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

Abstract

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

Methods: We measured plasma P-tau181 and P-tau217 (Meso Scale Discovery electrochemiluminescence) in patients with TES, mild cognitive impairment/dementia with biomarker-confirmed AD ("AD"), and healthy controls ("HC"). Patients underwent amyloid-beta (Aβ)-PET and a subset underwent tau-PET using [18F]Flortaucipir. We compared plasma P-tau levels controlling for age and sex and also performed AUC analyses to evaluate the accuracy of group differentiation. In patients with TES, 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(+) patients with TES (N = 10), but not Aβ(-) TES, had significantly higher plasma P-tau levels than HC (P-tau181: p < 0.001, d = 1.34; P-tau217: p < 0.001, d = 1.59). There was a trend for Aβ(+) TES having higher plasma P-tau than Aβ(-) TES (P-tau181: p = 0.06, d = 1.06; P-tau217: p = 0.09, 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 = 0.04), whereas classification accuracy of P-tau181 was slightly lower and not statistically significant (AUC = 0.71 [0.46-0.96], p = 0.13). Patients with AD 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 the 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. Currently, there 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 HCs; (2) low plasma P-tau may help identify patients with TES who do not have Alzheimer; and (3) plasma P-tau181 and P-tau217 are not useful biomarkers of patients with TES who do not have AD.

Figure 1. Plasma P-tau Levels in TES Vs HC

Plasma P-tau181 (A) and P-tau217 (B) levels in patients with TES (stratified by Aβ status) vs Aβ-PET negative HCs. A subset of participants with autopsy confirmation of neuropathologic diagnoses (arrows) include (A) High CTE (No ADNC), (B) High CTE + TDP-43 type B with motor neuron disease (No ADNC), (C) Low CTE + Lewy body disease (Low ADNC), and (D) Low CTE (High ADNC). ROC curves depict classification accuracy of plasma P-tau181 (teal) and P-tau217 (dark blue) for differentiating Aβ-PET negative (C) and Aβ-PET positive (D) participants with TES from HCs and differentiating Aβ-PET positive TES from Aβ-PET negative TES (E). *Large effect size (Cohen d > 1.0). ADNC = AD neuropathologic change; HC = healthy control; ROC = receiver operating characteristic; TES = traumatic encephalopathy syndrome.

Figure 2. Cumulative Years of Repetitive Head Trauma Exposure and Plasma P-tau Levels

There was no statistically significant association for P-tau181 (rho = −0.23, p = 0.39) or P-tau217 (rho = −0.28, p = 0.30).

Figure 3. Case Examples of Plasma P-tau and FTP-PET in TES and AD

Four TES participants with negative (N = 2) and positive (N = 2) FTP-PET scans (whole cortex; positivity threshold SUVR > 1.22) are shown with 2 AD participants with positive FTP-PET. Warmer colors represent regions of increased FTP tracer uptake. TES participants with positive FTP-PET exhibited increased tracer uptake in putative AD regions (posterior lateral temporal and parietal cortex), suggesting high likelihood of AD pathology as a primary contributor to clinical symptoms. Dorsal frontal regions, which commonly are associated with early CTE tau deposition, showed elevated FTP tracer uptake in patients both with and without prior repetitive head trauma exposure. All FTP-PET positive participants had positive Aβ-PET scans. These case examples also highlight the higher levels of plasma P-tau181 and P-tau217 (pg/mL) observed in participants with strong evidence of underlying AD pathology based on positive tau and Aβ-PET scans compared with those with no PET evidence of AD tau pathology. This was apparent in participants diagnosed with MCI/dementia due to AD and in participants with extensive prior head trauma diagnosed with TES confirmed to have underlying AD based on PET. Aβ-PET CLs = amyloid-PET Centiloids quantification; AD = Alzheimer disease; CDR-SB = Clinical Dementia Rating Sum of Boxes; CTE = chronic traumatic encephalopathy; FTP = flortaucipir; SUVR = standardized uptake value ratio; TES = traumatic encephalopathy syndrome.