Duration of Posttraumatic Amnesia Predicts Neuropsychological and Global Outcome in Complicated Mild Traumatic Brain Injury.

OBJECTIVES: Examine the effects of posttraumatic amnesia (PTA) duration on neuropsychological and global recovery from 1 to 6 months after complicated mild traumatic brain injury (cmTBI). PARTICIPANTS: A total of 330 persons with cmTBI defined as Glasgow Coma Scale score of 13 to 15 in emergency department, with well-defined abnormalities on neuroimaging. METHODS: Enrollment within 24 hours of injury with follow-up at 1, 3, and 6 months. MEASURES: Glasgow Outcome Scale-Extended, California Verbal Learning Test II, and Controlled Oral Word Association Test. Duration of PTA was retrospectively measured with structured interview at 30 days postinjury. RESULTS: Despite all having a Glasgow Coma Scale Score of 13 to 15, a quarter of the sample had a PTA duration of greater than 7 days; half had PTA duration of 1 of 7 days. Both cognitive performance and Extended Glasgow Outcome Scale outcomes were strongly associated with time since injury and PTA duration, with those with PTA duration of greater than 1 week showing residual moderate disability at 6-month assessment. CONCLUSIONS: Findings reinforce importance of careful measurement of duration of PTA to refine outcome prediction and allocation of resources to those with cmTBI. Future research would benefit from standardization in computed tomographic criteria and use of severity indices beyond Glasgow Coma Scale to characterize cmTBI

Changes in Plasma von Willebrand Factor and Cellular Fibronectin in MRI-Defined Traumatic Microvascular Injury

The neuropathology of traumatic brain injury (TB) is diverse, including primary injury to neurons, axons, glial cells, vascular structures, and secondary processes, such as edema and inflammation that vary between individual patients. Traumatic microvascular injury is an important endophenotype of TBI-related injury. We studied patients who sustained a TBI requiring ER evaluation and had an MRI performed within 48 h of injury. We classified patients into 3 groups based on their MRI findings: (1) those that had evidence of traumatic microvascular injury on susceptibility or diffusion weighted MRI sequences without frank hemorrhage [Traumatic Vascular Injury (TVI) group; 20 subjects]. (2) those who had evidence of intraparenchymal, subdural, epidural, or subarachnoid hemorrhage [Traumatic Hemorrhage (TH) group; 26 subjects], and (3) those who had no traumatic injuries detected by MRI [MRI-negative group; 30 subjects]. We then measured plasma protein biomarkers of vascular injury [von Willebrand Factor (vWF) or cellular fibronectin (cFn)] and axonal injury (phosphorylated neurofilament heavy chain; pNF-H). We found that the TVI group was characterized by decreased expression of plasma vWF (p < 0.05 compared to MRI-negative group; p < 0.00001 compared to TH group) <= 48 h after injury. cFN was no different between groups <= 48 h after injury, but was increased in the TVI group compared to the MRI-negative (p < 0.00001) and TH (p < 0.00001) groups when measured <= 48 h from injury. pNF-H was increased in both the TH and TVI groups compared to the MRI-negative group <= 48 h from injury. When we used the MRI grouping and molecular biomarkers in a model to predict Glasgow Outcome Scale-Extended (GOS-E) score at 30-90 days, we found that inclusion of the imaging data and biomarkers substantially improved the ability to predict a good outcome over clinical information alone. These data indicate that there is a distinct, vascular-predominant endophenotype in a subset of patients who sustain a TBI and that these injuries are characterized by a specific biomarker profile. Further work to will be needed to determine whether these biomarkers can be useful as predictive and pharmacodynamic biomarkers for vascular-directed therapies after TBI

Frontal traumatic brain injury in rats causes long-lasting impairments in impulse control that are differentially sensitive to pharmacotherapeutics and associated with chronic neuroinflammation.

Traumatic brain injury (TBI) affects millions yearly, and is increasingly associated with chronic neuropsychiatric symptoms. We assessed the long-term effects of different bilateral frontal controlled cortical impact injury severities (mild, moderate, severe) on the five-choice serial reaction time task, a paradigm with relatively independent measurements of attention, motor impulsivity and motivation. Moderately- and severely-injured animals exhibited impairments across all cognitive domains that were still evident 14 weeks post-injury, while mild-injured animals only demonstrated persistent deficits in impulse control. However, recovery of function varied considerably between subjects such that some showed no impairment (“TBI-resilient”), some demonstrated initial deficits that recovered (“TBI-vulnerable”) and some never recovered (“chronically-impaired”). Three clinically-relevant treatments for impulsecontrol or TBI, amphetamine, atomoxetine, and amantadine, were assessed for efficacy in treating injury-induced deficits. Susceptibility to TBI affected the response to pharmacological challenge with amphetamine. Whereas sham and TBI-resilient animals showed characteristic impairments in impulse control at higher doses, amphetamine had the opposite effect in chronically-impaired rats, improving task performance. In contrast, atomoxetine and amantadine reduced premature responding but increased omissions, suggesting psychomotor slowing. Analysis of brain tissue revealed that generalized neuroinflammation was associated with impulsivity even when accounting for the degree of brain damage. This is one of the first studies to characterize psychiatric-like symptoms in experimental TBI. Our data highlight the importance of testing pharmacotherapies in TBI models in order to predict efficacy, and suggest that neuroinflammation may represent a treatment target for impulse control problems following injury

MANUSCRIPT IN PRESS: DEMENTIA & GERIATRIC COGNITIVE DISORDERS: Molecular Neuropsychology: Creation of Test-Specific Blood Biomarker Algorithms

Prior work on the link between blood-based biomarkers and cognitive status has largely been based on dichotomous classifications rather than detailed neuropsychological functioning. The current project was designed to create serum-based biomarker algorithms that predict neuropsychological test performance

Can Genetic Analysis of Putative Blood Alzheimer’s Disease Biomarkers Lead to Identification of Susceptibility Loci?

Although 24 Alzheimer’s disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10-7. Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated

Effects of brain tissue oxygen (PbtO2) guided management on patient outcomes following severe traumatic brain injury: A systematic review and meta-analysis.

Monitoring and optimisation of brain tissue oxygen tension (PbtO2) has been associated with improved neurological outcome and survival in observational studies of severe traumatic brain injury (TBI). We carried out a systematic review of randomized controlled trials to determine if PbtO2-guided management is associated with differential neurological outcomes, survival, and adverse events. Searches were carried out to 10 February 2022 in Medline (OvidSP), 11 February in EMBASE (OvidSP) and 8 February in Cochrane library. Randomized controlled trials comparing PbtO2 and ICP-guided management to ICP-guided management alone were included. The primary outcome was survival with favourable neurological outcome at 6-months post injury. Data were extracted by two independent authors and GRADE certainty of evidence assessed. There was no difference in the proportion of patients with favourable neurological outcomes with PbtO2-guided management (relative risk [RR] 1.42, 95% CI 0.97 to 2.08; p = 0.07; I2 = 0%, very low certainty evidence) but PbtO2-guided management was associated with reduced mortality (RR 0.54, 95% CI 0.31 to 0.93; p = 0.03; I2 = 42%; very low certainty evidence) and ICP (mean difference (MD) - 4.62, 95% CI - 8.27 to - 0.98; p = 0.01; I2 = 63%; very low certainty evidence). There was no significant difference in the risk of adverse respiratory or cardiovascular events. PbtO2-guided management in addition to ICP-based care was not significantly associated with increased favourable neurological outcomes, but was associated with increased survival and reduced ICP, with no difference in respiratory or cardiovascular adverse events. However, based on GRADE criteria, the certainty of evidence provided by this meta-analysis was consistently very low. MESH: Brain Ischemia; Intensive Care; Glasgow Outcome Scale; Randomized Controlled Trial; Craniocerebral Trauma

COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury

Mild traumatic brain injury (mTBI) results in variable clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism in catechol-o-methyltransferase (COMT), an enzyme which degrades catecholamine neurotransmitters, may influence cognitive deficits following moderate and/or severe head trauma. However, this has been disputed, and its role in mTBI has not been studied. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val (158) Met polymorphism influences outcome on a cognitive battery 6 months following mTBI--Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), Trail Making Test (TMT) Trail B minus Trail A time, and California Verbal Learning Test, Second Edition Trial 1-5 Standard Score (CVLT-II). All patients had an emergency department Glasgow Coma Scale (GCS) of 13-15, no acute intracranial pathology on head CT, and no polytrauma as defined by an Abbreviated Injury Scale (AIS) score of ≥3 in any extracranial region. Results in 100 subjects aged 40.9 (SD 15.2) years (COMT Met (158) /Met (158) 29 %, Met (158) /Val (158) 47 %, Val (158) /Val (158) 24 %) show that the COMT Met (158) allele (mean 101.6 ± SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val (158) /Val (158) homozygotes (93.8 ± SE 3.0) after controlling for demographics and injury severity (mean increase 7.9 points, 95 % CI [1.4 to 14.3], p = 0.017). The COMT Val (158) Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val (158) Met may preferentially modulate nonverbal cognition following uncomplicated mTBI.Registry: ClinicalTrials.gov Identifier NCT01565551

Multimodal characterization of the late effects of traumatic brain injury: a methodological overview of the Late Effects of Traumatic Brain Injury Project

Epidemiological studies suggest that a single moderate-to-severe traumatic brain injury (TBI) is associated with an increased risk of neurodegenerative disease, including Alzheimer’s and Parkinson’s disease (AD and PD). Histopathological studies describe complex neurodegenerative pathologies in individuals exposed to single moderate-to-severe TBI or repetitive mild TBI, including chronic traumatic encephalopathy (CTE). However, the clinicopathological links between TBI and post-traumatic neurodegenerative diseases such as AD, PD, and CTE remain poorly understood. Here we describe the methodology of the Late Effects of TBI (LETBI) study, whose goals are to characterize chronic post-traumatic neuropathology and to identify in vivo biomarkers of post-traumatic neurodegeneration. LETBI participants undergo extensive clinical evaluation using National Institutes of Health TBI Common Data Elements, proteomic and genomic analysis, structural and functional MRI, and prospective consent for brain donation. Selected brain specimens undergo ultra-high resolution ex vivo MRI and histopathological evaluation including whole mount analysis. Co-registration of ex vivo and in vivo MRI data enables identification of ex vivo lesions that were present during life. In vivo signatures of postmortem pathology are then correlated with cognitive and behavioral data to characterize the clinical phenotype(s) associated with pathological brain lesions. We illustrate the study methods and demonstrate proof of concept for this approach by reporting results from the first LETBI participant, who despite the presence of multiple in vivo and ex vivo pathoanatomic lesions had normal cognition and was functionally independent until her mid-80s. The LETBI project represents a multidisciplinary effort to characterize post-traumatic neuropathology and identify in vivo signatures of postmortem pathology in a prospective study

Effect of TNF-α genetic variants and CCR5Δ32 on the vulnerability to HIV-1 infection and disease progression in Caucasian Spaniards

<p>Abstract</p> <p>Background</p> <p>Tumor necrosis factor alpha (TNF-α) is thought to be involved in the various immunogenetic events that influence HIV-1 infection.</p> <p>Methods</p> <p>We aimed to determine whether carriage of the <it>TNF-α-238G>A, -308G>A </it>and <it>-863 C>A </it>gene promoter single nucleotide polymorphisms (SNP) and the <it>CCR5Δ32 </it>variant allele influence the risk of HIV-1 infection and disease progression in Caucasian Spaniards. The study group consisted of 423 individuals. Of these, 239 were uninfected (36 heavily exposed but uninfected [EU] and 203 healthy controls [HC]) and 184 were HIV-1-infected (109 typical progressors [TP] and 75 long-term nonprogressors [LTNP] of over 16 years' duration). <it>TNF-α </it>SNP and the <it>CCR5Δ32 </it>allele were assessed using PCR-RFLP and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared using the χ 2 test and the Fisher exact test. Haplotypes were compared by logistic regression analysis.</p> <p>Results</p> <p>The distribution of <it>TNF-α-238G>A, -308G>A </it>and <it>-863 C>A </it>genetic variants was non-significantly different in HIV-1-infected patients compared with uninfected individuals: <it>-238G>A</it>, p = 0.7 and p = 0.3; <it>-308G>A</it>, p = 0.05 and p = 0.07; <it>-863 C>A</it>, p = 0.7 and p = 0.4, for genotype and allele comparisons, respectively. Haplotype analyses, however, indicated that carriers of the haplotype H3 were significantly more common among uninfected subjects (p = 0.04). Among the infected patients, the distribution of the three <it>TNF-α </it>genetic variants assessed was non-significantly different between TP and LTNP: <it>-238G>A</it>, p = 0.35 and p = 0.7; <it>-308G>A</it>, p = 0.7 and p = 0.6: <it>-863 C>A</it>, p = 0.2 and p = 0.2, for genotype and allele comparisons, respectively. Haplotype analyses also indicated non-significant associations. Subanalyses in the LTNP subset indicated that the <it>TNF-α-238A </it>variant allele was significantly overrepresented in patients who spontaneously controlled plasma viremia compared with those who had a detectable plasma viral load (genotype comparisons, p = 0.02; allele comparisons, p = 0.03). The <it>CCR5Δ32 </it>distribution was non-significantly different in HIV-1-infected patients with respect to the uninfected population (p = 0.15 and p = 0.2 for genotype and allele comparisons, respectively) and in LTNP vs TP (p = 0.4 and p = 0.5 for genotype and allele comparisons, respectively).</p> <p>Conclusions</p> <p>In our cohort of Caucasian Spaniards, <it>TNF-α </it>genetic variants could be involved in the vulnerability to HIV-1 infection. <it>TNF-α </it>genetic variants were unrelated to disease progression in infected subjects. The <it>-238G>A </it>SNP may modulate the control of viremia in LTNP. Carriage of the <it>CCR5Δ32 </it>variant allele had no effect on the risk of infection and disease progression.</p