Localized in vivo H-MRS of traumatic brain injury

¹H-MRS examinations were carried out on 14 patients, recovering from traumatic brain injury (TBI), who were in a stabilized clinical status and showed a good clinical outcome. Magnetic resonance spectra were recorded in subcortical (SC) and mid-brain (MB) areas where no detectable lesions appeared under magnetic resonance imaging. These two brain areas were selected because they are crucial sites of damage due to the physiopathologic mechanisms of TBI. A significant increase in inositol and choline peaks was found in MB compared to a control group of healthy individuals, whereas lower N-acetyl-aspartate peaks in the same area were detected. Reduced levels in the latter metabolite were also evident in the SC area. A significant correlation emerged between the inositol concentration in MB and the Glasgow Coma Scale Score measured just after the trauma. No correlation was found between the Glasgow Outcome Scale (GOS) at the time of the ¹H-MRS examination and the peaks of all the metabolites. Our study demonstrated that ¹H-MRS is a sensitive tool to evidentiate brain metabolic damage after TBI even in areas with lesions that are not detectable with current imaging techniques. The present research also shows an association between the alteration in one of the brain metabolites and the clinical parameters of TBI severity, but does not provide a clinical index of the patient's recovery. Further longitudinal studies on more conspicuous groups of patients with TBI could help to clarify whether metabolite modifications revealed by ¹H-MRS could be predictive of clinical outcome.     

Traumatic brain injury registry in Taiwan

Abstract

Th}s project was designed to examine the epidemiology of traumatic brain injury (TBJ) in Taiwan. A total of 58,563 cases of TBI was collected from 114 hospitals in Taiwan during the period july 1, 1988-june 3D, 1994. Traffic accident was the major cause of TBI (69.4%), followed by falls and assaults. Motorcyclists accounted for the vast majority of TBJ cases among traffic accident victims (64.5%). The Glasgow Coma Scale was used in assessing the severity. 41,646 cases (79.5%) were considered mild, 4,637 cases (8.9%) moderate, and 6,078 cases (11.6%) severe. Skull x-ray showed fracture in 7,663 cases (74.6%). Intracranial hemorrhage was identified in 28.6% of patients receiving CT scanning. Craniotomy was performed in 5,226 cases (9%). The outcome of TBI was determined by the Glasgow Outcome Scale. Death occurred in 2,621 cases (5.4%), vegetative state in 429 cases (0.9%), severe disability in 1,293 cases (2.6%), moderate disability in 1,890 cases (3.9%), and good recovery in 42,596 cases (87.2%).. The severity and outcome were worse than those of Western reports. In order to alleviate this problem, a helmet use persuasion program was conducted by the Police Department in Taipei City from january to june, 1994. Results of this program showed a significant reduction of TBI-related hospitalization, severity and fatality during this period of intervention. This study points out the seriousness of TBI in Taiwan and suggests some approaches and priorities for prevention. [Neural Res 1997; 19: 261–264]     

Fingolimod Therapy in Multiple Sclerosis Leads to the Enrichment of a Subpopulation of Aged NK Cells

Fingolimod is an approved oral treatment for relapsing–remitting multiple sclerosis (RRMS) that modulates agonistically the sphingosin-1-phosphate receptor (S1PR), inhibiting thereby the egress of lymphocytes from the lymph nodes. In this interventional prospective clinical phase IV trial, we longitudinally investigated the impact of fingolimod on frequencies of NK cell subpopulations by flow cytometry in 17 RRMS patients at baseline and 1, 3, 6, and 12 months after treatment initiation. Clinical outcome was assessed by the Expanded Disability Status Scale (EDSS) and annualized relapse rates (ARR). Over the study period, median EDSS remained stable from month 3 to month 12, and ARR decreased compared to ARR in the 24 months prior treatment. Treatment was paralleled by an increased frequency of circulating NK cells, due primarily to an increase in CD56^dimCD94^low mature NK cells, while the CD56^bright fraction and CD127⁺ innate lymphoid cells (ILCs) decreased over time. An unsupervised clustering algorithm further revealed that a particular fraction of NK cells defined by the expression of CD56^dimCD16⁺⁺KIR^+/−NKG2A⁻CD94⁻CCR7^+/−CX₃CR1^+/−NKG2C⁻NKG2D⁺NKp46⁻DNAM1⁺⁺CD127⁺ increased during treatment. This specific phenotype might reflect a status of aged, fully differentiated, and less functional NK cells. Our study confirms that fingolimod treatment affects both NK cells and ILC. In addition, our study suggests that treatment leads to the enrichment of a specific NK cell subset characterized by an aged phenotype. This might limit the anti-microbial and anti-tumour NK cell activity in fingolimod-treated patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01078-7.     

The impact of self-hypnosis and Johrei on lymphocyte subpopulations at exam time: a controlled study

In a prospective randomised controlled trial, 48 students were randomly assigned to stress reduction training before exams with self-hypnosis, Johrei or a mock neurofeedback relaxation control. Peripheral blood lymphocyte subpopulations and self-reported stress (Perceived Stress Scale) were measured before training and 1-2 months later as exams approached. Absolute number and percentages of CD3(+)CD4(+) and CD3(+)CD8(+) T lymphocytes, CD3(-)CD56(+) Natural Killer cells (NK cells) and NK cell cytotoxic activity was measured from venous blood. Stressed participants showed small but significant declines in both CD3(-)CD56(+) NK cell percentages and NK cell cytotoxic activity levels while CD3(+)CD4(+) T cell percentages increased, changes supported by correlations with perceived stress. The effects of stress were moderated in those who learned Johrei at exam time; 11/12 showed increases in CD3(-)CD56(+) NK cell percentages with decreased percentages of CD3(+)CD4(+) T cells, effects not seen in the relaxation control group. Stress was also buffered in those who learned and practised self-hypnosis in whom CD3(-)CD56(+) NK cell and CD3(+)CD4(+) T cell levels were maintained, and whose CD3(+)CD8(+) T cell percentages, shown previously to decline with exams, increased. The results compliment beneficial effects on mood of self-hypnosis and Johrei. The results are in keeping with beneficial influences of self-hypnosis and provide the first evidence of the suggestive value of the Japanese Johrei procedure for stress reduction, which clearly warrants further investigation.     

CSF Bcl-2 and cytochrome C temporal profiles in outcome prediction for adults with severe TBI

The biochemical cascades associated with cell death after traumatic brain injury (TBI) involve both pro-survival and pro-apoptotic proteins. We hypothesized that elevated cerebrospinal fluid (CSF) Bcl-2 and cytochrome C (CytoC) levels over time would reflect cellular injury response and predict long-term outcomes after TBI. Cerebrospinal fluid Bcl-2 and CytoC levels were measured for 6 days after injury for adults with severe TBI (N=76 subjects; N=277 samples). Group-based trajectory analysis was used to generate distinct temporal biomarker profiles that were compared with Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS) scores at 6 and 12 months after TBI. Subjects with persistently elevated temporal Bcl-2 and CytoC profiles compared with healthy controls had the worst outcomes at 6 and 12 months (P⩽0.027). Those with CytoC profiles near controls had better long-term outcomes, and those with declining CytoC levels over time had intermediate outcomes. Subjects with Bcl-2 profiles that remained near controls had better outcomes than those with consistently elevated Bcl-2 profiles. However, subjects with Bcl-2 values that started near controls and steadily rose over time had 100% good outcomes by 12 months after TBI. These results show the prognostic value of Bcl-2 and CytoC profiles and suggest a dynamic apoptotic and pro-survival response to TBI.     

Cognitive moderators in adjustment to chronic illness: Locus of control beliefs following traumatic brain injury

Abstract

Locus of control (LOC) beliefs and quality of life outcomes were assessed in 54 male patients with moderate (n = 32) or severe (n = 22) traumatic brain injuries (TBI). There were no differences in LOC beliefs between the moderate and severe groups as measured by either the Multidimensional Health Locus of Control Scale (MHLC) or the Revised Internal-External Scale (RIES). Correlation coefficients calculated between LOC scales and multidimensional measures of quality of life ranged from -0.22 to 0.42. Multiple regression analyses, in which Glasgow Coma Scale scores and years of education were initially “forced” as the primary initial predictors, indicated that LOC beliefs were related significantly to outcome, even after removing the influence of injury severity and education. The results suggest that postinjury, cognitive factors, such as LOC beliefs, may play an important role in recovery from TBI. Furthermore, these factors may be amenable to intervention by the rehabilitation team in a way that injury-related variables are not.     

Comparison of serum S-100 protein levels following stroke and traumatic brain injury

Temporal changes in serum S-100 protein levels were compared between patients with ischemic stroke, transient ischemic attack (TIA) and traumatic brain injury (TBI). In addition, S-100 levels were correlated with clinical severity and outcome. Measurements were done with a LIA-mat((R)) Sangtec((R)) 100 using an automated immunoluminometric assay. Serum S-100 was measured in 21 stroke patients, 18 TIA patients and ten TBI patients on days 1 (0-24 h), 2, 3, 4, 5 or 6 and 8 or 9. In a control group of 28 healthy volunteers one measurement was done. For the stroke and TIA patients, National Institutes of Health Stroke Scale (NIHSS) scores were obtained on admission and on day 10. For the TBI patients, Glasgow Coma Scale (GCS) scores were obtained on admission and Glasgow Outcome Scale (GOS) scores were obtained after 6 months. Changes in serum S-100 levels over the first 3 days were significantly different between stroke and TBI patients (P=0.014) and between stroke and TIA patients (P=0.006). Peak concentrations of S-100 were most often observed on day 3 or 4 after stroke and on day 1 or 2 after TBI. In the stroke patients individual S-100 peak levels correlated well with the NIHSS score on admission (r=0.58 P=0.014) and the change in NIHSS score between day 10 and day 1 (r=0.65, P=0. 005). In the TBI patients a good correlation between individual peak levels of S-100 and the GCS score on admission (r=-0.81, P=0.010) and the GOS score 6 months after the trauma was found (r=-0.87, P=0. 004). We conclude that there is a significant difference in temporal changes of S-100 levels between ischemic stroke and TBI patients. This suggests different pathophysiological mechanisms. The results of this study further confirm that peak levels of serum S-100 correlate with neurological deficit resulting from either stroke or TBI.     

A population of atypical CD56−CD16+ natural killer cells is expanded in PTSD and is associated with symptom severity

IntroductionPost-traumatic stress disorder (PTSD) has been associated with immune disturbances, including a higher incidence of infections and autoimmune diseases as well as a net pro-inflammatory state. Natural killer (NK) cells, a key component of the innate immune system, have been less well-studied in PTSD despite their importance in immunity.MethodsWe studied two independent samples of combat-exposed male war veterans with or without PTSD, the first (“Discovery Sample”) to generate hypotheses, and the second (“Validation Sample”) to replicate the findings. The Discovery Sample was comprised of 42 PTSD subjects and 42 controls. The Validation Sample was comprised of 25 PTSD subjects and 30 controls. Participants had fasting, morning blood samples collected for examination of the frequency of NK cell subsets, determined by flow cytometry. The current and lifetime Clinician Administered PTSD Scale (CAPS) was used to assess symptom severity. Statistical analyses were adjusted for age and BMI.ResultsPTSD subjects compared to controls had (i) a significantly higher relative frequency of atypical CD56⁻CD16⁺ NK cells in the Discovery Sample (p = 0.027), which was replicated in the Validation Sample (p = 0.004) and the combined sample (p < 0.001), and (ii) a non-significantly lower relative frequency of CD56^brightCD16⁻ NK cells in the two samples (p = 0.082; p = 0.118), which became statistically significant in the combined sample (p = 0.020). Further, within subjects with PTSD of both samples, the relative frequency of atypical CD56⁻CD16⁺ NK cells was near significantly positively correlated with lifetime PTSD severity (p = 0.074).DiscussionThis study is the first to characterize NK cell subsets in individuals with PTSD. The results suggest that combat-exposed men with PTSD exhibit an aberrant profile of NK cells with significantly higher frequencies of an atypical population of CD56⁻CD16⁺ cells and possibly lower frequencies of the functional CD56^brightCD16⁻ NK cell subsets. Higher proportions of dysfunctional CD56⁻CD16⁺ cells have been reported in certain chronic viral infections and in senescent individuals. It is possible that this could contribute to immune dysfunctions and prematurely senescent phenotypes seen in PTSD.     

Mitochondrial heat shock protein 60 is increased in cerebrospinal fluid following pediatric traumatic brain injury

Mitochondrial dysfunction occurs after traumatic brain injury (TBI) and contributes significantly to subsequent cell death. Heat shock protein 60 (hsp60) is a predominantly mitochondrial protein with important homeostatic functions. Induction of hsp60 has been demonstrated in cerebral ischemia models, possibly reflecting mitochondrial stress. We measured hsp60 concentration in the cerebrospinal fluid (CSF) of 34 infants and children after severe TBI and of 7 control patients by ELISA. Peak CSF hsp60 concentration was increased in TBI patients versus controls (0.84 ng/ml, range 0-44.59, vs. 0.0 ng/ml, range 0-0.48; p<0.05). Induction of hsp60 occurred early after the injury. Peak hsp60 concentration was independently associated with the severity of injury, defined as the admission Glasgow Coma Scale score. These data suggest that increased hsp60 in CSF might reflect the severity of early mitochondrial stress or damage after TBI.     

Human Umbilical Cord Blood CD45<Superscript>+</Superscript> Pan-Hematopoietic Cells Induced a Neurotherapeutic Effect in Mice with Traumatic Brain Injury: Immunophenotyping,Comparison of Maternal and Neonatal Parameters,and Immunomodulation

Human umbilical cord blood (HUCB) transplantation has become an alternative cell therapy for hematological and oncological malignancies in the clinic and is considered for neurological disorders. The heterogeneity in the content of the different stem and progenitor cells composing HUCB mononuclear cells (MNC) may influence their engraftment and neurotherapeutic effect. We hypothesized that CD45 pan-hematopoietic marker expression is heterogeneous in MNC, and therefore, CD45⁺ subpopulation enrichment for neurotherapy may provide a tool to overcome cellular variance in different HUCB units. We employed an immunomagnetic separation method to isolate and characterize HUCB CD45⁺ pan-hematopoietic subpopulation and to investigate whether the vaginal or cesarean deliveries influence their neurotherapeutic effect in a traumatic brain injury (TBI) mouse model. Adult C57BL/6J male mice were subjected to moderate TBI and intravenously xenotransplanted with 1?×?10⁶ CD45⁺ cells derived from either vaginal or cesarean HUCB units. A large heterogeneity in the expression of CD45 marker in MNC, both in vaginal and cesarean HUCB units, was found, regardless of the number of live births. A higher expression of hematopoietic markers was found in the CD45⁺ subpopulation while low expressional levels of typical mesenchymal markers were detected. Neurotherapeutic effects, evaluated with an established neurological severity score and novel object recognition test, indicated improved functional motor and memory recovery and found independent of delivery type. Cytokine analysis in extracts of TBI brain cortices indicated an acute immunomodulatory effect by HUCB CD45⁺ subpopulation upon xenotransplantation. These results may provide insights to CD45 marker as a predictor of HUCB units’ quality for neurotherapy in TBI.     

Cortisol kinetics in cerebrospinal fluid during bacterial meningitis

Bacterial meningitis (BM) remains an infectious disease with a significant morbidity and mortality. The aim of this study was to describe the kinetics of cerebrospinal fluid (CSF) cortisol levels during BM and to assess its relationship to disease severity and etiology. A total of 55 patients with BM were enrolled in the study. Elevated CSF cortisol upon admission and its rapid decrease after starting therapy were associated with increased BM severity as assessed by the Acute Physiology and Chronic Health Evaluation II score, the Sequential Organ Failure Assessment score, Glasgow Coma Scale score and the Glasgow Outcome Scale score. The comparison of CSF cortisol according to BM etiology revealed a trend toward higher concentrations in meningitis caused by Streptococcus pneumoniae compared to Neisseria meningitidis. Our results demonstrate that the initially elevated CSF cortisol concentrations decrease rapidly after administration of BM therapy (i.e. antibiotics and dexamethasone). Moreover, this rapid reduction of CSF cortisol was found in patients with high severity scores.     

Post-traumatic hydrocephalus following decompressive hemicraniectomy: Incidence and risk factors in a prospective cohort of severe TBI patients

BackgroundIn severe traumatic brain injury (TBI) patients undergoing decompressive hemicraniectomy (DHC), the rate of post-traumatic hydrocephalus (PTH) is high at 12–36%. Early diagnosis and shunt placement can improve outcomes. Herein, we examined the incidence of and predictors of PTH after craniectomy.MethodsA retrospective analysis of prospectively collected database of severe TBI patients at a single U.S. Level 1 trauma center from May 2000 to July 2014 was performed. Demographics, Injury Severity Score (ISS), Glasgow Coma Scale (GCS), bleeding pattern and time-to-cranioplasty were analyzed. Glasgow Outcome Scale (GOS) scores at 6 and 12-months were studied. Statistical significance was assessed at p < 0.05.ResultsA total of 402 patients were enrolled and 105 patients had DHC. Twenty-two (21.0%) of 105 required ventriculoperitoneal shunt (VPS), compared to 18 (6%) of 297 patients without DHC. There was increased odds ratio for shunting after DHC at 3.62 (95%CI:1.62–8.07; p < 0.01). Mean age at time of DHC was 43.8 ± 17.7 years old, and 81.9% were male. Subdural hematoma (SDH) was most common at 57.1%. Median time from admission to cranioplasty was 63 days. Patients who experienced PTH after DHC were younger (35.5 ± 17.7 versus 46.0 ± 17.7 years, p < 0.01) and had higher ISS scores (35 versus 26, p = 0.04) compared to patients without shunt after DHC.ConclusionsAfter severe TBI requiring hemicraniectomy, shunt-dependent hydrocephalus was 21%. Younger patients and higher ISS score were associated with PTH. Shunt-dependent patients achieved similar 6- and 12-month outcomes as those without PTH. Early diagnosis and shunt placement can enhance long-term neurological recovery.     

Apolipoprotein E epsilon 4 and short-term recovery from predominantly mild brain injury

OBJECTIVE: To determine whether APOE genotype explained variability in short-term recovery from predominantly mild traumatic brain injury (TBI). METHODS: A total of 87 adult patients presenting with mild or moderate TBI to a shock trauma center were enrolled prospectively. A battery of 13 neuropsychological tests was administered twice, at approximately 3 and 6 weeks after injury. Eighty of 87 patients were successfully genotyped for APOE using a buccal swab technique. RESULTS: Ninety percent of study patients had mild TBI (Glasgow Coma Scale score of 13 to 15); 18 (22.5%) had one APOE epsilon 4 and none had two epsilon 4 alleles. After adjusting for potential confounders, patients positive for the APOE epsilon 4 allele had lower mean scores on 12 of 13 neuropsychological outcomes at visit 1 compared with APOE epsilon 4-negative patients. Two of the differences were significant (grooved pegboard test, p = 0.005; paced auditory serial addition task 2.8-second trial, p = 0.004). At visit 2, APOE epsilon 4-positive patients had lower adjusted mean scores on 11 of the 13 neuropsychological outcomes. None of the differences was significant. CONCLUSIONS: APOE genotype may influence the severity of the acute injury. However, with no consistent pattern to the recovery curves, it is not clear if APOE genotype influences the rate of recovery.     

颅脑损伤后氨基末端脑利钠肽前体的应用价值研究

目的探讨血浆氨基末端脑利钠肽前体(NT-pro-BNP)在评估颅脑创伤(TBI)严重程度及颅内压(ICP)增高中的应用价值。方法选择2009年1月到2009年12月收入我院神经外科的63例颅脑创伤患者作为研究对象。收集的资料包括患者的性别、年龄、入院时GCS评分、受伤机制、颅内压数值、总住院天数、重症监护病房(ICU)住院天数。按照患者入院时最初的GCS评分将其分为轻度颅脑创伤组(GCS 13-15,n=14),中度颅脑创伤组(GCS 9-12,n=24),重度颅脑创伤组(GCS 3-8,n=25)三组。应用电化学发光免疫分析技术测定血浆NT-pro-BNP浓度。结果重度颅脑创伤组血浆NT-pro-BNP水平显著高于轻度颅脑创伤组及中度颅脑创伤组(F=12.590,P<0.01)。同ICP控制组(n=15)249.3 pg/ml±103.8 pg/ml及未行ICP监测组(n=40)221.9 pg/ml±142.7 pg/ml相比,ICP增高组(n=5)NT-pro-BNP血浆浓度520.2 pg/ml±153.5 pg/ml可出现显著增高(P<0.01)。血浆NT-pro-BNP水平与GCS评分及ICU住院天数存在相关性。结论颅脑创伤早期血浆NT-pro-BNP水平越高,其伤后颅内压控制难度越大。血浆NT-pro-BNP水平可作为判断颅脑创伤严重程度及颅内压增高程度的一个潜在评估指标,有助于及早预判颅内压增高并及时地对其进行干预。     

Mild head injury: facts and artifacts

While most would agree that mild traumatic brain injury (TBI) is associated with early neuropsychological problems, disagreement exists regarding their persistence and whether they are the cause of the disabilities experienced by some people. The aim of this study was to examine how the criteria used to define mild TBI and how the pre-injury characteristics of people affect their neuropsychological outcome. A total of 157 unselected hospitalized cases with Glasgow Coma Scale scores of 13-15 and 109 trauma controls were prospectively recruited and administered a number of cognitive measures at 1 month and 12 months after injury. The results indicated early impairments that decreased with time and the stringency of the definition of 'mild' TBI. The contribution of demographics was usually significant and often stronger than the mild TBI effect. Subtle variation of the demographics of the brain injured or the comparison subjects can be sufficient to mimic or mask mild brain injury effects.     

The role of microglial activation in the resolution of CNS lesions

Introduction:  Possession of the apolipoprotein E (APOE) ε4 allele is associated with increased deposition of amyloid β-protein in patients who die after traumatic brain injury (TBI) (Nicoll et al . Nat Medical 1995; 1 : 135), and unfavourable outcome after TBI (Teasdale et al . Lancet 1997; 350 : 1069) and subarachnoid haemorrhage (SAH) (Niskakangas et al . Stroke 2001; 32 : 1181). Evidence from experimental brain injury studies confirm that apolipoprotein E (ApoE=protein, APOE=gene) plays an important role in the response of the brain to injury. We report findings from a study testing the hypothesis that ApoE is altered in the cerebrospinal fluid (CSF) of patients after acute brain injury, and these alterations are related to injury severity and clinical outcome.
Materials and methods:  ApoE concentration was determined, by enzyme linked immunosorbant assay, in the CSF of patients with SAH ( N  = 19), TBI ( N  = 13), and controls ( N  = 13) investigated for hydrocephalus or suspected shunt dysfunction. Injury severity was determined using the Glasgow Coma Score (GCS) and clinical outcome using the Glasgow Outcome Score (GOS).
Results:  The concentration of ApoE was significantly lower in the CSF of patients with acute brain injury ( P  < 0.001) compared with controls, and the magnitude of the reduction correlated with injury severity.
Conclusion:  The concentration of ApoE in the CSF decreases substantially after acute brain injury despite the likely leakage of plasma ApoE into the subarachnoid space. We speculate that ApoE is retained within the parenchyma of the brain where it may participate in the injury response.     

An EEG severity index of traumatic brain injury

EEG spectral analyses were conducted from 19 scalp locations for patients with mild (n=40), moderate (n=25), and severe (n=43) traumatic brain injury (TBI), 15 days to 4 years after injury. Severity of TBI was judged by emergency hospital admission records (Glasgow Coma Score and duration of coma and amnesia). Highest-loading EEG variables on each factor that differed significantly between severe and mild TBI by univariate t-test were entered into a multivariate discriminant analysis, yielding 16 variables. Discriminant analysis between mild and severe TBI groups showed classification accuracy of 96.39%, sensitivity 95.45%, and specificity 97.44%. The EEG discriminant score also measured intermediate severity in moderate TBI patients. Results were cross-validated in 503 VA patients. Significant correlations between EEG discriminant scores, emergency admission measures, and post-trauma neuropsychological test scores validated the discriminant function as an index of severity of injury and a classifier of the extremes of severity.