Single- versus two-test criteria for cognitive impairment: associations with CSF and imaging markers in former American football players

Monica T Ly; Caroline Altaras; Yorghos Tripodis; Charles H Adler; Laura J Balcer; Charles Bernick; Henrik Zetterberg; Kaj Blennow; Elaine R Peskind; Sarah J Banks; William B Barr; Jennifer V Wethe; Steve Lenio; Mark W Bondi; Lisa M Delano-Wood; Robert C Cantu; Michael J Coleman; David W Dodick; Jesse Mez; Daniel H Daneshvar; Joseph N Palmisano; Brett Martin; Alexander P Lin; Inga K Koerte; Sylvain Bouix; Jeffrey L Cummings; Eric M Reiman; Martha E Shenton; Robert A Stern; Michael L Alosco

doi:10.1080/13854046.2025.2451828

Single- versus two-test criteria for cognitive impairment: associations with CSF and imaging markers in former American football players

Clin Neuropsychol. 2025 Jan 20:1-25. doi: 10.1080/13854046.2025.2451828. Online ahead of print.

Authors

Monica T Ly^{1

2}, Caroline Altaras^{1

2}, Yorghos Tripodis^{1

2

3}, Charles H Adler⁴, Laura J Balcer⁵, Charles Bernick^{6

7}, Henrik Zetterberg^{8

9

10

11

12

13}, Kaj Blennow^{12

13}, Elaine R Peskind^{14

15}, Sarah J Banks^{16

17}, William B Barr¹⁸, Jennifer V Wethe¹⁹, Steve Lenio^{1

2}, Mark W Bondi^{16

20}, Lisa M Delano-Wood^{16

20}, Robert C Cantu^{1

2}, Michael J Coleman²¹, David W Dodick^{4

22}, Jesse Mez^{1

2

23}, Daniel H Daneshvar^{24

25

26}, Joseph N Palmisano²⁷, Brett Martin²⁷, Alexander P Lin^{21

28}, Inga K Koerte^{21

29}, Sylvain Bouix^{21

30}, Jeffrey L Cummings³¹, Eric M Reiman^{32

33

34

35

36}, Martha E Shenton^{21

37}, Robert A Stern^{1

2

38

39}, Michael L Alosco^{1

2}

Affiliations

¹ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
² Boston University Alzheimer's Disease Research Center and Chronic Traumatic Encephalopathy Center, Boston, MA, USA.
³ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁴ Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.
⁵ Departments of Neurology, Population Health and Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA.
⁶ Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
⁷ Department of Neurology, University of Washington, Seattle, WA, USA.
⁸ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
⁹ UK Dementia Research Institute at UCL, UCL Institute of Neurology, University College London, London, United Kingdom.
¹⁰ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹¹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹³ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
¹⁴ VA Northwest Mental Illness Research, Education, and Clinical Center, Seattle, WA, USA.
¹⁵ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
¹⁶ Department of Psychiatry, University of California San Diego Health, La Jolla, CA, USA.
¹⁷ Department of Neurosciences, University of California, San Diego, CA, USA.
¹⁸ Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
¹⁹ Department of Psychiatry and Psychology, Mayo Clinic School of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.
²⁰ VA San Diego Healthcare System, San Diego, CA, USA.
²¹ Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.
²² Atria Academy of Science and Medicine, New York, NY, USA.
²³ Framingham Heart Study, Framingham, MA, USA.
²⁴ Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, USA.
²⁵ Department of Physical Medicine and Rehabilitation, Massachusetts General Hospital, Boston, MA, USA.
²⁶ Department of Physical Medicine and Rehabilitation, Mass General Brigham-Spaulding Rehabilitation, Charlestown, MA, USA.
²⁷ Biostatistics and Epidemiology Data Analytics Center (BEDAC), Boston University School of Public Health, Boston, MA, USA.
²⁸ Center for Clinical Spectroscopy, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁹ cBRAIN, Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Ludwigs-Maximilians-Universität, Munich, Germany.
³⁰ Department of Software Engineering and Information Technology, École de technologie supérieure, Université du Québec, Montréal, QC, Canada.
³¹ Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA.
³² Banner Alzheimer's Institute, Phoenix, AZ, USA.
³³ Evelyn F. McKnight Brain Institute, University of Arizona, Phoenix, AZ, USA.
³⁴ School of Life Sciences, Arizona State University, Phoenix, AZ, USA.
³⁵ Translational Genomics Research Institute, Phoenix, AZ, USA.
³⁶ Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
³⁷ Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³⁸ Department of Neurosurgery, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
³⁹ Department of Anatomy & Neurobiology and Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.

PMID: 39834028
DOI: 10.1080/13854046.2025.2451828

Abstract

Objective: Cognitive impairment is a core feature of traumatic encephalopathy syndrome (TES), the putative clinical syndrome of chronic traumatic encephalopathy-a neuropathological disease associated with repetitive head impacts (RHI). Careful operationalization of cognitive impairment is essential to improving the diagnostic specificity and accuracy of TES criteria. We compared single- versus two-test criteria for cognitive impairment in their associations with CSF and imaging biomarkers in male former American football players. Method: 169 participants from the DIAGNOSE CTE Research Project completed neuropsychological tests of memory and executive functioning. Cognitive impairment was identified by single-test criteria (z≤-1.5 on one test) and two-test criteria (z<-1 on two tests within a domain). ANCOVAs adjusting for age, race, education, body mass index, word-reading score, and APOE ε4 status assessed whether single- or two-test criteria predicted CSF markers (Aβ_1-42, p-tau₁₈₁, p-tau₁₈₁/Aβ_1-42, total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP]) and MRI markers (hippocampal volume, cortical thickness, white matter hyperintensities). Results: Ninety-nine participants met single-test criteria for cognitive impairment. Sixty-six met two-test criteria. Participants who met two-test criteria had greater exposure to RHI than those who did not (p=.04). Two-test criteria were -associated with higher CSF p-tau₁₈₁/Aβ_1-42 (q=.02) and CSF NfL (q=.02). The association between two-test criteria and CSF NfL remained after excluding amyloid-positive participants (q=.04). Single-test criteria were not associated with any biomarkers (q's>.05). Conclusions: Two-test but not single-test criteria for cognitive impairment were associated with markers of neurodegeneration. Future clinical research in TES may benefit from applying two-test criteria to operationalize cognitive impairment.

Keywords: axonal injury; cognitive impairment; neurodegeneration; repeated head trauma; repetitive head impact; traumatic encephalopathy syndrome.