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.

Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

Intrinsic functional connectivity of periaqueductal gray subregions in humans.

The periaqueductal gray matter (PAG) is a key brain region of the descending pain modulation pathway. It is also involved in cardiovascular functions, anxiety, and fear; however, little is known about PAG subdivisions in humans. The aims of this study were to use resting-state fMRI-based functional connectivity (FC) to parcellate the human PAG and to determine FC of its subregions. To do this, we acquired resting-state fMRI scans from 79 healthy subjects and (1) used a data-driven method to parcellate the PAG, (2) used predefined seeds in PAG subregions to evaluate PAG FC to the whole brain, and (3) examined sex differences in PAG FC. We found that clustering of the left and right PAG yielded similar patterns of caudal, middle, and rostral subdivisions in the coronal plane, and dorsal and ventral subdivisions in the sagittal plane. FC analysis of predefined subregions revealed that the ventolateral(VL)-PAG was supfunctionally connected to brain regions associated with descending pain modulation (anterior cingulate cortex (ACC), upper pons/medulla), whereas the lateral (L) and dorsolateral (DL) subregions were connected with brain regions implicated in executive functions (prefrontal cortex, striatum, hippocampus). We also found sex differences in FC including areas implicated in pain, salience, and analgesia including the ACC and the insula in women, and the MCC, parahippocampal gyrus, and the temporal pole in men. The organization of the human PAG thus provides a framework to understand the circuitry underlying the broad range of responses to pain and its modulation in men and women.

Can we characterize A-P/IAP behavioural phenotypes in people with chronic pain?

Two behavioural phenotypes in healthy people have been delineated based on their intrinsic attention to pain (IAP) and whether their reaction times (RT) during a cognitively-demanding task are slower (P-type) or faster (A-type) during experimental pain. These behavioural phenotypes were not previously studied in chronic pain populations to avoid using experimental pain in a chronic pain context. Since pain rumination (PR) may serve as a supplement to IAP without needing noxious stimuli, we attempted to delineate A-P/IAP behavioural phenotypes in people with chronic pain and determined if PR can supplement IAP. Behavioural data acquired in 43 healthy controls (HCs) and 43 age-/sex-matched people with chronic pain associated with ankylosing spondylitis (AS) was retrospectively analyzed. A-P behavioural phenotypes were based on RT differences between pain and no-pain trials of a numeric interference task. IAP was quantified based on scores representing reported attention towards or mind-wandering away from experimental pain. PR was quantified using the pain catastrophizing scale, rumination subscale. The variability in RT was higher during no-pain trials in the AS group than HCs but was not significantly different in pain trials. There were no group differences in task RTs in no-pain and pain trials, IAP or PR scores. IAP and PR scores were marginally significantly positively correlated in the AS group. RT differences and variability were not significantly correlated with IAP or PR scores. Thus, we propose that experimental pain in the A-P/IAP protocols can confound testing in chronic pain populations, but that PR could be a supplement to IAP to quantify attention to pain.

A Hidden Markov Model reveals magnetoencephalography spectral frequency-specific abnormalities of brain state power and phase-coupling in neuropathic pain.

Neuronal populations in the brain are engaged in a temporally coordinated manner at rest. Here we show that spontaneous transitions between large-scale resting-state networks are altered in chronic neuropathic pain. We applied an approach based on the Hidden Markov Model to magnetoencephalography data to describe how the brain moves from one activity state to another. This identified 12 fast transient (~80 ms) brain states including the sensorimotor, ascending nociceptive pathway, salience, visual, and default mode networks. Compared to healthy controls, we found that people with neuropathic pain exhibited abnormal alpha power in the right ascending nociceptive pathway state, but higher power and coherence in the sensorimotor network state in the beta band, and shorter time intervals between visits of the sensorimotor network, indicating more active time in this state. Conversely, the neuropathic pain group showed lower coherence and spent less time in the frontal attentional state. Therefore, this study reveals a temporal imbalance and dysregulation of spectral frequency-specific brain microstates in patients with neuropathic pain. These findings can potentially impact the development of a mechanism-based therapeutic approach by identifying brain targets to stimulate using neuromodulation to modify abnormal activity and to restore effective neuronal synchrony between brain states.

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.

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.

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.

White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.

Temporomandibular disorder (TMD) is a prevalent chronic pain disorder that remains poorly understood. Recent imaging studies reported functional and gray matter abnormalities in brain areas implicated in sensorimotor, modulatory, and cognitive function in TMD, but it is not known whether there are white matter (WM) abnormalities along the trigeminal nerve (CNV) or in the brain. Here, we used diffusion tensor imaging, and found that, compared to healthy controls, TMD patients had 1) lower fractional anisotropy (FA) in both CNVs; 2) a negative correlation between FA of the right CNV and pain duration; and 3) diffuse abnormalities in the microstructure of WM tracts related to sensory, motor, cognitive, and pain functions, with a highly significant focal abnormality in the corpus callosum. Using probabilistic tractography, we found that the corpus callosum in patients had a higher connection probability to the frontal pole, and a lower connection probability to the dorsolateral prefrontal cortex, compared to controls. Finally, we found that 1) FA in tracts adjacent to the ventrolateral prefrontal cortex and tracts coursing through the thalamus negatively correlated with pain intensity; 2) FA in the internal capsule negatively correlated with pain intensity and unpleasantness; and 3) decreases in brain FA were associated with increases in mean diffusivity and radial diffusivity, markers of inflammation and oedema. These data provide novel evidence for CNV microstructural abnormalities that may be caused by increased nociceptive activity, accompanied by abnormalities along central WM pathways in TMD.