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September 10, 2013; 81 (11) Article

Neuropathologic basis of white matter hyperintensity accumulation with advanced age

Deniz Erten-Lyons, Randall Woltjer, Jeffrey Kaye, Nora Mattek, Hiroko H. Dodge, Sarah Green, Huong Tran, Diane B. Howieson, Katherine Wild, Lisa C. Silbert
First published August 9, 2013, DOI: https://doi.org/10.1212/WNL.0b013e3182a43e45
Deniz Erten-Lyons
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.
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Randall Woltjer
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.
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Jeffrey Kaye
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.
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Nora Mattek
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.
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Hiroko H. Dodge
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.
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Sarah Green
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.
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Huong Tran
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.
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Diane B. Howieson
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.
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Katherine Wild
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.
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Lisa C. Silbert
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.
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Citation
Neuropathologic basis of white matter hyperintensity accumulation with advanced age
Deniz Erten-Lyons, Randall Woltjer, Jeffrey Kaye, Nora Mattek, Hiroko H. Dodge, Sarah Green, Huong Tran, Diane B. Howieson, Katherine Wild, Lisa C. Silbert
Neurology Sep 2013, 81 (11) 977-983; DOI: 10.1212/WNL.0b013e3182a43e45

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Abstract

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).

Conclusion: 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.

GLOSSARY

AD=
Alzheimer disease;
CDR=
Clinical Dementia Rating;
CI=
cognitive impairment;
CVD=
cerebrovascular disease;
NFT=
neurofibrillary tangle;
NP=
neuritic plaque;
TE=
echo time;
TR=
repetition time;
WMH=
white matter hyperintensity

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received February 25, 2013.
  • Accepted in final form June 11, 2013.
  • © 2013 American Academy of Neurology
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