Potential Metabolomic Linkage in Blood between Parkinson’s Disease and Traumatic Brain Injury

H OH OH metabolites Article Potential Metabolomic Linkage in Blood between Parkinson’s Disease and Traumatic Brain Injury Massimo S. Fiandaca 1,2,3, * , Thomas J. Gross 1,3 , Thomas M. Johnson 4 , Michele T. Hu 5,6 , Samuel Evetts 5 , Richard Wade-Martins 7 , Kian Merchant-Borna 8 , Jeffrey Bazarian 8 , Amrita K. Cheema 9,10 , Mark Mapstone 1 and Howard J. Federoff 1, * 1 2 3 4 5 6 7 8 9 10 * Translational Laboratory and Biorepository, Department of Neurology, University of California Irvine School of Medicine, Irvine, CA 92697-3910, USA; (T.J.G.); (M.M.) Department of Neurological Surgery, University of California Irvine School of Medicine, Irvine, CA 92697-3910, USA Department of Anatomy & Neurobiology, University of California Irvine School of Medicine, Irvine, CA 92697-3910, USA Intrepid Spirit Concussion Recovery Center, Naval Medical Center Camp Lejeune, Jacksonville, NC 28540, USA; Nuffield Department of Clinical Neurosciences, University of Oxford, 01865 Oxford, UK; (M.T.H.); (S.E.) Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals Trust, Oxford 01865, UK Department of Physiology, Anatomy and Genetics, Oxford Parkinson’s Disease Centre, University of Oxford, Oxford 01865, UK; Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14604, USA; (K.M.-B.); (J.B.) Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20001, USA; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20001, USA Correspondence: (M.S.F.); (H.J.F.); Tel.: +1-949-824-5579 (M.S.F.) Received: 24 July 2018; Accepted: 4 September 2018; Published: 7 September 2018



 Abstract: The etiologic basis for sporadic forms of neurodegenerative diseases has been elusive but likely represents the product of genetic predisposition and various environmental factors. Specific gene-environment interactions have become more salient owing, in part, to the elucidation of epigenetic mechanisms and their impact on health and disease. The linkage between traumatic brain injury (TBI) and Parkinson’s disease (PD) is one such association that currently lacks a mechanistic basis. Herein, we present preliminary blood-based metabolomic evidence in support of potential association between TBI and PD. Using untargeted and targeted high-performance liquid chromatography-mass spectrometry we identified metabolomic biomarker profiles in a cohort of symptomatic mild TBI (mTBI) subjects (n = 75) 3–12 months following injury (subacute) and TBI controls (n = 20), and a PD cohort with known PD (n = 20) or PD dementia (PDD) (n = 20) and PD controls (n = 20). Surprisingly, blood glutamic acid levels in both the subacute mTBI (increased) and PD/PDD (decreased) groups were notably altered from control levels. The observed changes in blood glutamic acid levels in mTBI and PD/PDD are discussed in relation to other metabolite profiling studies. Should our preliminary results be replicated in comparable metabolomic investigations of TBI and PD cohorts, they may contribute to an “excitotoxic” linkage between TBI and PD/PDD. Keywords: Parkinson’s disease; Parkinson’s disease dementia; subacute mild traumatic brain injury; glutamic acid; excitotoxicity; metabolomics Metabolites 2018, 8, 50; doi:10.3390/metabo8030050 www.mdpi.com/journal/metabolites Metabolites 2018, 8, 50 2 of 20 1. Introduction Compelling epidemiological observations associate moderate and severe traumatic brain injury (TBI) and Parkinson’s disease (PD) [1]. Whether mild TBI (mTBI) is a significant risk factor for the development of PD (and other neurodegenerative disorders) has been more difficult to prove, due to fewer controlled investigations [2–4], conflicting results [5], and a lack of agreement on diagnostic criteria [6]. We anticipate that molecular phenotyping may ultimately resolve the latter discrepancies in the definition of mTBI. Recent studies [7,8], however, have more strongly endorsed an association between PD and TBI (including mTBI) sustained both early or later in life. Absent a consensus regarding a potential post-traumatic etiology for PD (or dementing conditions), the future definition of such relationships likely requires comprehensive longitudinal investigations and novel biomarkers [9]. Despite the limitations in current knowledge, there is emerging agreement that chronic neuroinflammatory conditions are associated with clinical parkinsonism and/or dementia, if not true PD or Alzheimer’s disease (AD), and significant pathobiologic overlap exists (i.e., neuroinflammation, oxidative stress response, mitochondrial dysfunction, cognitive decline, and clinical depression) between neurodegenerative disorders (e.g., AD and D) and TBI [10,11]. The mechanisms underlying a precipitating event such as TBI to those downstream dysregulated networks associated with neurodegenerative diseases remains unknown. For this article, as well as our previous report on acute mild brain trauma biomarkers [12], we based our diagnosis of mTBI (including the term concussion) on diagnostic criteria provided by our medical co-authors and medical doctors involved in the assessment of study participants. We have reported a set of human plasma metabolites associated with acute mTBI (within 6 h of injury) that accurately classify concussed individuals from non-concussed controls [12]. In this extension of our mTBI biomarker efforts we sought to define metabolomic similarities and differences between plasma specimens from a subacute cohort that includes subjects 3 to 12 months following mTBI, the previously reported acute mTBI biomarker panel, and in a cross-sectional design, whether plasma metabolites with TBI provide novel insights related to potential future risk of PD. 2. Results 2.1. Study Population Differences A comparison of the demographics for the study cohorts is provided in Table 1. Our TBI cohort consisted of 75 cases and 20 controls. Described values are provided as the mean and standard deviation (S.D.). Frequency distribution of ages for the cases and controls in the TBI cohort did not follow a normal distribution, while ages in the PD cohort did. The TBI cases had a mean age of 24.9 ± 5.2 years, with 71 males and 4 females represented, and all of whom sustained a TBI during a three to twelve month interval prior to phlebotomy. The TBI controls (n = 20) had a mean age of 18.7 ± 0.8 years, included 8 males and 12 females, and did not have a history of a witnessed concussion or mTBI during the previous year prior to blood draw. Statistically significant age and sex differences existed between cases and controls in the TBI cohort. All TBI case and control participants attained the minimum of a high school graduate level of education. The number of injuries sustained by the TBI cases ranged from 1 to 9, with a mean of 2.0 ± 1.5. Th (...truncated)