Research Article: Distinguishing and phenotype monitoring of traumatic brain injury and post-concussion syndrome including chronic migraine in serum of Iraq and Afghanistan war veterans

Date Published: April 26, 2019

Publisher: Public Library of Science

Author(s): Jay S. Hanas, James R. S. Hocker, Megan R. Lerner, James R. Couch, Tally Largent-Milnes.


Traumatic Brain Injury (TBI) and persistent post-concussion syndrome (PCS) including chronic migraine (CM) are major health issues for civilians and the military. It is important to understand underlying biochemical mechanisms of these conditions, and be able to monitor them in an accurate and minimally invasive manner. This study describes the initial use of a novel serum analytical platform to help distinguish TBI patients, including those with post-traumatic headache (PTH), and to help identify phenotypes at play in these disorders. The hypothesis is that physiological responses to disease states like TBI and PTH and related bodily stresses are reflected in biomolecules in the blood in disease-specific manner. Leave one out (serum sample) cross validations (LOOCV) and sample randomizations were utilized to distinguished serum samples from the following TBI patient groups: TBI +PTSD + CM + severe depression (TBI “most affected” group) vs healthy controls, TBI “most affected” vs TBI, TBI vs controls, TBI + CM vs controls, and TBI + CM vs TBI. Inter-group discriminatory p values were ≤ 10−10, and sample group randomizations resulted in p non-significant values. Peptide/protein identifications of discriminatory mass peaks from the TBI “most affected” vs controls and from the TBI plus vs TBI minus CM groups yielded information of the cellular/molecular effects of these disorders (immune responses, amyloidosis/Alzheimer’s disease/dementia, neuronal development). More specific biochemical disease effects appear to involve blood brain barrier, depression, migraine headache, autoimmunity, and autophagy pathways. This study demonstrated the ability for the first time of a novel, accurate, biomarker platform to monitor these conditions in serum, and help identify biochemical relationships leading to better understanding of these disorders and to potential therapeutic approaches.

Partial Text

Traumatic brain injury (TBI) is a major health issue for civilians and for the military. Approximately 1.7 million TBIs are reported annually in the United States, with 275,000 hospitalizations, and 53,000 deaths [1]. A significant number of TBIs likely go unreported. TBI is problematic for the military with 15–20% of Soldiers deployed to Afghanistan and/or Iraq wars experiencing a deployment-related TBI (D-TBI) [2, 3]. A majority of TBIs, including in the military, are mild with loss of consciousness (LOC) <30 minutes [1–4]. TBI is often associated with the post-concussion syndrome (PCS) which can include chronic daily headache (CDH), post-traumatic stress disorder (PTSD), and/or depression, all of which are health concerns for both military personnel and civilians [5–7]. These PCS conditions can occur for extended periods of time after the D-TBI [1–4, 7–9]. Headache (HA) is the most frequent PCS symptom (referred to as post-traumatic headache-PTH), and is a problem that can persist/reoccur for months to years after the TBI [8–12]. Studies of veterans at 2–11 years after D-TBI, 98% reported continuing HA of which 45% had CDH (occurring ≥ 15 days/month); two thirds of these had chronic migraine (CM) [headache occurring ≥ 15 days/month with ≥ 8 of these being migraine]) [4, 13]. The prevalence of CM in deployed veteran controls (8%) was about four times the reported prevalence of CM in the civilian population of 1–2% [14, 15]. In these analyses 2–11 years after D-TBI, PTSD was found in about 60% of TBI patients and about 10% of controls [4]. Severe depression (SDep) was noted in 43% of the D-TBI patients and only in 6% of controls. D-TBI subjects with a combination of PTSD and/or severe depression was found in approximately 60% of those with CM. In patients with D-TBI and CM, the addition of PTSD and/or SDep make the headache severity worse and the diagnosis and treatment more complicated. These observations indicate in studies of TBI and PTH (including CM), especially associated with deployed veterans, consideration should be given to these related factors (PTSD and/or SDep) in an effort to better understand TBI PCS patient symptoms and their persistence and potential biochemical/physiological inter-relationships. Much research in the TBI and PCS field is focused on identifying short-term changes associated with TBI, while less attention has been paid to the long-term effects on patients. By observing individuals 5–14 years after the initial TBI, this present study focuses on the long-term physiological changes of PCS potentially induced by the TBI. By studying such long-term effects, it might be possible to obtain clues about mechanisms responsible for long-term persistence of PCS symptoms like chronic migraine headache. There are a number of unique aspects of this molecular and translational long-term study. The current experiments employ well-controlled subject group comparisons. The initial goal was to provide groups of D-TBI subjects who were recruited randomly from a listing, provided by the VA VISN 19 Data Repository, of approximately 6,000 Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans who had suffered a confirmed D-TBI, and control veterans drawn from the same repository of approximately 12,000 OEF/OIF individuals who did not have a D-TBI. Thus, the non-TBI group of deployed veterans experienced the same war theater conditions as the veteran volunteers who suffered a deployment-related TBI. This also holds for the deployed veterans who did not manifest PCS associated PTSD, severe depression, and/or CM versus those deployed veterans who did. And as described above, these D-TBI veterans are in the persistent phases of their PCS disorders (5–14 years after their D-TBI) versus most previous studies on these disorders were in the earlier initial acute phase (less than 90 days). Therefore, veteran sera biomolecule analyses performed in this study should be able to provide additional clues concerning the underlying mechanisms for maintaining such persistence. Patient health and demographic data are provided in Table 1 in the main text and in S1–S3 Tables. The minimal serum mass profiling platform utilized in this study, employing leave one out (serum sample) cross validation [LOOCV] was able to uniquely discriminate groups of TBI and PCS sequelae patients from each other and from controls, as well as provide a set of discriminatory LOOCV serum mass peaks whose identification should provide additional mechanistic clues about the biochemical nature of these disorders.   Source:


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