Neuropathologic basis of white matter hyperintensity accumulation with advanced age.
OBJECTIVE
To determine which vascular pathology measure most strongly correlates with white matter hyperintensity (WMH) accumulation over time, and whether Alzheimer disease (AD) neuropathology correlates with WMH accumulation.


METHODS
Sixty-six older persons longitudinally followed as part of an aging study were included for having an autopsy and >1 MRI scan, with last MRI scan within 36 months of death. Mixed-effects models were used to examine the associations between longitudinal WMH accumulation and the following neuropathologic measures: myelin pallor, arteriolosclerosis, microvascular disease, microinfarcts, lacunar infarcts, large-vessel infarcts, atherosclerosis, neurofibrillary tangle rating, and neuritic plaque score. Each measure was included one at a time in the model, adjusted for duration of follow-up and age at death. A final model included measures showing an association with p < 0.1.


RESULTS
Mean age at death was 94.5 years (5.5 SD). In the final mixed-effects models, arteriolosclerosis, myelin pallor, and Braak score remained significantly associated with increased WMH accumulation over time. In post hoc analysis, we found that those with Braak score 5 or 6 were more likely to also have high atherosclerosis present compared with those with Braak score 1 or 2 (p = 0.003).


CONCLUSIONS
Accumulating white matter changes in advanced age are likely driven by small-vessel ischemic disease. Additionally, these results suggest a link between AD pathology and white matter integrity disruption. This may be due to wallerian degeneration secondary to neurodegenerative changes. Alternatively, a shared mechanism, for example ischemia, may lead to both vascular brain injury and neurodegenerative changes of AD. The observed correlation between atherosclerosis and AD pathology supports the latter.
From the Department of Neurology (D.E.-L., J.K., L.C.S.), Veterans Affairs Medical Center, Portland, OR; and Departments of Neurology (D.E.-L., J.K., N.M., H.H.D., D.B.H., K.W., L.C.S.) and Pathology (R.W., S.G., H.T.), Oregon Health & Science University, Portland.
Deniz
D
Erten-Lyons
Randall
R
Woltjer
Jeffrey
J
Kaye
Nora
N
Mattek
Hiroko H
HH
Dodge
Sarah
S
Green
Huong
H
Tran
Diane B
DB
Howieson
Katherine
K
Wild
Lisa C
LC
Silbert
D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D001344:Autopsy; D001921:Brain / Q000473:pathology*; D002561:Cerebrovascular Disorders / Q000473:pathology*; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D016874:Neurofibrillary Tangles / Q000473:pathology; D012189:Retrospective Studies
D001057:Apolipoproteins E