Genetic polymorphisms associated with the risk of concussion in 1056 college athletes: a multicentre prospective cohort study.

BACKGROUND/AIM: To evaluate the association of genetic polymorphisms APOE, APOE G-219T promoter, microtubule associated protein(MAPT)/tau exon 6 Ser53Pro, MAPT/tau Hist47Tyr, IL-6572 G/C and IL-6RAsp358Ala with the risk of concussion in college athletes. METHODS: A 23-centre prospective cohort study of 1056 college athletes with genotyping was completed between August 2003 and December 2012. All athletes completed baseline medical and concussion questionnaires, and post-concussion data were collected for athletes with a documented concussion. RESULTS: The study cohort consisted of 1056 athletes of mean±SD age 19.7±1.5 years, 89.3% male, 59.4% Caucasian, 35.0% African-American, 5.6% other race. The athletes participated in American football, soccer, basketball, softball, men's wrestling and club rugby. A total of 133 (12.1% prevalence) concussions occurred during an average surveillance of 3 years per athlete. We observed a significant positive association between IL-6R CC (p=0.001) and a negative association between APOE4 (p=0.03) and the risk of concussion. Unadjusted and adjusted logistic regression analysis showed a significant association between IL-6R CC and concussion (OR 3.48; 95% CI 1.58 to 7.65; p=0.002) and between the APOE4 allele and concussion (OR 0.61; 95% CI 0.38 to 0.96; p=0.04), which persisted after adjustment for confounders. CONCLUSIONS: IL-6R CC was associated with a three times greater concussion risk and APOE4 with a 40% lower risk.

Exposure to sub-concussive head injury in boxing and other sports.

BACKGROUND: Current characterizations of chronic traumatic brain injury (CTBI) in boxing, football and other sports are reviewed in the context of the history of research on sub-concussive brain trauma in athletes. METHODS: The utility of exposure models for understanding CTBI in boxers is examined and concerns regarding the paucity of findings supportive of an exposure model for CTBI in football players are discussed. RESULTS AND CONCLUSIONS: Recommendations for development of exposure models for sport-specific phenotypic characterizations of CTBI are presented.

Reliability and equivalence of alternate forms for the Symbol Digit Modalities Test: implications for multiple sclerosis clinical trials.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS), but is seldom assessed in clinical trials investigating the effects of disease-modifying therapies. The Symbol Digit Modalities Test (SDMT) is a particularly promising tool due to its sensitivity and robust correlation with brain magnetic resonance imaging (MRI) and vocational disability. Unfortunately, there are no validated alternate SDMT forms, which are needed to mitigate practice effects. OBJECTIVE: The aim of the study was to assess the reliability and equivalence of SDMT alternate forms. METHODS: Twenty-five healthy participants completed each of five alternate versions of the SDMT - the standard form, two versions from the Rao Brief Repeatable Battery, and two forms specifically designed for this study. Order effects were controlled using a Latin-square research design. RESULTS: All five versions of the SDMT produced mean values within 3 raw score points of one another. Three forms were very consistent, and not different by conservative statistical tests. The SDMT test-retest reliability using these forms was good to excellent, with all r values exceeding 0.80. CONCLUSIONS: For the first time, we find good evidence that at least three alternate versions of the SDMT are of equivalent difficulty in healthy adults. The forms are reliable, and can be implemented in clinical trials emphasizing cognitive outcomes.

L-amphetamine improves memory in MS patients with objective memory impairment.

BACKGROUND: Memory impairment is prevalent in multiple sclerosis (MS), but no drugs are approved to treat these memory problems. OBJECTIVE: The objective of the study was to examine the effect of l-amphetamine versus placebo on auditory/verbal memory and visual/spatial memory in MS patients with and without baseline memory impairment. METHODS: We conducted a re-analysis of a previously published clinical trial in which MS patients were randomly assigned to treatment (30 mg l-amphetamine, N = 99) or placebo (N = 37) in a four-week, double-blind, parallel-group, dose titration trial. Auditory/verbal memory (CVLT-II: Long Delay Free Recall) and visual/spatial memory (BVMT-R: Delayed Recall) were assessed at baseline and follow-up across subgroups of patients with intact baseline memory (mean = 50th percentile) or impaired baseline memory (mean = 2nd percentile). Primary analyses: 2 (l-amphetamine, placebo) × 2 (baseline, follow-up), × 2 (baseline memory intact, baseline memory impaired) ANOVAs performed separately for auditory/verbal and visual/spatial memory. RESULTS: For both auditory/verbal and visual/spatial memory, we observed significant 2 × 2 × 2 interactions whereby l-amphetamine improved memory more than placebo, and this effect was specific to patients with baseline memory impairment. CONCLUSIONS: Among memory-impaired patients, memory improved about 48.5% for those on l-amphetamine, but only 1.0% on placebo. Treatment with l-amphetamine produced large memory gains among memory-impaired MS patients.

Clinical manifestations, risk factors and prognosis of patients with Morganella morganii sepsis.

BACKGROUND: There are few studies of Morganella bacteremia. We evaluated risk factors and outcome of patients with Morganella bacteremia. METHODS: Medical records of patients with Morganella bacteremia were reviewed (1997-2014). Control group patients with Escherichiacoli sepsis were matched by year of diagnosis and infection acquisition site. RESULTS: The study group included 136 adult patients. Mean age and gender of study and control groups were similar. Complicated soft tissue infection was more prevalent in the study group (30% versus 3.2%, p < 0.05). The Charlson Comorbidity Index (CCI) was higher in the study group (4.3 ± 2.5 versus 3.4 ± 2.8, p < 0.05). Only 78 (62%) of the study patients versus 101 (83%) of the control group (p < 0.05), received appropriate empirical antibiotic treatment. A significantly higher in-hospital mortality rate (42% versus 25%, p < 0.05) as well as longer length of stay (25 ± 22 versus 14 ± 16 days, p < 0.05) was observed in the study group. Multivariate analysis revealed that a debilitative state, a CCI > 4, septic shock and a clinical syndrome other than UTI were all significant risk factors for mortality (p < 0.05). CONCLUSIONS: Patients with Morganellamorganii sepsis had more co-morbidities and a worse degree of sepsis. There is an increased risk of inappropriate empirical treatment, longer hospitalization and higher death rate.

Sex differences in outcome following sports-related concussion.

OBJECT: Females comprise an increasing percentage of the athlete population across all age groups, and analysis of recent literature reveals that they sustain more concussions in collegiate sports. Results of human and animal studies indicate that females may have poorer outcomes after traumatic brain injury; however, no return-to-play guideline takes sex or other individual differences into account. In the present study the authors evaluated the influence of patient sex on objective neurocognitive performance and subjective reporting of symptoms following sports-related concussion. METHODS: According to preseason baseline neurocognitive computerized testing in 2340 male and female high school and collegiate athletes, individuals who sustained sports-related concussions (155 persons) were reevaluated using an alternate form of the cognitive test. Sex differences in the magnitude of cognitive change from baseline levels and the subjective experience of symptoms were analyzed. To account for the possible protective effects of helmets, comparisons were performed among females, males with helmets, and males without helmets; none of the female athletes wore helmets. Female athletes had significantly greater declines in simple and complex reaction times relative to preseason baseline levels, and they reported more postconcussion symptoms compared with males. As a group, females were cognitively impaired approximately 1.7 times more frequently than males following concussions. Furthermore, females experienced more objective and subjective adverse effects from concussion even after adjusting for the use of helmets by some groups of male athletes (for example, in football). CONCLUSIONS: Return-to-play decisions and concussion management must be objective and made on an individual basis, including consideration of factors such as patient sex rather than relying on a one-size-fits-all guideline.

Psychometric properties of the web-based work-readiness cognitive screen used as a neuropsychological assessment tool for schizophrenia.

Traditional neuropsychological tests have been essential in understanding the nature and magnitude of the cognitive deficits associated with schizophrenia. However, current health care practices demand a more cost-effective and time-efficient assessment tool. This study investigates the psychometric properties of the work-readiness cognitive screen (WCS), a web-based neuropsychological measure, as a tool for screening cognitive impairment in schizophrenia, and examines diagnostic group differences in cognitive functioning between those with schizophrenia and affective disorders using the WCS. Data from 185 outpatients with schizophrenia or schizoaffective disorder and 29 outpatients with a mood disorder was analyzed in this study. The 185 people with schizophrenia were further divided into higher- and lower-functioning groups to assess cognition as it relates to daily functioning. People with schizophrenia demonstrated cognitive impairment on the WCS measures of attention, working memory, immediate and delayed visual memory, and verbal recognition memory. The higher-functioning schizophrenia group tended to perform better on the WCS cognitive domains than the low-functioning group. Reliability ranged from moderate to high. Working memory was found to be the most significant factor distinguishing diagnostic groups. These preliminary studies suggest that the WCS is a useful, time- and cost-effective cognitive screening measure for schizophrenia.

Symptom-based assessment of the severity of a concussion.

OBJECT: Current grading systems of concussion and return-to-play guidelines have little empirical support. The authors therefore examined the relationships of the characteristics and symptoms of concussion and the history of concussion to three indicators of concussion severity-number of immediate symptoms, number of symptoms at the initial follow-up examination, and duration of symptoms--to establish an empirical basis for grading concussions. METHODS: Forty-seven athletes who sustained concussions were administered alternate forms of an Internet-based neurocognitive test until their performances were within normal limits relative to baseline levels. Assessments of observer-reported and self-reported symptoms at the sideline of the playing field on the day of injury, and at follow-up examinations were also obtained as part of a comprehensive concussion management protocol. Although loss of consciousness (LOC) was a useful indicator of the initial severity of the injury, it did not correlate with other indices of concussion severity, including duration of symptoms. Athletes reporting memory problems at follow-up examinations had significantly more symptoms in general, longer durations of those symptoms, and significant decreases in scores on neurocognitive tests administered approximately 48 hours postinjury. This decline of scores on neurocognitive testing was significantly associated with an increased duration of symptoms. A history of concussion was unrelated to the number and duration of symptoms. CONCLUSIONS: This paper represents the first documentation of empirically derived indicators of the clinical course of postconcussion symptom resolution. Self-reported memory problems apparent 24 hours postconcussion were robust indicators of the severity of sports-related concussion and should be a primary consideration in determining an athlete's readiness to return to competition. A decline on neurocognitive testing was the only objective measure significantly related to the duration of symptoms. Neither a brief LOC nor a history of concussion was a useful predictor of the duration of postconcussion symptoms.

Development and validation of a web-based neuropsychological test protocol for sports-related return-to-play decision-making.

The Concussion Resolution Index (CRI) is an online assessment tool designed to track resolution of symptoms following sports-related concussion. The CRI is composed of six subtests measuring reaction time, visual recognition, and speed of information processing. Three factors are derived from the subtests: Simple Reaction Time (SRT), Complex Reaction Time (CRT), and Processing Speed (PS). Multiple alternate forms within subtests afford simple, reliable, assessment of change, relative to a baseline test completed by an athlete. The test also assesses self-reported neurophysiological symptoms at the time of injury and tracks resolution of these symptoms. The data demonstrate the CRI is a valid and reliable measure of cognitive performance in a relatively heterogeneous group of athletes aged 13-35. Two methods of statistical analysis for assessing change from baseline were compared to establish a psychometric basis for return-to-play decision-making: the Reliable Change Index (RCI) and multiple regression. Multiple regression was more accurate than the RCI in determining a decline in performance relative to the baseline.

Reliability of a cognitive endpoint for use in a multiple sclerosis pharmaceutical trial.

OBJECTIVE: Determine reliability and basic psychometric properties of a composite cognitive endpoint, MS-COG, for monitoring change in cognitive function in MS drug trials. BACKGROUND: 50% of MS patients have cognitive impairment that impacts ability to work and quality of life. We selected neuropsychological tests based on sensitivity to MS cognitive impairment, availability of alternate forms, cross-cultural utility, and feasibility for multicenter trials, and assessed the reliability and validity of a composite endpoint, MS-COG. DESIGN/METHODS: Administered SRT, BVMT-R, PASAT, and SDMT to 60 MS patients at 4 US centers twice over 45days, along with symptom inventories by patients and informants. RESULTS: The MS-COG had test-retest reliability of 0.91. Processing Speed and Memory indices had reliabilities of 0.89 and 0.86, with modest practice effects. Reliability was high for the RR MS and SP MS subgroups as well, with correlations of .90 and .93, respectively for MS-COG. Overall, 42% of subjects obtained MS-COG scores in the impaired range, with SP MS subjects performing 0.8 SD below RR MS subjects. Impairment correlated well (r=0.37 to 0.40) with informant reports but was inconsistent with patient report, with the least reliable assessments by those with greater symptom severity. CONCLUSIONS: The MS-COG is a reliable, repeatable measure of MS cognitive functioning that is sensitive to cognitive impairment in SP MS and RR MS patients and feasible for multicenter clinical trials. Further development is warranted.

The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial.

Defects in processing speed and memory are common in multiple sclerosis (MS) patients. In other populations, amphetamines have been shown to enhance cognition, but their use is limited by adverse behavioral effects. The L-isomer may have equivalent cognition enhancement with less adverse effects due to decreased potency in subcortical areas. The aim of this study was to assess the safety and efficacy of L-amphetamine sulfate in the treatment of cognitive dysfunction in MS. This was a 2:1 randomized, placebo-controlled, double-blind trial, involving 33 MS clinics across the USA. One hundred and fifty-one clinically definite MS patients with documented cognitive dysfunction who were relapse free for >or=90 days, with an Expanded Disability Status Scale (EDSS)

Development and validation of a web-based screening tool for monitoring cognitive status.

OBJECTIVES: We acquired normative data for an Internet neurocognitive screening tool, the Cognitive Stability Index (CSI), and investigated its validity both for initial assessment and for detecting significant change. PARTICIPANTS: Normative data on a nationally representative sample of 284 individuals aged 18 to 89. Validity data was obtained for outpatient groups of mild-to-moderate TBI, attention deficit/hyperactivity disorder (AD/HD), and Alzheimer's disease. RESULTS: The CSI subtests resolve to four factors: attention, processing speed, motor speed, and memory with acceptable psychometric properties. Patterns of scores obtained by three groups of patient-participants provided reasonable evidence of clinical validity for screening and monitoring change. CONCLUSIONS: An Internet-based system holds promise for applying complex statistical models for routine monitoring of cognitive function.

Monitoring Resolution of Postconcussion Symptoms in Athletes: Preliminary Results of a Web-Based Neuropsychological Test Protocol.

OBJECTIVE: A new Web-based neuropsychological test was field tested to determine usefulness in detecting and monitoring resolution of symptoms after sport-related concussions and in providing objective information for return-to-play decisions. DESIGN AND SETTING: We obtained neuropsychological baseline data on all subjects. After concussion, subjects were administered alternate, equivalent follow-up tests until symptoms resolved. Follow-up testing typically occurred at 1- to 2-day intervals after the concussion. SUBJECTS: Baseline testing was obtained for 834 athletes as part of ongoing field trials. Subsequently, 26 athletes sustained concussions and were studied. MEASUREMENTS: We administered The Concussion Resolution Index (CRI) at baseline and alternate forms posttrauma. Follow-up tests included a self-report inventory of neurophysiologic symptoms. RESULTS: A total of 88% of patients were identified as symptomatic on initial postconcussion testing. The CRI appeared relatively resistant to retest effects, and multiple administrations tracked resolution of symptoms over short and extended time periods. CONCLUSIONS: Although the CRI is still in field trials, preliminary data indicate that the CRI may be a useful method for athletic trainers and other professionals to expeditiously track resolution of symptoms after sport-related concussion.