Factors Associated to Progression of Hippocampal Sclerosis: Contribution of a New Staging System

Abstract

AbstractBackgroundHippocampal sclerosis (HS) is a neuropathological condition with 5% to 30% of prevalence in the elderly (Nelson et al., 2013). HS is mostly associated with TDP‐43 proteinopathy, limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (Nelson et al., 2019), and usually coexists with other neurodegenerative disorders like Alzheimer´s (AD) and Lewy body disease (LBD). LATE is a progressive pathology that may combine with HS (LATE_HS+) in its advanced phases. We have developed a staging scheme for HS with a high correlation with TDP‐43 staging. Here we analyze the contribution of this classification system to understand the progression of HS in the context of focal TDP‐43 pathology in the medial temporal lobe (MTL).MethodA full postmortem neuropathological study was performed in 161 brains from a clinicopathological cohort of institutionalized dementia patients (Vallecas Alzheimer’s Center Study) (age at death = 87.4±6.6, sex ratio = 79% females) with a predominant primary diagnosis of AD (77.4%), followed by vascular dementia (11%) and LBD (7.3%), and a high prevalence of comorbid pathologies (TDP‐43 and various tauopathies). Four stages (1‐4) of HS, including early phases (pre‐HS), were applied based on histologic criteria. Demographic, clinical, and neuropathological variables showing correlation with HS stages were analyzed through factorial analysis.ResultSome stage of HS was present in 71.1% of patients, and 24% of them displayed an early HS stage. TDP‐43 inclusions were detected in 67.5% of the patients. Variables associated to HS stages were grouped in 4 factors. While age at death, survival time and MTL atrophy, grouped together (factor 1) explained 23% of total co‐variability, other factors included Braak tau and NIA‐B stages (20%) or alpha‐synuclein stages‐HS stages (4.5%). Interestingly, HS and TDP‐43 stages were also included in factor 1 and seggregated together into a further single factor (18%) as well.ConclusionOur staging scheme for hippocampal sclerosis identifies patients with LATE in early stages of HS, and suggests a complex interaction of factors involved in conversion of LATE_HS‐ to LATE_HS+. While TDP‐43 stages, age, survival time and atrophy stay closer to HS in the explanation of variability, Alzheimer’s tau and Lewy body pathologies appear as secondary co‐factors.