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. 2020 Oct 13;12(1):e12091.
doi: 10.1002/dad2.12091. eCollection 2020.

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

Mahsa Dadar  1 , Richard Camicioli  2 , Simon Duchesne  1   3 , D Louis Collins  4   5   6 ; Alzheimer's Disease Neuroimaging Initiative
Affiliations

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

Mahsa Dadar et al. Alzheimers Dement (Amst). .

Abstract

Introduction: 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.

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 (Aβ1-42) for 461 participants from the Alzheimer's Disease Neuroimaging Initiative. Linear regressions were used to assess the relationships among baseline WMH, GM, and Aβ1-42 to changes in WMH, GM, Aβ1-42, and cognition at 1-year follow-up.

Results: Baseline WMHs and Aβ1-42 predicted WMH increase and GM atrophy. Baseline WMHs and Aβ1-42 predicted worsening cognition. Only baseline Aβ1-42 predicted change in Aβ1-42.

Discussion: Baseline WMHs lead to greater future GM atrophy and cognitive decline, suggesting that WM damage precedes neurodegeneration and cognitive decline. Baseline Aβ1-42 predicted WMH increase, suggesting a potential role of amyloid in WM damage.

Keywords: Alzheimer's disease; mild cognitive impairment; neurodegenerative disease; small‐vessel disease; white matter hyperintensities.

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Conflict of interest statement

Mahsa Dadar is supported by a scholarship from the Canadian Consortium on Neurodegeneration in Aging in which Simon Duchesne and Richard Camicioli are co‐investigators as well as an Alzheimer Society Research Program (ASRP) postdoctoral award. The Consortium is supported by a grant from the Canadian Institutes of Health Research with funding from several partners including the Alzheimer Society of Canada, Sanofi, and Women's Brain Health Initiative. This work was also supported by grants from the Canadian Institutes of Health Research (MOP‐111169). The authors have no conflicts of interest to report.

Figures

FIGURE 1
FIGURE 1
Study flowchart. Aβ, amyloid beta; DBM, deformation‐based morphometry; FLAIR, fluid‐attenuated inversion recovery; MRI, magnetic resonance imaging; QC, quality control; WMH, white matter hyperintensity
FIGURE 2
FIGURE 2
Baseline measurements and longitudinal changes in WMHs (first row), GM (second row), and ADAS13 (third row). All variables are z‐scored. ΔWMH = WMHFollow‐up–WMHBaseline. ΔGM = GMFollow‐up–GMBaseline. ΔADAS13 = ADAS13Follow‐up–ADAS13Baseline. AD, Alzheimer's disease; ADAS, Alzheimer's Disease Assessment Scale‐13; CSF, cerebrospinal fluid; GM, gray matter; NA, normal aging; MCI, mild cognitive impairment; WMH, white matter hyperintensity
FIGURE 3
FIGURE 3
The relationship between CSF Aβ levels and longitudinal measurements (first row) and change in CSF Aβ levels and baseline measurements (second row). All variables are z‐scored. ΔAmyloid β = Amyloid β Follow‐up‐ Amyloid βBaseline. ΔWMH = WMHFollow‐up‐WMHBaseline. ΔGM = GMFollow‐up‐GMBaseline. ΔADAS13 = ADAS13Follow‐up‐ADAS13Baseline. Aβ, amyloid beta; AD, Alzheimer's disease; ADAS, Alzheimer's Disease Assessment Scale‐13; CSF, cerebrospinal fluid; GM, gray matter; NA, normal aging; MCI, mild cognitive impairment; WMH, white matter hyperintensity
FIGURE 4
FIGURE 4
The model summarizing the relationships among APOE4, vascular risk factors, and baseline and longitudinal measurements. ΔAmyloid β = Amyloid β Follow‐up‐ Amyloid β Baseline. ΔWMH = WMHFollow‐up‐WMHBaseline. ΔGM = GMFollow‐up‐GMBaseline. ΔADAS13 = ADAS13Follow‐up‐ADAS13Baseline. ADAS, Alzheimer's Disease Assessment Scale‐13; APOE, apolipoprotein E; GM, gray matter; WMH; white matter hyperintensity
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