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

Abstract

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.

Keywords: Chronic traumatic encephalopathy; Contact sports; Lewy body disease; REM sleep behavior disorder; Repetitive head impacts.

Fig. 1

Tau pathology in probable REM sleep behavior disorder in CTE. Extensive tau pathology is present in the median raphe nucleus in a participant with CTE and probable REM sleep behavior disorder. a,b Luxol fast blue hematoxylin and eosin stain of the dorsal and median raphe nucleus shown at 20x magnification bordered by the medial longitudinal fasciculus (mlf) and pontine white matter including pontocerebellar tracts (a, dorsal raphe: small white circle, median raphe: large white circle) and at 100x magnification (b). c α-synuclein immunostaining demonstrates an absence of Lewy pathology within the raphe nucleus. d Abundant tau pathology with neurofibrillary tangles (arrows) and tau-positive neurites and dots (arrowheads) as shown with AT8 immunostaining. Scale bar a, 500μm; b-d, l00μm