Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease that is associated with repetitive traumatic brain injury like those sustained in sport, military combat, and other activities with repetitive head impact exposure. Repetitive head impacts typically cause mild traumatic brain injury (mTBI) resulting in both concussive and subconcussive injury. Repeated mTBIs injuries appear to cause an abnormal accumulation of proteins, including hyperphosphorylated tau (p-tau) and TDP-43, progressive axonal failure with gradual structural degradation, microvascular disruption, breach of blood-brain barrier, neuroinflammation and microglial activation; each of these manifestations lead to axonal degeneration and neuronal death, which impairs neuronal pathways and are likely to give rise to CTE symptoms. CTE can be microscopically characterized mainly by p-tau accumulation in perivascular spaces and at the depths of the cortical sulci. Clinical presentation of CTE may include behavioral, mood, cognitive, or motor symptoms. Some of the common symptoms include impulsivity, aggression, anxiety, depression, memory impairment, dementia, and suicidality. The Locus Coeruleus (LC), a nucleus in the pons of the brainstem, is suspected to be involved in CTE. The LC provides the main source of norepinephrine to the entire brain and is critical for its control over arousal, behaviors, attention, and memory. Dysfunction of the locus coeruleus has shown to cause a wide array of symptoms, many of which are similar to those seen in CTE. Furthermore, the LC is affected in many other neurodegenerative diseases and is believed to be responsible for the progressive and widespread nature of the various diseases and their clinical symptoms. Although the LC has been implicated in CTE there have been no studies examining LC pathology in relation to the disease progression or its symptoms. We hypothesize LC CTE pathology should increase with the severity of CTE. Furthermore, increased CTE pathology in the LC should create disturbances to the LC and the LC-NE system and manifest clinically. Specifically, LC CTE pathology may be associated with age of onset of general behavioral and cognitive symptoms as well as individual symptoms and outcomes including impulsivity, depression, depressed mood and death by suicide. To determine this, a postmortem study was performed on 184 individuals with a history of RHI and no comorbid diseases examining the relationship between AT8-immunopositive tau density in the LC and various clinical variables. The study found that LC AT8 density showed a significant positive correlation with duration of repetitive head impact (RHI) exposure when controlled for age. There also was a significant increase in LC AT8-immunoreactive tau in cases with stage III and IV CTE compared to those with no CTE and stage I and II CTE, and AT8 density was predictive of CTE stage when controlled for age. There were no significant relationships found between density of LC AT8-immunoreactive tau and age of any CTE symptom onset or individual symptom (impulsivity, depressed mood, MDD, death by suicide) presence. Future studies should continue to evaluate CTE pathology in the LC and its effects on both the pathological and clinical characteristics of the disease.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/36529 |
| Date | 12 June 2019 |
| Creators | Healy, Ryan |
| Contributors | McKee, Ann, Cherry, Jon |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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