Over 15 million contact sports players and military veterans are at risk for the development of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with exposure to repetitive head impacts (RHI) that sometimes presents with parkinsonian motor symptoms, although very little is understood about how these individuals develop parkinsonism. CTE is characterized by accumulation of hyperphosphorylated tau protein (p-tau), and diagnosis requires the presence of neuronal tau in the form of neurofibrillary tangles at the depth of cortical sulci. We performed quantitative immunoassays for markers of neurovascular inflammation within the postmortem dorsolateral frontal cortex of participants with and without a history of RHI and CTE (n = 156), and tested for associations with RHI, microgliosis, and tau pathology measures. Levels of vascular injury-associated markers were increased in CTE compared to RHI-exposed and -naïve controls. Markers increased with RHI exposure duration and were associated with increased microglial density and tau pathology. Histologically, there was significantly increased ICAM1 staining of the microvasculature, extracellular space, and astrocytes at the sulcal depths in high stage CTE compared to both low stage CTE and controls. Multifocal perivascular immunoreactivity for serum albumin was present in all RHI-exposed individuals. These findings demonstrate that vascular injury markers are associated with RHI exposure, duration, and microgliosis, are elevated in CTE, and increase with disease severity. We next performed a cross-sectional analysis of all brain donors with CTE and without comorbid neurodegenerative disease (n=495) in the UNITE Brain Bank. Participants with parkinsonism (CTE-p, n=119) had a higher mean age at death (71.5 years (y)) than participants without parkinsonism (CTE-np, n=362, 54.1 y) and exhibited a higher rate of dementia than CTE-np participants. CTE-p participants had a more severe CTE stage and nigral pathology (NFTs, neuronal loss, and more frequent Lewy bodies), though the majority of cases were negative for nigral Lewy bodies. In American football players, simultaneous regression analysis demonstrated that nigral NFTs and neuronal loss mediate a connection between years of play and parkinsonism in CTE. In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation was associated with SN proteinopathy and neuronal loss, and these pathologies were associated with parkinsonism. Finally, in a postmortem cohort (n=392) of brain donors with CTE without comorbid neurodegenerative disease, we used linear regression modelling to analyze the associations between isodendritic core nuclei pathology (semiquantitative neurofibrillary tangles (NFTs), neurites, and neuronal loss scores) and CTE disease severity, RHI exposure duration (years of contact sport play), and informant-reported cognitive and daily function as assessed by the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ), respectively. Overall, isodendritic core (IC) NFT scores increase with disease stage, Initially in the locus coeruleus and finally in the median raphe nuclei. Neuronal loss occurred at later disease stages than NFT accumulation. RHI exposure was associated with p-tau pathology for all IC regions. NFTs and neuronal loss in the substantial nigra were associated with increased CDS scores (i.e., worse cognitive function), and neuronal loss in the substantia nigra and locus coeruleus were associated with increased FAQ scores (i.e., worse daily function). We are able to show CTE is similar in distribution of p-tau pathology to progressive supranuclear palsy (PSP), a disease that is thought to primarily affect subcortical regions, especially by end stage disease. These results demonstrate the vulnerability of the isodendritic core nuclei to p-tau pathology and neuronal loss in CTE, and suggest that their involvement contributes to cognitive and functional symptoms during life. This work highlights the possible linkage between neuroinflammation leading to nigral p-tau accumulation and neuron loss which likely underlies the development and progression of parkinsonian motor symptoms in CTE.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/48667 |
| Date | 27 April 2024 |
| Creators | Kirsch, Daniel |
| Contributors | McKee, Ann C. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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