Cited by 279Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

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Hippocampal sclerosis in advanced age: clinical and pathological features

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Nelson, Peter T., Schmitt, Frederick A., Lin, Yushun, Abner, Erin L., Jicha, Gregory A., Patel, Ela, Thomason, Paula C., Neltner, Janna H., Smith, Charles D., Santacruz, Karen S., Sonnen, Joshua A., Poon, Leonard W., Gearing, Marla, Green, Robert C., Woodard, John L., Van Eldik, Linda J., Kryscio, Richard J.·2011·Brain

DOI 10.1093/brain/awr053PMC PMC3097889

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Abstract

Hippocampal sclerosis is a relatively common neuropathological finding (∼10% of individuals over the age of 85 years) characterized by cell loss and gliosis in the hippocampus that is not explained by Alzheimer's disease. Hippocampal sclerosis pathology can be associated with different underlying causes, and we refer to hippocampal sclerosis in the aged brain as hippocampal sclerosis associated with ageing. Much remains unknown about hippocampal sclerosis associated with ageing. We combined three different large autopsy cohorts: University of Kentucky Alzheimer's Disease Centre, the Nun Study and the Georgia Centenarian Study to obtain a pool of 1110 patients, all of whom were evaluated neuropathologically at the University of Kentucky. We focused on the subset of cases with neuropathology-confirmed hippocampal sclerosis (n=106). For individuals aged≥95 years at death (n=179 in our sample), each year of life beyond the age of 95 years correlated with increased prevalence of hippocampal sclerosis pathology and decreased prevalence of 'definite' Alzheimer's disease pathology. Aberrant TAR DNA protein 43 immunohistochemistry was seen in 89.9% of hippocampal sclerosis positive patients compared with 9.7% of hippocampal sclerosis negative patients. TAR DNA protein 43 immunohistochemistry can be used to demonstrate that the disease is usually bilateral even when hippocampal sclerosis pathology is not obvious by haematoxylin and eosin stains. TAR DNA protein 43 immunohistochemistry was negative on brain sections from younger individuals (n=10) after hippocampectomy due to seizures, who had pathologically confirmed hippocampal sclerosis. There was no association between cases with hippocampal sclerosis associated with ageing and apolipoprotein E genotype. Age of death and clinical features of hippocampal sclerosis associated with ageing (with or without aberrant TAR DNA protein 43) were distinct from previously published cases of frontotemporal lobar degeneration TAR DNA protein 43. To help sharpen our ability to discriminate patients with hippocampal sclerosis associated with ageing clinically, the longitudinal cognitive profile of 43 patients with hippocampal sclerosis associated with ageing was compared with the profiles of 75 controls matched for age, gender, education level and apolipoprotein E genotype. These individuals were followed from intake assessment, with 8.2 (average) longitudinal cognitive assessments. A neuropsychological profile with relatively high-verbal fluency but low word list recall distinguished the hippocampal sclerosis associated with ageing group at intake (P<0.015) and also 5.5-6.5 years before death (P<0.005). This may provide a first step in clinical differentiation of hippocampal sclerosis associated with ageing versus pure Alzheimer's disease in their earliest stages. In summary, in the largest series of autopsy-verified patients with hippocampal sclerosis to date, we characterized the clinical and pathological features associated with hippocampal sclerosis associated with ageing.

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Authors: Nelson, P. T., Schmitt, F. A., Lin, Y., Abner, E. L., Jicha, G. A., Patel, E., Thomason, P. C., Neltner, J. H., Smith, C. D., Santacruz, K. S., Sonnen, J. A., Poon, L. W., Gearing, M., Green, R. C., Woodard, J. L., Van Eldik, L. J., & Kryscio, R. J.
Affiliations: University of Kentucky (US)
University of Minnesota (US)
University of Washington (US)
University of Georgia (US)
Emory University (US)
Boston University (US)
Wayne State University (US)
ORCID: Nelson, Peter T.
Schmitt, Frederick A.
Abner, Erin L.
Jicha, Gregory A.
Neltner, Janna H.
Smith, Charles D.
Sonnen, Joshua A.
Gearing, Marla
Green, Robert C.
Woodard, John L.
Kryscio, Richard J.
Venue: Brain
Publisher: Oxford University Press (OUP)
Published: 2011-05
Volume: 134
Issue: 5
Pages: 1506-1518
ISSN: 0006-8950 (ISSN-L)
1460-2156
DOI: 10.1093/brain/awr053
PMC: PMC3097889
OpenAlex: W2059980851
Cited by: 279
References: 77
Citations by year: 2026: 13 · 2025: 21 · 2024: 19 · 2023: 24 · 2022: 16 · 2021: 17 · 2020: 18 · 2019: 20 · 2018: 21 · 2017: 22 · 2016: 16 · 2015: 16 · 2014: 16 · 2013: 23 · 2012: 9
FWCI: 12.33
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Brain (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: University of Kentucky
National Institute on Aging (R01AG019241, P01-AG17553, R01 AG19241, P30AG028383, U01AG016976, P01AG017553, K24AG027841)
National Institute of Neurological Disorders and Stroke (R01NS061933, K08NS050110)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Keywords: hippocampal sclerosis, Alzheimer's disease, centenarians, gliosis, APOE genotype, frontotemporal lobar degeneration, cognitive profile, verbal fluency, word list recall, neuropathology, brain aging, differential diagnosis of dementia, Nun Study, Georgia Centenarian Study
MeSH terms: Aged, 80 and over, Aging, Alzheimer Disease, DNA-Binding Proteins, Female, Hippocampus, Humans, Male, Mental Status Schedule, Neuropsychological Tests, Sclerosis, Cohort Studies

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Hippocampal sclerosis in advanced age: clinical and pathological features

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