Association of probable REM sleep behavior disorder with pathology and years of contact sports play in chronic traumatic encephalopathy

Adams, Jason W; Alosco, Michael L.; Mez, Jesse; Alvarez, Victor E.; Huber, Bertrand R.; Tripodis, Yorghos; Adler, Charles H.; Kubilius, Carol; Cormier, Kerry; Mathais, Rebecca; Nicks, Raymond; Kelley, Hunter; Saltiel, Nicole; Uretsky, Madeline; Nair, Evan S; Aytan, Nurgül; Cherry, Jonathan D.; Nowinski, Christopher J.; Kowall, Neil W.; Goldstein, Lee E.; Dwyer, Brigid; Katz, Douglas I.; Cantu, Robert C.; Stern, Robert; McKee, Ann C.; Stein, Thor D.

doi:10.1007/s00401-020-02206-x

Cited by 23 publications

(23 citation statements)

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“…4,47 While these clinical features may be a consequence of p-tau pathology, 6 there is a growing appreciation for the contribution of mixed neuropathologies to clinical symptoms in neurodegenerative diseases 48 including CTE. 1,9,12,49 White matter degeneration and cerebrovascular disease are important pathologic contributors to the clinical presentation of CTE and other neurologic disorders associated with repetitive head impacts. 9,30 The study has several limitations.…”

Section: Discussionmentioning

confidence: 99%

Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts

et al. 2022

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Background and Objectives:Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathological correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH, and repetitive head impact exposure and informant-reported cognitive and daily function were tested.Methods:This imaging-pathological correlation study included symptomatic deceased men exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, and/or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathological assessments included semi-quantitative ratings of white matter rarefaction, cerebrovascular disease, p-tau severity (CTE stage, dorsolateral frontal cortex), and Aβ. Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p<0.05.Results:The sample included 75 donors: 67 football players and 8 non-football contact sport athletes and/or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log-TLV was associated with white matter rarefaction (OR=2.32, 95% CI=1.03,5.24, p=0.04), arteriolosclerosis (OR=2.38, 95% CI=1.02,5.52, p=0.04), CTE stage (OR=2.58, 95% CI=1.17,5.71, p=0.02), and dorsolateral frontal p-tau severity (OR=3.03, 95% CI=1.32,6.97, p=0.01). There was no association with Aβ. More years of football play was associated with log-TLV (b=0.04, 95% CI=0.01,0.06, p=0.01). Greater log-TLV correlated with higher FAQ (unstandardized beta=4.94, 95% CI=0.42,8.57, p=0.03) and CDS scores (unstandardized beta=15.35, 95% CI=-0.27,30.97, p=0.05).Discussion:WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging-pathological correlation studies are needed.Classification of Evidence:This study provides Class IV evidence of associations between FLAIR white matter hyperintensities, and neuropathological changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.

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Section: Discussionmentioning

confidence: 99%

Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts

et al. 2022

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“…In the current study, perceived cognitive decline was negatively correlated with elite level rugby league exposure (i.e., greater exposure to elite-level play was associated with less perceived cognitive decline), and there was no association between perceived cognitive decline and lifetime exposure to rugby league. Some researchers have reported that greater duration of contact/collision sport participation (primarily American football) is associated with probable REM sleep behavior disorder ( 64 ), white matter rarefaction and neurofibrillary tangles ( 65 ), cognitive decline reported by a collateral source (but not behavioral/mood symptoms) ( 66 ), self-reported cognition-related quality of life, ( 67 ) and extent of chronic traumatic encephalopathy pathology ( 68 , 69 ). In contrast, Fields et al ( 70 ) measured cognitive performance and mental health symptoms in 35 retired American football players and found no relationship between years played professionally and either objective cognitive performance or depressive symptoms.…”

Section: Discussionmentioning

confidence: 99%

Predictors and Correlates of Perceived Cognitive Decline in Retired Professional Rugby League Players

et al. 2021

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Objective: Rugby league is an international full-contact sport, with frequent concussive injuries. Participation in other full-contact sports such as American football has been considered to be a risk factor for neuropsychiatric sequelae later-in-life, but little research has addressed the mental and cognitive health of retired professional rugby league players. We examined predictors and correlates of perceived (self-reported) cognitive decline in retired National Rugby League (NRL) players.Methods: Participants were 133 retired male elite level rugby league players in Australia. Participants completed clinical interviews, neuropsychological testing, and self-report measures. The Informant Questionnaire on Cognitive Decline in the Elderly, self-report (IQCODE-Self), measured perceived cognitive decline.Results: The median age of the sample was 55.0 (M = 53.1, SD = 13.9, range = 30–89) and the median years of education completed was 12.0 (M = 11.9, SD = 2.6, range = 7–18). The retired players reported a median of 15.0 total lifetime concussions (M = 28.0, SD = 36.6, range = 0–200). The mean IQCODE-Self score was 3.2 (SD = 0.5; Range = 1.3–5.0); 10/133 (7.5%) and 38/133 (28.6%) scored above conservative and liberal cutoffs for cognitive decline on the IQCODE-Self, respectively. Perceived cognitive decline was positively correlated with current depressive symptoms, negatively correlated with years of professional sport exposure and resilience, and unrelated to objective cognition and number of self-reported concussions. A multiple regression model with perceived cognitive decline regressed on age, concussion history, professional rugby league exposure, depression, resilience, objective cognitive functioning, daytime sleepiness, and pain severity showed depression as the only significant predictor.Conclusion: This is the first large study examining subjectively experienced cognitive decline in retired professional rugby league players. Similar to studies from the general population and specialty clinics, no relationship was found between objective cognitive test performance and perceived cognitive decline. Depressive symptoms emerged as the strongest predictor of perceived cognitive decline, suggesting that subjective reports of worsening cognition in retired elite rugby league players might reflect psychological distress rather than current cognitive impairment.

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“…In particular, research has shown that exposure to repetitive head impacts (RHIs) from football, including RHIs resulting in symptomatic concussions and the more common subconcussive trauma, is associated with worse later-life cognitive 1 , 2 , 3 , 4 and neuropsychiatric function, 5 , 6 , 7 fluid and neuroimaging evidence of neurodegeneration, 8 , 9 , 10 , 11 , 12 , 13 and risk for postmortem diagnosis of neurodegenerative diseases, including chronic traumatic encephalopathy 14 , 15 , 16 , 17 and amyotrophic lateral sclerosis (ALS). 18 , 19 Professional football players are also at increased risk for sleep apnea, 20 rapid-eye-movement sleep behavior disorder, 21 cardiovascular disease (CVD), 22 atrial fibrillation, 23 and opioid use. 24 Despite the higher prevalence of CVD during life, mortality rate studies suggest that former National Football League (NFL) players live longer and have lower CVD mortality compared with men in the general US population, possibly because of greater physical activity and less cigarette smoking.…”

Section: Introductionmentioning

confidence: 99%

Association of Playing College American Football With Long-term Health Outcomes and Mortality

et al. 2022

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Association of probable REM sleep behavior disorder with pathology and years of contact sports play in chronic traumatic encephalopathy

Cited by 23 publications

References 75 publications

Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts

Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts

Predictors and Correlates of Perceived Cognitive Decline in Retired Professional Rugby League Players

Association of Playing College American Football With Long-term Health Outcomes and Mortality

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