Faculty Bibliography

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.

BACKGROUND: Approximately 3.8 million sports related TBIs occur per year. Genetic variation may affect both TBI risk and post-TBI clinical outcome. Limited research has focused on genetic risk for concussion among athletes. We describe the design, methods, and baseline characteristics of this prospective cohort study designed to investigate a potential association between genetic polymorphisms of apolipoprotein E gene, APOE promoter G-219T, and Tau gene exon 6 polymorphisms (Ser53 Pro and Hist47Tyr) with: 1) the risk of prospective concussion; 2) concussion severity; and 3) postconcussion neurocognitive recovery. METHODS: The prospective cohort study included a final population of 2947 college, high school, and professional athletes. Baseline data collection included a concussion/medical history questionnaire, neuropsychological (NP) testing, and genetic sampling for the genetic polymorphisms. Data collection on new concussions experienced utilized post-concussion history/mental status form, Lovell post-concussion symptom score, Standardized Assessment of Concussion (SAC) and/or the Sports Concussion Assessment Tool (SCAT)-1/SCAT-2, and post-concussion NP testing. RESULTS: This paper is focused on discussing the important methodological considerations, organizational challenges and lessons learned in the completion of a multi-center prospective cohort study. A total of 3740 subjects enrolled, with a total of 335 concussions experienced. CONCLUSIONS: Of critical importance to the success of a study of this type is to successfully recruit committed institutions with qualified local study personnel, obtain "buy-in" from study sites, and cultivate strong working relationships with study sites. The use of approved incentives may improve study site recruitment, enhance retention, and enhance compliance with study protocols. Future publications will detail the specific findings of this study. Collaborative research is very likely needed given the nature of this study population.

Abstract 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.

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.

Objective: To investigate associations between genotypes previously found to be associated with traumatic brain injury or other neurological disorders [APOE promoter G-219T, Tau exon 6 Ser53Pro, Tau exon 6 Hist47Tyr, Interleukin (IL)-6, IL-6R 572, PARP-1, tumor necrosis factor alpha (TNFalpha1), and TNF-alpha2] and prospectively occurring and self-reported prior sports-related concussions. Study Design: Multi-center prospective cohort study. Subjects: A total of 3247 college athletes who play football, soccer, and ice hockey at 21 universities. Observation Technique: Participants completed baseline self-report concussion/ medical history questionnaires, provided blood, buccal, or saliva samples for genotyping, were genotyped for the above noted polymorphisms, and were followed prospectively for witnessed acute concussion(s). Outcome Measures: Prospective and self-reported prior concussions. Results: A total of 335 concussions were documented prospectively. Prospective concussions were directly associated with a prior SRP concussion and being a male. By Chi-square analysis, prospectively diagnosed concussions were more common among those with the IL-6R CC genotype (P = 0.01) and less common among those with the IL-6R AA genotype (P = 0.007); and SRP concussions were more common among those with the IL-6R CC genotype (P = 0.07), and tended to be less common among those with an IL-6R A allele (P = 0.11). No statistically significant associations between IL-6 572 or any of the other genotypes with prospective concussion were observed. Conclusions: These findings suggest that persons with an IL-6R CC genotype may be at higher risk for concussion, but provide little support for associations of the other measured genotypes for the APOE, tau, PARP-1, or TNF proteins with concussion risk

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) x 2 (baseline, follow-up), x 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 x 2 x 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

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) <or=6.5, and with no other medical/psychiatric condition that may cause psychological dysfunction were randomized to 30 mg of oral L-amphetamine sulfate or placebo for 29 days, including a dose escalation period. A history of cardiac disease, uncontrolled hypertension or electrocardiograph abnormalities resulted in exclusion. The primary outcomes were the Subject Global Assessment of Change and Symbol Digit Modalities Test (SDMT). Secondary outcomes were the results from the California Verbal Learning Test, second edition (CVLT2), Brief Visual Memory Test-Revised (BVMTR), and Paced Auditory Serial Addition Test (PASAT). One hundred and thirty-six subjects completed the study. No differences were found at baseline in demographics or in the results of the neuropsychological tests. After treatment, the active group performed significantly better for total learning (P = 0.041) and delayed recall (P < 0.01) on the BVMTR, and for delayed recall (P = 0.012) on the CVLT2. Five patients (four from the treatment group, one placebo) withdrew due to intolerable adverse events. L-amphetamine sulfate was associated with improved learning and memory and was well tolerated in this study. However, because the positive findings were observed on secondary outcome measures, the study requires replication before L: -amphetamine sulfate can be recommended for the treatment of cognitive impairment in MS

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

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