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Evidence for Disease- and Mutation-Specific Pathologic Phenotype

James B. Leverenz, MD; Mark A. Fishel, MD; Elaine R. Peskind, MD; Thomas J. Montine, MD, PhD; David Nochlin, MD; Ellen Steinbart, RN, MA; Murray A. Raskind, MD; Gerard D. Schellenberg, PhD; Thomas D. Bird, MD; Debby Tsuang, MD, MS

Arch Neurol. 2006;63:370-376.

Background  The origin and significance of Lewy bodies and neurites (Lewy body pathology [LBP]) in Alzheimer disease (AD) are poorly understood.

Objective  To examine LBP in the brainstem, limbic cortex, and neocortex of a large number of familial AD cases with mutations in 2 presenilin (PSEN) genes.

Methods  Twenty-five familial AD cases with 9 known PSEN 1 mutations and 14 familial AD cases with a single PSEN 2 mutation (N141I) were examined for LBP using -synuclein immunohistochemistry and sampling of multiple brainstem and cortical regions.

Results  The amygdala was the most vulnerable site for LBP. In fact, virtually all (24 [96%] of 25 cases) of the PSEN 1 mutation cases had LBP in the amygdala. The PSEN 1 mutation cases also had more frequent LBP in the amygdala and neocortex than those with the PSEN 2 mutation. However, within families with a single mutation of either PSEN 1 or PSEN 2, there was frequent variability of the LBP.

Conclusion  These findings suggest that there are genetic influences on the presence of LBP in familial AD as demonstrated by the differences between PSEN 1 and PSEN 2 mutation cases.

Author Affiliations: Parkinson’s Disease (Dr Leverenz), Mental Illness (Drs Leverenz, Peskind, Raskind, Schellenberg, and Tsuang), and Geriatric (Drs Fishel, Peskind, Raskind, Schellenberg, Bird, and Tsuang and Ms Steinbart), Research, Education, and Clinical Centers, Veterans Affairs Puget Sound Health Care System, Seattle, Wash; and Departments of Neurology (Drs Leverenz, Fishel, and Bird) and Psychiatry and Behavioral Sciences (Drs Leverenz, Peskind, Raskind, and Tsuang), Division of Neuropathology, Department of Pathology (Drs Montine and Nochlin), and Division of Gerontology/Geriatrics, Department of Medicine (Dr Schellenberg), University of Washington School of Medicine, Seattle.

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