title: Hippocampal α-Synuclein in Dementia with Lewy Bodies Contributes to Memory Impairment and Is Consistent with Spread of Pathology.
abstract: Despite considerable research to uncover them, the anatomic and neuropathologic correlates of memory impairment in dementia with Lewy bodies (DLB) remain unclear. While some studies have implicated Lewy bodies in the neocortex, others have pointed to α-synuclein pathology in the hippocampus. We systematically examined hippocampal Lewy pathology and its distribution in hippocampal subfields in 95 clinically and neuropathologically characterized human cases of DLB, finding that α-synuclein pathology was highest in two hippocampal-related subregions: the CA2 subfield and the entorhinal cortex (EC). While the EC had numerous classic somatic Lewy bodies, CA2 contained mainly Lewy neurites in presumed axon terminals, suggesting the involvement of the EC → CA2 circuitry in the pathogenesis of DLB symptoms. Clinicopathological correlations with measures of verbal and visual memory supported a role for EC Lewy pathology, but not CA2, in causing these memory deficits. Lewy pathology in CA1-the main output region for CA2-correlated best with results from memory testing despite a milder pathology. This result indicates that CA1 may be more functionally relevant than CA2 in the context of memory impairment in DLB. These correlations remained significant after controlling for several factors, including concurrent Alzheimer's pathology (neuritic plaques and neurofibrillary tangles) and the interval between time of testing and time of death. Our data suggest that although hippocampal Lewy pathology in DLB is predominant in CA2 and EC, memory performance correlates most strongly with CA1 burden.SIGNIFICANCE STATEMENTThis study provides a detailed neuropathologic analysis of hippocampal Lewy pathology in human patients with autopsy-confirmed dementia with Lewy bodies. The approach-informed by regional molecular markers, concurrent Alzheimer's pathology analysis, and relevant clinical data-helps tease out the relative contribution of Lewy pathology to memory dysfunction in the disease. Levels of Lewy pathology were found to be highest in the hippocampal CA2 subregion and entorhinal cortex, implicating a potentially overlooked circuit in disease pathogenesis. However, correlation with memory performance was strongest with CA1. This unexpected finding suggests that Lewy pathology must reach a critical burden across hippocampal circuitry to contribute to memory dysfunction beyond that related to other factors, notably coexisting Alzheimer's disease tau pathology.
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093.|Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037.
authors.forename: David H
authors.identifier: 0000-0002-4769-9096
authors.initials: DH
authors.lastname: Adamowicz
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093.|Wisconsin Institute for Medical Research, University of Wisconsin-Madison, Madison, Wisconsin 53705, and.
authors.forename: Subhojit
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, dsalmon@ucsd.edu gage@salk.edu.
authors.forename: David P
authors.identifier: 0000-0003-4533-4090
authors.initials: DP
authors.lastname: Salmon
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Galasko
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093.|Department of Pathology, University of California, San Diego, La Jolla, California 92093.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Hansen
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093.|Department of Pathology, University of California, San Diego, La Jolla, California 92093.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037, dsalmon@ucsd.edu gage@salk.edu.
authors.forename: Fred H
authors.identifier: 0000-0002-0938-4106
authors.initials: FH
authors.lastname: Gage
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D027682:Cation Transport Proteins / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D020961:Lewy Body Disease / Q000150:complications*; D008297:Male; D008569:Memory Disorders / Q000209:etiology* / Q000473:pathology*; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D012044:Regression Analysis; D051843:Synucleins / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C102806:SLC30A3 protein, human; D051843:Synucleins; D051844:alpha-Synuclein
keywords: dementia with Lewy bodies; hippocampus; memory; spread; subregion; α-synuclein