In this study we examined the temporal stability of the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) within NCAA Division I athletes across various timepoints using an exhaustive ...series of statistical models.
Within a cohort design, 48 athletes completed repeated baseline ImPACT assessments at various timepoints. Intraclass correlation coefficients (ICC) were calculated using a two-way mixed effects model with absolute agreement.
Four ImPACT composite scores (Verbal Memory, Visual Memory, Visual Motor Speed, and Reaction Time) demonstrated moderate reliability (ICC = 0.51-0.66) across the span of a typical Division I athlete's career, which is below previous reliability recommendations (0.90) for measures used in individual decision-making. No evidence of fixed bias was detected within Verbal Memory, Visual Motor Speed, or Reaction Time composite scores, and minimal detectable change values exceeded the limits of agreement.
The demonstrated temporal stability of the ImPACT falls below the published recommendations, and as such, fails to provide robust support for the NCAA's recommendation to obtain a single preparticipation cognitive baseline for use in sports-related concussion management throughout an athlete's career. Clinical interpretation guidelines are provided for clinicians who utilize baseline ImPACT scores for later performance comparisons.
Concussion or mild traumatic brain injury (mTBI) in athletes can cause persistent symptoms, known as post-concussion syndrome (PCS), and repeated injuries may increase the long-term risk for an ...athlete to develop neurodegenerative diseases such as chronic traumatic encephalopathy (CTE), and Alzheimer's disease (AD). The Center for Disease Control estimates that up to 3.8 million sport-related mTBI are reported each year in the United States. Despite the magnitude of the phenomenon, there is a current lack of comprehensive prognostic indicators and research has shown that available monitoring tools are moderately sensitive to short-term concussion effects but less sensitive to long-term consequences. The overall aim of this review is to discuss novel, quantitative, and objective measurements that can predict long-term outcomes following repeated sports-related mTBIs. The specific objectives were (1) to provide an overview of the current clinical and biomechanical tools available to health practitioners to ensure recovery after mTBIs, (2) to synthesize potential biological mechanisms in animal models underlying the long-term adverse consequences of mTBIs, (3) to discuss the possible link between repeated mTBI and neurodegenerative diseases, and (4) to discuss the current knowledge about fluid biomarkers for mTBIs with a focus on novel exosomal biomarkers. The conclusions from this review are that current post-concussion clinical tests are not sufficiently sensitive to injury and do not accurately quantify post-concussion alterations associated with repeated mTBIs. In the current review, it is proposed that current practices should be amended to include a repeated symptom inventory, a cognitive assessment of executive function and impulse control, an instrumented assessment of balance, vestibulo-ocular assessments, and an improved panel of blood or exosome biomarkers.
Abstract INTRODUCTION Brain‐derived extracellular vesicles (BEVs) in blood allows for minimally‐invasive investigations of central nervous system (CNS) ‐specific markers of age‐related ...neurodegenerative diseases (NDDs). Polymer‐based EV‐ and immunoprecipitation (IP)‐based BEV‐enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS‐specificity of proteins associated with these protocols. METHODS NDD articles investigating BEVs in blood using polymer‐based and/or IP‐based BEV enrichment protocols were systematically identified, and protocols compared. Proteins used for BEV‐enrichment and/or post‐enrichment were assessed for CNS‐ and brain‐cell‐type‐specificity, extracellular domains (ECD+), and presence in EV‐databases. RESULTS A total of 82.1% of studies used polymer‐based (ExoQuick) EV‐enrichment, and 92.3% used L1CAM for IP‐based BEV‐enrichment. Centrifugation times differed across studies. A total of 26.8% of 82 proteins systematically identified were CNS‐specific: 50% ECD+, 77.3% were listed in EV‐databases. CONCLUSIONS We identified protocol steps requiring standardization, and recommend additional CNS‐specific proteins that can be used for BEV‐enrichment or as BEV‐biomarkers. Highlights Across NDDs, we identified protocols commonly used for EV/BEV enrichment from blood. We identified protocol steps showing variability that require harmonization. We assessed CNS‐specificity of proteins used for BEV‐enrichment or found in BEV cargo. CNS‐specific EV proteins with ECD+ or without were identified. We recommend evaluation of blood‐BEV enrichment using these additional ECD+ proteins.
Paralytic shellfish poisons (PSPs) are produced by freshwater cyanobacteria and pose a threat to human and animal drinking‐water supplies. The wide range of toxin analogues (and the likelihood that ...further analogues remain to be discovered) means that chromatographic methods are not always reliable indicators of toxicity. Although the mouse bioassay remains the method of choice in the seafood industry, its use is increasingly being questioned on ethical grounds. The cell‐based Neuro‐2A neuroblastoma toxicity assay is an alternative bioassay validated for testing shellfish extracts, so it was of interest to determine its applicability with the different suite of toxin analogues produced by cyanobacteria. Cyanobacterial bloom samples from Australia, Brazil, and France were assayed using the neuroblastoma assay, liquid chromatography—tandem mass spectrometry (LC‐MS/MS), high‐performance liquid chromatography with postcolumn derivatization and fluorescence detection, and the Jellett Rapid Test for PSP™. To assess interlaboratory variability, the neuroblastoma assay was set up in laboratories in Paris (France) and Adelaide (Australia). Neuroblastoma and chromatographic methods gave comparable results except in the case of the neurotoxic Brazilian samples: LC‐MS/MS did not detect the putative new PSPs contained in these samples. Inter‐ and intralaboratory variability of the neuroblastoma assay was typical of biological assays but no greater than that found for interassay variability between different chromatographic determinations. The batch of Jellett Rapid Tests for PSP used did not yield quantitative results. Overall, the neuroblastoma assay was useful as a screening assay for determination of toxicity caused by saxitoxin neurotoxins in freshwater cyanobacteria, having the advantage of being sensitive to unidentified toxins that currently cannot be quantified by chromatographic means.
An enriched environment is effective in stimulating learning and memory in animal models as well as in humans. Environmental enrichment increases brain-derived neurotrophic factor (BDNF) in aged rats ...and reduces levels of Alzheimer-related proteins in the blood, including amyloid-β (Aβ) peptides and misfolded toxic forms of tau. To address whether stimulation of curiosity, which is a form of enrichment, may provide a buffer against Alzheimer’s disease (AD), we measured levels of biomarkers associated with AD at baseline and after a 6-week intervention in older adults (>65 years of age) randomized to one of three different intervention conditions. Specifically, in this pilot study, we tested the effectiveness of a traditional, structured learning environment compared to a self-motivated learning environment designed to stimulate curiosity. There were no significant differences from baseline to post-intervention in any of the groups for Aβ42/Aβ40 ratio or t-tau (total-tau) plasma levels. Serum BDNF levels decreased significantly in the control group. Interestingly, individuals who had the lowest serum BDNF levels at baseline experienced significantly higher increases in BDNF over the course of the 6-week intervention compared to individuals with higher serum BDNF levels at baseline. As expected, older individuals had lower MoCA scores. Years of education correlated negatively with Aβ levels, suggesting a protective effect of education on levels of this toxic protein. ECog scores were negatively correlated with BDNF levels, suggesting that better performance on the ECog questionnaire was associated with higher BDNF levels. Collectively, these findings did not suggest that a 6-week cognitive training intervention focused on curiosity resulted in significant alterations in blood biomarkers but showed interesting correlations between cognitive scores and BDNF levels, further supporting the role of this trophic factor in brain health in older adults.
Parkinson's disease (PD) is a severe neurological disease for which there is no effective treatment or cure, and therefore it remains an unmet need in medicine. We present data from four participants ...who received autologous transplantation of small pieces of sural nerve tissue into either the basal forebrain containing the nucleus basalis of Meynert (NBM) or the midbrain substantia nigra (SN). The grafts did not exhibit significant cell death or severe host-tissue reaction up to 55 months post-grafting and contained peripheral cells. Dopaminergic neurites showed active growth in the graft area and into the graft in the SN graft, and cholinergic neurites were abundant near the graft in the NBM. These results provide a histological basis for changes in clinical features after autologous peripheral nerve tissue grafting into the NBM or SN in PD.
Anatoxin-a (ANTX) and homoanatoxin-a (HANTX), neurotoxins exclusively produced by cyanobacteria (LD
50 200–250
μg
kg
−1, i.p. mouse), are agonists of the nicotinic acetylcholine receptors (nAChRs) to ...which they tightly bind. We have exploited the high affinity of these neurotoxins for the nicotinic receptors to develop a non-radioactive ligand-binding assay using
Torpedo electrocyte membranes and biotinylated α-bungarotoxin (Biotin-BgTx) as tracer for detection of this class of toxins. The affinity of the
Torpedo nAChRs for Biotin-BgTx was determined by chemiluminescence (
K
d
=
1.2
×
10
−8
M Biotin-BgTx) or color development (
K
d
=
3.5
×
10
−8
M Biotin-BgTx). Binding of ANTX or HANTX to the nAChRs competitively inhibits the binding of Biotin-BgTx to the receptors in a concentration-dependent manner (chemiluminescence: IC
50: 6.2
×
10
−8
M ANTX; color development: IC
50: 1.7
×
10
−8
M ANTX). The proposed method was validated by HPLC/MS with detection in the single ion recording mode. The non-radioactive ligand receptor-binding assay was successfully applied to the analysis of extracts prepared from cyanobacteria in culture and from natural habitats, as well as from aqueous samples. This method is suitable for ANTX and HANTX early survey of environmental samples since it requires minimal manipulations, is highly sensitive and gives consistent signal-to-noise ratios.
Background
Evidence suggests that engagement in cognitively stimulating activities may reduce risk of cognitive deterioration and dementia. Mechanisms underlying these observations remain to be ...determined. Animal research indicates that brain‐derived neurotrophic factor (BDNF) plays an important role in neural plasticity, neurogenesis, synaptic growth, and cognitive performance. Working under the assumption that augmented BDNF levels benefit brain function, investigations of human subjects have focused on determining whether physical or mental activities can increase BDNF levels. Surprisingly little research has been devoted to linking alterations in BDNF to changes in cognition. This study aimed to determine whether changes in BDNF contribute to the enhancement of cognitive performance after computerized cognitive training (CCT). We have demonstrated that five weeks of CCT emphasizing working memory (WM) was associated with improvement on an untrained test of WM/processing speed, the Digit Symbol Test. Here, we investigated whether this improvement was mediated by changes in BDNF levels.
Method
Seventy‐five older adults, ages 65‐86, at two sites (USA and Sweden) were randomized to either Cogmed Adaptive (n=37) or Non‐Adaptive (active control) (n=38) CCT. Under the adaptive CCT, task difficulty was revised on a trial‐by‐trial basis to create a consistently high level of challenge. Under the active control condition, task load remained at a constant, relatively low level. CCT was performed in the homes of participants, five days per week, over five weeks. Serum BDNF levels and performance on Digit Symbol were measured pre‐ and post‐intervention.
Result
Analysis using linear mixed models demonstrated an interaction between time and intervention group for Digit Symbol score (p=.036) and BDNF level (p=.013) Only the adaptive CCT group demonstrated an augmentation of BDNF level (p=.014) and improvement in Digit Symbol scores (p<.001) after training. Mediation analysis revealed that changes in BDNF level accounted for the intervention‐related improvement in performance on Digit Symbol. Regression analysis indicated that changes in BDNF level predicted changes in Digit Symbol score (p=.010).
Conclusion
The results of this investigation suggest that increases in BDNF linked to cognitive training mediate improvement in cognitive performance. Additional research is needed to determine if these findings are specific to WM or are observed in other cognitive domains.
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