Prevalence, laterality, and comorbidity of hippocampal sclerosis in an autopsy sample

Hippocampal sclerosis (HS) is a common and often asymmetric neuropathological finding among elderly persons who experience progressive memory loss, but its cause is unknown and it is rarely diagnosed during life. In order to improve both understanding and diagnosis of late-life HS, bilateral hippocampi and cerebral hemispheres were reviewed in 130 consecutive autopsy cases drawn from a longitudinal study of subjects with subcortical ischemic vascular dementia (IVD), Alzheimer disease (AD) and normal aging. HS was found in 31 of 130 cases (24.5%). Of these, 45% were bilateral, 32% left-sided, and 23% right-sided. The majority of HS cases involved the entire rostral-caudal extent of the hippocampus. However, in 7 cases HS was focal in nature and was only found at or anterior to the lateral geniculate nucleus. In 77% of cases, HS was accompanied by other types of pathology (‘mixed’ HS), but in 23% of cases it was the sole neuropathologic finding (‘pure’ HS). TDP-43-positive cytoplasmic inclusions were found in dentate granule cells in 93% of all HS cases, 55% of AD cases with no HS, but 0% of IVD cases with no HS. MRI hippocampal volumes were significantly lower in bilateral HS compared to AD (p < 0.001) and in unilateral HS cases compared to cases with intact hippocampi (p < 0.001). Since HS may occur unilaterally in approximately a quarter of cases, its prevalence may be underestimated if only one cerebral hemisphere is examined. The presence of TDP-43 inclusions in HS cases, regardless of accompanying pathologies (e.g., AD, IVD, FTLD), is consistent with an underlying neurodegenerative pathogenetic mechanism. Further studies are warranted to determine whether greater severity of hippocampal atrophy on MRI may assist the clinical differentiation of HS from AD.