Acta Neuropathologica

, Volume 126, Issue 2, pp 161–177 | Cite as

Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease

  • Peter T. NelsonEmail author
  • Charles D. Smith
  • Erin L. Abner
  • Bernard J. Wilfred
  • Wang-Xia Wang
  • Janna H. Neltner
  • Michael Baker
  • David W. Fardo
  • Richard J. Kryscio
  • Stephen W. Scheff
  • Gregory A. Jicha
  • Kurt A. Jellinger
  • Linda J. Van Eldik
  • Frederick A. Schmitt


Hippocampal sclerosis of aging (HS-Aging) is a causative factor in a large proportion of elderly dementia cases. The current definition of HS-Aging rests on pathologic criteria: neuronal loss and gliosis in the hippocampal formation that is out of proportion to AD-type pathology. HS-Aging is also strongly associated with TDP-43 pathology. HS-Aging pathology appears to be most prevalent in the oldest-old: autopsy series indicate that 5–30 % of nonagenarians have HS-Aging pathology. Among prior studies, differences in study design have contributed to the study-to-study variability in reported disease prevalence. The presence of HS-Aging pathology correlates with significant cognitive impairment which is often misdiagnosed as AD clinically. The antemortem diagnosis is further confounded by other diseases linked to hippocampal atrophy including frontotemporal lobar degeneration and cerebrovascular pathologies. Recent advances characterizing the neurocognitive profile of HS-Aging patients have begun to provide clues that may help identify living individuals with HS-Aging pathology. Structural brain imaging studies of research subjects followed to autopsy reveal hippocampal atrophy that is substantially greater in people with eventual HS-Aging pathology, compared to those with AD pathology alone. Data are presented from individuals who were followed with neurocognitive and neuroradiologic measurements, followed by neuropathologic evaluation at the University of Kentucky. Finally, we discuss factors that are hypothesized to cause or modify the disease. We conclude that the published literature on HS-Aging provides strong evidence of an important and under-appreciated brain disease of aging. Unfortunately, there is no therapy or preventive strategy currently available.


TDP43 TDP-43 TARDBP Dementia Aging Neuropathology FTLD Epidemiology Genetics Cognition Neuroradiology MRI Hippocampus Pathology Arteriolosclerosis Cerebrovascular Oldest-old 



We are deeply grateful to all of the study participants who make this research possible. The authors thank Sonya Anderson and Ela Patel for technical support; Greg Cooper, MD, Nancy Stiles, MD and Allison Caban-Holt, PhD for the clinical evaluations; and Daron Davis, MD for pathological evaluations. The corresponding author Peter Nelson, MD PhD had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study funding: Research reported in this publication was supported by National Institutes of Health under award numbers P30 AG028383, R01 NR014189, R01 AG038651, TR000117, and S10 RR26489. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Peter T. Nelson
    • 1
    • 2
    Email author
  • Charles D. Smith
    • 1
    • 3
  • Erin L. Abner
    • 1
  • Bernard J. Wilfred
    • 1
  • Wang-Xia Wang
    • 1
  • Janna H. Neltner
    • 2
  • Michael Baker
    • 1
  • David W. Fardo
    • 4
  • Richard J. Kryscio
    • 1
    • 4
    • 5
  • Stephen W. Scheff
    • 1
    • 6
  • Gregory A. Jicha
    • 1
    • 3
  • Kurt A. Jellinger
    • 7
  • Linda J. Van Eldik
    • 1
    • 6
  • Frederick A. Schmitt
    • 1
    • 3
  1. 1.Sanders-Brown Center on AgingUniversity of KentuckyLexingtonUSA
  2. 2.Division of Neuropathology, Department of PathologySanders-Brown Center on Aging, University of KentuckyLexingtonUSA
  3. 3.Department of NeurologyUniversity of KentuckyLexingtonUSA
  4. 4.Department of BiostatisticsUniversity of KentuckyLexingtonUSA
  5. 5.Department of StatisticsUniversity of KentuckyLexingtonUSA
  6. 6.Department of Anatomy and NeurobiologyUniversity of KentuckyLexingtonUSA
  7. 7.Institute of Clinical NeurobiologyViennaAustria

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