Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population

Abstract

Hippocampal neuron loss is a common neuropathological feature in old age with various underlying etiologies. Hippocampal sclerosis of aging (HS-Aging) is neuropathologically characterized by severe CA1 neuronal loss and frequent presence of transactive response DNA-binding protein of 43 kDa (TDP-43) aggregations. Its etiology is unclear and currently no standardized approaches to measure HS-Aging exist. We developed a semi-quantitative protocol, which captures various hippocampal neuron loss patterns, and compared their occurrence in the context of HS-Aging, TDP-43, vascular and tau pathology in 672 brains (TDP-43 staining n = 642/672, 96%) donated for the population-based Cambridge City over-75s Cohort and the Cognitive Function and Ageing Study. HS-Aging was first evaluated independently from the protocol using the most common criteria defined in literature, and then described in detail through examination of neuron loss patterns and associated pathologies. 34 (5%) cases were identified, with a maximum of five pyramidal neurons in each of over half CA1 fields-of-view (x200 magnification), no vascular damage, no neuron loss in CA2-CA4, but consistent TDP-43 neuronal solid inclusions and neurites. We also report focal CA1 neuron loss with vascular pathology to affect predominantly CA1 bordering CA2 (Fisher's exact, P = 0.009), whereas neuron loss in the subicular end of CA1 was associated with TDP-43 inclusions (Fisher's exact, P < 0.001) and high Braak stage (Fisher's exact, P = 0.001). Hippocampal neuron loss in CA4-CA2 was not associated with TDP-43. We conclude that hippocampal neuron loss patterns are associated with different etiologies within CA1, and propose that these patterns can be used to form objective criteria for HS-Aging diagnosis. Finally, based on our results we hypothesize that neuron loss leading to HS-Aging starts from the subicular end of CA1 when it is associated with TDP-43 pathology, and that this neurodegenerative process is likely to be significantly more common than "end-stage" HS-Aging only.

Keywords: TDP-43; hippocampal sclerosis; hippocampus; neuron loss; population study.

Figure 1

HS‐Aging neuropathological characteristics on hematoxylin‐eosin‐staining. A. Hippocampal formation without significant pathological findings. Hippocampal subfields are marked. B. A hippocampus with HS‐Aging shows severe atrophy and complete neuron loss, and gliosis in the whole CA1 area and subiculum (arrowheads). Other hippocampal areas appear intact. C. Microglia and pale eosinophilic astrocytes populate the CA1 region in HS‐Aging. Magnifications: (A, B): 2.5x; scale bar (C): 50 μm. DG = Dentate Gyrus, Sub = Subiculum.

Figure 2

Schematic illustration of the hippocampal neuron loss scoring protocol workflow. Example (A) explains the scoring of a case with extensive severe neuron loss in CA1, and example (B) shows a case with a focal lesion in CA1 bordering CA2.

Figure 3

TDP‐43 inclusions and neurites pathology prevalence and severity in the hippocampus and entorhinal cortex by HS‐Aging status. All HS‐Aging cases were positive for dentate inclusions (A) as well as neurites (B) were significantly more prevalent and severe in all hippocampal regions compared to non‐HS‐Aging cases. Analogous, entorhinal cortex inclusions (C) and neurites (D) prevalence and severity were significantly higher in HS‐Aging than the remainder cohort. **P < 0.001, NSCI = TDP‐43‐positive neuronal solid cytoplasmic inclusions; SN = TDP‐43‐positive short neurites; HS = hippocampal sclerosis of aging.

Figure 4

Focal neuron loss characteristics in different locations of the CA1 sector. (A) Focal neuron loss due to a microinfarct in the beginning of the CA1. The circle marks (B), one field‐of‐view at 200x magnification showing a localized, well circumscribed complete loss of neurons, and a glial scar. (C) Focal neuron loss in the subicular end of CA1, possibly associated with neurodegeneration. Neurons are preserved more proximal of the lesion (arrowheads). The circle marks (D), one field‐of‐view at 200x magnification showing disseminated gliosis and severe neuron loss, without indications of a microinfarct. Scale bars: (A, C): 200 μm; (B, D): 100 μm. (E) Among cases with neuron loss, lesions in the CA2‐bordering third of CA1 are most likely affected with ischemia (*P = 0.009), whereas neuron loss with TDP‐43 inclusions associates with the subicular end of CA1 (**P < 0.001). NSCI = neuronal solid cytoplasmic inclusions.