Bridging Trauma and Parkinson's Disease: Mechanisms, Models, and Biomarkers of Post-Traumatic Parkinsonism.

Epidemiology of mild traumatic brain injury and neurodegenerative disease.

Introduction : Chronic traumatic encephalopathy is a state presenting with cognitive, behavioral, or motor abnormalities in athletes, especially within the boxing community and used to be referred to by various terms, such as `punch drunk,` `goofy,` and `slug-nutty`. Later, a more formal term was introduced bearing more medical validity - dementia pugilistica . By the end of the XX century it was concluded that this form of neurodegenerative disease was in fact similar to and yet different from other cases of neurodegeneration. As more evidence came forward about this condition a term coined by Miller became most widely used - chronic traumatic encephalopathy (CTE). The issue received more attention thanks to Omalu`s research. Materials and Methods : This review summarizes data from recent studies, findings and records in the literature on sport-related concussion in a significant number of cases of neuropathologically verified CTE and the detailed findings of CTE in 3 professional athletes, 1 football player and 2 boxers. Results : The clinical picture of CTE is associated with behavioral and personality changes, loss of attention and concentration, short-term memory loss, parkinsonism, and speech and gait abnormalities. Microscopically, CTE can be described as a tauopathy with preferential involvement of the superficial cortical layers, irregular patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular, and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of A-amyloid, most commonly as diffuse plaques, occurs in fewer than half of the cases. Conclusion : Chronic traumatic encephalopathy is a neuropathologically distinct slowly progressive tauopathy with a clear environmental etiology which suggests a significant public health risk for persons who suffer repetitive mild traumatic brain injuries (TBIs). Early identification and prevention of this disease has become a critical focus of current studies.

Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans (86% of whom were also athletes) and one individual who engaged in self-injurious head banging behaviour. Eighteen age- and gender-matched individuals without a history of repetitive mild traumatic brain injury served as control subjects. In chronic traumatic encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions, including the medial temporal lobe, thereby allowing a progressive staging of pathology from stages I-IV. Multifocal axonal varicosities and axonal loss were found in deep cortex and subcortical white matter at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions and neurites were also found in 85% of cases, ranging from focal pathology in stages I-III to widespread inclusions and neurites in stage IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of attention and concentration. Additional symptoms in stage II included depression, explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive impairment were found, and in stage IV, dementia, word-finding difficulty and aggression were characteristic. Data on athletic exposure were available for 34 American football players; the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), seven with Alzheimer's disease (11%), 11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration (6%). There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss. The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.

Chapter 4 - The neuropathology of traumatic brain injury

A new approach for the biochemical analysis of ascitic fluid: P. Paré, J. Talbot and R. Gauvin, l'Hôtel-Dieu de Québec, Québec, Canada, G1R 2J6

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that occurs in association with repetitive mild traumatic brain injury. It is associated with a variety of clinical symptoms in multiple domains, and there is a distinct pattern of pathological changes. The abnormal tau pathology in CTE occurs uniquely in those regions of the brain that are likely most susceptible to stress concentration during trauma. CTE has been associated with a variety of types of repetitive head trauma, most frequently contact sports. In cases published to date, the mean length of exposure to repetitive head trauma was 15.4 years. The clinical symptoms of the disease began after a mean latency of 14.5 years with a mean age of death of 59.3 years. Most subjects had a reported history of concussions with a mean of 20.3. However, 16 % of published CTE subjects did not have a history of concussion suggesting that subconcussive hits are sufficient to lead to the development of CTE. Overall, the number of years of exposure, not the number of concussions, was significantly associated with worse tau pathology in CTE. This suggests that it is the chronic and repetitive nature of head trauma, irrespective of concussive symptoms, that is the most important driver of disease. CTE and exposure to repetitive head trauma is also associated with a variety of other neurodegenerations, including Alzheimer disease. In fact, amyloid β peptide deposition is altered and accelerated in CTE and is associated with worse disease. Here, we review the current exposure, clinical, and pathological associations of CTE.

The annual incidence of mild traumatic brain injury (MTBI) is 3.8 million in the USA with 10–15% experiencing persistent morbidity beyond one year. Chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by accumulation of hyperphosphorylated tau, can occur with repetitive MTBI. Risk factors for CTE are challenging to identify because injury mechanisms of MTBI are heterogeneous, clinical manifestations and management vary, and CTE is a postmortem diagnosis, making prospective studies difficult. There is growing interest in the genetic influence on head trauma and development of CTE. Apolipoprotein epsilon 4 (APOE-ε4) associates with many neurologic diseases, and consensus on the ε4 allele as a risk factor is lacking. This review investigates the influence of APOE-ε4 on MTBI and CTE. A comprehensive PubMed literature search (1966 to 12 June 2018) identified 24 unique reports on the topic (19 MTBI studies: 8 athletic, 5 military, 6 population-based; 5 CTE studies: 4 athletic and military, 1 leucotomy group). APOE-ε4 genotype is found to associate with outcomes in 4/8 athletic reports, 3/5 military reports, and 5/6 population-based reports following MTBI. Evidence on the association between APOE-ε4 and CTE from case series is equivocal. Refining modalities to aid CTE diagnosis in larger samples is needed in MTBI.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease in individuals with a history of multiple concussions or other forms of repetitive brain injury. A definite diagnosis can only be made post‐mortem and it is unclear why some individuals appear more susceptible to progressive neurological symptoms following repetitive brain injury than others. CTE has become a major concern in individuals exposed to increased risk of concussion, for example, sports athletes and some military personnel, but its prevalence in such risk groups is unknown. The condition shares some molecular pathologies with other neurodegenerative disorders and it appears that repetitive concussion can initiate a degenerative process involving protein misfolding that may propagate over the brain many years after the trauma. Clinical manifestations of CTE include a wide range of neurological and psychiatric symptoms. These should be treated but presently there is no disease‐modifying therapy against CTE. In contrast to most other neurodegenerative diseases, the condition is preventable. Key Concepts Chronic traumatic encephalopathy (CTE) may develop secondary to repetitive mild traumatic brain injuries. A definite diagnosis of CTE can only be made post‐mortem. CTE can be prevented but not cured – prevention and symptomatic treatment are important. Brain changes in CTE should be possible to detect and monitor using biomarkers. It is important to study risk factors for CTE – why do some individuals appear to be more susceptible to chronic and sometimes progressive symptoms following traumatic brain injury than others?

Chronic traumatic encephalopathy (CTE) is a chronic neurodegenerative disease featured with tauopathy. CTE is tightly related with repetitive mild traumatic brain injury (mTBI), which is interchangeably known as concussion (McKee et al., 2009, 2013). This disease is differentiated by neuropathological features from other neurological diseases that involve tau protein aggregation and tangle formation abnormalities like Alzheimer's disease (AD), frontotemporal dementia, and Parkinsonism linked to chromosome 17 (FTDP-17). The differentiation of CTE from other neurodegenerative diseases provides helps on exploring the mechanism of etiology and seeking potential treatment for this disease. Repetitive mTBI is usually evident in civilians participating in contact sports and in military personnel engaging in combat. Due to the number of individuals partaking in these high-risk environments, the general public concern has heightened in concordance to the reveal of many new CTE cases. Despite increased awareness, the mechanisms of CTE are still unknown and there are no effective therapies to help slow the progression of the devastating disease. The heterogeneity of human CTE cases and the complexity of patients’ backgrounds make it difficult for scientists to specify the links between mTBI and CTE using epidemiological or clinical approaches; appropriate animal models are effective in exploring cause-and-effect relationships.

Repetitive mild traumatic brain injury (r-mTBI), commonly experienced by athletes and military personnel, causes changes in multiple intracellular pathways, one of which involves the tau protein. Tau phosphorylation plays a role in several neurodegenerative conditions including chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder linked to repeated head trauma. There is now mounting evidence suggesting that tau phosphorylation may be regulated by metal ions (such as iron, zinc and copper), which themselves are implicated in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Recent work has also shown that a single TBI can result in age-dependent and region-specific modulation of metal ions. As such, this review explores the linkage among TBI, CTE, aging, and neurodegeneration, with a specific focus on the involvement of (and interaction between) tau pathology and metal dyshomeostasis. The authors highlight that metal dyshomeostasis has yet to be investigated in the context of repeat head trauma or CTE. Given the evidence that metal dyshomeostasis contributes to the onset and/or progression of neurodegeneration, and that CTE itself is a neurodegenerative condition, this brings to light an uncharted link that should be explored. The development of adequate models of r-mTBI and/or CTE will be crucial in deepening our understanding of the pathological mechanisms that drive the clinical manifestations in these conditions and also in the development of effective therapeutics targeted toward slowing progressive neurodegenerative disorders.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease characterized by the presence of abnormally phosphorylated tau aggregates. Tau is a microtubule-associated protein expressed mainly in axons of neurons with a role in the regulation of microtubule dynamics and axonal transport. It is totally unknown when and how tau is abnormally hyperphosphorylated in CTE brains. Unlike other tauopathies such as Alzheimer’s disease, in which diseases start several decades before clinical symptoms and the time point of onset is not clear, in the case of CTE it is evident when and what impacts are given to cause the diseases. Repetitive mild traumatic brain injury (rmTBI) is a known causative factor for CTE, particularly in athletes engaged in contact sports, individuals involved in traffic accidents, and military personnel exposed to blast injuries. We hypothesized rmTBI to be a useful experimental paradigm for investigating the initial processes of tau hyperphosphorylation in CTE. Among the various experimental models for TBI reported to date, we focus on the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA), because it appears to replicate human TBI more faithfully than other models particularly regarding on the impact mechanism and pathology. After verifying that CHIMERA rmTBI induced brain injuries analogous to human CTE, we investigated tau pathology in wild-type (WT) and P301S human tau transgenic (Tg) mice subjected to CHIMERA rmTBI. While no hyperphosphorylated tau signal was observed in any region of the WT mouse brain, an increased number of AT8-positive cells were detected in the motor and sensory cortices of P301S Tg mouse brains, accompanied by dendritic abnormalities, after rmTBI. Further, we found that CHIMERA rmTBI enhanced the spreading of tau pathology in brains of WT mice when tau fibrils were inoculated. These results suggest a possibility that rmTBI constitutes a risk factor stimulating the progression and propagation of tau pathology, rather than causing the initial events, if tau aggregates are present in the brain and that CHIMERA rmTBI may serve as a valuable experimental model for investigating its molecular mechanisms.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-025-02177-8.

Traumatic brain injury (TBI) in collision sports: Possible mechanisms of transformation into chronic traumatic encephalopathy (CTE)

After US District Judge Judy Brody recently ruled that the consolidated multi-district concussion litigation cases against the National Football League (NFL) in the USA were to be transferred to a...

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.

Letter: Traumatic Encephalopathy Syndrome [TES] Is Not Chronic Traumatic Encephalopathy [CTE]: CTE Is Only a Subtype of TES.