Nothing Special   »   [go: up one dir, main page]
Skip to main content

Advertisement

Springer Nature Link
Log in

Beta-amyloid deposition in chronic traumatic encephalopathy

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

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

References

  1. Bloom GS (2014) Amyloid-β and tau. JAMA Neurol 71:505. doi:10.1001/jamaneurol.2013.5847

    Article  PubMed  Google Scholar 

  2. Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969. doi:10.1097/NEN.0b013e318232a379

    Article  CAS  PubMed  Google Scholar 

  3. Cloots RJH, Gervaise HMT, van Dommelen JAW, Geers MGD (2008) Biomechanics of traumatic brain injury: influences of the morphologic heterogeneities of the cerebral cortex. Ann Biomed Eng 36:1203–1215. doi:10.1007/s10439-008-9510-3

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Crary JF, Trojanowski JQ, Schneider JA et al (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128:755–766. doi:10.1007/s00401-014-1349-0

    Article  CAS  PubMed  Google Scholar 

  5. Cummings BJ, Satou T, Head E et al (1996) Diffuse plaques contain C-terminal A beta 42 and not A beta 40: evidence from cats and dogs. Neurobiol Aging 17:653–659

    CAS  PubMed  Google Scholar 

  6. DeKosky ST, Abrahamson EE, Ciallella JR et al (2007) Association of increased cortical soluble abeta42 levels with diffuse plaques after severe brain injury in humans. Arch Neurol 64:541–544. doi:10.1001/archneur.64.4.541

    Article  PubMed  Google Scholar 

  7. Falcone GJ, Radmanesh F, Brouwers HB et al (2014) APOE ε variants increase risk of warfarin-related intracerebral hemorrhage. Neurology 83:1139–1146. doi:10.1212/WNL.0000000000000816

    Article  PubMed  Google Scholar 

  8. Gandy S, DeKosky ST (2012) APOE 4 status and traumatic brain injury on the gridiron or the battlefield. Sci Transl Med 4:134ed4. doi:10.1126/scitranslmed.3004274

    Article  PubMed  Google Scholar 

  9. Gentleman SM, Greenberg BD, Savage MJ et al (1997) A beta 42 is the predominant form of amyloid beta-protein in the brains of short-term survivors of head injury. Neuroreport 8:1519–1522

    Article  CAS  PubMed  Google Scholar 

  10. Goldstein LE, Fisher AM, Tagge CA et al (2012) Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med 4:134ra60. doi:10.1126/scitranslmed.3003716

    PubMed Central  PubMed  Google Scholar 

  11. Gomperts SN, Locascio JJ, Marquie M et al (2012) Brain amyloid and cognition in Lewy body diseases. Mov Disord 27:965–973. doi:10.1002/mds.25048

    Article  PubMed Central  PubMed  Google Scholar 

  12. Güntert A, Döbeli H, Bohrmann B (2006) High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain. Neuroscience 143:461–475. doi:10.1016/j.neuroscience.2006.08.027

    Article  PubMed  Google Scholar 

  13. Heyman A, Wilkinson WE, Stafford JA et al (1984) Alzheimer’s disease: a study of epidemiological aspects. Ann Neurol 15:335–341. doi:10.1002/ana.410150406

    Article  CAS  PubMed  Google Scholar 

  14. Howlett DR, Hortobágyi T, Francis PT (2013) Clusterin associates specifically with Aβ40 in Alzheimer’s disease brain tissue. Brain Pathol 23:623–632. doi:10.1111/bpa.12057

    Article  CAS  PubMed  Google Scholar 

  15. Hyman BT, Phelps CH, Beach TG et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13. doi:10.1016/j.jalz.2011.10.007

    Article  PubMed Central  PubMed  Google Scholar 

  16. Ikonomovic MD, Uryu K, Abrahamson EE et al (2004) Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol 190:192–203. doi:10.1016/j.expneurol.2004.06.011

    Article  CAS  PubMed  Google Scholar 

  17. Johnson VE, Stewart W, Smith DH (2010) Traumatic brain injury and amyloid-β pathology: a link to Alzheimer’s disease? Nat Rev Neurosci 11:361–370. doi:10.1038/nrn2808

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Johnson VE, Stewart W, Smith DH (2012) Widespread τ and amyloid-β pathology many years after a single traumatic brain injury in humans. Brain Pathol 22:142–149. doi:10.1111/j.1750-3639.2011.00513.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Jordan BD, Relkin NR, Ravdin LD et al (1997) Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA 278:136–140

    Article  CAS  PubMed  Google Scholar 

  20. Kalaitzakis ME, Pearce RKB (2009) The morbid anatomy of dementia in Parkinson’s disease. Acta Neuropathol 118:587–598. doi:10.1007/s00401-009-0597-x

    Article  CAS  PubMed  Google Scholar 

  21. Katsnelson A (2011) Gene tests for brain injury still far from the football field. Nat Med 17:638. doi:10.1038/nm0611-638

    Article  CAS  PubMed  Google Scholar 

  22. Kern S, Mehlig K, Kern J et al (2015) The distribution of apolipoprotein E genotype over the adult lifespan and in relation to country of birth. Am J Epidemiol 181:214–217. doi:10.1093/aje/kwu442

    Article  PubMed  Google Scholar 

  23. Kutner KC, Erlanger DM, Tsai J et al (2000) Lower cognitive performance of older football players possessing apolipoprotein E epsilon4. Neurosurgery 47:651–657 (discussion 657–8)

    CAS  PubMed  Google Scholar 

  24. Lehman EJ, Hein MJ, Baron SL, Gersic CM (2012) Neurodegenerative causes of death among retired National Football League players. Neurology 79:1970–1974. doi:10.1212/WNL.0b013e31826daf50

    Article  PubMed Central  PubMed  Google Scholar 

  25. Masliah E, Rockenstein E, Veinbergs I et al (2001) Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci USA 98:12245–12250. doi:10.1073/pnas.211412398

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Mayeux R, Ottman R, Maestre G et al (1995) Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer’s disease. Neurology 45:555–557

    Article  CAS  PubMed  Google Scholar 

  27. Mayeux R, Ottman R, Tang MX et al (1993) Genetic susceptibility and head injury as risk factors for Alzheimer’s disease among community-dwelling elderly persons and their first-degree relatives. Ann Neurol 33:494–501. doi:10.1002/ana.410330513

    Article  CAS  PubMed  Google Scholar 

  28. McKay GJ, Silvestri G, Chakravarthy U et al (2011) Variations in apolipoprotein E frequency with age in a pooled analysis of a large group of older people. Am J Epidemiol 173:1357–1364. doi:10.1093/aje/kwr015

    Article  PubMed Central  PubMed  Google Scholar 

  29. McKee AC, Robinson ME (2014) Military-related traumatic brain injury and neurodegeneration. Alzheimers Dement 10:S242–S253. doi:10.1016/j.jalz.2014.04.003

    Article  PubMed Central  PubMed  Google Scholar 

  30. McKee AC, Stern RA, Nowinski CJ et al (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43–64. doi:10.1093/brain/aws307

    Article  PubMed Central  PubMed  Google Scholar 

  31. Mirra SS, Heyman A, McKeel D et al (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    Article  CAS  PubMed  Google Scholar 

  32. Montenigro PH, Baugh CM, Daneshvar DH et al (2014) Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome. Alzheimers Res Ther 6:68. doi:10.1186/s13195-014-0068-z

    Article  PubMed Central  PubMed  Google Scholar 

  33. Montenigro PH, Corp DT, Stein TD et al (2015) Chronic traumatic encephalopathy: historical origins and current perspective. Annu Rev Clin Psychol. doi:10.1146/annurev-clinpsy-032814-112814

    PubMed  Google Scholar 

  34. Montine TJ, Phelps CH, Beach TG et al (2011) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11. doi:10.1007/s00401-011-0910-3

    Article  PubMed Central  PubMed  Google Scholar 

  35. Mormino EC, Betensky RA, Hedden T et al (2014) Amyloid and APOE 4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology 82:1760–1767. doi:10.1212/WNL.0000000000000431

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Olsson A, Csajbok L, Ost M et al (2004) Marked increase of beta-amyloid(1-42) and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury. J Neurol 251:870–876. doi:10.1007/s00415-004-0451-y

    Article  CAS  PubMed  Google Scholar 

  37. Perez-Nievas BG, Stein TD, Tai H-C et al (2013) Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology. Brain 136:2510–2526. doi:10.1093/brain/awt171

    Article  PubMed Central  PubMed  Google Scholar 

  38. Plassman BL, Havlik RJ, Steffens DC et al (2000) Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 55:1158–1166

    Article  CAS  PubMed  Google Scholar 

  39. Roberts GW, Allsop D, Bruton C (1990) The occult aftermath of boxing. J Neurol Neurosurg Psychiatr 53:373–378

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Roberts GW, Gentleman SM, Lynch A et al (1994) Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease. J Neurol Neurosurg Psychiatr 57:419–425

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Roberts GW, Gentleman SM, Lynch A, Graham DI (1991) Beta A4 amyloid protein deposition in brain after head trauma. Lancet 338:1422–1423

    Article  CAS  PubMed  Google Scholar 

  42. Shen H (2015) Researchers seek definition of head-trauma disorder. Nature 518:466–467. doi:10.1038/518466a

    Article  CAS  PubMed  Google Scholar 

  43. Smith DH, Chen X-H, Iwata A, Graham DI (2003) Amyloid beta accumulation in axons after traumatic brain injury in humans. J Neurosurg 98:1072–1077. doi:10.3171/jns.2003.98.5.1072

    Article  CAS  PubMed  Google Scholar 

  44. Smith DH, Chen XH, Xu BN et al (1997) Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig. J Neuropathol Exp Neurol 56:822–834

    Article  CAS  PubMed  Google Scholar 

  45. Stein TD, Alvarez VE, McKee AC (2014) Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel. Alzheimers Res Ther 6:4. doi:10.1186/alzrt234

    Article  PubMed Central  PubMed  Google Scholar 

  46. Stern RA, Daneshvar DH, Baugh CM et al (2013) Clinical presentation of chronic traumatic encephalopathy. Neurology 81:1122–1129. doi:10.1212/WNL.0b013e3182a55f7f

    Article  PubMed Central  PubMed  Google Scholar 

  47. Takizawa C, Thompson PL, van Walsem A et al (2015) Epidemiological and economic burden of Alzheimer’s disease: a systematic literature review of data across Europe and the United States of America. J Alzheimers Dis 43:1271–1284. doi:10.3233/JAD-141134

    PubMed  Google Scholar 

  48. Terrell TR, Bostick RM, Abramson R et al (2008) APOE, APOE promoter, and tau genotypes and risk for concussion in college athletes. Clin J Sport Med 18:10–17. doi:10.1097/JSM.0b013e31815c1d4c

    Article  PubMed  Google Scholar 

  49. Tokuda T, Ikeda S, Yanagisawa N et al (1991) Re-examination of ex-boxers’ brains using immunohistochemistry with antibodies to amyloid beta-protein and tau protein. Acta Neuropathol 82:280–285

    Article  CAS  PubMed  Google Scholar 

  50. Wirth M, Villeneuve S, La Joie R et al (2014) Gene-environment interactions: lifetime cognitive activity, APOE genotype, and beta-amyloid burden. J Neurosci 34:8612–8617. doi:10.1523/JNEUROSCI.4612-13.2014

    Article  PubMed Central  PubMed  Google Scholar 

  51. Xia W, Yang T, Shankar G et al (2009) A specific enzyme-linked immunosorbent assay for measuring beta-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer disease. Arch Neurol 66:190–199. doi:10.1001/archneurol.2008.565

    Article  PubMed Central  PubMed  Google Scholar 

Download references

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

Authors
  1. Thor D. Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip H. Montenigro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victor E. Alvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weiming Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John F. Crary
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yorghos Tripodis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel H. Daneshvar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jesse Mez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Todd Solomon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gaoyuan Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Caroline A. Kubilus
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kerry A. Cormier
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Steven Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Katharine Babcock
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Patrick Kiernan
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Lauren Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Christopher J. Nowinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Brett Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Diane Dixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Robert A. Stern
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Robert C. Cantu
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Neil W. Kowall
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Ann C. McKee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thor D. Stein.

Electronic supplementary material

Below is the link to the electronic supplementary material.

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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-015-1435-y

Keywords

Search

Navigation