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. 2020;73(1):333-345.
doi: 10.3233/JAD-190687.

Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults

Konstantinos Arfanakis  1   2   3 , Arnold M Evia  1 , Sue E Leurgans  2   4 , Luis F C Cardoso  1 , Arman Kulkarni  1 , Nabil Alqam  1 , Lucas F Lopes  1 , Diego Vieira  1 , David A Bennett  2   4 , Julie A Schneider  2   4   5
Affiliations

Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults

Konstantinos Arfanakis et al. J Alzheimers Dis. 2020.

Abstract

Background: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood.

Objective: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults.

Methods: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies.

Results: WMH burden in the whole group was associated with both vascular and Alzheimer's disease (AD) pathologies: arteriolosclerosis (p < 10-4), gross (p < 10-4), and microscopic infarcts (p = 0.04), and amyloid-β plaques (p = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p = 10-4) and arteriolosclerosis (p < 10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p = 8×10-4) and arteriolosclerosis (p = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p = 0.038) and non-demented (p = 0.006) groups.

Conclusion: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.

Keywords: Cognition; magnetic resonance imaging; pathology; white matter hyperintensities.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

Figures

Figure 1.
Figure 1.. Examples of ex-vivo WMH burden.
Example axial slices of three hemispheres with ex-vivo WMH burden of (A) 1, (B) 2, and (C) 3.
Figure 2.
Figure 2.. Neuropathologic correlates of WMH burden.
Odds of higher ex-vivo WMH burden for different neuropathologies, based on a single model including all neuropathologies. The bars denote 95% confidence intervals (solid bars correspond to p<0.05, and dashed bars correspond to p≥0.05).
Figure 3.
Figure 3.. Participants with higher WMH burden ex-vivo compared to in-vivo have longer antemortem intervals.
Boxplot of the antemortem interval from in-vivo MRI to death for participants with unchanged (left) and higher (right) WMH burden ex-vivo compared to in-vivo. In both groups, the bold horizontal lines correspond to the respective medians, the ends of boxes correspond to the 25% and 75% of the observations, and the dashed bars correspond to the minimum and maximum values. This boxplot does not include participants with in-vivo WMH burden rated at the maximum level of 3, because a higher rating ex-vivo was not possible, regardless of AMI.
See this image and copyright information in PMC

References

    1. de Leeuw FE, de Groot JC, Achten E, Oudkerk M, Ramos LM, Heijboer R, Hofman A, Jolles J, van Gijn J, Breteler MM (2001) Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J. Neurol. Neurosurg. Psychiatry 70, 9–14. - PMC - PubMed
    1. DeCarli C, Massaro J, Harvey D, Hald J, Tullberg M, Au R, Beiser A, D’Agostino R, Wolf PA (2005) Measures of brain morphology and infarction in the framingham heart study: establishing what is normal. Neurobiol. Aging 26, 491–510. - PubMed
    1. Habes M, Sotiras A, Erus G, Toledo JB, Janowitz D, Wolk DA, Shou H, Bryan NR, Doshi J, Völzke H, Schminke U, Hoffmann W, Resnick SM, Grabe HJ, Davatzikos C (2018) White matter lesions: Spatial heterogeneity, links to risk factors, cognition, genetics, and atrophy. Neurology 91, e964–e975. - PMC - PubMed
    1. Scott JA, Braskie MN, Tosun D, Thompson PM, Weiner M, DeCarli C, Carmichael OT, Alzheimer’s Disease Neuroimaging Initiative (2015) Cerebral Amyloid and Hypertension are Independently Associated with White Matter Lesions in Elderly. Front. Aging Neurosci 7, 221. - PMC - PubMed
    1. Dufouil C, Chalmers J, Coskun O, Besançon V, Bousser M-G, Guillon P, MacMahon S, Mazoyer B, Neal B, Woodward M, Tzourio-Mazoyer N, Tzourio C, PROGRESS MRI Substudy Investigators (2005) Effects of Blood Pressure Lowering on Cerebral White Matter Hyperintensities in Patients With Stroke. Circulation 112, 1644–1650. - PubMed

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