Current Understanding of Biomarkers in Post Traumatic Stress Disorder and Mild Traumatic Brain Injury: A Systematic Review and Implications for Research and Treatment

For nearly 100 years, it was erroneously believed that the loss of consciousness and/or the altered mental status associated with a mild traumatic brain injury (mTBI) offered protection from the development of posttraumatic stress disorder (PTSD). However, it is now accepted that it is possible for PTSD to result from mTBI, and that the co-occurrence of these two conditions creates a more difficult condition to treat and worsens prognosis. In addition, it is known that the symptomology associated with PTSD and mTBI have a great deal of overlap, complicating diagnoses. The objective of this chapter is to review the current state of biomarkers aimed at diagnosing comorbid mTBI and PTSD that are useful on a single-patient basis and are not reliant on self-report or arduous interviews. Further, implications for future research and treatment are discussed

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Variation in general supportive and preventive intensive care management of traumatic brain injury: a survey in 66 neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study

Abstract Background General supportive and preventive measures in the intensive care management of traumatic brain injury (TBI) aim to prevent or limit secondary brain injury and optimize recovery. The aim of this survey was to assess and quantify variation in perceptions on intensive care unit (ICU) management of patients with TBI in European neurotrauma centers. Methods We performed a survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We analyzed 23 questions focused on: 1) circulatory and respiratory management; 2) fever control; 3) use of corticosteroids; 4) nutrition and glucose management; and 5) seizure prophylaxis and treatment. Results The survey was completed predominantly by intensivists (n = 33, 50%) and neurosurgeons (n = 23, 35%) from 66 centers (97% response rate). The most common cerebral perfusion pressure (CPP) target was > 60 mmHg (n = 39, 60%) and/or an individualized target (n = 25, 38%). To support CPP, crystalloid fluid loading (n = 60, 91%) was generally preferred over albumin (n = 15, 23%), and vasopressors (n = 63, 96%) over inotropes (n = 29, 44%). The most commonly reported target of partial pressure of carbon dioxide in arterial blood (PaCO2) was 36–40 mmHg (4.8–5.3 kPa) in case of controlled intracranial pressure (ICP) < 20 mmHg (n = 45, 69%) and PaCO2 target of 30–35 mmHg (4–4.7 kPa) in case of raised ICP (n = 40, 62%). Almost all respondents indicated to generally treat fever (n = 65, 98%) with paracetamol (n = 61, 92%) and/or external cooling (n = 49, 74%). Conventional glucose management (n = 43, 66%) was preferred over tight glycemic control (n = 18, 28%). More than half of the respondents indicated to aim for full caloric replacement within 7 days (n = 43, 66%) using enteral nutrition (n = 60, 92%). Indications for and duration of seizure prophylaxis varied, and levetiracetam was mostly reported as the agent of choice for both seizure prophylaxis (n = 32, 49%) and treatment (n = 40, 61%). Conclusions Practice preferences vary substantially regarding general supportive and preventive measures in TBI patients at ICUs of European neurotrauma centers. These results provide an opportunity for future comparative effectiveness research, since a more evidence-based uniformity in good practices in general ICU management could have a major impact on TBI outcome

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Negative consequences of early-life adversity on substance use as mediated by corticotropin-releasing factor modulation of serotonin activity

Early-life adversity is associated with increased risk for substance abuse in later life, with women more likely to report past and current stress as a mediating factor in their substance use and relapse as compared to men. Preclinical models of neonatal and peri-adolescent (early through late adolescence) stress all support a direct relationship between experiences of early-life adversity and adult substance-related behaviors, and provide valuable information regarding the underlying neurobiology. This review will provide an overview of these animal models and how these paradigms alter drug and alcohol consumption and/or seeking in male and female adults. An introduction to the corticotropin-releasing factor (CRF) and serotonin systems, their development and their interactions at the level of the dorsal raphe will be provided, illustrating how this particular stress system is sexually dimorphic, and is well positioned to be affected by stressors early in development and throughout maturation. A model for CRF-serotonin interactions in the dorsal raphe and how these influence dopaminergic activity within the nucleus accumbens and subsequent reward-associated behaviors will be provided, and alterations to the activity of this system following early-life adversity will be identified. Overall, converging findings suggest that early-life adversity has long-term effects on the functioning of the CRF-serotonin system, highlighting a potentially important and targetable mediator linking stress to addiction. Future work should focus on identifying the exact mechanisms that promote long-term changes to the expression and activity of CRF receptors in the dorsal raphe. Moreover, it is important to clarify whether similar neurobiological mechanisms exist for males and females, given the sexual dimorphism both in CRF receptors and serotonin indices in the dorsal raphe and in the behavioral outcomes of early-life adversity. Keywords: Early-life stress, Drug reward, Sex differences, Corticotropin-releasing factor, Dorsal raphe nucleus, Serotoni

Iron Oxide Nanoparticle Delivery of Peptides to the Brain: Reversal of Anxiety during Drug Withdrawal

Targeting neuropeptide systems is important for future advancements in treatment of neurological and psychiatric illnesses. However, many of the peptides and their analogs do not cross the blood-brain barrier (BBB) efficiently. Nanoparticles such as iron oxide can cross the BBB, and here we describe a novel method for the conjugation of a peptide antisauvagine-30 (ASV-30) to iron oxide nanoparticles. Previous research has shown that direct infusion of ASV-30 into the brain reduces anxiety-like behavior in animal models via actions on corticotropin releasing factor type 2 (CRF2) receptors. Therefore, we tested whether iron oxide+ASV-30 complexes cross the BBB of rats and then determined whether iron oxide+ASV-30 nanoparticles are localized with CRF2-expressing neurons. Finally we tested the hypothesis that systemic infusion of iron oxide+ASV-30 can reduce anxiety-like behavior. First we describe the synthesis and demonstrate the stability of iron oxide-peptide nanoparticle complexes. Next, nanoparticles (87.7 μg/kg Fe2O3) with or without ASV-30 (200 μg/kg, ip) were injected into male rats 30 min prior to transcardial perfusion and brain fixation for immunohistochemical analysis, or before testing on the elevated plus maze (EPM) in an amphetamine withdrawal model of anxiety. Systemically administered iron oxide+ASV-30 particles were present in the brain and associated with neurons, including those that express CRF2 receptors, but did not localize with the iron storage protein ferritin. Furthermore, systemic administration of ironoxide+ASV-30 reduced amphetamine withdrawal-induced anxiety without affecting locomotion, suggesting that the anxiolytic effects of ASV-30 were preserved and the bioavailability of ASV-30 was sufficient. The findings demonstrate a novel approach to peptide delivery across the BBB and provide insight as to the neural distribution and efficacy of this nanotechnology

Amphetamine Withdrawal Differentially Increases the Expression of Organic Cation Transporter 3 and Serotonin Transporter in Limbic Brain Regions

Amphetamine withdrawal increases anxiety and stress sensitivity related to blunted ventral hippocampus (vHipp) and enhances the central nucleus of the amygdala (CeA) serotonin responses. Extracellular serotonin levels are regulated by the serotonin transporter (SERT) and organic cation transporter 3 (OCT3), and vHipp OCT3 expression is enhanced during 24 hours of amphetamine withdrawal, while SERT expression is unaltered. Here, we tested whether OCT3 and SERT expression in the CeA is also affected during acute withdrawal to explain opposing regional alterations in limbic serotonergic neurotransmission and if respective changes continued with two weeks of withdrawal. We also determined whether changes in transporter expression were confined to these regions. Male rats received amphetamine or saline for two weeks followed by 24 hours or two weeks of withdrawal, with transporter expression measured using Western immunoblot. OCT3 and SERT expression increased in the CeA at both withdrawal timepoints. In the vHipp, OCT3 expression increased only at 24 hours of withdrawal, with an equivalent pattern seen in the dorsomedial hypothalamus. No changes were evident in any other regions sampled. These regionally specific changes in limbic OCT3 and SERT expression may partially contribute to the serotonergic imbalance and negative affect during amphetamine withdrawal

Relationships between Freezing of Gait Severity and Cognitive Deficits in Parkinson’s Disease

Freezing of gait (FOG) is one of the most debilitating motor symptoms experienced by patients with Parkinson’s disease (PD), as it can lead to falls and a reduced quality of life. Evidence supports an association between FOG severity and cognitive functioning; however, results remain debatable. PD patients with (PDFOG+, n = 41) and without FOG (PDFOG–, n = 39) and control healthy subjects (n = 41) participated in this study. The NIH toolbox cognition battery, the Montreal Cognitive Assessment (MoCA), and the interval timing task were used to test cognitive domains. Measurements were compared between groups using multivariable models and adjusting for covariates. Correlation analyses, linear regression, and mediation models were applied to examine relationships among disease duration and severity, FOG severity, and cognitive functioning. Significant differences were observed between controls and PD patients for all cognitive domains. PDFOG+ and PDFOG– exhibited differences in Dimensional Change Card Sort (DCCS) test, interval timing task, and MoCA scores. After adjusting for covariates in two different models, PDFOG+ and PDFOG– differed in both MoCA and DCCS scores. In addition, significant relationships between FOG severity and cognitive function (MoCA, DCCS, and interval timing) were also found. Regression models suggest that FOG severity may be a predictor of cognitive impairment, and mediation models show the effects of cognitive impairment on the relationship between disease severity and FOG severity. Overall, this study provides insight into the relationship between cognitive and FOG severity in patients with PD, which could aid in the development of therapeutic interventions to manage both