TY - JOUR
T1 - Contact sport participation and chronic traumatic encephalopathy are associated with altered severity and distribution of cerebral amyloid angiopathy
AU - Standring, Oliver J.
AU - Friedberg, Jacob
AU - Tripodis, Yorghos
AU - Chua, Alicia S.
AU - Cherry, Jonathan D.
AU - Alvarez, Victor E.
AU - Huber, Bertrand R.
AU - Xia, Weiming
AU - Mez, Jesse
AU - Alosco, Michael L.
AU - Nicks, Raymond
AU - Mahar, Ian
AU - Pothast, Morgan J.
AU - Gardner, Hannah M.
AU - Meng, Gaoyuan
AU - Palmisano, Joseph N.
AU - Martin, Brett M.
AU - Dwyer, Brigid
AU - Kowall, Neil W.
AU - Cantu, Robert C.
AU - Goldstein, Lee E.
AU - Katz, Douglas I.
AU - Stern, Robert A.
AU - McKee, Ann C.
AU - Stein, Thor D.
N1 - Funding Information:
Acknowledgements This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Clinical Sciences Research and Development Merit Award (I01-CX001038); Veterans Affairs Biorepository (BX002466); Alzheimer’s Association (NIRG-305779, NIRG-362697, AARF-17-529888); National Institute of Aging (RF1AG054156, R56AG057768, R01AG057768, K23AG046377, R01AG016495, R01AG033040, K23NS102399); National Institute of Neurological Disorders and Stroke (U01NS086659, F32NS096803, R01NS017950); National Institute of Aging Boston University AD Center (P30AG13846; supplement 0572063345-5); Department of Defense, Chronic Effects of Neurotrauma Consortium (CENC) Award W81XWH-13-2-0095 and Department of Veterans Affairs CENC Award I01-CX001135; National Heart, Lung, and Blood Institute, Framingham Heart Study (N01-HC-25195, HHSN268201500001I); Concussion Legacy Foundation. IM receives funding as a Fonds de Recherche du Québec - Santé (FRQS) postdoctoral scholar. This work was also supported by unrestricted gifts from the Andlinger Foundation and WWE. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We gratefully acknowledge the use of resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, MA), the outreach and recruitment contributions of Dr. Christopher Nowinski from the Concussion Legacy Foundation, and all the individuals whose participation and contributions made this work possible.
Funding Information:
This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Clinical Sciences Research and Development Merit Award (I01-CX001038); Veterans Affairs Biorepository (BX002466); Alzheimer’s Association (NIRG-305779, NIRG-362697, AARF-17-529888); National Institute of Aging (RF1AG054156, R56AG057768, R01AG057768, K23AG046377, R01AG016495, R01AG033040, K23NS102399); National Institute of Neurological Disorders and Stroke (U01NS086659, F32NS096803, R01NS017950); National Institute of Aging Boston University AD Center (P30AG13846; supplement 0572063345-5); Department of Defense, Chronic Effects of Neurotrauma Consortium (CENC) Award W81XWH-13-2-0095 and Department of Veterans Affairs CENC Award I01-CX001135; National Heart, Lung, and Blood Institute, Framingham Heart Study (N01-HC-25195, HHSN268201500001I); Concussion Legacy Foundation. IM receives funding as a Fonds de Recherche du Québec - Santé (FRQS) postdoctoral scholar. This work was also supported by unrestricted gifts from the Andlinger Foundation and WWE. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We gratefully acknowledge the use of resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, MA), the outreach and recruitment contributions of Dr. Christopher Nowinski from the Concussion Legacy Foundation, and all the individuals whose participation and contributions made this work possible.
Funding Information:
& Johnson (New Brunswick, NJ) / Janssen Research & Development, LLC (Raritan, NJ) and Rebiscan, Inc. (Cambridge, MA). He has received funding from the WWE and Ivivi Health Sciences. Robert A. Stern has received research funding from the NFL, the NFL Players Association, and Avid Radiopharmaceuticals, Inc. (Philadelphia, PA,
Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Cerebral amyloid angiopathy (CAA) consists of beta-amyloid deposition in the walls of the cerebrovasculature and is commonly associated with Alzheimer’s disease (AD). However, the association of CAA with repetitive head impacts (RHI) and with chronic traumatic encephalopathy (CTE) is unknown. We evaluated the relationship between RHI from contact sport participation, CTE, and CAA within a group of deceased contact sport athletes (n = 357), a community-based cohort (n = 209), and an AD cohort from Boston University AD Center (n = 241). Unsupervised hierarchal cluster analysis demonstrated a unique cluster (n = 11) with increased CAA in the leptomeningeal vessels compared to the intracortical vessels (p < 0.001) comprised of participants with significantly greater frequencies of CTE (7/11) and history of RHI. Overall, participants with CTE (n = 251) had more prevalent (p < 0.001) and severe (p = 0.010) CAA within the frontal leptomeningeal vessels compared to intracortical vessels. Compared to those with AD, participants with CTE had more severe CAA in frontal than parietal lobes (p < 0.001) and more severe CAA in leptomeningeal than intracortical vessels (p = 0.002). The overall frequency of CAA in participants with CTE was low, and there was no significant association between contact sport participation and the presence of CAA. However, in those with CAA, a history of contact sports was associated with increased CAA severity in the frontal leptomeningeal vessels (OR = 4.01, 95% CI 2.52–6.38, p < 0.001) adjusting for AD, APOE ε4 status, and age. Participants with CAA had increased levels of sulcal tau pathology and decreased levels of the synaptic marker PSD-95 (p’s < 0.05), and CAA was a predictor of dementia (OR = 1.75, 95% CI 1.02–2.99, p = 0.043) adjusting for age, sex, and comorbid pathology. Overall, contact sport participation and CTE were associated with more severe frontal and leptomeningeal CAA, and CAA was independently associated with worse pathological and clinical outcomes.
AB - Cerebral amyloid angiopathy (CAA) consists of beta-amyloid deposition in the walls of the cerebrovasculature and is commonly associated with Alzheimer’s disease (AD). However, the association of CAA with repetitive head impacts (RHI) and with chronic traumatic encephalopathy (CTE) is unknown. We evaluated the relationship between RHI from contact sport participation, CTE, and CAA within a group of deceased contact sport athletes (n = 357), a community-based cohort (n = 209), and an AD cohort from Boston University AD Center (n = 241). Unsupervised hierarchal cluster analysis demonstrated a unique cluster (n = 11) with increased CAA in the leptomeningeal vessels compared to the intracortical vessels (p < 0.001) comprised of participants with significantly greater frequencies of CTE (7/11) and history of RHI. Overall, participants with CTE (n = 251) had more prevalent (p < 0.001) and severe (p = 0.010) CAA within the frontal leptomeningeal vessels compared to intracortical vessels. Compared to those with AD, participants with CTE had more severe CAA in frontal than parietal lobes (p < 0.001) and more severe CAA in leptomeningeal than intracortical vessels (p = 0.002). The overall frequency of CAA in participants with CTE was low, and there was no significant association between contact sport participation and the presence of CAA. However, in those with CAA, a history of contact sports was associated with increased CAA severity in the frontal leptomeningeal vessels (OR = 4.01, 95% CI 2.52–6.38, p < 0.001) adjusting for AD, APOE ε4 status, and age. Participants with CAA had increased levels of sulcal tau pathology and decreased levels of the synaptic marker PSD-95 (p’s < 0.05), and CAA was a predictor of dementia (OR = 1.75, 95% CI 1.02–2.99, p = 0.043) adjusting for age, sex, and comorbid pathology. Overall, contact sport participation and CTE were associated with more severe frontal and leptomeningeal CAA, and CAA was independently associated with worse pathological and clinical outcomes.
KW - Alzheimer’s disease
KW - American football
KW - Cerebral amyloid angiopathy
KW - Chronic traumatic encephalopathy
KW - Mild traumatic brain injury
KW - Repetitive head impacts
UR - http://www.scopus.com/inward/record.url?scp=85067280043&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067280043&partnerID=8YFLogxK
U2 - 10.1007/s00401-019-02031-x
DO - 10.1007/s00401-019-02031-x
M3 - Article
C2 - 31183671
AN - SCOPUS:85067280043
VL - 138
SP - 401
EP - 413
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 3
ER -