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Considering the wide range of outcomes following sport-related concussions, biomarkers are needed to detect underlying pathological changes. The objective was to analyze the use of plasma phosphorylated tau 181 (pTau181) as a non-invasive measure of underlying brain changes in a cohort of retired contact sports athletes at risk of neurodegeneration.Fifty-four retired contact sport athletes and 27 healthy controls whose blood plasma was analyzed for pTau181 were included. A portion (N = 21) of retired athletes had a 2-years follow-up visit. All participants had completed a neuropsychological battery and MRI imaging.Plasma pTau181 was significantly higher in retired athletes compared to healthy controls (8.94 ± 5.08 pg/mL vs. 6.00 ± 2.53 pg/mL, respectively; 95% BCa CI 1.38-4.62; p = 0.02); and was significantly associated with fornix fractional anisotropy values only in the athletes group (β = - 0.002; 95% BCa CI - 0.003 to - 0.001; p = 0.002). When the retired athletes cohort was divided into high vs. normal pTau181 groups, the corpus callosum (CC) volume and white-matter integrity was significantly lower in high pTau181 compared to older healthy controls (CC volume: 1.57 ± 0.19 vs. 2.02 ± 0.32, p = 0.002; CC medial diffusivity: 0.96 ± 0.04 × 10Although high plasma pTau181 levels were associated with abnormalities in CC and fornix, baseline pTau181 did not predict longitudinal changes in regional brain volumes or white-matter integrity in the athletes. pTau181 may be useful for identifying those with brain abnormalities related to repeated concussion but not for predicting progression.

This study quantified the occurrence of an underlying synucleinopathy in 50 patients with idiopathic normal pressure hydrocephalus by means of real-time quaking-induced conversion, a highly sensitive and specific technique capable of detecting and amplifying misfolded aggregated forms of α-synuclein in the cerebrospinal fluid. Seven patients were positive and they did not differ from negative cases, except for a more frequent L-dopa responsiveness and gait characterized by a wider base. The two groups did not differ in terms of response rate to tap test or shunt surgery, although step length and gait velocity improved by a lesser extent in positive cases. ANN NEUROL 2022;92:985-991.

Introduction: Frontotemporal lobar degeneration (FTLD)-related syndrome includes progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). PSP is usually caused by a tauopathy but can have associated Alzheimer's disease (AD) while CBS can be caused by tauopathy, transactive response DNA binding protein 43 kDa, or AD pathology. Our aim was to compare the parkinsonian syndromes presenting without AD biomarkers (CBS/PSP-non-AD) to parkinsonian syndromes with AD biomarkers (CBS/PSP-AD).Materials and Methods: Twenty-four patients [11 males, 13 females; age (68.46 ± 7.23)] were recruited for this study. The whole cohort was divided into parkinsonian syndromes without AD biomarkers [N = 17; diagnoses (6 CBS, 11 PSP)] and parkinsonian syndromes with AD biomarkers [N = 7; diagnoses (6 CBS-AD, 1 PSP-AD)]. Anatomical MRI and PET imaging with tau ligand [18F]-AV1451 tracer was completed. Cerebrospinal fluid analysis or [18F]-AV1451 PET imaging was used to assess for the presence of AD biomarkers. Progressive supranuclear palsy rating scale (PSPRS) and unified Parkinson's disease rating scale (UPDRS) motor exam were implemented to assess for motor disturbances. Language and cognitive testing were completed.Results: The CBS/PSP-non-AD group [age (70.18 ± 6.65)] was significantly older (p = 0.028) than the CBS/PSP-AD group [age (64.29 ± 7.32)]. There were no differences between the groups in terms of gender, education, years of disease duration, and disease severity as measured with the Clinical Dementia Rating scale. The CBS/PSP-non-AD group had significantly lower PET Tau Standard Volume Uptake Ratio (SUVR) values compared to the CBS/PSP-AD group in multiple frontal and temporal areas, and inferior parietal (all p < 0.03). The CBS/PSP-non-AD group had significantly higher scores compared to the CBS/PSP-AD group on PSPRS (p = 0.004) and UPDRS motor exam (p = 0.045). The CBS/PSP-non-AD group had higher volumes of inferior parietal, precuneus, and hippocampus (all p < 0.02), but lower volume of midbrain (p = 0.02), compared to the CBS/PSP-AD group.Discussion: The CBS/PSP-non-AD group had higher motor disturbances compared to the CBS/PSP-AD group; however, both groups performed similarly on neuropsychological measures. The AD biomarker group had increased global uptake of PET Tau SUVR and lower volumes in AD-specific areas. These results show that the presenting phenotype of CBS and PSP syndromes and the distribution of injury are strongly affected by the presence of AD biomarkers.

Background/objective This study aimed to evaluate serum neurofilament light chain (NF-L) levels in former professional contact sports athletes with multiple concussions (ExPro) as a potential biomarker of neurodegeneration and predictor of white-matter (WM) abnormality progression. Methods Concentrations of NF-L in the serum of fifty-two cognitively normal ExPro and twenty-one healthy controls (HC) with no history of concussions were measured using single molecule array (Simoa) technology. Both groups underwent neuroimaging at the time of serum collection. Eighteen of the participants in the ExPro underwent follow-up imaging after 2 years. Results Levels of serum NF-L were not significantly different between the ExPro and HC. However, in the ExPro group, NF-L levels were positively correlated with the mean diffusivity (MD) of corpus callosum (CC) and fornix, and total ventricular volume. Moreover, NF-L levels in the ExPro group at the first visit were positively correlated with the amount of increase in CC MD at the 2-year follow-up. Conclusions NF-L levels reflect neuronal changes in the ExPro group and predict the extent of decrease in white matter integrity over time. Serum NF-L might be a biomarker of neurodegeneration and WM abnormality progression in ExPro.

Background Concussion and its associated sequel, postconcussion syndrome (PCS), have a debilitating impact on the lives of concussed patients. However, a diagnostic biomarker for this condition is lacking. Recently, there has been a surge of interest in using oculomotor function testing as an objective assessment of patients with PCS. Objectives To systematically synthesize, appraise, and summarize all published empirical studies that have assessed alteration of oculomotor functions in patients with PCS. Methods Medline, Embase, PsychINFO, and CINAHL databases searched up to July 2016 for studies that used oculomotor function assessment in patients with postconcussion symptoms. Results The search identified 1637 citations, and finally 8 case-control studies were included. Of these, 5 studies used a similar task with a target moving in a circular trajectory. Three other studies measured conventional oculomotor tasks such as saccade, vergence, and smooth pursuit eye movements. Conclusions Currently, there is limited support for the recommendation of oculomotor function assessments for diagnosis and identification of patients with PCS following head trauma. Therefore, more rigorous studies assessing oculomotor function changes in patients with PCS are warranted.

ObjectiveTo identify CSF biomarkers that are related to decreased white matter (WM) integrity and poor cognitive performance in former professional athletes with a history of multiple concussions.MethodsConcentrations of phosphorylated tau181, total tau (t-tau), and β-amyloid in the CSF were measured in 3 groups: 22 former professional athletes with multiple concussions (mean ± SD age 55.9 ± 12.2 years), 5 healthy controls (age 57.4 ± 5.2 years), and 12 participants (age 60.0 ± 6.6 years) diagnosed with Alzheimer disease (AD). All participants in the former athletes group underwent diffusion tensor imaging to determine WM tract integrity and completed neuropsychological testing. We divided the former athletes group into those with normal (300 pg/mL) CSF t-tau.ResultsCSF t-tau in the former athletes group was significantly higher than in the healthy control group (349.3 ± 182.6 vs 188.8 ± 39.9 pg/mL, p = 0.003) and significantly lower than in the patients with AD (349.3 ± 182.6 vs 857.0 ± 449.3 pg/mL, p = 0.007). Fractional anisotropy values across all the tracts were significantly lower in the high CSF t-tau group compared to the normal CSF t-tau group (p = 0.036). Participants in the high CSF t-tau group scored significantly lower on the Trail Making Test (TMT) Part B compared to the normal CSF t-tau group (t scores 45.6 ± 18.8 vs 62.3 ± 10.1, p = 0.017).ConclusionOur findings indicate that former athletes with multiple concussions are at increased risk of elevated levels of CSF t-tau and that high CSF t-tau is associated with reduced WM integrity and worse scores on the TMT Part B.

The aim of this study was to examine the potential utility of a self-paced saccadic eye movement as a marker of post-concussion syndrome (PCS) and monitoring the recovery from PCS. Fifty-nine persistently symptomatic participants with at least two concussions performed the self-paced saccade (SPS) task. We evaluated the relationships between the number of SPSs and 1) number of self-reported concussion symptoms, and 2) integrity of major white matter (WM) tracts (as measured by fractional anisotropy [FA] and mean diffusivity) that are directly or indirectly involved in saccadic eye movements and often affected by concussion. These tracts included the uncinate fasciculus (UF), cingulum (Cg) and its three subcomponents (subgenual, retrosplenial, and parahippocampal), superior longitudinal fasciculus, and corpus callosum. Mediation analyses were carried out to examine whether specific WM tracts (left UF and left subgenual Cg) mediated the relationship between the number of SPSs and 1) interval from last concussion or 2) total number of self-reported symptoms. The number of SPSs was negatively correlated with the total number of self-reported symptoms (r = -0.419, p = 0.026). The number of SPSs were positively correlated with FA of left UF and left Cg (r = 0.421, p = 0.013 and r = 0.452, p = 0.008; respectively). FA of the subgenual subcomponent of the left Cg partially mediated the relationship between the total number of symptoms and the number of SPSs, while FA of the left UF mediated the relationship between interval from last concussion and the number of SPSs. In conclusion, SPS testing as a fast and objective assessment may reflect symptom burden in patients with PCS. In addition, since the number of SPSs is associated with the integrity of some WM tracts, it may be useful as a diagnostic biomarker in patients with PCS.

Highlights • Cortical PET tau was compared between APOE4 carriers and non-carriers. • APOE4 carriers had higher cortical PET tau comparing to non-carriers. • APOE4 as a risk factor for tau accumulation in former contact sports athletes., Background Genetic polymorphisms like apolipoprotein E (APOE) and microtubule-associated protein tau (MAPT) genes increase the risk of neurodegeneration. Methods 38 former players (age 52.63±14.02) of contact sports underwent neuroimaging, biofluid collection, and comprehensive neuropsychological assessment. The [F-18]AV-1451 tracer signal was compared in the cortical grey matter between APOE4 allele carriers and non-carriers as well as carriers of MAPT H1H1 vs non-H1H1. Participants were then divided into the high (N = 13) and low (N = 13) groups based on cortical PET tau standard uptake value ratios (SUVRs) for comparison. Findings Cortical grey matter PET tau SUVR values were significantly higher in APOE4 carriers compared to non-carriers (p = 0.020). In contrast, there was no significant difference in SUVR between MAPT H1H1 vs non-H1H1 carrier genes (p = 1.00). There was a significantly higher APOE4 allele frequency in the high cortical grey matter PET tau group, comparing to low cortical grey matter PET tau group (p = 0.048). No significant difference in neuropsychological function was found between APOE4 allele carriers and non-carriers. Interpretation There is an association between higher cortical grey matter tau burden as seen with [F-18]AV-1451 PET tracer SUVR, and the APOE4 allele in former professional and semi-professional players at high risk of concussions. APOE4 allele may be a risk factor for tau accumulation in former contact sports athletes at high risk of neurodegeneration. Funding Toronto General and Western Hospital Foundations; Weston Brain Institute; Canadian Consortium on Neurodegeneration in ageing; Krembil Research Institute. There was no role of the funders in this study.

Background: Post concussion syndrome (PCS) can affect up to 30% of patients with concussion. Biomarkers of this condition would be beneficial for diagnosis and management. We hypothesized that eye tracking parameters would correlate with microstructural changes of white matter integrity, as measured by diffusion tensor imaging (DTI), in patients with PCS. Methods: Sixty patients with PCS and at least 2 concussions participated in our prospective study. Attention and executive function were tested using Visual Attention Scanning Technology (VAST). In a matching task, the normalized number of visits to master image before making the first selection is used as a surrogate of working memory. We related performance on VAST to white matter integrity using Tract-Based Spatial Statistics of diffusion tensor imaging data. Results: 60 participants (mean age 34.3 years, SD 13.8) had a mean of 4 concussions. There were negative correlations between fractional anisotropy (FA) of the genu, body, and splenium of the corpus callosum and normalized number of visits to master image before first selection (r=-0.432, p=0.001; r=-0.504, pConclusions: Impaired performance on eye tracking measures of attention and executive function may reflect alterations in white matter tracts.

Objective To compare the efficacy of celecoxib for treatment of withdrawal headache vs prednisone in patients with medication overuse headache (MOH). Methods In this prospective, double-blind, parallel-group clinical trial, 97 consecutive subjects with MOH were randomized (simple randomization using computer-generated numbers) for treatment with either 400 mg/day celecoxib (for the first 5 days then decreased at a rate of 100 mg every 5 days) or prednisone 75 mg/day orally (for the first 5 days then tapered off every 5 days). Subjects who met the International Headache Society criteria for MOH were included in the trial. The change in headache days and intake of rescue medication were considered as primary outcomes while the change in headache severity defined as a secondary outcome. Results Patients treated with celecoxib experienced lower headache intensity during the first 3 weeks after withdrawal (after 3 weeks, the median of visual analog scale was 3 for patients in celecoxib group vs 4.5 for prednisone group [P

Conclusions In this double-blind, randomized study extended-release venlafaxine 150 mg/day found to be effective in chronic migraine. Our study showed a clear effect that was in subgroup of subjects with medication overuse. In addition, in this study, the low number of adverse events showed venlafaxine to be well tolerated. Future controlled trials expended lon ger with larger sample size, should also support the effectiveness and safety of venlafaxine in patients suffering from chronic migraine. No conflict of interest.