Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

Abstract

The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of 'signature' pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer's disease (AD), Down's syndrome (DS), sporadic Creutzfeldt-Jakob disease, and variant Creutzfeldt-Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick's disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson's disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders.

Hippocampal α-Synuclein in Dementia with Lewy Bodies Contributes to Memory Impairment and Is Consistent with Spread of Pathology

“…As in the DLB Consortium report, 0 corresponds to complete absence of Lewy pathology, 1 corresponds to sparse LBs/LNs, 2 corresponds to Ͼ1 LB/high power field (HPF; equivalent to 0.1 mm 2 ) and sparse LNs, 3 corresponds to Ն4 LBs/HPF and scattered LNs, and 4 corresponds to numerous LBs/LNs (McKeith et al, 2005). We used the same anatomical definitions of hippocampal subregions as Armstrong and Cairns (2015), with the addition of mossy fiber (MF) staining using the marker calbindin to define the CA2/CA3 boundary, which is difficult to distinguish solely based on H&E staining. Plaque and tangle counts were obtained from each subregion through standard UCSD ADRC procedures using Thio-S staining, which also allowed for determination of Braak stage and Thal phase, as described above briefly and in previous studies (Salmon et al, 2015).…”

“…In AD, CA1 is preferentially affected by plaque and tangle pathology, which may account for the severe amnesia that characterizes the disease; tangle pathology first emerges in the transentorhinal cortex, followed by entorhinal cortex (EC), a gateway region between the hippocampus and the rest of cortex (Hyman et al, 1984;Arnold et al, 1991;Braak and Braak, 1995). Lewy pathology is also found in CA1 and EC in DLB (Armstrong and Cairns, 2015), often coexisting with AD pathology (Hansen et al, 1993;Harding and Halliday, 2001;Horimoto et al, 2003;Tsuboi and Dickson, 2005). However, the relative contributions of Lewy and AD pathology in these regions to memory dysfunction remain unknown.…”

“…Although CA1 Lewy pathology may contribute to memory dysfunction, CA1 is less affected by Lewy pathology than other hippocampal subfields in either DLB (Dickson et al, 1994;Armstrong and Cairns, 2015) or sporadic PD (Braak et al, 2003;Bertrand et al, 2004;Armstrong et al, 2013). CA2/3 is usually cited as the predominant site of hippocampal Lewy pathology, due to difficulty in anatomically identifying the boundary between these subfields (Woodhams et al, 1993;Lein et al, 2005).…”

Can neurodegenerative disease be defined by four ‘primary determinants’: anatomy, cells, molecules, and morphology?

“…Nevertheless, there is often selective anatomical degeneration within this group. For example, in FTLD with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43)-immunoreactive inclusions, atrophy of the frontal lobe and temporal pole is seen in 97% of cases, but the hippocampus and subcortical areas are less affected [11,22,69]. In FTD and parkinsonism linked to chromosome 17 (FTDP-17) and CBD, however, degeneration largely affects the globus pallidus and substantia nigra and is accompanied by pathological changes in the cerebral cortex and subcortical areas [143].…”

“…A major problem in attempting to apply this approach on a larger scale, however, is the lack of comparative quantitative data of sufficient scope, detail, quality, and consistency to define all possible cases. Most quan- titative studies of a disorder quantify only signature pathological lesions [11], while others confine observations to a restricted number of anatomical regions or cell types, whereas all aspects of anatomy, cells, molecules, and morphology would need to be measured in each case. Nevertheless, the recent detailed comparative study of a large number of cases of ten neurodegenerative diseases, albeit using semi-quantitative data [25], demonstrates that it is feasible to collect comparative data across a large number of cases and disorders, enabling a descriptive system to be developed based on the four primary determinants.…”