18F-Flortaucipir (AV1451) imaging identifies grey matter atrophy in retired athletes.

BACKGROUND: The long-term consequences of concussions may include pathological neurodegeneration as seen in Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Tau-PET showed promise as a method to detect tau pathology of CTE, but more studies are needed OBJECTIVE: This study aimed (1) to assess the association of imaging evidence of tau pathology with brain volumes in retired athletes and (2) to examine the relationship between tau-PET and neuropsychological functioning. METHODS: Former contact sport athletes were recruited through the Canadian Football League Alumni Association or the Canadian Concussion Centre clinic. Athletes completed MRI, [18F]flortaucipir tau-PET, and a neuropsychological battery. Memory composite was created by averaging the Rey Auditory Verbal Learning Test and Rey Visual Design Learning Test z-scores. Grey matter (GM) volumes were age/intracranial volume corrected using normal control MRIs. Tau-PET % positivity in GM was calculated as the number of positive voxels (≥ 1.3 standardized uptake value ratio (SUVR)/total voxels). RESULTS: 47 retired contact sport athletes negative for AD (age:51 ± 14; concussions/athlete:15 ± 2) and 54 normal controls (age:50 ± 13) were included. Tau-PET positive voxels had significantly lower GM volumes, compared to tau-PET negative voxels (- 0.37 ± 0.41 vs. - 0.31 ± 0.37, paired p = .006). There was a significant relationship between GM tau-PET % positivity and memory composite score (r = - .366, p = .02), controlled for age, PET scanner, and PET scan duration. There was no relationship between tau-PET measures and concussion number, or years of sport played. CONCLUSION: A higher tau-PET signal was associated with reduced GM volumes and lower memory scores. Tau-PET may be useful for identifying those at risk for neurodegeneration.

Slow wave sleep is associated with forgetting in patients with temporal lobe epilepsy.

While time spent in slow wave sleep (SWS) after learning promotes memory consolidation in the healthy brain, it is unclear if the same benefit is obtained in patients with temporal lobe epilepsy (TLE). Interictal epileptiform discharges (IEDs) are potentiated during SWS and thus may disrupt memory consolidation processes thought to depend on hippocampal-neocortical interactions. Here, we explored the relationship between SWS, IEDs, and overnight forgetting in patients with TLE. Nineteen patients with TLE studied object-scene pairs and memory was tested across a day of wakefulness (6 hrs) and across a night of sleep (16 hrs) while undergoing continuous scalp EEG monitoring. We found that time spent in SWS after learning was related to greater forgetting overnight. Longer duration in SWS and number of IEDs were each associated with greater forgetting, although the number of IEDs did not mediate the relationship between SWS and memory. Further research, particularly with intracranial recordings, is required to identify the mechanisms by which SWS and IEDs can be pathological to sleep-dependent memory consolidation in patients with TLE.

Functional connectivity changes in neurodegenerative biomarker-positive athletes with repeated concussions.

Multimodal biomarkers may identify former contact sports athletes with repeated concussions and at risk for dementia. Our study aims to investigate whether biomarker evidence of neurodegeneration in former professional athletes with repetitive concussions (ExPro) is associated with worse cognition and mood/behavior, brain atrophy, and altered functional connectivity. Forty-one contact sports athletes with repeated concussions were divided into neurodegenerative biomarker-positive (n = 16) and biomarker-negative (n = 25) groups based on positivity of serum neurofilament light-chain. Six healthy controls (negative for biomarkers) with no history of concussions were also analyzed. We calculated cognitive and mood/behavior composite scores from neuropsychological assessments. Gray matter volume maps and functional connectivity of the default mode, salience, and frontoparietal networks were compared between groups using ANCOVAs, controlling for age, and total intracranial volume. The association between the connectivity networks and sports characteristics was analyzed by multiple regression analysis in all ExPro. Participants presented normal-range mean performance in executive function, memory, and mood/behavior tests. The ExPro groups did not differ in professional years played, age at first participation in contact sports, and number of concussions. There were no differences in gray matter volume between groups. The neurodegenerative biomarker-positive group had lower connectivity in the default mode network (DMN) compared to the healthy controls and the neurodegenerative biomarker-negative group. DMN disconnection was associated with increased number of concussions in all ExPro. Biomarkers of neurodegeneration may be useful to detect athletes that are still cognitively normal, but with functional connectivity alterations after concussions and at risk of dementia.

Acetazolamide as an effective treatment for pilomotor seizures in autoimmune encephalitis.

Pilomotor seizures are strongly associated with autoimmune encephalitis (AE), particularly anti-LGI1 encephalitis. The carbonic anhydrase inhibitor acetazolamide may have special efficacy for treating AE-associated pilomotor seizures. Six patients with AE (five anti-LGI1, one seronegative) and temporal lobe pilomotor seizures (five with seizures inducible by hyperventilation) were treated with acetazolamide, administered in a cycling (2-days-ON, 4-days-OFF) regimen to offset tolerance. Seizures were assessed during epilepsy monitoring unit (EMU) recordings in four inpatients (one of whom also maintained an outpatient seizure diary chronicling 1203 seizures over 1079 days); two outpatients self-reported seizure frequencies. The extended diary revealed an inverse correlation between acetazolamide and proportion of seizures/day: 6%, 2% (days 1, 2 ON); 3%, 13%, 31%, 45% (days 1, 2, 3, 4 OFF). This patient later developed focal status epilepticus upon wean of antiseizure medications during a seropositive AE relapse that was remarkably aborted with acetazolamide monotherapy. The other three EMU patients averaged .56 seizures/day ON, and 3.81 seizures/day OFF (p = .004). The two outpatients reported seizure reductions from 3-5/day to 2/week, and 15-20/day to none, respectively, after initiation of cycling acetazolamide. Likely related to cerebral CO2/pH sensitivity, acetazolamide can be unusually effective in controlling pilomotor seizures in AE, chronically or in acute settings.

Misfolded α-Synuclein in Cerebrospinal Fluid of Contact Sport Athletes.

BACKGROUND: Misfolded α-synuclein in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) can be detected using the real-time quaking-induced conversion (RT-QuIC) technique in cerebrospinal fluid (CSF). OBJECTIVES: The objectives are (1) to examine misfolded CSF α-synuclein incidence, and (2) to compare clinical presentation, sports history, brain volumes, and RT-QuIC α-synuclein positivity in former athletes. METHODS: Thirty former athletes with magnetic resonance imaging, neuropsychological testing, and CSF analyzed for phosphorylated tau 181 (p-tau), total tau (t-tau), amyloid-ß 42 (Aß42), and neurofilament light chain (NfL). CSF α-synuclein was detected using RT-QuIC. RESULTS: Six (20%) former athletes were α-synuclein positive. α-Synuclein positive athletes were similar to α-synuclein negative athletes on demographics, sports history, clinical features, CSF p-tau, t-tau, Aß42, and NfL; however, had lower grey matter volumes in the right inferior orbitofrontal, right anterior insula and right olfactory cortices. CONCLUSIONS: α-Synuclein RT-QuIC analysis of CSF may be useful as a prodromal biofluid marker of PD and DLB. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Beamforming Seizures from the Temporal Lobe Using Magnetoencephalography.

BACKGROUND: Surgical treatment of drug-resistant temporal lobe epilepsy (TLE) depends on proper identification of the seizure onset zone (SOZ) and differentiation of mesial, temporolimbic seizure onsets from temporal neocortical seizure onsets. Noninvasive source imaging using electroencephalography (EEG) and magnetoencephalography (MEG) can provide accurate information on interictal spike localization; however, EEG and MEG have low sensitivity for epileptiform activity restricted to deep temporolimbic structures. Moreover, in mesial temporal lobe epilepsy (MTLE), interictal spikes frequently arise in neocortical foci distant from the SOZ, rendering interictal spike localization potentially misleading for presurgical planning. METHODS: In this study, we used two different beamformer techniques applied to the MEG signal of ictal events acquired during EEG-MEG recordings in six patients with TLE (three neocortical, three MTLE) in whom the ictal source localization results could be compared to ground truth SOZ localizations determined from intracranial EEG and/or clinical, neuroimaging, and postsurgical outcome evidence. RESULTS: Beamformer analysis proved to be highly accurate in all cases and was able to identify focal SOZs in mesial, temporolimbic structures. In three patients, interictal spikes were absent, too complex for dipole modeling, or localized to anterolateral temporal neocortex distant to a mesial temporal SOZ, and thus unhelpful in presurgical investigation. CONCLUSIONS: MEG beamformer source reconstruction is suitable for analysis of ictal events in TLE and can complement or supersede the traditional analysis of interictal spikes. The method outlined is applicable to any type of epileptiform event, expanding the information value of MEG and broadening its utility for presurgical recording in epilepsy.

Investigating the use of plasma pTau181 in retired contact sports athletes.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (ß = - 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 × 10-3 mm2/s vs. 0.90 ± 0.03 × 10-3 mm2/s, p = 0.003; CC axial diffusivity: 1.49 ± 0.04 × 10-3 mm2/s vs. 1.41 ± 0.02 × 10-3 mm2/s, p < 0.001, respectively). CONCLUSIONS: Although 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.

Brain Connectivity Changes in Postconcussion Syndrome as the Neural Substrate of a Heterogeneous Syndrome.

Background: Postconcussion syndrome (PCS) or persistent symptoms of concussion refers to a constellation of symptoms that persist for weeks and months after a concussion. To better capture the heterogeneity of the symptoms of patients with PCS, we aimed to separate patients into clinical subtypes based on brain connectivity changes. Methods: Subject-specific structural and functional connectomes were created based on diffusion weighted and resting state functional magnetic resonance imaging, respectively. Following an informed dimensionality reduction, a Gaussian mixture model was used on patient-specific structural and functional connectivity matrices to find potential patient clusters. For validation, the resulting patient subtypes were compared in terms of cognitive, neuropsychiatric, and postconcussive symptom differences. Results: Multimodal analyses of brain connectivity were predictive of behavioral outcomes. Our modeling revealed two patient subtypes: mild and severe. The severe subgroup showed significantly higher levels of depression, anxiety, aggression, and a greater number of symptoms than the mild patient subgroup. Conclusion: This study suggests that structural and functional connectivity changes together can help us better understand the symptom severity and neuropsychiatric profiles of patients with PCS. This work allows us to move toward precision medicine in concussions and provides a novel machine learning approach that can be applicable to other heterogeneous conditions.

Electromagnetic evidence that benign epileptiform transients of sleep are traveling, rotating hippocampal spikes.

OBJECTIVE: Benign epileptiform transients of sleep (BETS) have a unique voltage topography and a posteriorly propagating, inferiorly rotating diphasic EEG pattern. The source generators of BETS have not been definitively identified. We aimed to clarify the cerebral localization of BETS using MEG and electromagnetic source imaging (EMSI). METHODS: We analyzed BETS recorded with simultaneous MEG and EEG in four patients with epilepsy. Magnetic source imaging (MSI) and EMSI using equivalent current, single moving and rotating dipole inverse models was performed on averaged BETS potentials. MEG beamforming was performed in one case with abundant BETS. RESULTS: MSI and EMSI revealed hippocampal dipole source maxima in all cases, with current flow direction rotating from inferomedial to superomedial or superolateral between the first and second BETS peaks. Moving dipole analyses revealed spatiotemporal propagation along the anterior-posterior hippocampal axis and concomitant electromagnetic field rotation. Beamformer source reconstruction revealed an identical hippocampal localization. CONCLUSIONS: Converging evidence from different electromagnetic inverse modeling methods indicates that BETS are traveling, rotating hippocampal spikes, whose diphasic waveform is due to back and forth propagation along the anterior-posterior axis of the hippocampus. SIGNIFICANCE: The hippocampal localization and longitudinal, rotating propagation pattern of BETS raises the possibility of a sleep-related functional role for these hippocampal spikes.

Interaction of APOE4 alleles and PET tau imaging in former contact sport 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.

Elevated cerebrospinal fluid total tau in former professional athletes with multiple concussions.

OBJECTIVE: To 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. METHODS: Concentrations of phosphorylated tau181, total tau (t-tau), and ß-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) and high (>300 pg/mL) CSF t-tau. RESULTS: CSF 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). CONCLUSION: Our 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.

Age, Gender and Mechanism of Injury Interactions in Post-Concussion Syndrome.

BACKGROUND: Certain factors such as age and gender seem to affect the risk of developing post-concussion syndrome (PCS). We assessed the interactions between age, gender, concussion history and mechanism of injury in PCS patients so that a better understanding could guide the development of targeted prevention strategies. METHODS: Demographic data including age, gender, concussion mechanism of injury and concussion history were collected from (1) a prospective study evaluating PCS biomarkers and (2) a retrospective chart review of PCS patients. A total of 437 PCS patients who were assessed at the Canadian Concussion Centre or Toronto Western Hospital, Toronto, ON, were included. RESULTS: Overall, there were more men with PCS; however, a greater percentage of women had PCS after a single concussion. The results showed that age, gender and concussion history are conditionally dependent on the mechanism of injury, and independent of one another. The relative frequency of having PCS was greater in the following instances: (1) being a woman and having had concussion from a fall or motor vehicle collision (MVC), (2) being older and having had concussion from a fall or MVC or (3) having a single concussion with cause being MVC or fall. CONCLUSION: In patients with PCS, age and gender interact with the mechanism of injury to influence the risk of concussion. Targeted prevention strategies may be essential to prevent injuries leading to PCS.

A Nonliquid Crystal Display Screen Computer for Treatment of Photosensitivity and Computer Screen Intolerance in Post-Concussion Syndrome.

Liquid crystal display (LCD) screens refresh at a rate of 60 times per second, which can be perceived by concussed individuals who have photosensitivity, leading to computer intolerance. A non-LCD computer screen that refreshes at a much lower rate could relieve this photosensitivity and computer screen intolerance in patients with post-concussion syndrome (PCS). Twenty-nine patients with PCS, computer intolerance, and photosensitivity performed a reading task for a maximum of 30 min, with an LCD computer or a non-LCD device, and were given a comprehension test after completion of the reading task. The Sport Concussion Assessment Tool 3 was administered before and after each reading task. Symptom scores, amount of time spent reading, and performance on the comprehension tests were compared between the two devices. Patients also completed a self-report questionnaire of their subjective experience. The LCD screen computer produced significantly greater symptom exacerbation (median difference = 5, W = 315, p < 0.01) and a greater number of symptoms (median difference = 1, W = 148, p < 0.01) than the non-LCD screens. The non-LCD screen resulted in a longer symptom-free reading time (median = 48 sec, W = 147, p < 0.01), but not a greater number of words read (median = 281, W = 148, p = 0.098). Females were more likely to have greater symptom exacerbation with the LCD screen (U = 14.0, p < 0.01). No significant difference was found in performance on the comprehension test. Subjective reports showed that the non-LCD experience was more favorable, and most patients stated they would recommend this device for other patients with PCS. This study is the first to show the clinical utility of non-LCD screen computers in the management of photosensitivity and computer screen intolerance in patients with PCS. The non-LCD screen computer has the potential to facilitate return-to-work or return-to-school in concussed individuals.

The relationship between brain atrophy and cognitive-behavioural symptoms in retired Canadian football players with multiple concussions.

Multiple concussions, particularly in contact sports, have been associated with cognitive deficits, psychiatric impairment and neurodegenerative diseases like chronic traumatic encephalopathy. We used volumetric and deformation-based morphometric analyses to test the hypothesis that repeated concussions may be associated with smaller regional brain volumes, poorer cognitive performance and behavioural symptoms among former professional football players compared to healthy controls. This study included fifty-three retired Canadian Football League players, 25 age- and education-matched healthy controls, and controls from the Cambridge Centre for Aging and Neuroscience database for validation. Volumetric analyses revealed greater hippocampal atrophy than expected for age in former athletes with multiple concussions than controls and smaller left hippocampal volume was associated with poorer verbal memory performance in the former athletes. Deformation-based morphometry confirmed smaller bilateral hippocampal volume that was associated with poorer verbal memory performance in athletes. Repeated concussions may lead to greater regional atrophy than expected for age.

Decreased Number of Self-Paced Saccades in Post-Concussion Syndrome Associated with Higher Symptom Burden and Reduced White Matter Integrity.

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.

Motor Function in Former Professional Football Players with History of Multiple Concussions.

The objective of this study was to assess the incidence of motor impairment in former professional Canadian Football League (ex-CFL) players with multiple concussions. We investigated motor symptoms and signs in 45 ex-CFL players with multiple concussions and 25 age- and education-matched healthy controls with no history of concussion. Neurological assessment included items from the SCAT3 (Sport Concussion Assessment Tool 3) and the Unified Parkinson's Disease Rating Scale part III (UPDRS-Part III). A performance-based measurement of manual motor function was undertaken using the Grooved Pegboard test. Cognition was measured with patient-reported outcomes for memory, executive and behavioral symptoms as well as performance-based measures of memory and executive function. Symptoms of anxiety and depression were measured using the Personality Assessment Inventory. There was no significant difference between the ex-CFL players and controls on the UPDRS-Part III scores, and neither group reported clinically significant motor complaints. Ex-CFL players did not perform differently from control subjects on the Grooved Pegboard test. In contrast, with regard to cognitive and mood testing, players were more symptomatic: The ex-CFL players reported significantly more memory (77.8% vs. 16%, respectively, p < 0.001), executive (53.3% vs. 8%, respectively, p < 0.001), and behavioral symptoms (66.7% vs. 20%, respectively, p < 0.001). No significant differences were found when comparing ex-CFL players and controls in performance on memory and executive tests. In summary, in a group of retired CFL players who self-reported declines in memory, executive and behavioral symptoms, no motor symptoms were reported and no motor signs were detected.

Chronic Traumatic Encephalopathy and Movement Disorders: Update.

Association of repetitive brain trauma with progressive neurological deterioration has been described since the 1920s. Punch drunk syndrome and dementia pugilistica (DP) were introduced first to explain symptoms in boxers, and more recently, chronic traumatic encephalopathy (CTE) has been used to describe a neurodegenerative disease in athletes and military personal with a history of multiple concussions. Although there are many similarities between DP and CTE, a number of key differences are apparent especially when comparing movement impairments. The aim of this review is to compare clinical and pathological aspects of DP and CTE with a focus on disorders of movement.