Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy

Author:

Walker Jamie M12,Richardson Timothy E123,Farrell Kurt456,Iida Megan A456,Foong Chan7,Shang Ping7,Attems Johannes8,Ayalon Gai9,Beach Thomas G10,Bigio Eileen H11,Budson Andrew12,Cairns Nigel J13,Corrada María14,Cortes Etty4,Dickson Dennis W15,Fischer Peter16,Flanagan Margaret E11,Franklin Erin13,Gearing Marla17,Glass Jonathan17,Hansen Lawrence A18,Haroutunian Vahram19,Hof Patrick R456,Honig Lawrence20,Kawas Claudia14,Keene C Dirk21,Kofler Julia22,Kovacs Gabor G16,Lee Edward B23,Lutz Mirjam I24,Mao Qinwen10,Masliah Eliezer18,McKee Ann C12,McMillan Corey T25,Mesulam M Marsel11,Murray Melissa15,Nelson Peter T26,Perrin Richard13,Pham Thao27,Poon Wayne14,Purohit Dushyant P4,Rissman Robert A18,Sakai Kenji28,Sano Mary19,Schneider Julie A29,Stein Thor D12,Teich Andrew F30,Trojanowski John Q23,Troncoso Juan C31,Vonsattel Jean-Paul30,Weintraub Sandra11,Wolk David A25,Woltjer Randall L27,Yamada Masahito28,Yu Lei29,White Charles L7,Crary John F456

Affiliation:

1. From the Department of Pathology, University of Texas Health Science Center, San Antonio, Texas, USA

2. Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, Texas, USA

3. Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York, USA

4. Department of Pathology and Nash Family Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA

5. Neuropathology Brain Bank & Research Core, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

6. Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA

7. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

8. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom

9. Department of Neuroscience, Genentech Inc., South San Francisco, California, USA

10. Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA

11. Department of Pathology, Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

12. Department of Pathology, VA Medical Center & Boston University School of Medicine, Boston, Massachusetts, USA

13. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

14. Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, California, USA

15. Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA

16. Department of Laboratory Medicine and Pathobiology, University of Toronto, Laboratory Medicine Program, University Health Network, and Tanz Centre for Research in Neurodegenerative Disease, Krembil Brain Institute, Toronto, Ontario, Canada

17. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA

18. Departments of Neurosciences and Pathology, University of California, San Diego, La Jolla, California, USA

19. Department of Psychiatry and Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA

20. Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA

21. Department of Pathology, University of Washington, Seattle, Washington, USA

22. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

23. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

24. Institute of Neurology, Medical University of Vienna, Vienna, Austria

25. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

26. Department of Pathology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA

27. Department of Pathology, Oregon Health Sciences University, Portland, Oregon, USA

28. Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

29. Departments of Pathology and Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA

30. Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA

31. Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Abstract

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

Funder

UK Medical Research Council

NIH

Publisher

Oxford University Press (OUP)

Subject

Cellular and Molecular Neuroscience,Neurology (clinical),Neurology,General Medicine,Pathology and Forensic Medicine

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