Hippocampal sclerosis: a common pathological feature of dementia in very old (≥80 years of age) humans

Abstract

In a neuropathological study of 81 brains of prospectively studied subjects of 80 years of age or older at the time of death, 13 cases (16%), including 4 men and 9 women, had hippocampal sclerosis (HpScl) affecting the vulnerable region of the hippocampus. In demented subjects of 80 years of age or older, the frequency of HpScl was even higher, 26%. Cases with HpScl had significantly fewer hippocampal senile plaques (SP) and neurofibrillary tangles (NFT) and parahippocampal NFT than cases without HpScl, but did not differ significantly in any of the other measured pathological parameters. Enzyme-linked analysis of synaptic protein immunoreactivity in a subset of 33 cases demonstrated significant decreases in the hippocampus, but not in frontal, temporal, parietal or parahippocampal cortices. All but 1 of the cases with HpScl had Blessed information, memory and concentration scores (BIMC) of 8 or more, and all were considered to be demented. In some patients memory disturbance was disproportionate to deficits in other cognitive areas. All but 4 of the cases with HpScl had many non-neuritic, amyloid plaques in the neocortex meeting NIA criteria for Alzheimer's disease (AD); however, given the advanced age of the subjects, amyloid plaques were considered to represent age-related cerebral amyloid deposition ("pathological aging") in most cases. Only 3 cases had both many SP and NFT in multiple cortical regions consistent with AD. Another case had brain stem and cortical Lewy bodies consistent with diffuse Lewy body disease (DLBD). A few ballooned neurons were present in the limbic cortices in 3 cases, including one case of dementia with argyrophilic grains (DAG) in limbic and orbital frontal and temporal cortices. The 8 cases without AD, DLBD or DAG included 4 cases in which no other obvious cause of dementia was detected and 4 cases in which HpScl was accompanied by either multiple cerebral infarcts or leukoencephalopathy, or both, that could have contributed to dementia. Patients with HpScl had risk factors, clinical signs and post-mortem pathological findings of cardiovascular disease, but due to the high prevalence of these conditions in very old humans, no significant correlation with HpScl was detected. This study demonstrates that HpScl is a common post-mortem finding in demented, but not normal, elderly subjects. It may contribute to. or be a marker for, the increased risk of dementia in subjects with documented cardiovascular disease or a history of myocardial infarction.

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

“…CA1 neuron loss is the key characteristic of old‐age HS‐Aging, as initially described by Dickson et al 18, but little systematic research on the pattern and severity of neuron loss within HS‐Aging has been conducted before this work. Recently, presence of TDP‐43‐pathology in the hippocampus has been used as an additional diagnostic criterion 5, 34.…”

“…Our initial assessment of HS‐Aging in the CC75C cohort was done independently by two raters according to CA1 neuron loss and gliosis descriptions in literature 16, 18, 36, 43, and diagnosis was confirmed by an experienced neuropathologist. Because all three raters agreed on all the cases, the likelihood of false HS‐Aging case inclusion or exclusion is low.…”

“…The original description of HS‐Aging by Dickson et al include “one case [where] the lesion was more extensive and associated with partial cyst formation” 18. Cavitary lesions are discussed controversially in literature ‐ cases with CA1 cavitary lesions are either specifically included 36 or excluded 14, 42, 56, 58, or not addressed in HS‐Aging diagnosis.…”

“…Because we used criteria for definitive severe (end‐stage) HS‐Aging in CC75C according to most common descriptions in literature 16, 18, 36, 43, it is likely, that potential “pre‐HS‐Aging” cases with less neuronal loss were not categorized as HS‐Aging. Our finding of TDP‐43 pathology in all cases that were captured with our neuron loss evaluation protocol for extensive CA1 neuron loss, but who did not fulfill the criteria for HS‐Aging, is suggestive of this situation.…”

“…In contrast, hippocampal sclerosis of aging (HS‐Aging) is considered as a distinct, dementia‐related pathology 18, 31, 35, 56, 58, neuropathologically characterized by severe neuron loss and gliosis in the CA1 area. The subiculum may be affected, but CA4, CA3 and are CA2 spared 16, 41, 43.…”