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Acta Neuropathologica

, Volume 130, Issue 1, pp 21–34 | Cite as

Beta-amyloid deposition in chronic traumatic encephalopathy

  • Thor D. Stein
  • Philip H. Montenigro
  • Victor E. Alvarez
  • Weiming Xia
  • John F. Crary
  • Yorghos Tripodis
  • Daniel H. Daneshvar
  • Jesse Mez
  • Todd Solomon
  • Gaoyuan Meng
  • Caroline A. Kubilus
  • Kerry A. Cormier
  • Steven Meng
  • Katharine Babcock
  • Patrick Kiernan
  • Lauren Murphy
  • Christopher J. Nowinski
  • Brett Martin
  • Diane Dixon
  • Robert A. Stern
  • Robert C. Cantu
  • Neil W. Kowall
  • Ann C. McKee
Original Paper

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.

Keywords

Chronic traumatic encephalopathy Alzheimer’s disease Beta-amyloid Neurodegenerative disorders Dementia Tau 

Abbreviations

AD

Alzheimer’s disease

CTE

Chronic traumatic encephalopathy

CTE-AD

Chronic traumatic encephalopathy with AD

CERAD

Consortium to establish a registry of AD

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

Notes

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.

Supplementary material

401_2015_1435_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 15 kb)
401_2015_1435_MOESM2_ESM.tiff (4.5 mb)
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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Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2015

Authors and Affiliations

  • Thor D. Stein
    • 1
    • 2
    • 3
    • 4
  • Philip H. Montenigro
    • 3
    • 5
  • Victor E. Alvarez
    • 3
    • 6
  • Weiming Xia
    • 2
  • John F. Crary
    • 7
    • 8
    • 9
  • Yorghos Tripodis
    • 10
    • 11
  • Daniel H. Daneshvar
    • 3
    • 6
  • Jesse Mez
    • 3
    • 6
  • Todd Solomon
    • 3
    • 6
  • Gaoyuan Meng
    • 1
  • Caroline A. Kubilus
    • 3
    • 6
  • Kerry A. Cormier
    • 3
    • 6
  • Steven Meng
    • 3
  • Katharine Babcock
    • 3
  • Patrick Kiernan
    • 3
    • 6
  • Lauren Murphy
    • 3
    • 6
  • Christopher J. Nowinski
    • 3
    • 12
  • Brett Martin
    • 3
    • 11
  • Diane Dixon
    • 3
    • 11
  • Robert A. Stern
    • 3
    • 5
    • 6
    • 13
  • Robert C. Cantu
    • 5
    • 12
    • 13
    • 14
  • Neil W. Kowall
    • 1
    • 3
    • 6
  • Ann C. McKee
    • 1
    • 2
    • 3
    • 4
    • 6
  1. 1.VA Boston Healthcare SystemBostonUSA
  2. 2.Department of Veterans Affairs Medical CenterBedfordUSA
  3. 3.Alzheimer’s Disease CenterBoston University School of MedicineBostonUSA
  4. 4.Department of Pathology and Laboratory MedicineBoston University School of MedicineBostonUSA
  5. 5.Department of Anatomy and NeurobiologyBoston University School of MedicineBostonUSA
  6. 6.Department of NeurologyBoston University School of MedicineBostonUSA
  7. 7.Department of PathologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  8. 8.Fishberg Department of NeuroscienceIcahn School of Medicine at Mount SinaiNew YorkUSA
  9. 9.The Ronald M. Loeb Center for Alzheimer’s DiseaseIcahn School of Medicine at Mount SinaiNew YorkUSA
  10. 10.Department of BiostatisticsBoston University School of MedicineBostonUSA
  11. 11.Data Coordinating CenterBoston University School of Public HealthBostonUSA
  12. 12.Sports Legacy InstituteWalthamUSA
  13. 13.Department of NeurosurgeryBoston University School of MedicineBostonUSA
  14. 14.Department of NeurosurgeryEmerson HospitalConcordUSA

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