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Hippocampal sclerosis in advanced age: clinical and pathological features
Open accessAbstract
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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“Relatively isolated HS may occur in very old individuals, and in this context it is associated with TDP-43-immunoreactive inclusions and with cognitive impairment [45,47].”
From National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach (2012) · cites this paper as [47]
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“Relatively isolated HS may occur in very old individuals, and in this context it is associated with TDP-43-immunoreactive inclusions and with cognitive impairment [45,47].”
From National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach (2012) · cites this paper as [47]
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Hyman, B. T., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Carrillo, M. C., Dickson, D. W., Duyckaerts, C., Frosch, M. P., Masliah, E., et al. (2012) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.10.007 · Cited by 3,092
Self-citationMontine, T. J., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Dickson, D. W., Duyckaerts, C., Frosch, M. P., Masliah, E., Mirra, S. S., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-011-0910-3 · Cited by 2,894
“Relatively isolated HS may occur in very old individuals, and in this context it is associated with TDP-43–immunoreactive inclusions and with cognitive impairment [45, 47].”
Self-citationNelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050
“Examples of these include hippocampal sclerosis (a prevalent disease that plays a strong deleterious role in extreme old age and is distinct from the disease linked to epilepsy in younger individuals [211]), α-synucleinopathies, hematomas, argyrophilic grain disease, neuropsychiatric disorders and their therapies, fai…”
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Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report
Nelson, P. T., Dickson, D. W., Trojanowski, J. Q., Jack, C. R., Boyle, P. A., Arfanakis, K., Rademakers, R., Alafuzoff, I., Attems, J., Brayne, C., et al. (2019) · Brain · doi:10.1093/brain/awz099 · Cited by 1,547
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Metadata
- 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
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-05
- Volume
- 134
- Issue
- 5
- Pages
- 1506-1518
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- 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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