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Multicenter Study
. 2024 Aug 1;7(8):e2428687.
doi: 10.1001/jamanetworkopen.2024.28687.

Repetitive Head Impacts and Perivascular Space Volume in Former American Football Players

Leonard B Jung  1   2 , Tim L T Wiegand  1   2 , Fatima Tuz-Zahra  3 , Yorghos Tripodis  3   4 , Jeffrey J Iliff  5   6   7 , Juan Piantino  8 , Hector Arciniega  1   9 , Cara L Kim  1   2 , Lara Pankatz  1   2 , Sylvain Bouix  1   10 , Alexander P Lin  1   11 , Michael L Alosco  12 , Daniel H Daneshvar  13 , Jesse Mez  12 , Farshid Sepehrband  14 , Yogesh Rathi  1   15 , Ofer Pasternak  1   15   16 , Michael J Coleman  1 , Charles H Adler  17 , Charles Bernick  18 , Laura Balcer  19   20   21 , Jeffrey L Cummings  22 , Eric M Reiman  23 , Robert A Stern  12   24   25 , Martha E Shenton  1   15   16 , Inga K Koerte  1   2   15   26 ; DIAGNOSE CTE Research Project
Collaborators, Affiliations
Multicenter Study

Repetitive Head Impacts and Perivascular Space Volume in Former American Football Players

Leonard B Jung et al. JAMA Netw Open. .

Abstract

Importance: Exposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role.

Objective: To investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration.

Design, setting, and participants: This cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses.

Exposure: Prior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts).

Main outcomes and measures: Individual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume.

Results: Analyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (β = 2.71 × 10-8 [95% CI, 0.50 × 10-8 to 4.93 × 10-8]; P = .03) and CHII-G (β = 2.24 × 10-6 [95% CI, 0.35 × 10-6 to 4.13 × 10-6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (β = -0.74 [95% CI, -1.35 to -0.13]; P = .04).

Conclusions and relevance: These findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.

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Conflict of interest statement

Dr Iliff reported serving on an advisory board for Applied Cognition, including compensation and stock options, outside the submitted work. Dr Piantino reported serving on an advisory board for Applied Cognition, including compensation and stock options, outside the submitted work. Dr Lin reported serving as a cofounder of BrainSpec and receiving grants from Biomarin Pharmaceuticals and personal fees from Moncton MRI outside the submitted work. Dr Alosco reported receiving grants from Life Molecular Imaging and Rainwater Charitable Foundation and personal fees from Oxford University Press and Michael J Fox Foundation outside the submitted work. Dr Daneshvar reported receiving personal fees from StataDx and for expert medicolegal testimony outside the submitted work. Dr Mez reported receiving grants from the National Institutes of Health (NIH) outside the submitted work. Dr Bernick reported receiving grants from Boston University during the conduct of the study. Dr Cummings reported receiving grants from National Institute of General Medical Sciences, National Institute on Aging, Alzheimer’s Disease Drug Discovery Foundation, Ted and Maria Quirk Endowment, and Joy Chambers-Grundy Endowment during the conduct of the study; receiving personal fees from Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, BioXcel, Bristol-Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Mangrove Therapeutics, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, ONO, Optoceutics, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Sinaptica, Suven, TrueBinding, Vaxxinity, and Wren outside the submitted work; owning the copyright of the Neuropsychiatric Inventory; and having stocks or options in Artery, Vaxxinity, Behrens, Alzheon, MedAvante-Prophase, and Acumen. Dr Reiman reported serving as a cofounder and advisor for AlzPath; serving as an advisor for Alzheon, Denali, and Vaxxinity; receiving personal fees from Enigma and Retromer Therapeutics outside the submitted work. Dr Stern reported receiving personal fees from Biogen, Lundbeck, Psychological Assessment Resources, and Eisai and grants from Concussion Legacy Foundation and owning stock and serving on the board of directors for King-Devick Technologies outside the submitted work. Dr. Koerte reported receiving grants from Abbott and owning stock from Siemens. No other disclosures were reported.

Figures

Figure 1.
Figure 1.
Example of a Perivascular Space (PVS) Segmentation and 3-Dimensional Rendering
Figure 2.
Figure 2.
Cumulative Head Impact Indices and Perivascular Space (PVS) Volume Analyses are adjusted for age at the time of magnetic resonance imaging, body mass index, systolic blood pressure, use of antihypertensive medication, and use of blood-brain barrier permeable β-adrenergic receptor blockers (propranolol, metoprolol, nebivolol) intake specifically, diabetes, use of antidiabetic medication, hypercholesterolemia, use of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors intake, APOE ε4-carrier vs noncarrier status, years of education, and imaging site. Covariates were chosen based on previous evidence of associations with PVS clearance or head impacts. CHII indicates Cumulative Head Impact Index; G, linear acceleration; R, rotational acceleration. BBB indicates blood-brain barrier; BMI, body mass index.
Figure 3.
Figure 3.
Covariates and Perivascular Space (PVS) in Former American Football Players BBB indicates blood-brain barrier; BMI, body mass index.
See this image and copyright information in PMC

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