Introduction: Hippocampal sclerosis of aging (HS) is defined by end-stage histological findings, strongly associated with limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). We aimed to characterize features of early HS to refine the understanding of its role within combined pathology. Methods:We studied 159 brain donations from the multimodal Vallecas Alzheimer's Center Study. A staging system (0 to IV) was developed to account for HS progression and analyzed in relation to pre-mortem cognitive and magnetic resonance imaging (MRI) data.Results: Our HS staging system displayed a significant correlation with disease duration, cognitive performance, and combined neuropathologies, especially with LATE. Two-level assessment along the hippocampal longitudinal axis revealed an anteriorposterior gradient of HS severity. In vivo MRI showed focally reduced hippocampal gray matter density as a function of HS staging. Discussion:The association of this staging system with clinical progression and structural differences supports its utility in the characterization and potential in vivo monitoring of HS.

INTRODUCTION: Hippocampal sclerosis of aging (HS) is defined by end-stage histological findings, strongly associated with limbic-predominant age-related TDP-43 encephalopathy (LATE). We aimed to characterize features of early HS to refine the understanding of its role within combined pathology. METHODS: We studied 159 brain donations from the multimodal Vallecas Alzheimers Center Study. A staging system (0 to IV) was developed to account for HS progression and analyzed in relation to pre-mortem cognitive and MRI data. RESULTS: Our HS staging system displayed a significant correlation with disease duration, cognitive performance and combined neuropathologies, especially with LATE. Two-level assessment along the hippocampal longitudinal axis revealed an anterior-posterior gradient of HS severity. In vivo MRI showed focally reduced hippocampal grey matter density as a function of HS staging. DISCUSSION: The association of this staging system with clinical progression and structural differences supports its utility in the characterization and potential in vivo monitoring of HS.

BackgroundThe hippocampus plays a crucial role in memory encoding and retrieval and is highly vulnerable to age‐related pathologic alterations. Hippocampal sclerosis (HS) is a prominent histologic finding in dementia patients which results in worsening of cognitive symptoms but has been so far understudied. Contrary to HS developed in epilepsy, HS of aging specially affects individuals over 85 years old. It is defined by severe neuronal loss and gliosis in CA1 and subiculum areas, which is disproportionate to the expected damage from other pathologies that commonly coexist with HS, such as AD and TDP‐43 pathology.MethodWe studied a cohort of dementia patients who underwent follow‐up at the CIEN Foundation (Madrid, Spain) and selected 45 subjects with in vivo MRI and post‐mortem pathological diagnosis. In this neuropathological evaluation, the presence of gliosis without neuronal loss in relevant areas of the hippocampus has been considered a precursor stage of HS, as suggested by previous studies (Hokkannen et al., Brain Pathol 2018). Based on this criterium, a staging system (0‐IV) for HS has been proposed including precursor stages as part of the pathology spectrum. We have explored relations between this staging system and pre‐mortem anatomical differences via analysis of MRI scans. Specifically, we used SPM software to perform voxel‐based morphometry and FreeSurfer to obtain segmentations of hippocampal subfields.ResultWe found that the extent of HS measured with this staging system is associated with a bilateral reduction in grey matter density in the hippocampus detectable in vivo. These effects are obtained after controlling for other neuropathologies, indicating an independent contribution of HS to atrophy. Additionally, a reduction in volume is observed at most severe stages of HS in all subfields of the hippocampal cortex, rather than exclusively in CA1 and subiculum. We also found volume differences notable at more than 5 years before death via longitudinal analysis of earlier MRI timepoints.ConclusionOur results validate this staging system as an accurate description of HS progression and provide hints towards a clinical diagnosis of HS of aging supported by MRI.