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. 2023 Oct;13(10):e3209.
doi: 10.1002/brb3.3209. Epub 2023 Aug 3.

White matter hyperintensities influence distal cortical β-amyloid accumulation in default mode network pathways

Doaa G Ali  1   2 , Ahmed A Bahrani  1   3 , Riham H El Khouli  4 , Brian T Gold  1   5 , Yang Jiang  1   2 , Valentinos Zachariou  5 , Donna M Wilcock  1   6 , Gregory A Jicha  1   2   3
Affiliations

White matter hyperintensities influence distal cortical β-amyloid accumulation in default mode network pathways

Doaa G Ali et al. Brain Behav. 2023 Oct.

Abstract

Background and purpose: Cerebral small vessel disease (SVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Yet, the role of SVD in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that WMHs influence amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults.

Methods: Regional standard uptake value ratios (SUVr) from Aβ-PET and white matter hyperintensity (WMH) volumes from three-dimensional magnetic resonance imaging FLAIR images were analyzed across a sample of 72 clinically unimpaired (mini-mental state examination ≥26), older adults (mean age 74.96 and standard deviation 8.13) from the Alzheimer's Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ-PET SUVr in the connected cortical DMN regions was analyzed using linear regression models adjusted for age, sex, ApoE, and total brain volumes.

Results: The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus were associated with increased regional SUVr in the inferior parietal lobule (p = .011).

Conclusion: The findings suggest that the relation between Aβ in parietal cortex is associated with SVD in downstream white matter (WM) pathways in preclinical AD. The biological relationships and interplay between Aβ and WM microstructure alterations that precede overt WMH development across the continuum of AD progression warrant further study.

Keywords: default mode network; neuroimaging; preclinical Alzheimer's disease; regional standardized uptake value ratio; white matter hyperintensities.

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Conflict of interest statement

The authors do not have any conflicts of interest in relation to the submitted manuscript to disclose.

Figures

FIGURE 1
FIGURE 1
Diagram of the tract‐related white matter hyperintensity (WMH) volume quantification protocol. Total WMH volumes in each tract were calculated by multiplying the registered binary tract to the WMH mask to derive the WMH volume within each specific fiber tract. (a) shows the scatterplot of the fitted regression line of the WMH volumes in SLF as independent variable and IPL SUVr as the dependent variable. (b) shows the scatterplot of the fitted regression line of the WMH volumes in IFOF as independent variable and MPF SUVr as the dependent variable. (c) shows the scatterplot of the fitted regression line of the WMH volumes in cingulum as independent variable and PCC SUVr as the dependent variable. (d) shows the scatterplot of the fitted regression line of the WMH volumes in cingulum. hippocampus tract as independent variable and MTL SUVr as the dependent variable.
FIGURE 2
FIGURE 2
Scatterplots show association between white matter hyperintensity (WMH) volume IN JHU‐ICBM‐tracts atlas and amyloid β (Aβ) burden in default mode network (DMN) regions. Figure 2 shows the scatterplot of the fitted regression line of the WMH volumes as independent variable and regional standard uptake value ratio (SUVr) as the dependent variable. All p‐values are adjusted for the covariates age, sex, ApoE, and total intracranial volumes. R 2 is the proportion of variance in the DMN regions SUVr that was explained by the WMH volumes in JHU‐ICBM‐tracts without any adjustment. CING‐hippo, cingulum–hippocampus tract; IFOF, inferior fronto‐occipital fasciculus; IPL, inferior parietal lobules; MPFC, medial prefrontal cortex; MTL, medial temporal lobe; PCC, posterior cingulate; SLF, superior longitudinal fasciculus. (a) shows the scatterplot of the fitted regression line of the WMH volumes in SLF as independent variable and IPL SUVras the dependent variable. (b) shows the scatterplot of the fitted regression line of the WMH volumes in IFOF as independent variable and MPF SUVr as the dependent variable. (c) shows the scatterplot of the fitted regression line of the WMH volumes in cingulum as independent variable and PCC SUVr as the dependent variable. (d) shows the scatterplot of the fitted regression line of the WMH volumes in cingulum. hippocampus tract as independent variable and MTL SUVras the dependent variable.
FIGURE 3
FIGURE 3
White matter hyperintensities (WMH) influence distal cortical β‐amyloid accumulation in default mode network pathways: (a) this study aimed to test the hypothesis that vascular injury (WMH) distal to the neuronal cell body might upregulate amyloid production in connected cortical regions initiating and or accelerating the pathogenesis of Alzheimer's disease (AD) in cognitively normal older adults with early amyloid β (Aβ) deposition (preclinical AD [pAD]). (b) After the evaluation of the association of WMH volumes in major fiber tracts projecting from cortical default mode network (DMN) regions and Aβ‐PET standard uptake value ratio (SUVr) in the connected cortical DMN regions, we found increased WMH volumes in the superior longitudinal fasciculus (SLF) were associated with increased regional SUVr in the inferior parietal lobule (IPL).
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