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Repetitive Head Impact Exposure and Later-Life Neurochemistry: A Magnetic Resonance Spectroscopy Investigation in Symptomatic Former NFL Players
Michael Alosco1, Benjamin Rowland2, Yorghos Tripodis3, Hujun Liao2, Alicia Chua 3, Brett Martin4, Ofer Pasternak5, Sarina Karmacharya5, Johnny Jarnagin6, Christine Chaisson4, Robert C Cantu7,8, Martha E Shenton5, Richard Greenwald9,10, Michael McClean11, Neil W Kowall12,13, Ann C McKee12,14,15, Robert A Stern16, and Alexander P Lin2

1Neurology, Boston University School of Medicine, Boston, MA, United States, 2Radiology, Center for Clinical Spectroscopy, Brigham and Women's Hospital, Harvard Medical School, MA, 3Biostatistics, Boston University School of Public Health, 4Data Coordinating Center, Boston University School of Public Health, MA, 5Psychiatry, Psychiatry Neuroimaging Laboratory, Radiology, Brigham and Women's Hospital, Harvard Medical School, MA, 6Neurology, Boston University School of Medicine, MA, 7Neurology, Neurosurgery, Boston University School of Medicine, MA, 8Concussion Legacy Foundation, 9Simbex, 10Thayer School of Engineering, Dartmouth College, 11Environmental Health, Boston University School of Public Health, MA, 12Neurology, Pathology and Laboratory Medicine, Boston University School of Medicine, 13Neurology Service, VA Boston Healthcare System, 14VA Boston Healthcare System, 15Department of Veterans Affairs Medical Center, Bedford, 16Neurology, Neurosurgery, Anatomy & Neurobiology, Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, MA

Synopsis

This study examined magnetic resonance spectroscopy (MRS) as a potential biomarker for chronic traumatic encephalopathy (CTE). 79 former National Football League players and 23 same-age controls completed MRS. Cumulative head impact index (CHII) estimated repetitive head impact (RHI) exposure. Principal component analysis derived clinical composites. Former NFL players had lower parietal white matter (PWM) NAA (p=0.048). Higher CHII predicted lower PWM creatine (p=0.028). Anterior cingulate gyrus (ACG) metabolites correlated with visual memory (p=0.008-0.044). ACG glutamate (p=0.032) and glutamate/glutamine (p=0.012) predicted psychomotor/executive function. Posterior cingulate gyrus myo-inositol predicted verbal memory (p=0.048). MRS may facilitate detection of RHI-related neurological conditions, including CTE.

PURPOSE

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease found in individuals with a history of repetitive head impact (RHI) exposure, particularly American football players.1,2 The diagnostic lesion of CTE is the perivascular deposition of p-tau at the sulcal depths.2 Validated in vivo biomarkers for CTE do not yet exist and therefore CTE cannot currently be diagnosed during life, precluding the ability to conduct clinical research on risk factors, epidemiology, treatment, and prevention for CTE. Magnetic resonance spectroscopy (MRS) measures physiological metabolism in vivo and is a safe and practical method for detection of neurodegenerative diseases, like Alzheimer’s disease.3 MRS may have diagnostic utility in CTE, as evidenced by the neuropathology of CTE (widespread neurodegeneration, neuroinflammation, axonal and white matter degeneration) and previous research linking RHI exposure with acute and long-term neurochemical alterations.4-7 We examined MRS as a potential biomarker for CTE through an investigation of RHI exposure and later-life neurochemistry in symptomatic former National Football League (NFL) players.

METHODS

The sample included 79 male former NFL players and 23 same-age male controls without head trauma history. Eligibility criteria for the former NFL players maximized recruitment of a sample at high risk for CTE: male, aged 40-69, a minimum of two seasons in the NFL and a minimum of twelve years of organized football, and self-reported complaints of cognitive, and/or behavioral/mood symptoms. Inclusion criteria for the same-age controls included no history of participation in contact sports, service in the military, self-reported TBI or concussion, and were asymptomatic. Subjects completed athletic and clinical histories, cognitive and behavioral/mood evaluations, and neuroimaging, among other exams. Single voxel PRESS (TR=2sec, TE=30ms, 2x2x2 cm3 voxel size, 128 averages) measured concentrations of N-acetyl aspartate (NAA), glutamate/glutamine (Glx), choline (Cho), myo-Inositol (mI), creatine (Cr), and glutathione (GSH) in the posterior (PCG) and anterior (ACG) cingulate gyrus, and parietal white matter (PWM). The raw data was processed using singular value decomposition (SVD) based channel combination, spectral registration to correct any frequency drift, and residual water suppression using the Hankel SVD method.8 Metabolites were fit using using LCModel. Cramer-Rao lower bounds < 20% were included in analyses. Concentrations were partial volume corrected by segmenting gray matter, white matter, and CSF within the voxel and correcting for the water concentration.9 Cumulative head impact index (CHII) (based on self-reported football history, and head impact frequencies from published helmet accelerometer studies) estimated RHI exposure.10 Principal component analysis derived psychomotor speed/executive function, behavior/mood, and verbal and visual memory composite scores. Mixed-effect models examined between group metabolite differences. Partial correlations tested associations between metabolites and CHII and clinical function. Bootstrap analysis on 500 replicates was performed.

RESULTS

Former NFL players had lower PWM NAA levels, compared to controls (p=0.048). No other between group differences emerged. Higher CHII predicted lower PWM Cr (p=0.028); no other CHII and metabolite correlations were observed. All ACG metabolites, except GSH, correlated with visual memory (p=0.008 to 0.044). Notably, lower NAA (p=0.044) and Cr (p=0.016) predicted worse visual memory. Increased ACG Glu (p=0.032) and Glx (p=0.012) correlated with better psychomotor speed/executive function. Higher PCG mI predicted worse verbal memory (p=0.048).

DISCUSSION

This is the first study to examine MRS in a large cohort of former NFL players. There was lower NAA in the PWM in former NFL players compared to controls, and greater RHI exposure correlated with lower later-life Cr in the PWM. NAA is produced in neurons and transported down axons, and lower PWM NAA in the former NFL players reflects axonal and neuronal loss. Recurrent head trauma exposure may have precluded axonal and neuronal recovery.11 Alternatively, CTE affects the parietal lobe in the early stages of disease and lower PWM NAA could be CTE-related. Given the correlation between RHI and PWM Cr, a marker of cellular energy metabolism, RHI exposure may result in reduced brain energetics.12 PWM metabolites were not associated with clinical function; however, striking effects between later-life ACG neurochemistry and clinical function were present. Neurochemical alterations from RHI exposure may be a robust contributor to later-life clinical function in former NFL players. The null group differences and lack of correlation with the CHII with many of the metabolites may partially involve the cross-sectional design (neurochemicals can fluctuate across the time continuum of active RHI exposure, retirement from football, and aging), and use of one-dimensional MRS.

CONCLUSIONS

MRS provides evidence of white matter neuronal loss in former NFL players, when compared to controls and reduced brain energetics may be a long-term consequence of RHI exposure. Anterior cingulate metabolism contributes to clinical function in former NFL players.

Acknowledgements

This work was supported by grants from the NIH (P30 AG13846; R01 NS 078337; R56 9500304025; U01 NS093334; 1F32NS096803-01). This publication was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through BU-CTSI Grant Number 1UL1TR001430.

References

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Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)
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