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This Article Figures Only Full Text Full Text (PDF) Take the CME quiz CME: Take the course for this article: Volume 71, Number 11, September 9, 2008 Data Supplement All Versions of this Article: 01.wnl.0000319691.50117.54v1 71/11/804    most recent Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Young, V. G. Articles by Kril, J. J. PubMed PubMed Citation Articles by Young, V. G. Articles by Kril, J. J. Related Collections MRI All Cerebrovascular disease/Stroke All Cognitive Disorders/Dementia

Neuropathologic correlates of white matter hyperintensities

From the Disciplines of Medicine (V.G.Y., J.J.K.) and Pathology (J.J.K.), The University of Sydney; and Prince of Wales Medical Research Institute and the University of New South Wales (G.M.H.), Sydney NSW, Australia.

Address correspondence and reprint requests to Dr. Jillian J. Kril, Department of Pathology, University of Sydney, Sydney, 2006, Australia jilliank{at}med.usyd.edu.au

Objective: White matter hyperintensities (WMH) are commonly seen on neuroimaging scans, but their underlying histopathologic substrate is unclear. The aim of this work was to establish the pathologic correlates of WMH in unselected elderly cases using two study designs. To avoid potential bias from comparisons of different anatomic regions, study 1 compared, region-by-region, the severity of WMH determined in vivo with measures of each of the major white matter (WM) components. Study 2 compared the histopathology of WMH with normal WM.

Methods: Study 1: The periventricular and deep WM regions of three lobes in 23 brains with in vivo MRI scans were investigated using histologic and immunohistochemical stains. The severity of each pathologic measure was correlated with WMH severity determined using the Scheltens scale. Study 2: Lesioned and nonlesioned areas identified by postmortem MRI in the frontal WM of 20 brains were examined histologically and immunohistochemically.

Results: No single pathologic variable correlated with the severity of WMH; however, a multiple stepwise regression analysis revealed that vascular integrity predicted total Scheltens score (β = –0.53, p = 0.01). Comparison of lesioned and nonlesioned areas demonstrated that vascular integrity was reduced in WMH [t(18) = 3.79, p = 0.001]. Blood–brain barrier integrity was also found to be reduced in WMH [t(5) = –5.31, p = 0.003].

Conclusions: White matter hyperintensities (WMH) involve a loss of vascular integrity, confirming the vascular origin of these lesions. This damage to the vasculature may in turn impair blood–brain barrier integrity and be one mechanism by which WMH evolve.

Abbreviations: AD = Alzheimer disease; APP = amyloid precursor protein; dMBP = degraded myelin basic protein; FLAIR = fluid-attenuated inversion recovery; GFAP = glial fibrillary acidic protein; hGLUT-5 = human glucose transporter-5; HLA-DR = human leukocyte antigen-DR domain; PM = postmortem; WM = white matter; WMH = white matter hyperintensities.

Supplemental data at www.neurology.org

e-Pub ahead of print on August 6, 2008, at www.neurology.org.

Supported by a grant from the Australian Brain Foundation and used material from the Australian Brain Donor Programs, which receives support from the National Health and Medical Research Council of Australia. V.Y. is the recipient of an Australian Postgraduate Research Award scholarship. The authors are grateful for the assistance of Patricia Waley and the staff of the Prince of Wales Medical Research Centre Tissue Resource Centre.

Disclosure: The authors report no disclosures.

Received September 25, 2007. Accepted in final form May 1, 2008.

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