Plasma P-tau181 and P-tau217 in Patients with Traumatic Encephalopathy Syndrome with and Without Evidence of Alzheimer Disease Pathology

Breton M. Asken, Jeremy A. Tanner, Lawren Vandevrede, William G. Mantyh, Kaitlin B. Casaletto, Adam M. Staffaroni, Renaud La Joie, Leonardo Iaccarino, David Soleimani-Meigooni, Julio C. Rojas, Raquel C. Gardner, Bruce L. Miller, Lea T. Grinberg, Adam L. Boxer, Joel H. Kramer, Gil D. Rabinovici

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Abstract

BACKGROUND: Traumatic encephalopathy syndrome (TES) has overlapping clinical symptoms with Alzheimer's disease (AD). AD pathology commonly co-occurs with chronic traumatic encephalopathy (CTE) pathology. There are currently no validated CTE biomarkers. AD-specific biomarkers like plasma P-tau181 and P-tau217 may help to identify TES patients who have AD pathology.

METHODS: We measured plasma P-tau181 and P-tau217 (Meso Scale Discovery electrochemiluminescence) in patients with TES, MCI/dementia with biomarker-confirmed AD ("AD"), and healthy controls ("HC"). Patients underwent Aβ-PET and a subset underwent tau-PET using [18F]Flortaucipir. We compared plasma P-Tau levels controlling for age and sex and also used AUC analyses to evaluate accuracy of group differentiation. In TES patients, we evaluated associations between plasma P-Tau, years of repetitive head impact exposure, and tau-PET. Four TES patients with autopsy-confirmed CTE were described qualitatively.

RESULTS: The sample included 131 participants (TES, N=18; AD, N=65; HC, N=48). Aβ(+) TES patients (N=10), but not Aβ(-) TES, had significantly higher plasma P-Tau levels than HC (P-tau181: p<.001; d=1.34; P-tau217: p<.001; d=1.59). There was a trend for Aβ(+) TES having higher plasma P-Tau than Aβ(-) TES (P-tau181: p=.06, d=1.06; P-tau217: p=.09, d=0.93). AUC analyses showed good classification of Aβ(+) TES from HC for P-tau181 (AUC=0.87 [0.71-1.00]) and P-tau217 (AUC=0.93 [0.86-1.00]). Plasma P-tau217 showed fair differentiation of Aβ(+) TES from Aβ(-) TES (AUC=0.79 [0.54-1.00], p=.04), while classification accuracy of P-tau181 was slightly lower and not statistically significant (AUC=0.71 [0.46-0.96], p=.13). AD patients had higher tau-PET tracer uptake than Aβ(+) TES and were well differentiated using P-tau181 (AUC=0.81 [0.68-0.94]) and P-tau217 (AUC=0.86 [0.73-0.98]). Plasma P-Tau correlated with tau-PET signal in Aβ(+) TES but not in Aβ(-) TES, and there was no association between plasma P-Tau and years of repetitive head impact exposure. TES patients with severe CTE and no AD at autopsy had low P-tau181 and P-tau217 levels.

DISCUSSION: Measuring P-tau181 and P-tau217 in plasma may be a feasible and scalable fluid biomarker for identifying AD pathology in TES. Low plasma P-Tau levels may be used to increase clinical suspicion of CTE over AD as a primary pathology in TES. There currently is no support for P-tau181 or P-tau217 as in vivo biomarkers of CTE tau. Larger studies of patients with pathologically confirmed CTE are needed.

CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that (1) among patients with TES and abnormal Aβ-PET scans, elevated plasma P-tau can differentiate between affected individuals and healthy controls; (2) low plasma P-tau may help identify TES patients who do not have Alzheimer's and (3) plasma P-tau181 and P-tau 217 are not useful biomarkers of TES patients who do not have Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)E594-E604
JournalNeurology
Volume99
Issue number6
DOIs
StatePublished - Aug 9 2022

Bibliographical note

Funding Information:
The authors thank the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) for sample storage, which receives government support under a cooperative agreement grant (U24AG21886) awarded by the National Institute of Aging (NIA). The authors also thank contributors who collected samples used in this study as well as the following funding sources that have supported our work: NIH ADRC (P30AG062422) and PPG (P01AG019724) to BLM; NIH (R01AG045611, U01AG057195) and Rainwater Charitable Foundation to GDR; NIH (R01(s) AG032289 and AG048234) and Larry L. Hillblom Network Grant (2014-A-004-NET) to JHK; NIH (R01AG060477, R01AG064314, R21AG069252, U54NS100717) to LTG; NIH (R01AG072475) to KBC; NIH (K23AG061253) to AMS; NIH (K23AG059888) to JCR; NIH (U19AG063911, U54NS092089, R01AG038791) to ALB; NIH (K23NS095755), American Federation for Aging Research, and Global Brain Health Institute to RCG; Robert W. Katzman, MD, Clinical Research Training Scholarship in Alzheimer's and Dementia Research to WGM; and NIH (K99AG065501) and Alzheimer's Association (AARF-16-443,577) to RLJ.

Funding Information:
A.M. Staffaroni has served as a consultant for Passage Bio and Takeda. J.C. Rojas reports being a site PI for clinical trials sponsored by Eli Lilly. J.H. Kramer has provided consultation to Biogen. G.D. Rabinovici has served as consultant for Eli Lilly, Eisai, Genentech, Roche, Johnson & Johnson, Merck, and Axon Neurosciences. L.T. Grinberg has received grant funding from Eli Lilly and consulted for CuraSen Inc. A.L. Boxer has served as a consultant for Aeton, Abbvie, AGCT, Amgen, Arkuda, Arvinas, Ascenuron, Eisai, Ionis, Lundbeck, Novartis, Passage BIO, Sangamo, Samumed, Third Rock, Toyama, and UCB. All authors deny conflicts of interest directly pertaining to this study. Go to Neurology.org/N for full disclosures.

Publisher Copyright:
© American Academy of Neurology.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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