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The introduction of low cost optical 3D motion tracking sensors provides new options for effective quantification of motor dysfunction. The present study aimed to evaluate the Kinect V2 sensor against a gold standard motion capture system with respect to accuracy of tracked landmark movements and accuracy and repeatability of derived clinical parameters. Nineteen healthy subjects were concurrently recorded with a Kinect V2 sensor and an optical motion tracking system (Vicon). Six different movement tasks were recorded with 3D full-body kinematics from both systems. Tasks included walking in different conditions, balance and adaptive postural control. After temporal and spatial alignment, agreement of movements signals was described by Pearson's correlation coefficient and signal to noise ratios per dimension. From these movement signals, 45 clinical parameters were calculated, including ranges of motions, torso sway, movement velocities and cadence. Accuracy of parameters was described as absolute agreement, consistency agreement and limits of agreement. Intra-session reliability of 3 to 5 measurement repetitions was described as repeatability coefficient and standard error of measurement for each system. Accuracy of Kinect V2 landmark movements was moderate to excellent and depended on movement dimension, landmark location and performed task. Signal to noise ratio provided information about Kinect V2 landmark stability and indicated larger noise behaviour in feet and ankles. Most of the derived clinical parameters showed good to excellent absolute agreement (30 parameters showed ICC(3,1) > 0.7) and consistency (38 parameters showed r > 0.7) between both systems. Given that this system is low-cost, portable and does not require any sensors to be attached to the body, it could provide numerous advantages when compared to established marker- or wearable sensor based system. The Kinect V2 has the potential to be used as a reliable and valid clinical measurement tool.

Motor signs such as dyspraxia and abnormal gait are characteristic features of autism spectrum disorder (ASD). However, motor behavior in adults with ASD has scarcely been quantitatively characterized. In this pilot study, we aim to quantitatively examine motor signature of adults with ASD without intellectual impairment using marker-less visual-perceptive motion capture. 82 individuals (37 ASD and 45 healthy controls, HC) with an IQ > 85 and aged 18 to 65 years performed nine movement tasks and were filmed by a 3D-infrared camera. Anatomical models were quantified via custom-made software and resulting kinematic parameters were compared between individuals with ASD and HCs. Furthermore, the association between specific motor behaviour and severity of autistic symptoms (Autism Diagnostic Observation Schedule 2, Autism Spectrum Quotient) was explored. Adults with ASD showed a greater mediolateral deviation while walking, greater sway during normal, tandem and single leg stance, a reduced walking speed and cadence, a greater arrhythmicity during jumping jack tasks and an impaired manual dexterity during finger tapping tasks ( p  < 0.05 and |D|> 0.48) compared to HC. Furthermore, in the ASD group, some of these parameters correlated moderately to severity of ASD symptoms. Adults with ASD seem to display a specific motor signature in this disorder affecting movement timing and aspects of balance. The data appear to reinforce knowledge about motor signs reported in children and adolescents with ASD. Also, quantitative motor assessment via visual-perceptive computing may be a feasible instrument to detect subtle motor signs in ASD and perhaps suitable in the diagnosis of ASD in the future.

Background Hyperreflective retinal foci (HRF) visualized by optical coherence tomography (OCT) potentially represent clusters of microglia. We compared HRF frequencies and their association with retinal neurodegeneration between people with clinically isolated syndrome (pwCIS), multiple sclerosis (pwMS), aquaporin 4‐IgG positive neuromyelitis optica spectrum disorder (pwNMOSD), and healthy controls (HC)—as well as between eyes with (ON+eyes) and without a history of optic neuritis (ON−eyes). Methods Cross‐sectional data of pwCIS, pwMS, and pwNMOSD with previous ON and HC were acquired at Charité—Universitätsmedizin Berlin. HRF analysis was performed manually on the central macular OCT scan. Semi‐manual OCT segmentation was performed to acquire the combined ganglion cell and inner plexiform layer (GCIPL), inner nuclear layer (INL), and peripapillary retinal nerve fiber layer (pRNFL) thickness. Group comparisons were performed by linear mixed models. Results In total, 227 eyes from 88 patients (21 pwCIS, 32 pwMS, and 35 pwNMOSD) and 35 HCs were included. HRF in GCIPL and INL were more frequently detected in pwCIS, pwMS, and pwNMOSD than HCs (p < 0.001 for all comparisons) with pwCIS exhibiting the greatest numbers. ON+eyes of pwMS had less HRF in GCIPL than ON−eyes (p = 0.036), but no difference was seen in pwCIS and pwNMOSD. HRF GCIPL were correlated to GCIPL thickness in ON+eyes in pwMS (p = 0.040) and pwNMOSD (p = 0.031). Conclusion HRF occur in ON+eyes and ON−eyes across neuroinflammatory diseases. In pwMS and pwNMOSD, HRF frequency was positively associated with GCIPL thickness indicating that HRF formation might be dependent on retinal ganglion cells.

ObjectiveOur aim was to study the evolution of ataxia and neurological symptoms before and after ataxia onset in the most common spinocerebellar ataxias (SCAs), SCA1, SCA2, SCA3 and SCA6. We therefore jointly analysed the data of the EUROSCA and RISCA studies, which recruited ataxic and non-ataxic mutation carriers.MethodsWe used mixed effect models to analyse the evolution of Scale for the Rating and Assessment of Ataxia (SARA) scores, SCA Functional Index (SCAFI) and Inventory of Non-Ataxia Signs (INAS) counts. We applied multivariable modelling to identify factors associated with SARA progression. In the time interval 5 years prior to and after ataxia onset, we calculated sensitivity to change ratios (SCS) of SARA, SCAFI and INAS.Results2740 visits of 677 participants were analysed. All measures showed non-linear progression that was best fitted by linear mixed models with linear, quadratic and cubic time effects. R2 values indicating quality of the fit ranged from 0.70 to 0.97. CAG repeat was associated with faster progression in SCA1, SCA2 and SCA3, but not SCA6. 5 years prior to and after ataxia onset, SARA had the highest SCS of all measures with a mean of 1.21 (95% CI: 1.20, 1.21) in SCA1, 0.94 (0.93, 0.94) in SCA2 and 1.23 (1.22, 1.23) in SCA3.InterpretationOur data have important implications for the understanding of disease progression in SCA1, SCA2, SCA3 and SCA6 across the lifespan. Furthermore, our study provides information for the design of interventional trials, especially in pre-ataxic mutation carriers close to ataxia onset and patients in early disease stages.

Background The most common spinocerebellar ataxias (SCA)—SCA1, SCA2, SCA3, and SCA6—are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset. Methods We combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log-normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age. Results For SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (−0.105±0.005 and −0.056±0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: −0.049±0.002 and −0.090±0.009, respectively; normal: +0.013±0.005 and −0.029±0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age. Conclusions These estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies. ClinicalTrials.gov, number NCT01037777 and NCT00136630 for the French patients.

Objective Retrograde trans‐synaptic neuroaxonal degeneration is considered a key pathological factor of subclinical retinal neuroaxonal damage in multiple sclerosis (MS). We aim to evaluate the longitudinal association of optic radiation (OR) lesion activity with retinal neuroaxonal damage and its role in correlations between retinal and brain atrophy in people with clinically isolated syndrome and early MS (pweMS). Methods Eighty‐five pweMS were retrospectively screened from a prospective cohort (Berlin CIS cohort). Participants underwent 3T magnetic resonance imaging (MRI) for OR lesion volume and brain atrophy measurements and optical coherence tomography (OCT) for retinal layer thickness measurements. All pweMS were followed with serial OCT and MRI over a median follow‐up of 2.9 (interquartile range: 2.6–3.4) years. Eyes with a history of optic neuritis prior to study enrollment were excluded. Linear mixed models were used to analyze the association of retinal layer thinning with changes in OR lesion volume and brain atrophy. Results Macular ganglion cell‐inner plexiform layer (GCIPL) thinning was more pronounced in pweMS with OR lesion volume increase during follow‐up compared to those without (Difference: −0.82 μm [95% CI:‐1.49 to −0.15], p = 0.018). Furthermore, GCIPL thinning correlated with both OR lesion volume increase (β [95% CI] = −0.27 [−0.50 to −0.03], p = 0.028) and brain atrophy (β [95% CI] = 0.47 [0.25 to 0.70], p < 0.001). Correlations of GCIPL changes with brain atrophy did not differ between pweMS with or without OR lesion increase (ηp2 = 5.92e−7, p = 0.762). Interpretation Faster GCIPL thinning rate is associated with increased OR lesion load. Our results support the value of GCIPL as a sensitive biomarker reflecting both posterior visual pathway pathology and global brain neurodegeneration.

Perfusion changes in white matter (WM) lesions and normal‐appearing brain regions play an important pathophysiological role in multiple sclerosis (MS). However, most perfusion imaging methods require exogenous contrast agents, the repeated use of which is discouraged. Using resting‐state functional MRI (rs‐fMRI), we aimed to investigate differences in perfusion between white matter lesions and normal‐appearing brain regions in MS and healthy participants. A total of 41 MS patients and 41 age‐ and sex‐matched healthy participants received rs‐fMRI, from which measures of cerebral hemodynamics and oxygenation were extracted and compared across brain regions and study groups using within‐ and between‐group nonparametric tests, linear mixed models, and robust multiple linear regression. We found longer blood arrival times and lower blood volumes in lesions than in normal‐appearing WM. Higher blood volumes were found in MS patients' deep WM lesions compared to healthy participants, and blood arrival time was more delayed in MS patients' deep WM lesions than in healthy participants. Delayed blood arrival time in the cortical grey matter was associated with greater cognitive impairment in MS patients. Perfusion imaging using rs‐fMRI is useful for WM lesion characterization. rs‐fMRI‐based blood arrival times and volumes are associated with cognitive function. The BOLD signal low‐frequency oscillations in multiple sclerosis lesions are more delayed and have a higher coefficient of variation (CoV) than age‐related microangiopathic white matter lesions.

Background We compared the prognostic value of serum neurofilament light chain (sNFL) and glial fibrillary acidic protein (sGFAP) for clinical and radiologic disease activity among patients with clinically isolated syndrome or early multiple sclerosis (MS) with optic neuritis (pwON) and non‐optic neuritis (pwNON) as the first manifestation. Methods Patients within 7 months (pwON and pwNON) from disease onset and patients with MS with a disease duration longer than 12 months (pwMS) as controls were included. sNFL and sGFAP were analyzed at baseline and at follow‐ups using SIMOA technology. Linear mixed models and Cox regression analyses were applied. Results We included 165 samples of 86 patients (18 pwON, 46 pwNON, 21 pwMS). Median follow‐up time was 80 months. Mean sNFL z scores were higher in pwNON (1.06) than pwON (0.53) and pwMS (0.94). In pwNON, but not pwON, higher sNFL z scores were associated with an elevated risk for a subsequent attack (pwNON: HR 1.63 [95% CI 1.12 to 2.27], p = 0.005; pwON: HR 0.80 [95% CI 0.51–2.27], p = 0.318) and new MRI T2 lesions (pwNON: HR 1.66 [95% CI 1.31 to 2.11], p < 0.001; pwON: HR 1.16 [95% CI 0.82 to 1.63], p = 0.404). sGFAP z scores were associated with a lower risk of a subsequent attack in pwON (HR 0.34 [95% CI 0.12 to 0.98], p = 0.047). Conclusion sNFL but not sGFAP predicted future clinical and MRI disease activity only in pwNON, potentially suggesting that the prognostic value of sNFL may depend on the type of the first manifestation.

Objectives Genetic variant classification is a challenge in rare adult‐onset disorders as in SCA‐PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA‐PRKCG a comprehensive phenotype description from a German multi‐center cohort, including standardized 3D MR imaging. Methods This cross‐sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). Results Our sample included 25 cases confirmed as SCA‐PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA‐PRKCG included slowly progressive ataxia (onset at 4–50 years), preceded in some by early‐onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive‐affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA‐PRKCG cases but in none of the controls. Interpretation In this largest cohort to date, SCA‐PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non‐ataxia movement disorders and cognitive‐affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA‐PRKCG.

Multiple Sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), with a largely unknown etiology, where mitochondrial dysfunction likely contributes to neuroaxonal loss and brain atrophy. Mirroring the CNS, peripheral immune cells from patients with MS, particularly CD4 + T cells, show inappropriate mitochondrial phenotypes and/or oxidative phosphorylation (OxPhos) insufficiency, with a still unknown contribution of mitochondrial DNA (mtDNA). We hypothesized that mitochondrial genotype in CD4 + T cells might influence MS disease activity and progression. Thus, we performed a retrospective cross-sectional and longitudinal study on patients with a recent diagnosis of either Clinically Isolated Syndrome (CIS) or Relapsing–Remitting MS (RRMS) at two timepoints: 6 months (VIS1) and 36 months (VIS2) after disease onset. Our primary outcomes were the differences in mtDNA extracted from CD4 + T cells between: ( I ) patients with CIS/RRMS (PwMS) at VIS1 and age- and sex-matched healthy controls (HC), in the cross-sectional analysis, and ( II ) different diagnostic evolutions in PwMS from VIS1 to VIS2, in the longitudinal analysis. We successfully performed mtDNA whole genome sequencing (mean coverage: 2055.77 reads/base pair) in 183 samples (61 triplets). Nonetheless, mitochondrial genotype was not associated with a diagnosis of CIS/RRMS, nor with longitudinal diagnostic evolution.