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Beta-amyloid deposition in chronic traumatic encephalopathy

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Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer’s disease (AD). Although trauma has been suggested to increase amyloid β peptide (Aβ) levels, the extent of Aβ deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that Aβ deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that Aβ deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, Aβ deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p < 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with Aβ plaques and those without. Aβ deposition was significantly associated with the presence of the APOE ε4 allele (p = 0.035), older age at symptom onset (p < 0.001), and older age at death (p < 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (β = 2.43, p = 0.018), co-morbid Lewy body disease (OR = 5.01, p = 0.009), and dementia (OR = 4.45, p = 0.012). A subset of subjects met the diagnostic criteria for both CTE and AD, and in these subjects both Aβ plaques and total levels of Aβ1-40 were increased at the depths of the cortical sulcus compared to the gyral crests. Overall, these findings suggest that Aβ deposition is altered and accelerated in a cohort of CTE subjects compared to normal aging and that Aβ is associated with both pathological and clinical progression of CTE independent of age.

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Abbreviations

AD:

Alzheimer’s disease

CTE:

Chronic traumatic encephalopathy

CTE-AD:

Chronic traumatic encephalopathy with AD

CERAD:

Consortium to establish a registry of AD

Aβ:

Amyloid β peptide

APP:

Amyloid precursor protein

NP:

Neuritic plaques

DP:

Diffuse plaques

RTBI:

Repetitive traumatic brain injury

ELISA:

Enzyme-linked immunosorbent assay

OR:

Odds ratio

ptau231:

Tau phosphorylated at threonine 231

PET:

Positron emission tomography

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Acknowledgments

We gratefully acknowledge the use of resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, MA) as well as all the individuals whose participation and contributions made this work possible. This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Clinical Sciences Research and Development Merit Award; Alzheimer’s Association (NIRG-305779); Veterans Affairs Biorepository (CSP 501); Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS) Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B6796-C); National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering (U01NS086659-01); National Institute of Aging Boston University AD Center (P30AG13846; supplement 0572063345-5); Department of Defense Peer Reviewed Alzheimer’s Research Program (DoD-PRARP #13267017); Sports Legacy Institute. This work was also supported by unrestricted gifts from the Andlinger Foundation and WWE.

Conflict of interest

Other than the stated grants the authors have no conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. VA Boston Healthcare System, Boston, MA, 02130, USA

    Thor D. Stein, Gaoyuan Meng, Neil W. Kowall & Ann C. McKee

  2. Department of Veterans Affairs Medical Center, Bedford, MA, 01730, USA

    Thor D. Stein, Weiming Xia & Ann C. McKee

  3. Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA, 02118, USA

    Thor D. Stein, Philip H. Montenigro, Victor E. Alvarez, Daniel H. Daneshvar, Jesse Mez, Todd Solomon, Caroline A. Kubilus, Kerry A. Cormier, Steven Meng, Katharine Babcock, Patrick Kiernan, Lauren Murphy, Christopher J. Nowinski, Brett Martin, Diane Dixon, Robert A. Stern, Neil W. Kowall & Ann C. McKee

  4. Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, 02118, USA

    Thor D. Stein & Ann C. McKee

  5. Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, 02118, USA

    Philip H. Montenigro, Robert A. Stern & Robert C. Cantu

  6. Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA

    Victor E. Alvarez, Daniel H. Daneshvar, Jesse Mez, Todd Solomon, Caroline A. Kubilus, Kerry A. Cormier, Patrick Kiernan, Lauren Murphy, Robert A. Stern, Neil W. Kowall & Ann C. McKee

  7. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    John F. Crary

  8. Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    John F. Crary

  9. The Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    John F. Crary

  10. Department of Biostatistics, Boston University School of Medicine, Boston, MA, 02118, USA

    Yorghos Tripodis

  11. Data Coordinating Center, Boston University School of Public Health, Boston, MA, 02118, USA

    Yorghos Tripodis, Brett Martin & Diane Dixon

  12. Sports Legacy Institute, Waltham, MA, 02451, USA

    Christopher J. Nowinski & Robert C. Cantu

  13. Department of Neurosurgery, Boston University School of Medicine, Boston, MA, 02118, USA

    Robert A. Stern & Robert C. Cantu

  14. Department of Neurosurgery, Emerson Hospital, Concord, MA, 01742, USA

    Robert C. Cantu

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  1. Thor D. Stein
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  2. Philip H. Montenigro
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  3. Victor E. Alvarez
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  19. Diane Dixon
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  20. Robert A. Stern
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Correspondence to Thor D. Stein.

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Supplementary material 1 (DOCX 15 kb)

401_2015_1435_MOESM2_ESM.tiff

Supplementary Figure 1: Levels of tau phosphorylated at threonine 231 (ptau231) in the middle frontal gyrus measured with ELISA. Subjects with CTE and neuritic Aβ plaques (CTE + NPs) had significantly more ptau231 than subjects with CTE alone (p = 0.045). Subjects with CTE and AD (CTE-AD) had the greatest amount of ptau231 and had levels similar to subjects with Braak & Braak stage V-VI AD (AD, n = 4, Student’s t-test) (TIFF 4588 kb)

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Stein, T.D., Montenigro, P.H., Alvarez, V.E. et al. Beta-amyloid deposition in chronic traumatic encephalopathy. Acta Neuropathol 130, 21–34 (2015). https://doi.org/10.1007/s00401-015-1435-y

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