HJAR Sep/Oct 2023

CTE 34 SEP / OCT 2023 I  HEALTHCARE JOURNAL OF ARKANSAS determined whether the donor met criteria for dementia 60 . Contact sport and traumatic brain injury (TBI) history Retrospective assessment of contact sport and TBI histories from informants were similar in both brain banks and have been described previously 1,5,59 . For each CCS sport exposure (football or otherwise), informants provided a history of levels played, years played at each level, and age of first exposure. Football position at each level was also recorded. In addition, athletic history for professional football players was verified with a comprehensive database maintained by Hidden Game Sports/24-7 Baseball LLC, which has been previously used for research purposes 1,5,61 . Informants were also asked if donors had any military service or combat exposure. Each donor’s TBI history was queried from informants, including assessing the total number of con- cussions experienced. Following amend- ments made to study protocols, informants for donors included in the study after Jan- uary 2014 were read a formal definition of concussion in advance of being asked how many concussions each donor experienced 6 . Neuropathological examination Methods for brain tissue processing and evaluation have been described previ- ously 1,4 . Neuropathologists were blinded to the donor’s exposure history, all clinical his- tory, and medical diagnoses. All pathologic diagnoses were reviewed by four neuropa- thologists (A.C.M., B.R.H., T.D.S., V.E.A.) and discrepancies were resolved by discussion. Gross and microscopic examination were conducted following previously published methods 62 . Well-established criteria were used for the neuropathologic diagnosis of neurodegenerative diseases, including Alzheimer’s disease (NIA-Reagan criteria of high or intermediate likelihood) 63 , Lewy body disease 64 , frontotemporal lobar degen- eration 65,66 , and motor neuron disease 67 . CTE was diagnosed using NINDS/NIBIB neu- ropathological criteria 3 . Donors with CTE were staged (I to IV, in order of increasing severity) based on previously published cri- teria 4,68 , which were later classified as low- stage CTE (stages I and II) and high-stage CTE (stages III and IV). Neuropathologists also recorded semi-quantitative NFT bur- den on a 0–3 scale with increasing severity across 11 brain regions implicated in CTE: dorsolateral frontal cortex, middle frontal cortex, orbitofrontal cortex, hippocampus regions CA1, CA2, CA3/4, substantia nigra, amygdala, entorhinal cortex, inferior pari- etal cortex, and locus coeruleus. Cumula- tive neurofibrillary tangle (NFT) burden was defined as the sum score across these 11 regions. Helmet sensor study literature review and creation of the positional exposure matrix (PEM) We created a PEM that quantified RHI features specific to football position and level of play, adapting the template of the job exposure matrix, which is used in the field of occupational health to retrospectively Fig. 3 | Study inclusion and exclusion criteria for FHS and VA-BU-CLF study brain donors. Source data are provided as a Source Data file. BU Boston University, CLF Concussion Legacy Foundation, FHS Framingham Heart Study, VA Veterans Affairs.