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 STATEMENT This 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.

Keywords: dementia with Lewy bodies; hippocampus; memory; spread; subregion; α-synuclein.

Figure 1.

Visualization of hippocampal Lewy pathology in DLB. A–D, Phospho-synuclein staining in a representative case reveals mostly Lewy neurites in CA2 (A), Lewy bodies with surrounding Lewy grains in entorhinal cortex (D), and lighter, mixed staining in CA1 in between (B, C). Insets show 4× and 20× magnification (H&E counterstain).

Figure 2.

Localization of Lewy neurite pathology using molecular markers. A, Lewy pathology, labeled by P-syn staining in green, localizes to CA2 mainly just beyond where mossy fibers from DG, labeled using calbindin in magenta, taper off (20× magnification composite). B, Confirmation using additional markers for mossy fibers and oligomeric α-synuclein: SLC30A3 (ZnT3) in magenta and Syn-O2 in green (20× magnification). C, Subcellular localization using CA2 marker SCGN in magenta and Syn-F2 in green (20× magnification composite, 20× maximum intensity projection for inset).

Figure 3.

Distribution and severity of Lewy pathology show differential regional involvement. A, Heat map of Lewy pathology in hippocampal subfields from DLB cases (n = 95) shows increased burden in area CA2 and entorhinal cortex. The DG is relatively free of pathology by comparison. The color-coded scale is based on average pathology rating per subregion. Major known hippocampal projections are displayed as solid lines, whereas the suspected EC–CA2 circuit is shown as a dashed line (hippocampal diagram adapted with permission from Yang et al., 2008). B, Graphical representation of heat map data. Sub, Subiculum. Error bars indicate ± SE.

Figure 4.

Increasing Lewy pathology burden is associated with decreasing memory performance. A, Relationship between ratings of CA1 Lewy pathology and score on the CVLT Trial 1–5 learning measure (added interpolation line). B, C, Relationship between ratings of CA1 Lewy pathology and score on the Visual Reproduction test in immediate (B) and delay (C) conditions. D, Relationship between ratings of entorhinal cortex Lewy pathology and score on the CVLT Trial 1–5 learning measure. Error bars indicate ± SE.