Progression of tau pathology within cholinergic nucleus basalis neurons in chronic traumatic encephalopathy: A chronic effects of neurotrauma consortium study

Abstract

Objective: To test the hypothesis that the nucleus basalis of Meynert (nbM), a cholinergic basal forebrain (CBF) cortical projection system, develops neurofibrillary tangles (NFTs) during the progressive pathological stages of chronic traumatic encephalopathy (CTE) in the brain of athletes.

Method: To characterize NFT pathology, tau-antibodies marking early, intermediate and late stages of NFT development in CBF tissue obtained at autopsy from eighteen former athletes and veterans with a history of repetitive mild traumatic brain injury (TBI) were used.

Results: Analysis revealed that cholinergic nbM neurons develop intracellular tau-immunoreactive changes progressively across the pathological stages of CTE. In particular, there was an increase in pre-tangle (phosphorylated pS422) and oligomeric (TOC1 and TNT1) forms of tau in stage IV compared to stage II CTE cases. The nbM neurons also displayed pathologic TDP-43 inclusions and diffuse extracellular and vascular amyloid-β (Aβ) deposits in CTE. A higher percentage of pS422/p75^NTR, pS422 and TNT1 labelled neurons were significantly correlated with age at symptom onset, interval between symptom onset and death and age at death.

Conclusion: The development of NFTs within the cholinergic nbM neurons could contribute to an axonal disconnection in CTE. Further studies are needed to determine the mechanism driving NFT formation in the nbM neurons and its relation to chronic cognitive dysfunction in CTE.

Keywords:

• Cognition
• head injury
• memory
• mild brain injury
• traumatic brain injury

Acknowledgements

The authors gratefully acknowledge the use of the resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, MA). We thank Ms. L. Shao and Ms. D. Waters for technical assistance and Dr. W. Klunk (University of Pittsburgh) for providing X-34.

Declaration of interest

The authors report no conflicts of interest. This material is based upon work supported by the US Army Medical Research and Material Command and from the US Department of Veterans Affairs [2] under Award No. W81XWH-13-2-0095. The US Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014 is the awarding and administering acquisition office. Any opinions, findings, conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the US Government, or the US Department of Veterans Affairs, and no official endorsement should be inferred. This work was also supported by an award from the Department of Veterans Affairs No. I01 RX001774, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering (U01NS086659-01) and National Institute of Aging, Boston University AD Center (P30AG13846; supplement 0572063345-5), the Veterans Affairs Biorepository (CSP 501), the National Operating Committee on Standards for Athletic Equipment, the Concussion Legacy Foundation, the Andlinger Foundation and the World Wrestling Entertainment and the National Football League.