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Cortical microinfarcts and demyelination affect cognition in cases at high risk for dementia

From the Departments of Psychiatry (E.K., A.C., C.B., P.G.) and Geriatrics (G.G., F.R.H.), University of Geneva School of Medicine, and Service of Old Age Psychiatry (P.G.), University of Lausanne School of Medicine, Switzerland; and Fishberg Research Center for Neurobiology and Kastor Neurobiology of Aging Laboratories (P.R.H., C.B.) and Departments of Geriatrics and Adult Development and Ophthalmology (P.R.H.), Mount Sinai School of Medicine, New York, NY.

Address correspondence and reprint requests to Dr. G. Gold, Hôpital des Trois-Chêne, 3 Chemin du Pont-Bochet, 1226 Thônex–Geneva, Switzerland; e-mail: gabriel.gold{at}hcuge.ch; Dr. E. Kövari, Division of Neuropsychiatry, University of Geneva Hospitals, 1225 Chêne-Bourg, Switzerland; e-mail: eniko.kovari{at}hcuge.ch

Objective: To investigate the possible synergistic effect of microvascular lesions with mild Alzheimer disease (AD) pathology in mixed cases.

Methods: We assessed the cognitive impact of cortical microinfarcts, deep white matter and periventricular demyelination, as well as diffuse and focal gliosis in a large series of 43 prospectively evaluated autopsy cases scored Braak neurofibrillary tangle stage III, but without macroscopic vascular pathology or substantial non-AD, nonvascular microscopic lesions. We included bilateral assessment of all types of microvascular lesions and used multivariate models that control for the possible confounding effect of age and amyloid ß-protein (Aß) deposits.

Results: Only cortical microinfarcts and periventricular demyelination were significantly associated with the Clinical Dementia Rating Scale (CDR) score. In a univariate model, the cortical microinfarct score explained 9% of the variability in CDR scores and periventricular demyelination score 7.3%. Aß deposition explained only 3.5% of the CDR variability. In a logistic regression model, both variables were strongly associated with the presence of dementia (R = 0.45; p < 0.05). When the CDR sum of the boxes was used, Aß staging explained 8.9% of cognitive variability, the addition of cortical microinfarct predicted an extra 15.5%, and that of periventricular demyelination an extra 9%.

Conclusions: Cortical microinfarcts and, to a lesser degree, periventricular demyelination contribute to the cognitive decline in individuals at high risk for dementia. Both should be taken into account when defining the neuropathologic criteria for mixed dementia.

*These authors contributed equally to this work.

Supported by grants AG02219 and AG05138 from the NIH, Bethesda, MD (P.R.H.), and the Jérôme Tissières Foundation, Geneva, Switzerland (P.G.).

Disclosure: The authors report no conflicts of interest.

Received Mary 16, 2006. Accepted in final form November 22, 2006.

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