Vida Motamedi

Nightmares in United States Military Personnel With Sleep Disturbances

STUDY OBJECTIVES Sleep disturbances are common in United States military personnel. Despite their exposure to combat and trauma, little is known about nightmares in this population. The purpose of this study was to describe the prevalence and associated clinical and polysomnographic characteristics of nightmares in United States military personnel with sleep disturbances. METHODS Retrospective review of 500 active duty United States military personnel who underwent a sleep medicine evaluation and polysomnography at our sleep center. The Pittsburgh Sleep Quality Index and the Pittsburgh Sleep Quality Index-Addendum were used to characterize clinically significant nightmares. Subjective and objective sleep attributes were compared between groups. RESULTS At least weekly nightmares were present in 31.2%; yet, only 3.9% reported nightmares as a reason for evaluation. Trauma-related nightmares occurred in 60% of those patients with nightmares. Patients with nightmares had increased sleep onset latency (SOL) and rapid eye movement (REM) sleep latency (mean SOL/REM sleep latency 16.6/145 minutes, P = .02 and P = .01 respectively) compared to those without (mean SOL/REM sleep latency 12.5/126 minutes). The comorbid disorders of depression (P ≤ .01, relative risk [RR] 3.55 [95% CI, 2.52-4.98]), anxiety (P ≤ .01, RR 2.57 [95% CI, 1.93-3.44]), posttraumatic stress disorder (P ≤ .01, RR 5.11 [95% CI, 3.43-7.62]), and insomnia (P ≤ .01, RR 1.59 [95% CI, 1.42-1.79]) were all associated with nightmares. CONCLUSIONS Clinically significant nightmares are highly prevalent in United States military personnel with sleep disturbances. Nightmares are associated with both subjective and objective sleep disturbances and are frequently comorbid with other sleep and mental health disorders. COMMENTARY A commentary on this article appears in this issue on page 303.

Moderate blast exposure results in increased IL-6 and TNFα in peripheral blood

A unique cohort of military personnel exposed to isolated blast was studied to explore acute peripheral cytokine levels, with the aim of identifying blast-specific biomarkers. Several cytokines, including interleukin (IL) 6, IL-10 and tumor necrosis factor alpha (TNFα) have been linked to pre-clinical blast exposure, but remained unstudied in clinical blast exposure. To address this gap, blood samples from 62 military personnel were obtained at baseline, and daily, during a 10-day blast-related training program; changes in the peripheral concentrations of IL-6, IL-10 and TNFα were evaluated using an ultrasensitive assay. Two groups of trainees were matched on age, duration of military service, and previous history of blast exposure(s), resulting in moderate blast cases and no/low blast controls. Blast exposures were measured using helmet sensors that determined the average peak pressure in pounds per square inch (psi). Moderate blast cases had significantly elevated concentrations of IL-6 (F1,60=18.81, p<0.01) and TNFα (F1,60=12.03, p<0.01) compared to no/low blast controls; levels rebounded to baseline levels the day after blast. On the day of the moderate blast exposure, the extent of the overpressure (psi) in those exposed correlated with IL-6 (r=0.46, p<0.05) concentrations. These findings indicate that moderate primary blast exposure results in changes, specifically acute and transient increases in peripheral inflammatory markers which may have implications for neuronal health.

Exosomes in Acquired Neurological Disorders: New Insights into Pathophysiology and Treatment

Exosomes are endogenous nanovesicles that play critical roles in intercellular signaling by conveying functional genetic information and proteins between cells. Exosomes readily cross the blood-brain barrier and have promise as therapeutic delivery vehicles that have the potential to specifically deliver molecules to the central nervous system (CNS). This unique feature also makes exosomes attractive as biomarkers in diagnostics, prognostics, and therapeutics in the context of multiple significant public health conditions, including acquired neurological disorders. The purpose of this review is to summarize the state of the science surrounding the relevance of extracellular vesicles (EVs), particularly exosomes, to acquire neurological disorders, specifically traumatic brain injury (TBI), spinal cord injury (SCI), and ischemic stroke. In total, ten research articles were identified that examined exosomes in the context of TBI, SCI, or stroke; these manuscripts were reviewed and synthesized to further understand the current role of exosomes in the context of acquired neurological disorders. Of the ten published studies, four focused exclusively on TBI, one on both TBI and SCI, and five on ischemic stroke; notably, eight of the ten studies were limited to pre-clinical samples. The present review is the first to discuss the current body of knowledge surrounding the role of exosomes in the pathophysiology, diagnosis, and prognosis, as well as promising therapeutic strategies in TBI, SCI, and stroke research.

Higher exosomal phosphorylated tau and total tau among veterans with combat-related repetitive chronic mild traumatic brain injury

ABSTRACT Objective: The objective of the study is to measure plasma and exosomal levels of tau, phosphorylated tau (p-tau), and amyloid beta (Aβ) in Veterans with historical mild traumatic brain injury (mTBI) and chronic neuropsychological symptoms. Methods: Tau, p-tau, Aβ40, and Aβ42 were measured by ultrasensitive immunoassay in plasma and exosomes from 195 Veterans enrolled in the Chronic Effects of Neurotrauma Consortium Multicenter Observational Study. Protein biomarkers were compared among groups with and without mTBI with loss of consciousness (LOC) or post-traumatic amnesia (PTA), and also in those with and without repetitive (≥3) mTBI (rTBI) compared to those with 0 (TBI-neg) and 1–2 mTBI. Results: There were no differences in measures of plasma and exosomal protein levels among mTBI with LOC or PTA, mTBI with alteration of consciousness only or TBI-neg. Exosomal tau and exosomal p-tau were elevated in rTBI compared to those with 2 or fewer mTBIs and TBI-neg (p < 0.05). Elevations of exosomal tau and p-tau significantly correlated with post-traumatic and post-concussive symptoms, with exosomal tau also relating specifically to cognitive, affective, and somatic post-concussive symptoms (p < 0.05). Conclusion: rTBI is associated with elevations of exosomal p-tau and exosomal tau, suggesting that blood-based exosomes may provide a peripheral source of informative, centrally derived biomarkers in remote mTBI and that rTBI may contribute to chronic neuropsychological symptoms.

Glial fibrillary acidic protein elevations relate to neuroimaging abnormalities after mild TBI

Objectives To determine whether a panel of blood-based biomarkers can discriminate between patients with suspected mild traumatic brain injury (mTBI) with and without neuroimaging findings (CT and MRI). Methods Study participants presented to the emergency department with suspected mTBI (n = 277) with a CT and MRI scan and healthy controls (n = 49). Plasma concentrations of tau, glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and neurofilament light chain (NFL) were measured using the single-molecule array technology. Results Concentrations of GFAP, tau, and NFL were higher in patients with mTBI, compared with those of controls (ps < 0.01). GFAP yielded an area under the curve (AUC) of 0.93 (95% confidence interval [CI] 0.90–0.96), confirming its discriminatory power for distinguishing mTBI from controls. Levels of GFAP, tau, and NFL were higher in patients with trauma-related intracranial findings on CT compared with those with normal CT, with the only significant predictor being GFAP (AUC 0.77, 95% CI 0.70–0.84). Among patients with mTBI, tau, NFL, and GFAP differentiated subjects with and without MRI abnormalities with an AUC of 0.83, with GFAP being the strongest predictor. Combining tau, NFL, and GFAP showed a good discriminatory power (AUC 0.80, 95% CI 0.69–0.90) for detecting MRI abnormalities, even in patients with mTBI with a normal CT. Conclusion Our study confirms GFAP as a promising marker of brain injury in patients with acute mTBI. A combination of various biomarkers linked to different pathophysiologic mechanisms increases diagnostic subgroup accuracy. This multimarker strategy may guide medical decision making, facilitate the use of MRI scanning, and prove valuable in the stratification of patients with brain injuries in future clinical trials. Classification of evidence Class I evidence that blood concentrations of GFAP, tau, and NFL discriminate patients with mTBI with and without neuroimaging findings.

COMISA (Comorbid Insomnia and Sleep Apnea): a Practical Approach

Purpose of ReviewComorbid insomnia and sleep apnea (COMISA) is prevalent and carries significant morbidity but lacks a standardized diagnostic and therapeutic approach. Through a critical evaluation of the literature, we propose a novel approach to COMISA that incorporates the underlying etiology and existence of different phenotypes in this disorder.Recent FindingsA low arousal threshold and/or hyperarousability may underlie the development of COMISA. Pretreatment symptoms may serve as baseline predictors of response to positive airway pressure therapy in COMISA and differentiate insomnia secondary to OSA from independent insomnia. A variety of therapeutic strategies for COMISA have been put forward with evidence supporting the use of monotherapy or combined therapy in the appropriate clinical setting.SummaryPatients with either OSA or insomnia must be effectively screened for both disorders based on presenting symptoms and response to therapy. Recognition of the underlying etiology of COMISA and the different COMISA phenotypes can guide therapy.

Higher exosomal tau, amyloid-beta 42 and IL-10 are associated with mild TBIs and chronic symptoms in military personnel

ABSTRACT Objective: Identify biomarkers in peripheral blood that relate to chronic post-concussive and behavioural symptoms following traumatic brain injuries (TBIs) to ultimately improve clinical management. Research design: We compared military personnel with mild TBIs (mTBIs) (n = 42) to those without TBIs (n = 22) in concentrations of tau, amyloid-beta (Aβ42) and cytokines (tumour necrosis factor alpha (TNFα, interleukin (IL)-6 and -10) in neuronal-derived exosomes from the peripheral blood. We utilized nanosight technology coupled with ultra-sensitivity immunoassay methods. We also examined the impact of post-concussive and behavioural symptoms including depression and post-traumatic stress disorder (PTSD) on these neuronal-derived markers. Results: We report that concentrations of exosomal tau (F1, 62 = 10.50), Aβ42 (F1, 61 = 5.32) and IL-10 (F1, 59 = 4.32) were elevated in the mTBI group compared to the controls. Within the mTBI group, regression models show that post-concussive symptoms were most related to exosomal tau elevations, whereas exosomal IL-10 levels were related to PTSD symptoms. Conclusions: These findings suggest that chronic post-concussive symptoms following an mTBI relate to altered exosomal activity, and that greater tau pathology may underlie chronic post-concussive symptoms that develop following mTBIs. It also suggests that central inflammatory activity contributes to PTSD symptoms following an mTBI, providing necessary insights into the role of inflammation in chronic PTSD symptoms.