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ObjectiveTo examine the characteristics of those who fulfil the recent National Institute of Neurological Disease and Stroke (NINDS) Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome (TES) and test whether they show differences in MRI-based regional brain volumes, cognitive domains, and certain plasma biomarkers.MethodsProfessional fighters 35 years of age or older and/or retired were included. Participants were categorised as either having TES (TES+) or not (non-TES). TES+ participants were further subtyped by their cognitive profile. Multiple linear regression models were used to compare MRI-based regional brain volumes, cognitive performance, plasma tau and neurofilament light levels between TES– and TES+ groups.Results176 participants (110 boxers and 66 MMA) were included in the analysis. 72 (41%)/176 were categorised as having TES, the likelihood of TES increasing with age. TES+ participants tended to be boxers, started fighting at a younger age, had more professional fights and knocked out more frequently. The TES+ group had lower regional brain volumes including both grey and white matter structures. TES+ also had lower scores on simple and choice reaction time, psychomotor speed and Trails A .ConclusionThe new TES criteria does distinguish a group of fighters with differences in regional brain volumes and reduced cognitive function. Our findings support the use of the NINDS criteria for TES in further research of the long-term effects of repetitive head impacts.

ABSTRACTObjectives: Determine, through video reviews, how often concussions occur in combat sport matches, what influence they have on the outcome, and how well non-physician personnel can be trained to recognize concussions.Methods: This is a retrospective video analysis by an 8-person panel of 60 professional fights (30 boxing and 30 mixed martial arts). Through video review, physician and non-physician personnel recorded details about each probable concussion and determined if and when they would have stopped the fight compared to the official stoppage time.Results: A concussion was recorded in 47/60 fights. The mean number of concussions per minute of fight time was 0.061 (0.047 for boxers and 0.085 for MMA). When stratifying by outcome of the bout, the mean number of concussions per minute for the winner was 0.010 compared to the loser at 0.111 concussions per minute. The fighter that sustained the first concussion ultimately lost 98% of the time. The physician and non-physician raters had high agreement regarding the number of concussions that occurred to each fighter per match. The physician raters judged that 24 of the 60 fights (11 boxing [37%]; 13 MMA [43%]) should have been stopped sooner than what occurred.Conclusion: Recognizing that the concussions often occur in combat sport matches, that the losing fighter almost always is concussed first and tends to sustain more concussions during the fight, along with the demonstration that non-physician personnel can be taught to recognize concussion, may guide policy changes that improve brain health in combat sports.

IMPORTANCE: Many studies have investigated the imaging findings showing sequelae of repetitive head trauma, with mixed results. OBJECTIVE: To determine whether fighters (boxers and mixed martial arts fighters) with cavum septum pellucidum (CSP) and cavum vergae (CV) have reduced volumes in various brain structures or worse clinical outcomes on cognitive and mood testing. DESIGN, SETTING, AND PARTICIPANTS: This cohort study assessed participants from the Professional Fighters Brain Health Study. Data were collected from April 14, 2011, to January 17, 2018, and were analyzed from September 1, 2018, to May 23, 2019. This study involved a referred sample of 476 active and retired professional fighters. Eligible participants were at least 18 years of age and had at least a fourth-grade reading level. Healthy age-matched controls with no history of trauma were also enrolled. EXPOSURES: Presence of CSP, CV, and their total (additive) length (CSPV length). MAIN OUTCOMES AND MEASURES: Information regarding depression, impulsivity, and sleepiness among study participants was obtained using the Patient Health Questionnaire depression scale, Barrett Impulsiveness Scale, and the Epworth Sleepiness Scale. Cognition was assessed using raw scores from CNS Vital Signs. Volumes of various brain structures were measured via magnetic resonance imaging. RESULTS: A total of 476 fighters (440 men, 36 women; mean [SD] age, 30.0 [8.2] years [range, 18-72 years]) and 63 control participants (57 men, 6 women; mean [SD] age, 30.8 [9.6] years [range, 18-58 years]) were enrolled in the study. Compared with fighters without CV, fighters with CV had significantly lower mean psychomotor speed (estimated difference, –11.3; 95% CI, –17.4 to –5.2; P = .004) and lower mean volumes in the supratentorium (estimated difference, –31 191 mm3; 95% CI, –61 903 to –479 mm3; P = .05) and other structures. Longer CSPV length was associated with lower processing speed (slope, –0.39; 95% CI, –0.49 to –0.28; P < .001), psychomotor speed (slope, –0.43; 95% CI, –0.53 to –0.32; P < .001), and lower brain volumes in the supratentorium (slope, –1072 mm3 for every 1-mm increase in CSPV length; 95% CI, –1655 to –489 mm3; P < .001) and other structures. CONCLUSIONS AND RELEVANCE: This study suggests that the presence of CSP and CV is associated with lower regional brain volumes and cognitive performance in a cohort exposed to repetitive head trauma.

New treatments for neurodegenerative disease are urgently needed, and clinical trial methods are an essential component of new drug development. Although a parallel-group study design for neurological disorder clinical trials is commonly used to test the effectiveness of a new treatment as compared to placebo, it does not efficiently use information from the on-going study to increase the success rate of a trial or to stop a trial earlier when the new treatment is indeed ineffective.

The results of this study suggest that the imaging biomarkers the authors identified by using a multivariate analysis can be used to detect and track the progression of brain damage related to cognitive decline in subjects with repeated head trauma.

ABSTRACTCombat sports are growing in popularity, viewership, and participation. The nature of these sports involves repetitive head contact, yet unlike most other professional contact sports, there are no endorsed guidelines or mandates for graduated and systematic return to play following concussion. Here, we review the literature related to concussion and fighting sports, and propose guidelines for concussion management and safe return to play following concussion.

The search for disease modifying therapies in Alzheimers disease (AD) has recently led to promising results but also revealed design issues in clinical trials themselves. Of particular importance is the potential statistical challenges that can arise when dosages change after an interim analysis, which is not uncommon in contemporary AD trials. Following the recent Aducanumab trials, we sought to study the implications of dose changes on the statistical power of an AD trial. We conducted extensive simulations to calculate statistical power when the relationship between treatment effect size and time is linear or non-linear, and the investigated drug has delayed treatment effect or not. Statistical power depends on many design factors including the dose change time, correlation, population homogeneity, and treatment effect time. We recommend that researchers conduct simulation studies at the interim analysis to justify the modified sample size and/or follow-up time modification meanwhile the type I and II error rates are controlled.

A personal narrative is presented which explores author's experience of long distance running with brother in the U.S.

The purpose of this study was to determine the frequency of thiamine deficiency in individuals with mild to moderate Alzheimer's disease. We reviewed results of fasting thiamine, cobalamine, and folic [...]

To investigate the vascular contribution to longitudinal changes in Alzheimer disease (AD) biomarkers.

To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS).

BACKGROUND Factors that affect the rate of progression of Alzheimer disease (AD) need to be considered in the clinical trial designs of potential disease-modifying therapies. OBJECTIVE To determine the influence of age on AD course in a clinical trial setting. DESIGN Pooled cohort study from 3 AD clinical trials of 18-month duration conducted by the Alzheimer Disease Cooperative Study group. SETTING Alzheimer disease research centers from across the United States. PATIENTS Four hundred seventy-one subjects with mild to moderate AD assigned to the placebo arm of 3 clinical trials. MAIN OUTCOME MEASURES The relationships between baseline age and rate of change in the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog) 11, Mini-Mental State Examination, Clinical Dementia Rating scale Sum of Boxes score, Alzheimer Disease Cooperative Study–activities of daily living scale, and Neuropsychiatric Inventory were analyzed using a mixed-effect regression model. Sample size calculation for possible future AD clinical trials lasting 18 months using the results of the change in ADAS-cog 11 by tertiles of age groups. RESULTS Older age at baseline was associated with a slower rate of decline in the ADAS-cog 11 and the Mini-Mental State Examination scores. Almost twice as many subjects aged 80 years and older compared with those aged younger than 70 years would be required to demonstrate a 30% treatment effect on the ADAS-cog 11 in an 18-month AD trial. CONCLUSION Subject age is an important factor to consider when defining the study population in and analyzing data from AD trials of potential disease-modifying therapies.

Cerebral microvascular disease may be a risk factor for the development of dementia in elderly persons. We describe the association of retinal microvascular signs with cognitive function and dementia among older individuals.

OBJECTIVES: To examine the association of antihypertensive regimen with magnetic resonance imaging (MRI) white matter hyperintensity and with cognitive impairment in older adults.

Using a telephone survey, patients with probable Alzheimer's disease (n = 31) and vascular dementia (n = 14) were compared with elderly normal controls (n = 43) in preferences for different foods. Patients with Alzheimer's disease had a greater preference than normal controls for relatively high‐fat, sweet foods and for high‐sugar, low‐fat foods, but did not significantly differ in preference for other foods, including those high in complex carbohydrates and protein. Vascular dementia patients showed a similar pattern, not significantly different from that for Alzheimer's patients. Results did not consistently support a hypothesis that increased sweet preference is a nonspecific form of disinhibited behavior related to declining mental status, nor was a hypothesis relating sweet preference to serotonin activity within the brain consistently supported. Results provide preliminary evidence that craving for sweet food may be a significant part of the clinical syndrome of dementia, but further research is needed to delineate the psychological and biological mechanisms accounting for it.

To determine whether progression of MRI-defined vascular disease predicts subsequent vascular events in the elderly.

Restless legs syndrome (RLS) is a poorly understood, often distressing condition that is particularly prevalent among patients with chronic renal failure. A wide variety of medications have been used to treat RLS with variable results. In order to evaluate the efficacy of carbidopa/levodopa therapy, eight consecutive uremic patients with RLS on maintenance hemodialysis were treated with doses ranging from 25/100 to 25/250 twice daily. Six of eight patients obtained satisfactory relief which has continued for 3 months follow-up. Carbidopa/levodopa appears to be an effective option in management of RLS in patients with chronic renal failure.

• Progressive multifocal leukoencephalopathy (PML) occurred in a heterosexual Haitian man with acquired immune deficiency syndrome (AIDS). The patient initially had focal neurologic signs and nonenhancing lesions on a computed tomographic scan. Although PML is rare, it should be included in the differential diagnosis of opportunistic infections associated with AIDS. Brain biopsy is suggested in patients suspected of having PML who might benefit from antiviral therapy.

As even any casual American sports enthusiast can attest, the football season occupies a special position in the popular imagination. Fans flock to stadiums and televisions to watch their teams perform in this increasingly violent contact sport, and among these fans, children may come to idolize star players and be almost irresistibly drawn to the gridiron. Parents and coaches may also exert substantial pressure on children to take up the sport. Whereas the benefits of physical exercise are undeniable for the promotion of cardiovascular health and psychological well-being, participation in football may result in neurologic sequelae ranging from mild traumatic brain injury (mTBI)1to death,2and repetitive mTBI has been associated with a degenerative dementia in later life known as chronic traumatic encephalopathy (CTE).3Football has the highest injury rate among team sports, and given that 70% of all football players in the United States are under the age of 14 and that every child aged 9–12 can be exposed to 240 head impacts during a single football season,4a better understanding of neurobehavioral sequelae among children who play football is urgently needed. Wide gaps exist in our knowledge, but an area of particularly limited information is the long-term outcome of repetitive mTBI among children in whom recovery from the acute event was apparently complete.

ObjectiveCollect head impact dose data in young athletes, using an instrumented mouthguard validated per NFL specification. Compare theses doses with published concussive head impact data.DesignProspective, cross-sectionalSettingCalibrate an instrumented mouthguard head impact dosimeter in laboratory on Hybrid III (HIII) dummy. Collect young athlete non-concussive head impacts on playing field using this dosimeter. Compare these doses to published concussion doses from adult American footballers.ParticipantsYoung American footballers and boxers, n=12, ages 10–21. IRB #13–899.Assessment of risk factorsSingle head impact doses, signs/symptoms of concussion.Outcome measuresNational Football League (NFL) validity specifications for laboratory testing, head kinematics, presence/absence of concussion.Main results177 non-concussive head impact doses were identified. Apparent overlap between non-concussive mouthguard doses and published concussion helmet doses from Rowson et al, (2012) was found. Mouthguard dosimeter meets NFL validity specifications set forth by Siegmund & Guskiewicz et al. (2016) up to 123 g and 7320 rad/s2.ConclusionsThe mouthguard dosimeter meets the NFL laboratory validity specifications. In human tests, 177 non-concussive, asymptomatic head impacts were measured. Young athlete mouthguard-measured head impact doses (up to 62 g, 4470 rad/s2) had apparent overlap with concussion doses reported from adult athletes wearing instrumented helmets. The overlap may be due to individual concussion tolerance variability, differences in dosimeter accuracy, or peak acceleration magnitude being an insufficient concussion metric. Accurate dosimeter monitoring may be useful in the future to limit play once a certain dose is reached, or to identify dangerous impacts that may have not been observed by the caregiver.Competing interestsBartsch/Samorezov/Benzel/Miele – Cleveland Clinic has entered into an exclusive license agreement with Prevent Biometrics for Intelligent Mouthguard technology on which the Authors (AB, SS, EB, VM) are inventors. AB & SS are also paid consultants of Prevent Biometrics.AB, EB and VM are – members of Prevent Biometrics’ Scientific Advisory Panel. Under terms of these agreements there is potential for fee-for-service payments, royalties and/or equity arising from commercialization of head impact measurement and/or head impact safety product(s). The conflicts disclosed here are managed by the Cleveland Clinic Conflict Management Board. Complete details can be found at https://my.clevelandclinic.org/ccf/media/files/About/COI.pdf. These authors also receive research support from the National Institutes of Health, Department of Transportation, Cleveland Clinic, Case Western Reserve University and Rawlings Sporting Goods.Alberts – as of 4/30/2015, Dr. Alberts has reported a financial relationship and may receive future financial benefits from the Cleveland Clinic for inventions or discoveries commercialised through i-COMET Technologies, IncBernick – as of 5/10/2016, Dr. Bernick has reported financial relationships as a paid consultant, speaker or member of an advisory committee for the following companies: Allergan. Dr. Bernick also receives research support from Ultimate Fighting Championship (UFC), Haymon Boxing, Spike TV, Home Box Office Inc. (HBO) and Top Rank Boxing Inc.Brett – Dr. Brett is an Officer in Prevent Biometrics, and sub-awardee on federally funded grants from Cleveland Clinic.Figler, Gray, Russman – None.