ObjectiveTo systematically review the scientific literature regarding factors to consider when providing advice or guidance to athletes about retirement from contact or collision sport following sport-related concussion (SRC), and to define contraindications to children/adolescent athletes entering or continuing with contact or collision sports after SRC. Data sourcesMedline, Embase, SPORTSDiscus, APA PsycINFO, CINAHL and Cochrane Central Register of Controlled Trials were searched systematically. Study eligibility criteriaStudies were included if they were (1) original research, (2) reported on SRC as the primary source of injury, (3) evaluated the history, clinical assessment and/or investigation of findings that may preclude participation in sport and (4) evaluated mood disturbance and/or neurocognitive deficits, evidence of structural brain injury or risk factors for increased risk of subsequent SRC or prolonged recovery. ResultsOf 4355 articles identified, 93 met the inclusion criteria. None of the included articles directly examined retirement and/or discontinuation from contact or collision sport. Included studies examined factors associated with increased risk of recurrent SRC or prolonged recovery following SRC. In general, these were low-quality cohort studies with heterogeneous results and moderate risk of bias. Higher number and/or severity of symptoms at presentation, sleep disturbance and symptom reproduction with Vestibular Ocular Motor Screen testing were associated with prolonged recovery and history of previous concussion was associated with a risk of further SRC. ConclusionNo evidence was identified to support the inclusion of any patient-specific, injury-specific or other factors (eg, imaging findings) as absolute indications for retirement or discontinued participation in contact or collision sport following SRC. PROSPERO registration numberCRD42022155121.

This study evaluated the intrafractional auto-matching uncertainties of prostate-implanted fiducial markers when using the ExacTrac v6.5 (Brainlab, Feldkirchen, Germany) X-ray stereoscopic system. A customised phantom with 3 implanted gold seeds was initially positioned at the isocentre using a cone beam CT (CBCT) prior to intrafractional imaging. Progressive offsets were applied to the phantom in all six directions (3 translational, 3 rotational) of 0 mm, 1 mm, 2 mm, 0°, 1° and 2°. Subsequently, the ability of the ExacTrac image-matching functions to detect and correct these offsets was tested. For comparison, this procedure was repeated, but without a CBCT for pre-treatment positioning. The auto-matching uncertainties when a CBCT was introduced into the workflow were significantly reduced, and overall, the auto-matching statistics using the implanted marker (seeds) matching function was found to be more precise than the bony anatomy function in-phantom. The total standard deviations for the translational shifts using the implanted marker and bony anatomy functions respectively were 0.1 mm and 0.3 mm vertically, 0.1 mm and 0.3 mm longitudinally, and 0.1 mm and 0.4 mm laterally. The standard deviations for the rotational shifts using the implanted marker and bony anatomy matching functions respectively were 0.2° and 1.2° for the yaw (angle vert), 0.3° and 1.1° for the pitch (angle long), and 0.2° and 1.2° for the roll (angle lat) directions. The reduced uncertainties from introducing a CBCT for initial localisation resulted in decreased probability of inhibits due to false positives during treatment.

Objective To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). Methods A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES, April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). Results Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. Conclusions New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.

BACKGROUND:Auditory naming tests are superior to visual confrontation naming tests in revealing word-finding difficulties in many neuropathological conditions.OBJECTIVE:To delineate characteristics of auditory naming most likely to reveal anomia in patients with dementia, and possibly improve diagnostic utility, we evaluated a large sample of patients referred with memory impairment complaints.METHODS:Patients with dementia (N = 733) or other cognitive impairments and normal individuals (N = 69) were evaluated for frequency of impairment on variables of the Auditory Naming Test (ANT) of Hamberger & Seidel versus the Boston Naming Test (BNT).RESULTS:Naming impairment occurred more frequently using the ANT total score (φ= 0.41) or ANT tip-of-the tongue score (TOT; φ= 0.19) but not ANT mean response time compared to the BNT in patients with dementia (p < 0.001). Significantly more patients were impaired on ANT variables than on the BNT in Alzheimer's disease (AD), vascular dementia (VaD), mixed AD/VaD, and multiple domain mild cognitive impairment (mMCI) but not in other dementias or amnestic MCI (aMCI). This differential performance of patients on auditory versus visual naming tasks was most pronounced in older, well-educated, male patients with the least cognitive impairment. Impaired verbal comprehension was not contributory. Inclusion of an ANT index score increased sensitivity in the dementia sample (92%). Poor specificity (41%) may be secondary to the inherent limitation of using the BNT as a control variable.CONCLUSION:The ANT index score adds diagnostic utility to the assessment of naming difficulties in patients with suspected dementia.

Traumatic brain injury (TBI) may be encountered in any sport and is considered an important public health concern. In view of the clinical data suggesting a possible genetic influence on neurological outcome after TBI, further understanding of the physiological functions of Apolipoprotein E is necessary. TBI in sports has the propensity to be associated with significant morbidity and possible mortality. Accordingly, identifying potential risk factors for TBI in sports is of paramount importance. Amyloid deposition is a potentially important neuropathological consequence associated with TBI. Evidence of axonal injury has also been documented in milder forms of TBI. Animal studies suggest that cholinergic neurotransmission may be selectively vulnerable to the effects of TBI and that this disruption is partially responsible for the cognitive impairment associated with TBI. Human studies have provided additional evidence of altered cholinergic transmission following TBI.

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [18F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [18F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [18F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

BACKGROUND:In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer's disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation.OBJECTIVE:To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine.METHODS:A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome.RESULTS:Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOEɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOEɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002).CONCLUSION:Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

April 23, 2018April 10, 2018Free AccessThe New MULES: A Sideline-Friendly Test of Rapid Picture Naming for Concussion (P2.169)Omar Akhand, Matthew Galetta, Lisena Hasanaj, Lucy Cobbs, Nikki Webb, Julia Brandt, Prin Amorapanth, … Show All … , John-Ross Rizzo, Liliana Serrano, Rachel Nolan, Janet Rucker, Arlene Silverio, Barry Jordan, Steven Galetta, and Laura Balcer Show FewerAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement)https://doi.org/10.1212/WNL.90.15_supplement.P2.169 Letters to the Editor

Objective: The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming that is under investigation for concussion. MULES captures an extensive visual network, including pathways for eye movements, color perception, memory and object recognition. The purpose of this study was to introduce the MULES to visual assessment of patients with MS, and to examine associations with other tests of afferent and efferent visual function. Methods: We administered the MULES in addition to binocular measures of low-contrast letter acuity (LCLA), high-contrast visual acuity (VA) and the King-Devick (K-D) test of rapid number naming in an MS cohort and in a group of disease-free controls. Results: Among 24 patients with MS (median age 36 years, range 20-72, 64% female) and 22 disease-free controls (median age 34 years, range 19-59, 57% female), MULES test times were greater (worse) among the patients (60.0 vs. 40.0 s). Accounting for age, MS vs. control status was a predictor of MULES test times (P =.01, logistic regression). Faster testing times were noted among patients with MS who had greater (better) performance on binocular LCLA at 2.5% contrast (P <.001, linear regression, accounting for age), binocular high contrast VA (P <.001), and K-D testing (P <.001). Both groups demonstrated approximately 10-s improvements in MULES test times between trials 1 and 2 (P <.0001, paired t-tests). Conclusion: The MULES test, a complex task of rapid picture naming involves an extensive visual network that captures eye movements, color perception and the characterization of objects. Color recognition, a key component of this novel assessment, is early in object processing and requires area V4 and the inferior temporal projections. MULES scores reflect performance of LCLA, a widely-used measure of visual function in MS clinical trials. These results provide evidence that the MULES test can add efficient visual screening to the assessment of patients with MS.

Objective: Measures of rapid automatized naming (RAN) have been used for over 50 years to capture vision based aspects of cognition. The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming under investigation for detection of concussion and other neurological disorders. MULES was designed as a series of 54 grouped color photographs (fruits, random objects, animals) that integrates saccades, color perception and contextual object identification. Recent changes to the MULES test have been made to improve ease of use on the athletic sidelines. Originally an 11 x 17-inch single-sided paper, the test has been reduced to a laminated 8.5 x 11-inch double-sided version. We identified performance changes associated with transition to the new, MULES, now sized for the sidelines, and examined MULES on the sideline for sports-related concussion. Methods: We administered the new laminated MULES to a group of adult office volunteers as well as youth and collegiate athletes during pre-season baseline testing. Athletes with concussion underwent sideline testing after injury. Time scores for the new laminated MULES were compared to those for the larger version (big MULES). Results: Among 501 athletes and office volunteers (age 16 7 years, range 6-59, 29% female), average test times at baseline were 44.4 14.4 s for the new laminated MULES (n = 196) and 46.5 16.3 s for big MULES (n = 248). Both versions were completed by 57 participants, with excellent agreement (p < 0.001, linear regression, accounting for age). Age was a predictor of test times for both MULES versions, with longer times noted for younger participants (p < 0.001). Among 6 athletes with concussion thus far during the fall sports season (median age 15 years, range 11-21) all showed worsening of MULES scores from pre-season baseline (median 4.0 s, range 2.1-16.4). Conclusion: The MULES test has been converted to an 11 x 8.5-inch laminated version, with excellent agreement between versions across age groups. Feasibly administered at pre-season and in an office setting, the MULES test shows preliminary evidence of capacity to identify athletes with sports-related concussion.

Various organisations and experts have published numerous statements and recommendations regarding different aspects of sports-related concussion including definition, presentation, treatment, management and return to play guidelines. 1-7 To date, there have been no written consensus statements specific for combat sports regarding management of combatants who have suffered a concussion or for return to competition after a concussion. In combat sports, head contact is an objective of the sport itself. Accordingly, management and treatment of concussion in combat sports should, and must, be more stringent than for non-combat sports counterparts.The Association of Ringside Physicians (an international, non-profit organisation dedicated to the health and safety of the combat sports athlete) sets forth this consensus statement to establish management guidelines that ringside physicians, fighters, referees, trainers, promoters, sanctioning bodies and other healthcare professionals can use in the ringside setting. We also provide guidelines for the return of a combat sports athlete to competition after sustaining a concussion. This consensus statement does not address the management of moderate to severe forms of traumatic brain injury, such as intracranial bleeds, nor does it address the return to competition for combat sports athletes who have suffered such an injury. These more severe forms of brain injuries are beyond the scope of this statement. This consensus statement does not address neuroimaging guidelines in combat sports.

Objective Systematic review of possible long-term effects of sports-related concussion in retired athletes. Data sources Ten electronic databases. Study selection Original research; incidence, risk factors or causation related to long-term mental health or neurological problems; individuals who have suffered a concussion; retired athletes as the subjects and possible long-term sequelae defined as >10 years after the injury. Data extraction Study population, exposure/outcome measures, clinical data, neurological examination findings, cognitive assessment, neuroimaging findings and neuropathology results. Risk of bias and level of evidence were evaluated by two authors. Results Following review of 3819 studies, 47 met inclusion criteria. Some former athletes have depression and cognitive deficits later in life, and there is an association between these deficits and multiple prior concussions. Former athletes are not at increased risk for death by suicide (two studies). Former high school American football players do not appear to be at increased risk for later life neurodegenerative diseases (two studies). Some retired professional American football players may be at increased risk for diminishment in cognitive functioning or mild cognitive impairment (several studies), and neurodegenerative diseases (one study). Neuroimaging studies show modest evidence of macrostructural, microstructural, functional and neurochemical changes in some athletes. Conclusion Multiple concussions appear to be a risk factor for cognitive impairment and mental health problems in some individuals. More research is needed to better understand the prevalence of chronic traumatic encephalopathy and other neurological conditions and diseases, and the extent to which they are related to concussions and/or repetitive neurotrauma sustained in sports.

Chronic post-concussive syndromes are a major source of morbidity and mortality and can develop into neurodegenerative disorders such as chronic traumatic encephalopathy (CTE). Methods of assessment and prediction of outcome are major areas of research focus, in particular molecular neuroimaging with positron emission tomography (PET) using ligands for neuropathological lesions such as plaques and tangles. CTE is characterized pathologically by the presence of neurofibrillary tau deposits. In living persons, advances in diagnosis have been made through positron emission tomography (PET) using tracers binding to aggregated tau. Here we examined [18F]T807 uptake in athletes with mild traumatic brain injury resulting from multiple concussions. College and professional athletes were included if they reported >1 concussion and cognitive affective or behavioral complaints. LOC > than an hour was exclusionary. Controls without head injury, psychiatric or neurological conditions were matched to age and gender (all males, 24 athletes age 52 ± 9.589; 4 controls, age 48 ± 5.629). Consented participants were evaluated as part of a research study. All subjects underwent PET for tau ([18F]T807/AV-1451) and amyloid ([18F]florbetapir/AV-45), MRI and neuropsychological and clinical assessment. We report here on 24 athletes and 4 controls. There were minimal differences on cognition between athletes and controls and significant differences in behavioral and affective symptoms. All subjects were negative for [18F]florbetapir. Eight of 24 (33%) athletes had abnormal [18F]T807 ligand retention and none of the controls did. While the amount of ligand retention varied in athletes, the pattern resembles postmortem CTE, with tau distribution in the sulci. Our study of in vivo imaging of tau deposition in the brains of retired athletes provides insight into the phenomenology and pathogenesis, of CTE. Tauopathy imaging may provide useful diagnostic or prognostic screening information. This research was supported by a grant from the Alzheimer's Disease Drug Foundation.

PURPOSE: To determine the boxing exposure of a representative cohort of retired professional boxers who competed in modern era boxing. METHODS: Boxing records of a previously studied cohort of 338 professional boxers who were applying for license to box professionally in New York State in the 1980’s were reviewed. Boxing exposure was extracted from boxing records provided by BoxRec. RESULTS: Of the 338 boxers previously studied, boxing records of 282 professional boxers were located and reviewed. The mean age of the boxers at the time of extraction was 51.9 years (range 31-66). All boxers were presumed to be retired. The mean age at the time of first professional bout was 21.6 years (range 16-30). The mean duration of the professional boxing career was 8.1 years (range 1-38). The mean number of total professional bouts 22.1 (range 1-129) with an average of 12 wins (range 0-79) and 9.3 losses (range 0-102). The average number of wins and losses by technical knockout/knockout (TKO/KO) was 7.3 (range 0-84) and 4.5 (range 0-35), respectively. The average number of total rounds boxed was 113 (range 1-735). The mean number of annual bouts and rounds was 3.2 (range 0-27) and 14.5 (range 0-165), respectively. CONCLUSION: The range of exposure to boxing among a representative sample of retired professional boxers is highly varied. To the best of our knowledge this is the only documentation of professional boxing exposure in modern era (late 20th Century) boxing. Follow-up of this cohort may serve as a representative sample of retired professional boxers to study the chronic effects of repetitive brain trauma, such as chronic traumatic encephalopathy (CTE).

Reduced brain glucose metabolism is a consistent feature of Alzheimer's disease (AD), and predicts progression from amnestic mild cognitive impairment (aMCI) to AD dementia. Greater decreases in F18fluorodeoxyglucose uptake with positron emission tomography (FDG-PET) correlate with greater cognitive impairment along the continuum from normal cognitive status to aMCI to AD dementia. In spite of the tight linkage of glucose metabolism to brain function and the decline in AD, only a very limited number of studies have tried to understand why glucose utilization is diminished or tried to reverse this AD-related deficit. Thiamine-dependent enzymes are critical components of glucose metabolism and are reduced in brains of AD patients. Increasing thiamine in humans or animals increases glucose utilization, improves brain metabolism and cognition, including memory. The most effective way to increase blood and brain thiamine is with benfotiamine because of superior pharmacokinetics. Our aim is to test the effect of administering benfotiamine on brain glucose metabolism (FDG-PET) and clinical impact as measured by changes in Assessment Scale-Cognitive subscale (ADAS-Cog) over time in patients with aMCI or AD. A randomized, double-blind, placebo-controlled clinical trial with benfotiamine in patients with aMCI or mild AD was initiated. The primary objective is to determine whether increasing thiamine availability with benfotiamine can slow cognitive decline compared to placebo, as measured by a change in the ADAS Cog score over the twelve-month trial. The secondary objective is to test whether benfotiamine will slow the decline in glucose utilization in patients as measured by FDG-PET. Using blocked, stratified randomization, 76 patients will be assigned to the treatment or placebo group. Stratification is based on Mini Mental Status Exam score (>21) to better understand if treatment responses differ according to initial cognitive impairment. Of the 464 patients screened, 45 patients have been enrolled. Patient characteristics will be detailed in the poster. The trial will determine whether benfotiamine provides clinical or underlying biological benefit for aMCI/AD patients and if this correlates with changes in glucose utilization.

Many patients with presumptive Alzheimer’s disease (AD) or other dementias may show minimal impairment on the Boston Naming Test (BNT), a visual confrontation naming measure. We sought to determine whether a semantic naming test, the Auditory Naming Test (ANT), would improve accuracy for identifying naming deficits in patients diagnosed with dementia ( N = 458) at an outpatient memory disorders clinic. Factor analysis revealed that both tests measured the same broad construct. Frequency of naming impairment with the ANT was significantly greater than with the BNT for patients with AD, regardless of dementia severity or levels of education ( p < .01). Effect size was moderate (φ = 0.45). BNT but not ANT performance declined with age in patients with AD. Sex differences were found for the BNT, but not the ANT, in the AD population. Accuracy rate of naming impairment diagnosis with the ANT in patients with AD was good (72%). Specificity (81%) and positive predictive value (PPV) (89%) with the ANT in AD were excellent, whereas sensitivity (69%) and negative predictive value (NPV) (58%) were modest. Receiver operating characteristic with area under the curve (ROC AUC) was excellent (0.958). A similar pattern was seen in patients with vascular dementia (VaD) or mixed AD/VaD. There was no significant effect in patients with amnestic mild cognitive impairment (aMCI). It is concluded that the ANT substantially improves the ability to diagnose naming impairment in patients with AD, VaD, and mixed AD/VaD dementia, and should be included in a neuropsychological battery administered to elderly patients with suspected dementia.