Hippocampal sclerosis of aging

Peter T Nelson MD PhD (Dr. Nelson of the University of Kentucky has no relevant financial relationships to disclose.)
Gregory A Jicha MD PhD (Dr. Jicha of the University of Kentucky received grants from Alltech, Esai, and Lilly as a principal investigator.)
Martin R Farlow MD, editor. (Dr. Farlow of Indiana University received research grant support from Accera, Biogen, Eisai,  Eli Lilly, Genentech, Roche, Lundbeck, Chase Pharmaceuticals and Boehringer Ingelheim; honorariums from Eisai, Forest Laboratories, Pfizer, Eli Lilly and Company and Novartis for speaking engagements; and fees from Accera,  Alltech, Avanir,   Biogen, Eisai Med Res, Inc., Eli Lilly and Company, FORUM Pharmaceuticals, Genentech, Inc., Grifols, Helicon, INC Research, Lundbeck, Medavante, Medivation, Merck,  Neurotrope Biosciences, Novartis, Pfizer, Prana, QR Pharm., Riovant Sciences Inc., Roche, Sanofi-Aventis, Schering-Plough, Toyama Pharm and UCB Pharma for consultancy. His spouse was employed by Eli Lilly.)
Originally released May 24, 2014; expires May 24, 2017

This article includes discussion of hippocampal sclerosis of aging and hippocampal sclerosis dementia. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Hippocampal sclerosis of aging refers to a disease in older individuals characterized by neuronal loss and gliosis in the hippocampal formation that is out of proportion to Alzheimer disease–type pathology. Currently, the terminology is confusing: hippocampal sclerosis of aging is different from other diseases that cause hippocampal sclerosis and notably unrelated to epilepsy-related syndromes that affect younger patients. Hippocampal sclerosis of aging is a neurodegenerative disease strongly associated with TDP-43 pathology in the hippocampal formation. It appears to be most prevalent in the oldest-old: autopsy series indicate that 5% to 30% of nonagenarians have hippocampal sclerosis of aging pathology. The presence of hippocampal sclerosis of aging pathology correlates with significant cognitive impairment, which is often misdiagnosed as Alzheimer disease clinically. The antemortem diagnosis is further confounded by other diseases linked to hippocampal atrophy, including frontotemporal lobar degeneration and cerebrovascular/metabolic-related pathologies. As is the rule for neurodegenerative diseases, there is currently no clinically proven disease-specific therapy for hippocampal sclerosis of aging.

Key points


• Hippocampal sclerosis of aging is a disease that, by definition, involves cell loss and gliosis in the hippocampus of aged persons that is out of proportion to Alzheimer-type plaques and tangles in the same brain areas.


• Hippocampal sclerosis of aging is pathogenetically different from other subtypes of hippocampal sclerosis (linked to epilepsy, hypoxia, hypoglycemia, or frontotemporal lobar degeneration).


• Hippocampal sclerosis of aging has high prevalence in older populations (more than 15% of individuals are past 85 years of age).


• Hippocampal sclerosis of aging is associated with hippocampal TDP-43 pathology.


• As yet, there is not a specific clinical biomarker for hippocampal sclerosis of aging.


• Genetic contribution to risk for hippocampal sclerosis of aging has been established for ABCC9, GRN, and TMEM106B.

Historical note and terminology

Hippocampal sclerosis in aged persons with cognitive impairment has been noted for some time, yet the “border zones” between hippocampal sclerosis pathology seen at autopsy and other diseases linked to dementia (Alzheimer disease, cerebrovascular disease, and frontotemporal lobar degeneration) are still only imperfectly understood (Dickson et al 1994; Jellinger 1994). Prior to, and parallel with, work done at the University of Kentucky, seminal contributions were made by Dennis Dickson, Kurt Jellinger, James Leverenz, Claudia Kawas, Chris Zarow, and others (Pao et al 2011; Zarow et al 2012; Nelson et al 2013).

The term “hippocampal sclerosis of aging” is meant to help distinguish the disease among very old persons from the other diseases that also are termed “hippocampal sclerosis.” However, there is still no specific and universal nomenclature for dementia-linked hippocampal sclerosis among very old individuals. One group refers to a disease category very similar to hippocampal sclerosis of aging as “hippocampal sclerosis,” and some may refer to this condition as “hippocampal sclerosis dementia” (Probst et al 2007; Dickson et al 2010; Pao et al 2011). In a very recent paper, a panel of experts discussed hippocampal sclerosis pathologic classification terminology (Rauramaa et al 2013). This study focused on a patient cohort mostly younger than 80 years at death, which in the authors' experience, shows a pathologic spectrum incompletely overlapping with the boundaries of hippocampal sclerosis of aging pathology. Hippocampal sclerosis of aging is also strongly linked to aberrant TDP-43 pathology (Neumann et al 2006; Amador-Ortiz et al 2007).

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