54±80 and 27±78 days ± standard deviation, respectively).…”