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Joshua A. Sonnen, MD; Eric B. Larson, MD, MPH; Kiri Brickell, MBChB; Paul K. Crane, MD, MPH; Randall Woltjer, MD, PhD; Thomas J. Montine, MD, PhD; Suzanne Craft, PhD

Arch Neurol. 2009;66(3):(doi:10.1001/archneurol.2008.579).

Background  Diabetes mellitus (DM) increases the risk of dementia in the elderly. However, its underlying mechanisms, its connection with Alzheimer disease and vascular cognitive impairment, and effects of therapy remain unclear.

Objective  To test the hypothesis that DM promotes specific neuropathologic processes that contribute to dementia and that these processes may be suppressed by antidiabetic therapy.

Design  A comprehensive neuropathologic assessment of all cases from a community-based study of incident dementia (Adult Changes in Thought Study) that underwent autopsies (n = 259) and had information on DM status (n = 196). Biochemical analysis was conducted on a subset of these cases with rapidly frozen brain tissue (n = 57).

Participants  Autopsy cases were divided into 4 groups: no DM/no dementia (DM–/dementia–), DM/no dementia (DM+/dementia–), no DM/dementia (DM–/dementia+), and DM/dementia (DM+/dementia+). Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnosis of dementia was assigned through a consensus of experts following biennial cognitive and physical evaluations. Diabetes was diagnosed based on information obtained from participants' extensive medical records.

Results  In cases without dementia (n = 125), neuropathologic and biochemical end points did not differ significantly by DM status. However, we observed 2 patterns of injury in patients with dementia (n = 71) by their DM status. Individuals without DM but with dementia (DM–/dementia+) had a greater amyloid-β peptide load and increased levels of F₂-isoprostanes in the cerebral cortex, while DM+/dementia+ patients had more microvascular infarcts and an increased cortical IL-6 (interleukin 6) concentration. The number of microvascular infarcts was greater in deep cerebral structures in patients with dementia whose diabetes was treated, whereas amyloid plaque load tended to be greater for untreated diabetic patients with dementia.

Conclusions  These novel characterizations of 2 different patterns of cerebral injury in patients with dementia depending on DM status may have etiologic and therapeutic implications.

Published online: January 12, 2009 (doi:10.1001/archneur.2008.579).

Author Affiliations: Departments of Pathology (Drs Sonnen and Montine), Medicine (Dr Larson), and Psychiatry and Behavioral Sciences (Drs Brickell and Craft), University of Washington; Center for Health Studies, Group Health Cooperative (Drs Larson and Crane); and Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System (Dr Craft), Seattle; and Department of Pathology, Oregon Health & Sciences University, Portland (Dr Woltjer).

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