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

OBJECTIVE: The objective of the study is to measure plasma and exosomal levels of tau, phosphorylated tau (p-tau), and amyloid beta (Aß) in Veterans with historical mild traumatic brain injury (mTBI) and chronic neuropsychological symptoms. METHODS: Tau, p-tau, Aß40, and Aß42 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.

Hypoaminoacidemia Characterizes Chronic Traumatic Brain Injury.

Individuals with a history of traumatic brain injury (TBI) are at increased risk for a number of disorders, including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. However, mediators of the long-term morbidity are uncertain. We conducted a multi-site, prospective trial in chronic TBI patients (∼18 years post-TBI) living in long-term 24-h care environments and local controls without a history of head injury. Inability to give informed consent was exclusionary for participation. A total of 41 individuals (17 moderate-severe TBI, 24 controls) were studied before and after consumption of a standardized breakfast to determine if concentrations of amino acids, cytokines, C-reactive protein, and insulin are potential mediators of long-term TBI morbidity. Analyte concentrations were measured in serum drawn before (fasting) and 1 h after meal consumption. Mean ages were 44 ± 15 and 49 ± 11 years for controls and chronic TBI patients, respectively. Chronic TBI patients had significantly lower circulating concentrations of numerous individual amino acids, as well as essential amino acids (p = 0.03) and large neutral amino acids (p = 0.003) considered as groups, and displayed fundamentally altered cytokine-amino acid relationships. Many years after injury, TBI patients exhibit abnormal metabolic responses and altered relationships between circulating amino acids, cytokines, and hormones. This pattern is consistent with TBI, inducing a chronic disease state in patients. Understanding the mechanisms causing the chronic disease state could lead to new treatments for its prevention.

Brief communication: pituitary volume and function in competing and retired male boxers.

BACKGROUND: Pituitary consequences of chronic head trauma in boxing have not been investigated in detail. OBJECTIVE: To investigate the pituitary function in retired or active amateur boxers. DESIGN: Cross-sectional, observational study. SETTING: Turkey. PARTICIPANTS: 61 actively competing (n = 44) or retired (n = 17) male boxers of the Turkish National Boxing Team. MEASUREMENTS: Body composition variables, pituitary volume (in 38 of 61 boxers), and pituitary function. RESULTS: 9 of 61 boxers (15%) had growth hormone (GH) deficiency and 5 of 61 boxers (8%) had adrenocorticotropic hormone deficiency. All boxers with GH deficiency except 1 were retired from boxing. Of 17 retired boxers, 8 (47%) had GH deficiency. Retired boxers with GH deficiency had significantly lower pituitary volume than retired boxers with normal GH. LIMITATION: Pituitary volume was measured in only 38 of 61 boxers, and the study had no comparison group. CONCLUSION: This study suggests that retired boxers have a high rate of pituitary dysfunction. Therefore, investigation of pituitary function in boxers, particularly retired ones, is recommended.

Diagnostic value of Elecsys S100 as a marker of acute brain injury in the emergency department.

The aim of this study was to evaluate the screening and diagnostic validity of the initial serum S100 levels by Elecsys S100 immunoassay in an emergency department. We measured serum S100 in 101 acute brain injury (ABI) patients, in 40 healthy subjects, and in 41 chronic brain injury (CBI) patients (the control group). The ABI patients were divided in several groups according to the Glasgow Coma Scale (GCS), injury type and findings of brain imaging. Of the 101 patients, the 66 cranial computed tomography (CCT) or brain magnetic resonance imaging (MRI)-positive patients showed higher S100 levels than did the 35 CCT/MRI-negative patients (P=0.028). At a cutoff of 0.105 microg/L, the sensitivity was 84.8% and the specificity 74.3% for all of the ABI patients, and the sensitivity was increased to 96.9% for the traumatic ABI patients for detecting image-positive ABI. There was no significant difference of S100 levels among the groups on the CCT or MRI pathological findings (P=0.478). In conclusion, serum S100 levels can be used in the emergency department as an additional screening tool to identify CCT- or MRI-positive ABI.

Blood 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and melatonin levels in patients with either Huntington's disease or chronic brain injury.

Following a study of oxidative tryptophan metabolism to kynurenines, we have now analysed the blood of patients with either Huntington's disease or traumatic brain injury for levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and melatonin. There were no differences in the baseline levels of these compounds between patients and healthy controls. Tryptophan depletion did not reduce 5-HT levels in either the controls or in the patients with Huntington's disease, but it increased 5-HT levels in patients with brain injury and lowered 5-HIAA in the control and Huntington's disease groups. An oral tryptophan load did not modify 5-HT levels in the patients but increased 5-HT in control subjects. The tryptophan load restored 5-HIAA to baseline levels in controls and patients with brain injury, but not in those with Huntington's disease, in whom 5-HIAA remained significantly depressed. Melatonin levels increased on tryptophan loading in all subjects, with levels in patients with brain injury increasing significantly more than in controls. Baseline levels of neopterin and lipid peroxidation products were higher in patients than in controls. It is concluded that both groups of patients exhibit abnormalities in tryptophan metabolism, which may be related to increased inflammatory status and oxidative stress. Interactions between the kynurenine, 5-HT and melatonin pathways should be considered when interpreting changes of tryptophan metabolism.

Hemodynamic steroid responsiveness is predictive of neurological outcome after traumatic brain injury.

INTRODUCTION: To determine the impact of physiologic doses of hydrocortisone on neurologic outcome after traumatic brain injury (TBI). METHODS: We conducted a retrospective study in a neurocritical care unit at a university teaching hospital. We included 29 patients with moderate and severe TBI requiring vasoactive drugs to maintain adequate arterial blood pressure who received corticosteroid. Infected patients were excluded. Blood cortisol levels were measured before and 30 and 60 minutes after the administration of a high-dose corticotropin stimulation test (HDST). Patients received hydrocortisone replacement therapy (200-300 mg/day) and vasoactive drugs requirements were noted. Intracranial pressure was managed according to a predefined protocol. RESULTS: A total of 14 out of 29 (48%) of patients were classified as responders to hydrocortisone (stopping vasoactive drugs within 3 days of starting hydrocortisone). The Glasgow Outcome Score (GOS) was used to assess neurologic outcome at 6 months. A favorable outcome (GOS 4 and 5) was observed in 11 out of 14 (79%) of responders and five out of 15 (33%) of nonresponders (p = 0.03). Of the responders, 12 out of 14 (85%) had a baseline cortisol below 414 nmol/L, and five out of 14 (36%) had primary adrenal insufficiency (AI) (primary AI: low baseline cortisol, and poor response to the HDST). Age, severity of injury, and response to hydrocortisone were predictive of outcome in multiple logistic regression analysis. CONCLUSIONS: Adrenal insufficiency is frequent after TBI, and hydrocortisone replacement therapy seems to be associated with a favorable neurologic outcome.

Orally disintegrating olanzapine for the treatment of psychotic and behavioral disturbances associated with dementia.

Orally disintegrating olanzapine is a recently marketed form of olanzapine that dissolves rapidly on contact with saliva. We describe six demented patients resistant to treatment with common oral antipsychotic medications who were successfully treated with the formulation. The importance of these case reports is to make physicians aware that orally disintegrating olanzapine may be useful for the management of psychobehavioral disturbances in demented patients who resist or have difficulty taking standard oral medications.

Traumatic brain injury: influence of blood alcohol level on post-acute cognitive function.

Alcohol intoxication frequently contributes to the occurrence of traumatic brain injury. Few studies, however, have examined whether acute pre-injury alcohol intoxication or premorbid history of alcohol abuse exacerbate cognitive impairments that commonly result from traumatic brain injury. This study examined the influence of blood alcohol level at time of hospital admission on cognitive functioning during the post-acute stage of recovery from traumatic brain injury. After controlling for pre-injury history of alcohol abuse, hospital admission blood alcohol level was predictive of poorer delayed verbal memory, greater decrement in verbal memory over time, and poorer visuospatial functioning. Moreover, there were non-significant trends for higher blood alcohol levels to predict poorer performance on measures of immediate verbal memory and perseveration.