Assessment of Multiple Concussive Athletes with Dual Task Triple Stroop and Aerobic Exercise

BACKGROUND: Athletic concussion testing has mostly recently relied on a sedentary computer neurocognitive test battery called the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). Previous tests directly compare baseline with post-concussion analysis of patient in regards to different cognitive aspects including; working memory, processing speed, and response time. No physical tests are included in the ImPACT analysis for return-to-play action. PURPOSE: In previous studies from our lab in these populations we concluded that the combination of a physical neural impediment with cognitive tests (dual-task with balance impairment) created a greater degree of impairment not observed in the sedentary ImPACT test. However, changes in the Post-concussed group were significant but not statistically significant in the participants with 5 or more concussions without a concussion diagnosed in the past month. Thus we hypothesized that increasing the degree of neural impediment with exercise at a moderate workload during treadmill exercise while completing a neurocognitive test (Triple Stroop) would show a higher cognitive impairment in the Post-concussed participants. METHODS: In this test participants were asked to come back to the lab within a week of completing their hour long cognitive battery to assess potential neurocognitive deficits of post concussive symptoms similar to our previous work. During the follow-up visit that participants completed the battery of Triple Dual Task Stroop while on a treadmill. After a brief 4 minute walking warm up, participants were tasked with increasing their speed in one minute speed increases until they reached their age and resting heart rate calculated 60% of heart rate reserve. At that point they were given a random sequence from the 4 possible patterns of the Triple Stroop 120 question cognitive test which asks the shape, color of the work, the word color, and/or the color of the shape. RESULTS: Of those who participated in the study (9 non-concussed and 7 multi-concussed) there is significant differneces in the cognitive deficites between the two groups of control and multi-concussed tested. However, there is a time deficit on average in the multi-concussed group, 108 seconds to complete as opposed to the non-concussed (84 sec) In addition the number of correct per minute was higher in the control than the multi-concussed group.DISCUSSION: These results have shown that it takes multi-concussed participants a greater time to process the cognitive testing while having the distraction of a physical test. The ultimate concern associated with the cognitive and reaction time deficits can be that atheltic trainers and/or coaches are allowing their athletes to participate in the event placing the athlete at a greater risk for additional head injury in sports with higher incidence of concussion including football, basketball, soccer and hockey. In addition to testing non-concussed and multi-concussed athletes, we aim to conduct the procedure on those who are recently diagnosed as post-concussed to determin whether a more appropriate field test like the Triple Stroop would show a more sensitive assessment of cognitive deficit in sports concussion protocols

Baseline and Post-concussive Neurocognitive and Physiological Assessments in Minor Student Athletes

BACKGROUND: There is a higher risk of post-concussion syndrome among minor athletes. This has resulted in The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), which is currently the primary test for collegiate and high school athletes for concussion assessment and return to play. Previous work from our lab has indicated a significant detection of cognitive deficit with a battery of cognitive testing including the Test of Variables of Attention (TOVA) and dual task testing incorporating balance testing along with the Stroop and number recall. In the previous findings these tests identified cognitive decline including reaction time and fine motor deficiencies either not tested by the ImPACT or determined non-deficient in the Post-concussive participants already determined fit to return to play. However the results from the ImPACT are variable and may not be sensitive enough to detect the same abnormalities in younger minor patients. PURPOSE: To determine whether there is a significant difference in neurocognitive function between prepubescent and pubescent minor students age 10-18 during our battery of cognitive testing and if there is a greater decline in function in young minor athletes. Additionally we aimed to compare baseline and post-concussed minors in order to determine whether mild traumatic brain injury causes a change in neurocognitive abilities. METHODS: Participants were asked to perform the measurements of the SCAT 3, the dual task Stroop, Minnesota Spatial Recognition (MSR) test, the Perdue Peg Board (PPB), a Reaction Time test (RTT) using a weighted dowel, and the administration of the TOVA to assess the Attention Comparison Score: a composite cutoff score comparing the subject’s performance to a study of independently diagnosed ADHD individual. RESULTS: Significant declines between the minor concussed and controls were found in the incorrect answers during the Stroop and the follow-up balanced dual task Stroop, Hopkins Verbal Learning Task, dominant right hand RTT, and MSR time and increasing errors for both hands. When comparing the pubescent and pre-pubescent boys control groups there is a significant negative scoring in pre-pubescent scores on left had RTT, Stroop errors, PPB mistakes, MSR mistakes and time, Dual-task Stroop balance error and number balance correction foot taps. Finally, the TOVA Attention Comparison Score in the concussed versus non-concussed minors indicates a significant difference with the concussed indicating symptoms of moderate ADHD. CONCLUSION: The complexities of a large cognitive battery for assessing concussive symptoms for return to play protocols for the minor athletes have been shown in the results from this study. As hypothesized the hour long battery indicates a broad area of significant identification markers of neurocognitive and neurophysiological dysfunction compared to non-concussed. The tests also reveal the difficulties in assessing concussive symptoms in minor athletes as there are a large number of differences in the battery between pre-pubescent and pubescent children

Exposure of Monocytic Cells to Lipopolysaccharide Induces Coordinated Endotoxin Tolerance, Mitochondrial Biogenesis, Mitophagy, and Antioxidant Defenses

In order to limit the adverse effects of excessive inflammation, anti-inflammatory responses are stimulated at an early stage of an infection, but during sepsis these can lead to deactivation of immune cells including monocytes. In addition, there is emerging evidence that the up-regulation of mitochondrial quality control mechanisms, including mitochondrial biogenesis and mitophagy, is important during the recovery from sepsis and inflammation. We aimed to describe the relationship between the compensatory immune and mitochondrial responses that are triggered following exposure to an inflammatory stimulus in human monocytic cells. Incubation with lipopolysaccharide resulted in a change in the immune phenotype of THP-1 cells consistent with the induction of endotoxin tolerance, similar to that seen in deactivated septic monocytes. After exposure to LPS there was also early evidence of oxidative stress, which resolved in association with the induction of antioxidant defenses and the stimulation of mitochondrial degradation through mitophagy. This was compensated by a parallel up-regulation of mitochondrial biogenesis that resulted in an overall increase in mitochondrial respiratory activity. These observations improve our understanding of the normal homeostatic responses that limit the adverse cellular effects of unregulated inflammation, and which may become ineffective when an infection causes sepsis

Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family.

The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease

Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family

The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease

Metabolic effects of bezafibrate in mitochondrial disease

Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600-1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV-immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF-21), growth and differentiation factor 15 (GDF-15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long-term sequelae

The highly prevalent BRCA2 mutation c.2808_2811del (3036delACAA) is located in a mutational hotspot and has multiple origins

BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germ line mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with 11 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 [west Castilla y León (WCL)], 20 [east Castilla y León (ECL)] and 6 (South of Spain) families. Mutation age was estimated with the Disequilibrium Mapping using Likelihood Estimation software in a range of 45–68 and 45–71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G > A, were located in a double-hairpin loop structure (c.2794–c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923 bp fragment of BRCA2, and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G > A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin loop of c.2808_2811del, and one affected the same position (c.2808A > G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG, BRCA2- c.5946delT and c.8537delAG, are concentrated in hairpin loops, suggesting that these structures may represent mutational hotspots

Genetic variation in the TLL1 gene is not associated with fibrosis in patients with metabolic associated fatty liver disease

Metabolic associated fatty liver disease (MAFLD) is the most prevalent liver disease in Western nations, with high heritability. A recent study of Japanese patients with the disease suggested that TLL1 rs17047200 is associated with fibrosis; whether a similar association is observed in Caucasian patients with MAFLD is unknown. We investigated the association of the TLL1 rs17047200 polymorphism with liver fibrosis in a cohort of Caucasian patients with MAFLD (n = 728). We also investigated whether TLL1 expression is altered during liver injury in humans, in murine models of fibrosis, and in in-vitro. While TLL1 expression is upregulated in the liver of humans with MAFLD and in mice, the rs17047200 variant was not associated with fibrosis or any other histological features, or with hepatic TLL1 expression. In conclusion, the TLL1 rs17047200 variant is not a risk variant for fibrosis in Caucasian patients with MAFLD. However, TLL1 could be involved in the pathogenesis of liver fibrosis