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The temporal relationships between white matter hyperintensities, neurodegeneration, amyloid beta, and cognition.

ABSTRACT: Introduction:Cognitive decline in Alzheimer's disease is associated with amyloid beta (A?) accumulation, neurodegeneration, and cerebral small vessel disease, but the temporal relationships among these factors is not well established. Methods:Data included white matter hyperintensity (WMH) load, gray matter (GM) atrophy and Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS13) scores for 720 participants and cerebrospinal fluid amyloid (A?1-42) for 461 participants from the Alzheimer's Disease Neuroimaging Initiative. Linear regressions were used to assess the relationships among baseline WMH, GM, and A?1-42 to changes in WMH, GM, A?1-42, and cognition at 1-year follow-up. Results:Baseline WMHs and A?1-42 predicted WMH increase and GM atrophy. Baseline WMHs and A?1-42 predicted worsening cognition. Only baseline A?1-42 predicted change in A?1-42. Discussion:Baseline WMHs lead to greater future GM atrophy and cognitive decline, suggesting that WM damage precedes neurodegeneration and cognitive decline. Baseline A?1-42 predicted WMH increase, suggesting a potential role of amyloid in WM damage.

SUBMITTER: Dadar M

PROVIDER: S-EPMC7552231 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The temporal relationships between white matter hyperintensities, neurodegeneration, amyloid beta, and cognition.

Dadar Mahsa M Camicioli Richard R Duchesne Simon S Collins D Louis DL

Alzheimer's & dementia (Amsterdam, Netherlands) 20201013 1

<h4>Introduction</h4>Cognitive decline in Alzheimer's disease is associated with amyloid beta (Aβ) accumulation, neurodegeneration, and cerebral small vessel disease, but the temporal relationships among these factors is not well established.<h4>Methods</h4>Data included white matter hyperintensity (WMH) load, gray matter (GM) atrophy and Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS13) scores for 720 participants and cerebrospinal fluid amyloid (Aβ1-42) for 461 participants from the ...[more]

PMID: 33083512

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Project description:Background:Patients with Parkinson's disease (PD) present with a broad spectrum of nonmotor features including autonomic disorders. More severe autonomic dysfunction in PD is associated with increased cognitive deficits. The presence of cerebral small-vessel disease, measured by T2-weighted magnetic resonance imaging white matter hyperintensity (WMH) burden, is also observed in patients with PD with faster cognitive decline. Objective:To investigate whether baseline orthostatic hypotension and autonomic dysfunction in early-stage PD affect later cognitive decline via mediation through cerebral small-vessel disease. Methods:De novo PD patients (N = 365) and age-matched controls (N = 174) with baseline T2-weighted/ fluid-attenuated inversion recovery scans were selected from the Parkinson's Progression Markers Initiative. WMHs were automatically segmented. Mediation analysis was used to assess whether WMH load mediates the effect of orthostatic hypotension and autonomic dysfunction (measured by Scales for Outcomes in Parkinson's Disease-Autonomic) on future cognitive decline (measured by Montreal Cognitive Assessment) in an average of 4 years of follow-up. Results:Mediation analysis supported the existence of a full mediation of WMHs on the effect of diastolic orthostatic hypotension in patients with PD and future cognitive decline (average causal mediation effect: ab = -0.032, 95% confidence interval = -0.064 to -0.01, P = 0.01). There was also a partial mediation for overall autonomic dysfunction (ab = -0.027, 95% confidence interval = -0.054 to 0.00, P = 0.02). Conclusions:WMHs fully mediate the effect of diastolic orthostatic hypotension and partially mediate the effect of autonomic dysregulation on future cognitive decline in patients with PD. Our findings support the hypothesis that autonomic dysfunction in early clinical stages predisposes the brain to WMHs through dysregulation of the blood flow in the small vessels. This in turn increases the risk of future cognitive impairment in early PD.

Project description:Abstract White matter hyperintensities (WMHs) have a heterogeneous aetiology, associated with both vascular risk factors and amyloidosis due to Alzheimer’s disease. While spatial distribution of both amyloid and WM lesions carry important information for the underlying pathogenic mechanisms, the regional relationship between these two pathologies and their joint contribution to early cognitive deterioration remains largely unexplored. We included 662 non-demented participants from three Amyloid Imaging to Prevent Alzheimer’s disease (AMYPAD)-affiliated cohorts: EPAD-LCS (N = 176), ALFA+ (N = 310), and EMIF-AD PreclinAD Twin60++ (N = 176). Using PET imaging, cortical amyloid burden was assessed regionally within early accumulating regions (medial orbitofrontal, precuneus, and cuneus) and globally, using the Centiloid method. Regional WMH volume was computed using Bayesian Model Selection. Global associations between WMH, amyloid, and cardiovascular risk scores (Framingham and CAIDE) were assessed using linear models. Partial least square (PLS) regression was used to identify regional associations. Models were adjusted for age, sex, and APOE-e4 status. Individual PLS scores were then related to cognitive performance in 4 domains (attention, memory, executive functioning, and language). While no significant global association was found, the PLS model yielded two components of interest. In the first PLS component, a fronto-parietal WMH pattern was associated with medial orbitofrontal–precuneal amyloid, vascular risk, and age. Component 2 showed a posterior WMH pattern associated with precuneus-cuneus amyloid, less related to age or vascular risk. Component 1 was associated with lower performance in all cognitive domains, while component 2 only with worse memory. In a large pre-dementia population, we observed two distinct patterns of regional associations between WMH and amyloid burden, and demonstrated their joint influence on cognitive processes. These two components could reflect the existence of vascular-dependent and -independent manifestations of WMH-amyloid regional association that might be related to distinct primary pathophysiology. Lorenzini et al. describe two distinct regional patterns of association between white matter hyperintensities (WMHs) and early amyloid deposition, differentially related to vascular risk factors and cognitive performance. These results suggest the existence of vascular-dependent and -independent manifestations of WMH-amyloid regional association that might be related to distinct primary pathophysiology. Graphical Abstract Graphical abstract

Dataset Information

The temporal relationships between white matter hyperintensities, neurodegeneration, amyloid beta, and cognition.

Publications

The temporal relationships between white matter hyperintensities, neurodegeneration, amyloid beta, and cognition.

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