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Reproduction is a key feature of all organisms, yet the way in which it is achieved varies greatly across the tree of life. One striking example of this variation is the stick insect genus Bacillus , in which five different reproductive modes have been described: sex, facultative and obligate parthenogenesis, and two highly unusual reproductive modes: hybridogenesis and androgenesis. Under hybridogenesis, the entire genome from the paternal species is eliminated and replaced each generation by mating with the corresponding species. Under androgenesis, an egg is fertilized, but the developing diploid offspring bear two paternal genomes and no maternal genome, as a consequence of unknown mechanisms. Here, we reevaluate the previous descriptions of Bacillus lineages and the proposed F1 hybrid ancestries of the hybridogenetic and obligately parthenogenetic lineages (based on allozymes and karyotypes) from Sicily, where all these reproductive modes are found. We generate a chromosome-level genome assembly for a facultative parthenogenetic species (B. rossius) and combine extensive field sampling with RADseq and mtDNA data. We identify and genetically corroborate all previously described species and confirm the ancestry of hybrid lineages. All hybrid lineages have fully retained their F1 hybrid constitution throughout the genome, indicating that the elimination of the paternal genome in hybridogens is always complete and that obligate parthenogenesis in Bacillus hybrid species is not associated with an erosion of heterozygosity as known in other hybrid asexuals. Our results provide a stepping stone toward understanding the transitions between reproductive modes and the proximate mechanisms of genome elimination. [ABSTRACT FROM AUTHOR]

This study aimed to identify quantitative biomarkers of motor function for cerebellar ataxia by evaluating gait and postural control using an RGB-depth camera-based motion analysis system. In 28 patients with degenerative cerebellar ataxia and 33 age- and sex-matched healthy controls, motor tasks (short-distance walk, closed feet stance, and stepping in place) were selected from a previously reported protocol, and scanned using Kinect V2 and customized software. The Clinical Assessment Scale for the Assessment and Rating of Ataxia (SARA) was also evaluated. Compared with the normal control group, the cerebellar ataxia group had slower gait speed and shorter step lengths, increased step width, and mediolateral trunk sway in the walk test (all P < 0.001). Lateral sway increased in the stance test in the ataxia group (P < 0.001). When stepping in place, the ataxia group showed higher arrhythmicity of stepping and increased stance time (P < 0.001). In the correlation analyses, the ataxia group showed a positive correlation between the total SARA score and arrhythmicity of stepping in place (r = 0.587, P = 0.001). SARA total score (r = 0.561, P = 0.002) and gait subscore (ρ = 0.556, P = 0.002) correlated with mediolateral truncal sway during walking. These results suggest that the RGB-depth camera-based motion analyses on mediolateral truncal sway during walking and arrhythmicity of stepping in place are useful digital motor biomarkers for the assessment of cerebellar ataxia, and could be utilized in future clinical trials. [ABSTRACT FROM AUTHOR]

Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. In fact, any phenotype for an organism is dictated by the interplay among these scales. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls. Multilayer networks were constructed using mutual information for topological analysis, and Boolean simulations were constructed using Pearson correlation to identified paths within and among all layers. The path more commonly found from the Boolean simulations connects protein MK03, with total T cells, the thickness of the retinal nerve fiber layer (RNFL), and the walking speed. This path contains nodes involved in protein phosphorylation, glial cell differentiation, and regulation of stress-activated MAPK cascade, among others. Specific paths identified were subsequently analyzed by flow cytometry at the single-cell level. Combinations of several proteins (GSK3AB, HSBP1 or RS6) and immune cells (Th17, Th1 non-classic, CD8, CD8 Treg, CD56 neg, and B memory) were part of the paths explaining the clinical phenotype. The advantage of the path identified from the Boolean simulations is that it connects information about these known biological pathways with the layers at higher scales (retina damage and disability). Overall, the identified paths provide a means to connect the molecular aspects of MS with the overall phenotype. Author summary: Complex diseases such as Multiple Sclerosis (MS) involve the contribution of a wide range of biological processes. We conducted a systems biology study of MS based on network analysis and deep phenotyping in a prospective cohort of patients with clinical, imaging, genetics, and omics assessments. The genes, proteins and cell paths explained variation in central nervous system damage, and in metrics of disease severity. Such multilayer paths explain the different phenotypes of the disease and can be developed as biomarkers of MS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence. Objectives and methods: An open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS). Results: Prior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces TH1, TH17 and B cell activity as well as sNfL, yet the addition of oral GlcNAc dose-dependently lowered serum IFNγ, IL-17, IL-6 and NfL. Oral GlcANc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is increased in the brain of MS patients. 30% of treated patients displayed confirmed improvement in neurological disability, with an average EDSS score decrease of 0.52 points. Conclusions: Oral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc's potential to control residual brain inflammation, myelin repair and neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

Background and purpose: Thinning of the retinal combined ganglion cell and inner plexiform layer (GCIP) as measured by optical coherence tomography (OCT) is a common finding in patients with multiple sclerosis. This study aimed to investigate whether a single retinal OCT analysis allows prediction of future disease activity after a first demyelinating event. Methods: This observational cohort study included 201 patients with recently diagnosed clinically isolated syndrome or relapsing–remitting multiple sclerosis from two German tertiary referral centers. Individuals underwent neurological examination, magnetic resonance imaging, and OCT at baseline and at yearly follow‐up visits. Results: Patients were included at a median disease duration of 2.0 months. During a median follow‐up of 59 (interquartile range = 43–71) months, 82% of patients had ongoing disease activity as demonstrated by failing the no evidence of disease activity 3 (NEDA‐3) criteria, and 19% presented with confirmed disability worsening. A GCIP threshold of ≤77 μm at baseline identified patients with a high risk for NEDA‐3 failure (hazard ratio [HR] = 1.7, 95% confidence interval [CI] = 1.1–2.8, p = 0.04), and GCIP measures of ≤69 μm predicted disability worsening (HR = 2.2, 95% CI = 1.2–4.3, p = 0.01). Higher rates of annualized GCIP loss increased the risk for disability worsening (HR = 2.5 per 1 μm/year increase of GCIP loss, p = 0.03). Conclusions: Ganglion cell thickness as measured by OCT after the initial manifestation of multiple sclerosis may allow early risk stratification as to future disease activity and progression. [ABSTRACT FROM AUTHOR]

Background: Retinal degeneration leading to optical coherence tomography (OCT) changes is frequent in patients with multiple sclerosis (PwMS). Objective: To investigate associations among OCT changes, MRI measurements of global and regional brain volume loss, and physical and cognitive impairment in PwMS. Methods: 95 PwMS and 52 healthy controls underwent OCT and MRI examinations. Mean peripapillary retinal nerve fiber layer (pRNFL) thickness and ganglion cell/inner plexiform layer (GCIPL) volume were measured. In PwMS disability was quantified with the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Associations between OCT, MRI, and clinical measures were investigated with multivariable regression models. Results: In PwMS, pRNFL and GCIPL were associated with the volume of whole brain (p < 0.04), total gray matter (p < 0.002), thalamus (p ≤ 0.04), and cerebral cortex (p ≤ 0.003) –both globally and regionally–, but not white matter. pRNFL and GCIPL were also inversely associated with T2-lesion volume (T2LV), especially in the optic radiations (p < 0.0001). The brain volumes associated with EDSS and SDMT significantly overlapped with those correlating with pRNFL and GCIPL. Conclusions: In PwMS, pRNFL and GCIPL reflect the integrity of clinically-relevant gray matter structures, underling the value of OCT measures as markers of neurodegeneration and disability in multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: We evaluated the hydrostatic pressure of the renal pelvis (RPP) as a radiation-free alternative to fluoroscopic nephrostogram to assess ureteral patency after percutaneous nephrolithotomy (PCNL). Methods: Retrospective non-inferiority study analyzing 248 PCNL-patients (86 female (35%) and 162 males (65%)) between 2007 and 2015. Postoperatively, RPP was measured using a central venous pressure manometer in cmH2O. The primary endpoint was to assess RPP depending on the patency of the ureter and the nephrostomy tube removal. Secondary, the upper limit of normal RPP of ≤ 20 cmH2O was assessed as an indicator of an unobstructed patency. Results: The median procedure duration was 141 min (112–171.5) with a stone free rate of 82% (n = 202). RPP was significantly higher in patients with obstructive nephrostogram with 25.0 mmH2O (21.0–32.0) versus 20.0 mmH2O (16.0–24.0; p < 0.001). The pressure was lower in successful nephrostomy removal with 18 cmH2O (15–21) versus 23 cmH2O (20–29) in the leakage group (p < 0.001). The analysis of a cut-off of ≤ 20 cmH2O showed a sensitivity of 76.9% (95% CI [60.7%; 88.9%]) and a specificity of 61.5% (95% CI [54.6%; 68.2%]). The negative predictive value was 93.4% (95% CI: [87.9%; 97.0%]) and the positive predictive value 27.3% (95% CI [19.2%; 36.6%]). The accuracy of the model showed an AUC = 0.795 (95% CI [0.668; 0.862]). Conclusion: The hydrostatic RPP seems to allow a bedside evaluation of ureteral patency after PCNL. [ABSTRACT FROM AUTHOR]

Background: Large-scale disease overarching longitudinal data are rare in the field of neuroimmunology. However, such data could aid early disease stratification, understanding disease etiology and ultimately improve treatment decisions. The Berlin Registry of Neuroimmunological Entities (BERLimmun) is a longitudinal prospective observational study, which aims to identify diagnostic, disease activity and prognostic markers and to elucidate the underlying pathobiology of neuroimmunological diseases. Methods: BERLimmun is a single-center prospective observational study of planned 650 patients with neuroimmunological disease entity (e.g. but not confined to: multiple sclerosis, isolated syndromes, neuromyelitis optica spectrum disorders) and 85 healthy participants with 15 years of follow-up. The protocol comprises annual in-person visits with multimodal standardized assessments of medical history, rater-based disability staging, patient-report of lifestyle, diet, general health and disease specific symptoms, tests of motor, cognitive and visual functions, structural imaging of the neuroaxis and retina and extensive sampling of biological specimen. Discussion: The BERLimmun database allows to investigate multiple key aspects of neuroimmunological diseases, such as immunological differences between diagnoses or compared to healthy participants, interrelations between findings of functional impairment and structural change, trajectories of change for different biomarkers over time and, importantly, to study determinants of the long-term disease course. BERLimmun opens an opportunity to a better understanding and distinction of neuroimmunological diseases. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of multiple sclerosis (MS) requires demyelinating events that are disseminated in time and space. Peripapillary retinal nerve fiber layer (pRNFL) thickness as measured by optical coherence tomography (OCT) distinguishes eyes with a prior history of acute optic neuritis (ON) and may provide evidence to support a demyelinating attack. Objective: To investigate whether a deep learning (DL)‐based network can distinguish between eyes with prior ON and healthy control (HC) eyes using peripapillary ring scans. Methods: We included 1033 OCT scans from 415 healthy eyes (213 HC subjects) and 510 peripapillary ring scans from 164 eyes with prior acute ON (140 patients with MS). Data were split into 70% training, 15% validation, and 15% test data. We included 102 OCT scans from 80 healthy eyes (40 HC) and 61 scans from 40 ON eyes (31 MS patients) from an independent second center. Receiver operating characteristic curve analyses with area under the curve (AUC) were used to investigate performance. Results: We used a dilated residual convolutional neural network for the classification. The final network had an accuracy of 0.85 and an AUC of 0.86, whereas pRNFL only had an AUC of 0.77 in recognizing ON eyes. Using data from a second center, the network achieved an accuracy of 0.77 and an AUC of 0.90 compared to pRNFL, which had an AUC of 0.84. Interpretation: DL‐based disease classification of prior ON is feasible and has the potential to outperform thickness‐based classification of eyes with and without history of prior ON. [ABSTRACT FROM AUTHOR]

Optic neuritis (ON) in neuromyelitis optica spectrum disorders (NMOSD) regularly leads to more profound vision loss compared to multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein-antibody associated disease (MOGAD). Here we investigate ON-related vision loss in NMOSD compared to MS and MOGAD in order to identify neuroaxonal and retinal contributors to visual dysfunction. In this retrospective study we included patients with aquaporin-4-antibody seropositive NMOSD (n = 28), MOGAD (n = 14), MS (n = 29) and controls (n = 14). We assessed optic nerve damage and fovea morphometry by optical coherence tomography. Visual function was assessed as high (HCVA) and low contrast visual acuity (LCVA), and visual fields' mean deviation (MD). In all diseases, lower visual function was associated with peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell and inner plexiform layer (GCIP) thinning following a broken stick model, with pRNFL and GCIP cutoff point at ca. 60 µm. HCVA loss per µm pRNFL and GCIP thinning was stronger in NMOSD compared with MOGAD. Foveal inner rim volume contributed to MD and LCVA in NMOSD eyes, only. Together these data supports that visual dysfunction in NMOSD is associated with neuroaxonal damage beyond the effect seen in MS and MOGAD. A primary retinopathy, respectively Müller cell pathology, may contribute to this effect. [ABSTRACT FROM AUTHOR]

Background: Serum neurofilament light (sNfL) chain is a promising biomarker reflecting neuro-axonal injury in multiple sclerosis (MS). However, the ability of sNfL to predict outcomes in real-world MS cohorts requires further validation. Objective: The aim of the study is to investigate the associations of sNfL concentration, magnetic resonance imaging (MRI) and retinal optical coherence tomography (OCT) markers with disease worsening in a longitudinal European multicentre MS cohort. Methods: MS patients (n = 309) were prospectively enrolled at four centres and re-examined after 2 years (n = 226). NfL concentration was measured by single molecule array assay in serum. The patients' phenotypes were thoroughly characterized with clinical examination, retinal OCT and MRI brain scans. The primary outcome was disease worsening at median 2-year follow-up. Results: Patients with high sNfL concentrations (⩾8 pg/mL) at baseline had increased risk of disease worsening at median 2-year follow-up (odds ratio (95% confidence interval) = 2.8 (1.5–5.3), p = 0.001). We found no significant associations of MRI or OCT measures at baseline with risk of disease worsening. Conclusion: Serum NfL concentration was the only factor associated with disease worsening, indicating that sNfL is a useful biomarker in MS that might be relevant in a clinical setting. [ABSTRACT FROM AUTHOR]

Late Cenozoic climate change led to the progressive aridification of Australia over the past 15 million years. This gradual biome turnover fundamentally changed Australia's ecosystems, opening new niches and prompting diversification of plants and animals. One example are termites of the Australian Amitermes group (AAG), consisting of the Australian Amitermes and affiliated genera. Although the most speciose and diverse higher termite group in Australia, little is known about its evolutionary history. We used ancestral range reconstruction and diversification analyses to illuminate 1) phylogenetic relationships of the AAG, 2) biogeographical processes leading to the current continent‐wide distribution and 3) timing and pattern of diversification in the context of late Cenozoic climate change. By estimating the largest time‐calibrated phylogeny for this group to date, we demonstrate monophyly of the AAG and confirm that their ancestor arrived in Australia ~11–10 million years ago (Mya) from Southeast Asia. Ancestral range reconstruction indicates that Australia's monsoon region was the launching point for a continental radiation shaped by dispersal and within‐biome speciation rather than vicariance. We found that multiple arid‐zone species diversified from mesic and tropical ancestors in the Plio‐Pleistocene, but also observed diversification in the opposite direction. Finally, we show that diversification steadily increased from ~8 to 9 Mya during the 'Hill Gap' and accelerated from ~4 Mya in concert with major ecological change during the Pliocene. Consistent with rapid diversification, species accumulation then slowed down into the present, likely caused by progressive niche saturation. This study provides a stepping stone for predicting future responses of Australia's termite fauna in the face of human‐mediated climate change. [ABSTRACT FROM AUTHOR]

Reliable biomarkers quantifying neurodegeneration and neuroinflammation in central nervous system disorders such as Multiple Sclerosis, Alzheimer's dementia or Parkinson's disease are an unmet clinical need. Intraretinal layer thicknesses on macular optical coherence tomography (OCT) images are promising noninvasive biomarkers querying neuroretinal structures with near cellular resolution. However, changes are typically subtle, while tissue gradients can be weak, making intraretinal segmentation a challenging task. A robust and efficient method that requires no or minimal manual correction is an unmet need to foster reliable and reproducible research as well as clinical application. Here, we propose and validate a cascaded two-stage network for intraretinal layer segmentation, with both networks being compressed versions of U-Net (CCU-INSEG). The first network is responsible for retinal tissue segmentation from OCT B-scans. The second network segments eight intraretinal layers with high fidelity. At the post-processing stage, we introduce Laplacian-based outlier detection with layer surface hole filling by adaptive non-linear interpolation. Additionally, we propose a weighted version of focal loss to minimize the foreground–background pixel imbalance in the training data. We train our method using 17,458 B-scans from patients with autoimmune optic neuropathies, i.e., multiple sclerosis, and healthy controls. Voxel-wise comparison against manual segmentation produces a mean absolute error of 2.3 μm, outperforming current state-of-the-art methods on the same data set. Voxel-wise comparison against external glaucoma data leads to a mean absolute error of 2.6 μm when using the same gold standard segmentation approach, and 3.7 μm mean absolute error in an externally segmented data set. In scans from patients with severe optic atrophy, 3.5% of B-scan segmentation results were rejected by an experienced grader, whereas this was the case in 41.4% of B-scans segmented with a graph-based reference method. The validation results suggest that the proposed method can robustly segment macular scans from eyes with even severe neuroretinal changes. [ABSTRACT FROM AUTHOR]

Background: Decreased motion perception has been suggested as a marker for visual pathway demyelination in optic neuritis (ON) and/or multiple sclerosis (MS). Objectives: To examine the influence of neuro-axonal damage on motion perception in MS and neuromyelitis optica spectrum disorders (NMOSD). Methods: We analysed motion perception with numbers-from-motion (NFM), visual acuity, (multifocal (mf)) VEP, optical coherence tomography in patients with MS (n = 38, confirmatory cohort n = 43), NMOSD (n = 13) and healthy controls (n = 33). Results: NFM was lower compared with controls in MS (B = −12.37, p < 0.001) and NMOSD (B = −34.5, p < 0.001). NFM was lower in ON than in non-ON eyes (B = −30.95, p = 0.041) in NMOSD, but not MS. In MS and NMOSD, lower NFM was associated with worse visual acuity (B = −139.4, p < 0.001/ B = −77.2, p < 0.001) and low contrast letter acuity (B = 0.99, p = 0.002/ B = 1.6, p < 0.001), thinner peripapillary retinal nerve fibre layer (B = 1.0, p < 0.001/ B = 0.92, p = 0.016) and ganglion cell/inner plexiform layer (B = 64.8, p < 0.001/ B = 79.5, p = 0.006), but not with VEP P100 latencies. In the confirmatory MS cohort, lower NFM was associated with thinner retinal nerve fibre layer (B = 1.351, p < 0.001) and increased mfVEP P100 latencies (B = −1.159, p < 0.001). Conclusions: Structural neuro-axonal visual pathway damage is an important driver of motion perception impairment in MS and NMOSD. [ABSTRACT FROM AUTHOR]

Background: The standardized T1-weighted/T2-weighted (sT1w/T2w) ratio for the middle cerebellar peduncle (MCP) has been reported to be sensitive for detecting degenerative changes in the cerebellar subtype of multiple system atrophy (MSA-C), even in the early stages. We aimed to investigate the diagnostic value of the MCP sT1w/T2w ratio for differentiating between MSA-C and spinocerebellar ataxia (SCA). Methods: We included 32 MSA-C, 8 SCA type 3 (SCA3), 16 SCA type 6 (SCA6) patients, and 17 controls, and the MCP sT1w/T2w ratio was analyzed using a region-of-interest approach. The diagnostic performance of the MCP sT1w/T2w ratio in discriminating among MSA-C, SCA3, and SCA6 was assessed and compared with diagnosis based on visual interpretation of MCP hyperintensities and the "hot cross bun" (HCB) sign. Results: MCP sT1w/T2w ratio values were markedly lower in patients with MSA-C than in those with SCA3, those with SCA6, and controls (p < 0.001). The MCP sT1w/T2w ratio showed high diagnostic accuracy for distinguishing MSA-C from SCA3 (area under curve = 0.934), SCA6 (area under curve = 0.965), and controls (area under curve = 0.980). The diagnostic accuracy of the MCP sT1w/T2w ratio for differentiating MSA-C from SCA3 or SCA6 (90.0% for MSA-C vs. SCA3, and 91.7% for MSA-C vs. SCA6) was comparable to or superior than that of visual interpretation of MCP hyperintensities (80.0–87.5% in MSA-C vs. SCA3 and 87.6–97.9% in MSA-C vs. SCA6) or the HCB sign (72.5–80.0% in MSA-C vs. SCA3 and 77.1–93.8% in MSA-C vs. SCA6). Conclusions: The MCP sT1w/T2w ratio might be a sensitive imaging-based marker for detecting MSA-C-related changes and differentiating MSA-C from SCA3 or SCA6. [ABSTRACT FROM AUTHOR]

Background: Instrumented assessment of motor symptoms has emerged as a promising extension to the clinical assessment of several movement disorders. The use of mobile and inexpensive technologies such as some markerless motion capture technologies is especially promising for large-scale application but has not transitioned into clinical routine to date. A crucial step on this path is to implement standardized, clinically applicable tools that identify and control for quality concerns. Objective: The main goal of this study comprises the development of a systematic quality control (QC) procedure for data collected with markerless motion capture technology and its experimental implementation to identify specific quality concerns and thereby rate the usability of recordings. Methods: We developed a post hoc QC pipeline that was evaluated using a large set of short motor task recordings of healthy controls (2010 recordings from 162 subjects) and people with multiple sclerosis (2682 recordings from 187 subjects). For each of these recordings, 2 raters independently applied the pipeline. They provided overall usability decisions and identified technical and performance-related quality concerns, which yielded respective proportions of their occurrence as a main result. Results: The approach developed here has proven user-friendly and applicable on a large scale. Raters' decisions on recording usability were concordant in 71.5%-92.3% of cases, depending on the motor task. Furthermore, 39.6%-85.1% of recordings were concordantly rated as being of satisfactory quality whereas in 5.0%-26.3%, both raters agreed to discard the recording. Conclusions: We present a QC pipeline that seems feasible and useful for instant quality screening in the clinical setting. Results confirm the need of QC despite using standard test setups, testing protocols, and operator training for the employed system and by extension, for other task-based motor assessment technologies. Results of the QC process can be used to clean existing data sets, optimize quality assurance measures, as well as foster the development of automated QC approaches and therefore improve the overall reliability of kinematic data sets. [ABSTRACT FROM AUTHOR]

Background: Cross-sectional studies suggest normal appearing white matter (NAWM) integrity loss may lead to cortical atrophy in late-stage relapsing-remitting multiple sclerosis (MS). Objective: To investigate the relationship between NAWM integrity and cortical thickness from first clinical presentation longitudinally. Methods: NAWM integrity and cortical thickness were assessed with 3T magnetic resonance imaging (MRI) in 102 patients with clinically isolated syndrome or early MS (33.2 (20.1–60.1) years old, 68% female) from first clinical presentation over 2.8 ± 1.6 years. Fifty healthy controls (HCs) matched for age and sex were included. NAWM integrity was evaluated using the standardized T1w/T2w ratio (sT1w/T2w). The association between sT1w/T2w and cortical thickness was assessed using linear mixed models. The effect of disease activity was investigated using the No Evidence of Disease Activity (NEDA-3) criteria. Results: At baseline, sT1w/T2w (p = 0.152) and cortical thickness (p = 0.489) did not differ from HCs. Longitudinally, decreasing sT1w/T2w was associated with cortical thickness and increasing lesion burden (marginal R 2 = 0.061). The association was modulated by failing NEDA-3 (marginal R 2 = 0.097). Conclusion: sT1w/T2w may be a useful MRI biomarker for early MS, detecting relevant NAWM damage over time using conventional MRI scans, although with less sensitivity compared to quantitative measures. [ABSTRACT FROM AUTHOR]

Health-related quality of life (HRQoL) is an essential complementary parameter in the assessment of disease burden and treatment outcome in multiple sclerosis (MS) and can be affected by neuropsychiatric symptoms, which in turn are sensitive to psychological stress. However, until now, the impact of neurobiological stress and relaxation on HRQoL in MS has not been investigated. We thus evaluated whether the activity of neural networks triggered by mild psychological stress (elicited in an fMRI task comprising mental arithmetic with feedback) or by stress termination (i.e., relaxation) at baseline (T0) predicts HRQoL variations occurring between T0 and a follow-up visit (T1) in 28 patients using a robust regression and permutation testing. The median delay between T0 and T1 was 902 (range: 363–1,169) days. We assessed HRQoL based on the Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and accounted for the impact of established HRQoL predictors and the cognitive performance of the participants. Relaxation-triggered activity of a widespread neural network predicted future variations in overall HRQoL (t = 3.68, p family−wise error [FWE]-corrected = 0.008). Complementary analyses showed that relaxation-triggered activity of the same network at baseline was associated with variations in the HAQUAMS mood subscale on an αFWE = 0.1 level (t = 3.37, p FWE = 0.087). Finally, stress-induced activity of a prefronto-limbic network predicted future variations in the HAQUAMS lower limb mobility subscale (t = −3.62, p FWE = 0.020). Functional neural network measures of psychological stress and relaxation contain prognostic information for future HRQoL evolution in MS independent of clinical predictors. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to use a novel MRI contrast, the standardized T1-weighted/T2-weighted (sT1w/T2w) ratio, to assess damage of the white matter and gray matter in multiple system atrophy (MSA). Furthermore, this study investigated whether the sT1w/T2w ratio was associated with cognitive impairment in MSA. Methods: The white matter and gray matter sT1w/T2w ratio of 37 MSA patients and 19 healthy controls were measured. Correlation analyses were used to evaluate the relationship between sT1w/T2w ratio values and clinical variables, and a multivariate analysis was used to identify independent factors associated with cognitive impairment in MSA. Results: MSA patients showed a higher white matter sT1w/T2w ratio value than controls (p < 0.001), and the white matter sT1w/T2w ratio value was significantly correlated with the International Cooperative Ataxia Rating Scale score (r = 0.377, p = 0.021) and the Addenbrooke's cognitive examination III score (r = −0.438, p = 0.007). Cognitively impaired MSA patients had a significantly higher white matter sT1w/T2w ratio value than cognitively preserved MSA patients (p = 0.010), and the multiple logistic regression analysis revealed that the median white matter sT1w/T2w ratio value was independently associated with cognitive impairment in MSA. Conclusion: The sT1w/T2w ratio is sensitive to degenerative changes in the white matter that is associated with cognitive ability in MSA patients. [ABSTRACT FROM AUTHOR]

Sex strongly impacts genome evolution via recombination and segregation. In the absence of these processes, haplotypes within lineages of diploid organisms are predicted to accumulate mutations independently of each other and diverge over time. This so-called "Meselson effect" is regarded as a strong indicator of the long-term evolution under obligate asexuality. Here, we present genomic and transcriptomic data of three populations of the asexual oribatid mite species Oppiella nova and its sexual relative Oppiella subpectinata. We document strikingly different patterns of haplotype divergence between the two species, strongly supporting Meselson effect-like evolution and long-term asexuality in O. nova: I) variation within individuals exceeds variation between populations in O. nova but vice versa in O. subpectinata; II) two O. nova sublineages feature a high proportion of lineage-specific heterozygous single-nucleotide polymorphisms (SNPs), indicating that haplotypes continued to diverge after lineage separation; III) the deepest split in gene trees generally separates the two haplotypes in O. nova, but populations in O. subpectinata; and IV) the topologies of the two haplotype trees match each other. Our findings provide positive evidence for the absence of canonical sex over evolutionary time in O. nova and suggest that asexual oribatid mites can escape the dead-end fate usually associated with asexual lineages. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI)‐based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human‐led validated consensus quality control criteria (OSCAR‐IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI‐based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five‐point expansion of the OSCAR‐IB criteria to embrace AI (OSCAR‐AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines. [ABSTRACT FROM AUTHOR]

Background and purpose: Foveal changes were reported in aquaporin‐4 antibody (AQP4‐Ab) seropositive neuromyelitis optica spectrum disorder (NMOSD) patients; however, it is unclear whether they are independent of optic neuritis (ON), stem from subclinical ON or crossover from ON in fellow eyes. Fovea morphometry and a statistical classification approach were used to investigate if foveal changes in NMOSD are independent of ON and progressive. Methods: This was a retrospective longitudinal study of 27 AQP4‐IgG + NMOSD patients (49 eyes; 15 ON eyes and 34 eyes without a history of ON [NON eyes]), follow‐up median (first and third quartile) 2.32 (1.33–3.28), and 38 healthy controls (HCs) (76 eyes), follow‐up median (first and third quartile) 1.95 (1.83–2.54). The peripapillary retinal nerve fibre layer thickness and the volume of combined ganglion cell and inner plexiform layer as measures of neuroaxonal damage from ON were determined by optical coherence tomography. Nineteen foveal morphometry parameters were extracted from macular optical coherence tomography volume scans. Data were analysed using orthogonal partial least squares discriminant analysis and linear mixed effects models. Results: At baseline, foveal shape was significantly altered in ON eyes and NON eyes compared to HCs. Discriminatory analysis showed 81% accuracy distinguishing ON vs. HCs and 68% accuracy in NON vs. HCs. NON eyes were distinguished from HCs by foveal shape parameters indicating widening. Orthogonal partial least squares discriminant analysis discriminated ON vs. NON with 76% accuracy. In a follow‐up of 2.4 (20.85) years, no significant time‐dependent foveal changes were found. Conclusion: The parafoveal area is altered in AQP4‐Ab seropositive NMOSD patients suggesting independent neuroaxonal damage from subclinical ON. Longer follow‐ups are needed to confirm the stability of the parafoveal structure over time. [ABSTRACT FROM AUTHOR]

Objective: We aimed to investigate the use of a myelin-sensitive MRI contrast, the standardized T1-weighted/T2-weighted (sT1w/T2w) ratio, for detecting early changes in the middle cerebellar peduncle (MCP) in cerebellar subtype multiple system atrophy (MSA-C) patients. Methods: We included 28 MSA-C patients, including a subset of 17 MSA-C patients within 2 years of disease onset (early MSA-C), and 28 matched healthy controls. T1w and T2w scans were acquired using a 3-T MR system. The sT1w/T2w ratio in MCP was analyzed using SPM12 by utilizing a region-of-interest approach in normalized space. The diagnostic performance of the MCP sT1w/T2w ratio in discriminating MSA-C and the subgroup of early MSA-C from the matched controls was assessed. Correlation analyses were performed to evaluate the relationship between the MCP sT1w/T2w ratio and other clinical parameters including the International Cooperative Ataxia Scale (ICARS) score for quantifying cerebellar ataxia. Results: Compared to controls, the sT1w/T2w ratio in the MCP was markedly lower in all (p < 0.001) MSA-C patients and 17 early (p < 0.001) MSA-C patients. The MCP sT1w/T2w ratio had high sensitivity (96%) and specificity (100%) to distinguish MSA-C from controls (area under the curve = 0.99), even for the early MSA-C group (area under the curve = 0.99; sensitivity = 94%, specificity = 100%). The MCP sT1w/T2w ratio correlated with the ICARS score in early MSA-C. Conclusions: The sT1w/T2w ratio can detect MSA-C-related changes in the MCP, even in the early stages of the disorder, and could be a sensitive biomarker for MSA-C. Key Points: • The sT1w/T2w ratio can detect MSA-C-related changes in the middle cerebellar peduncle, even in the early stages of the disorder. • The middle cerebellar peduncle sT1w/T2w ratio correlated with a cerebellar ataxia score in early MSA-C patients. [ABSTRACT FROM AUTHOR]

Background: Clinical outcomes in neuromyelitis optica spectrum disorders (NMOSD) vary across different regions. Objective: To describe clinical profiles in Japanese and German NMOSD patients. Methods: Medical records of aquaporin-4-immunoglobulin G (AQP4-IgG) positive NMOSD patients from Japan (n = 54) and Germany (n = 38) were retrospectively analyzed. Results: The disability status was similar between both cohorts, although Japanese patients had a longer disease duration (13.3 ± 11.1 vs. 8.1 ± 6.9 years, p = 0.018) but similar relapse rates. Optic neuritis and myelitis were the most frequent attacks in both cohorts. Brain attacks occurred more frequently in Japanese patients (40.7% vs. 15.8%, p = 0.020). The time from disease onset (median [interquartile range] 2.3 [0.3-10.1] vs. 0.6 [0.2-1.9] years, p = 0.009) and the number of attacks (2.5 [1-7] vs. 2 [1-3], p = 0.047) until start of the first immunotherapy were higher in the Japanese cohort. Rituximab was the most common drug in the German cohort (52.6%) and not given in the Japanese cohort (p < 0.001), where oral prednisolone was the most common drug (92.6% vs. 15.8%, p < 0.001). The frequency of autoimmune comorbidities was higher in the German cohort (39.5% vs. 18.5%, p = 0.047). Conclusion: Compared with Japanese NMOSD patients, German patients presented with similar disability despite shorter disease duration and earlier and more frequent immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG+) NMOSD.Methods: sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG+ patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG+ patients over a median observation period of 4.25 years.Results: In patients with AQP4-IgG+ NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG+ patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG+, but not MOG-IgG+ patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = - 1.28, p = 0.01). While in AQP4-IgG+, but not MOG-IgG+ patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = - 1.75, p = 0.06) in patients with AQP4-IgG+ NMOSD. Patients with AQP4-IgG+ NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3-105.6], p = 0.03). In contrast, baseline sNfL levels above the 75th age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG+ NMOSD.Conclusion: These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG+ NMOSD in phases of clinical remission. [ABSTRACT FROM AUTHOR]

Background: Epigallocatechin gallate (EGCG) is an anti-inflammatory agent and has proven neuroprotective properties in animal models of multiple sclerosis (MS). Optical coherence tomography (OCT) assessed retinal thickness analysis can reflect treatment responses in MS. Objective: To analyze the influence of EGCG treatment on retinal thickness analysis as secondary and exploratory outcomes of the randomized controlled Sunphenon in Progressive Forms of MS trial (SUPREMES, NCT00799890). Methods: SUPREMES patients underwent OCT with the Heidelberg Spectralis device at a subset of visits. We determined peripapillary retinal nerve fiber layer (pRNFL) thickness from a 12° ring scan around the optic nerve head and thickness of the ganglion cell/inner plexiform layer (GCIP) and inner nuclear layer (INL) within a 6 mm diameter grid centered on the fovea from a macular volume scan. Longitudinal OCT data were available for exploratory analysis from 31 SUPREMES participants (12/19 primary/secondary progressive MS (PPMS/SPMS); mean age 51 ± 7 years; 12 female; mean time since disease onset 16 ± 11 years). We tested the null hypothesis of no treatment*time interaction using nonparametric analysis of longitudinal data in factorial experiments. Results: After 2 years, there were no significant differences in longitudinal retinal thickness changes between EGCG treated and placebo arms in any OCT parameter (Mean change [confidence interval] ECGC vs. Placebo: pRNFL: −0.83 [1.29] μm vs. −0.64 [1.56] μm, p = 0.156; GCIP: −0.67 [0.67] μm vs. −0.14 [0.47] μm, p = 0.476; INL: −0.06 [0.58] μm vs. 0.22 [0.41] μm, p = 0.455). Conclusion: Retinal thickness analysis did not reveal a neuroprotective effect of EGCG. While this is in line with the results of the main SUPREMES trial, our study was probably underpowered to detect an effect. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT00799890. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Autosomal-dominant spinocerebellar ataxias (SCA) are neurodegenerative diseases characterized by progressive ataxia. Here, we report on neurometabolic alterations in spinocerebellar ataxia type 1 (SCA1; SCA-ATXN1) and 14 (SCA14; SCA-PRKCG) assessed by non-invasive 1H magnetic resonance spectroscopy. Three Tesla 1H magnetic resonance spectroscopy was performed in 17 SCA14, 14 SCA1 patients, and in 31 healthy volunteers. We assessed metabolites in the cerebellar vermis, right cerebellar hemisphere, pons, prefrontal, and motor cortex. Additionally, clinical characteristics were obtained for each patient to correlate them with metabolites. In SCA14, metabolic changes were restricted to the cerebellar vermis compared with widespread neurochemical alterations in SCA1. In SCA14, total N-acetylaspartate (tNAA) was reduced in the vermis by 34%. In SCA1, tNAA was reduced in the vermis (24%), cerebellar hemisphere (26%), and pons (25%). SCA14 patients showed 24% lower glutamate+glutamine (Glx) and 46% lower γ-aminobutyric acid (GABA) in the vermis, while SCA1 patients showed no alterations in Glx and GABA. SCA1 revealed a decrease of aspartate (Asp) in the vermis (62%) and an elevation in the prefrontal cortex (130%) as well as an elevation of myo-inositol (Ins) in the cerebellar hemisphere (51%) and pons (46%). No changes of Asp and Ins were detected in SCA14. Beyond, glucose (Glc) was increased in the vermis of both SCA14 (155%) and SCA1 (247%). 1H magnetic resonance spectroscopy revealed differing neurochemical profiles in SCA1 and SCA14 and confirmed metabolic changes that may be indicative for neuronal loss and dysfunctional energy metabolism. Therefore, 1H magnetic resonance spectroscopy represents a helpful tool for in-vivo tracking of disease-specific pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Clinical outcomes in neuromyelitis optica spectrum disorders (NMOSD) vary across different regions. Objective: To describe clinical profiles in Japanese and German NMOSD patients. Methods: Medical records of aquaporin-4-immunoglobulin G (AQP4-IgG) positive NMOSD patients from Japan (n = 54) and Germany (n = 38) were retrospectively analyzed. Results: The disability status was similar between both cohorts, although Japanese patients had a longer disease duration (13.3 ± 11.1 vs. 8.1 ± 6.9 years, p = 0.018) but similar relapse rates. Optic neuritis and myelitis were the most frequent attacks in both cohorts. Brain attacks occurred more frequently in Japanese patients (40.7% vs. 15.8%, p = 0.020). The time from disease onset (median [interquartile range] 2.3 [0.3-10.1] vs. 0.6 [0.2-1.9] years, p = 0.009) and the number of attacks (2.5 [1-7] vs. 2 [1-3], p = 0.047) until start of the first immunotherapy were higher in the Japanese cohort. Rituximab was the most common drug in the German cohort (52.6%) and not given in the Japanese cohort (p < 0.001), where oral prednisolone was the most common drug (92.6% vs. 15.8%, p < 0.001). The frequency of autoimmune comorbidities was higher in the German cohort (39.5% vs. 18.5%, p = 0.047). Conclusion: Compared with Japanese NMOSD patients, German patients presented with similar disability despite shorter disease duration and earlier and more frequent immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disorder that damages optic nerves, brainstem, and spinal cord. In vivo corneal confocal microscopy (IVCM) is a noninvasive technique that provides corneal images with dendritic cells (DCs) and corneal subbasal nerve plexus (SBP), which arises from the trigeminal nerve. Objective: We investigated corneal SBP changes in NMOSD and proposed IVCM as a potential new disease severity biomarker for NMOSD. Methods: Seventeen age-sex matched NMOSD patients and 19 healthy participants underwent complete neurologic and ophthalmologic examinations. The duration of disease, first symptom, presence of optic neuritis attack, antibody status, Expanded Disability Status Scale(EDSS) score and disease severity score(DSS) were recorded. Retinal nerve fibre layer (RNFL) thickness was measured with optical coherence tomography, and corneal SBP images were taken with IVCM. Results: NMOSD patients had significantly reduced corneal nerve fibre lenght-density and corneal nerve branch lenght-density compared with controls, while DC density was increased. NMOSD patients also showed significantly reduced RNFL thickness compared with controls. EDSS,DSS levels were inversely correlated with IVCM parameters. Conclusion: We observed significant corneal nerve fibre loss in NMOSD patients in relation to disease severity. IVCM can be a candidate noninvasive imaging method for axonal damage assessment in NMOSD that warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Quantification of motor performance has a promising role in personalized medicine by diagnosing and monitoring, e.g. neurodegenerative diseases or health problems related to aging. New motion assessment technologies can evolve into patient-centered eHealth applications on a global scale to support personalized healthcare as well as treatment of disease. However, uncertainty remains on the limits of generalizability of such data, which is relevant specifically for preventive or predictive applications, using normative datasets to screen for incipient disease manifestations or indicators of individual risks. Objective: This study explored differences between healthy German and Japanese adults in the performance of a short set of six motor tests. Methods: Six motor tasks related to gait and balance were recorded with a validated 3D camera system. Twenty-five healthy adults from Chiba, Japan, participated in this study and were matched for age, sex, and BMI to a sample of 25 healthy adults from Berlin, Germany. Recordings used the same technical setup and standard instructions and were supervised by the same experienced operator. Differences in motor performance were analyzed using multiple linear regressions models, adjusted for differences in body stature. Results: From 23 presented parameters, five showed group-related differences after adjustment for height and weight (R2 between.19 and.46, p<.05). Japanese adults transitioned faster between sitting and standing and used a smaller range of hand motion. In stepping-in-place, cadence was similar in both groups, but Japanese adults showed higher knee movement amplitudes. Body height was identified as relevant confounder (standardized beta >.5) for performance of short comfortable and maximum speed walks. For results of posturography, regression models did not reveal effects of group or body stature. Conclusions: Our results support the existence of a population-specific bias in motor function patterns in young healthy adults. This needs to be considered when motor function is assessed and used for clinical decisions, especially for personalized predictive and preventive medical purposes. The bias affected only the performance of specific items and parameters and is not fully explained by population-specific ethnic differences in body stature. It may be partially explained as cultural bias related to motor habits. Observed effects were small but are expected to be larger in a non-controlled cross-cultural application of motion assessment technologies with relevance for related algorithms that are being developed and used for data processing. In sum, the interpretation of individual data should be related to appropriate population-specific or even better personalized normative values to yield its full potential and avoid misinterpretation. [ABSTRACT FROM AUTHOR]

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disorder that damages optic nerves, brainstem, and spinal cord. In vivo corneal confocal microscopy (IVCM) is a noninvasive technique that provides corneal images with dendritic cells (DCs) and corneal subbasal nerve plexus (SBP), which arises from the trigeminal nerve. Objective: We investigated corneal SBP changes in NMOSD and proposed IVCM as a potential new disease severity biomarker for NMOSD. Methods: Seventeen age-sex matched NMOSD patients and 19 healthy participants underwent complete neurologic and ophthalmologic examinations. The duration of disease, first symptom, presence of optic neuritis attack, antibody status, Expanded Disability Status Scale (EDSS) score and disease severity score (DSS) were recorded. Retinal nerve fibre layer (RNFL) thickness was measured with optical coherence tomography, and corneal SBP images were taken with IVCM. Results: NMOSD patients had significantly reduced corneal nerve fibre lenght-density and corneal nerve branch lenght-density compared with controls, while DC density was increased. NMOSD patients also showed significantly reduced RNFL thickness compared with controls. EDSS, DSS levels were inversely correlated with IVCM parameters. Conclusion: We observed significant corneal nerve fibre loss in NMOSD patients in relation to disease severity. IVCM can be a candidate noninvasive imaging method for axonal damage assessment in NMOSD that warrants further investigation. [ABSTRACT FROM AUTHOR]

Using quantitative multi-parameter mapping (MPM), studies can investigate clinically relevant microstructural changes with high reliability over time and across subjects and sites. However, long acquisition times (20 min for the standard 1-mm isotropic protocol) limit its translational potential. This study aimed to evaluate the sensitivity gain of a fast 1.6-mm isotropic MPM protocol including post-processing optimized for longitudinal clinical studies. 6 healthy volunteers (35±7 years old; 3 female) were scanned at 3T to acquire the following whole-brain MPM maps with 1.6 mm isotropic resolution: proton density (PD), magnetization transfer saturation (MT), longitudinal relaxation rate (R1), and transverse relaxation rate (R2*). MPM maps were generated using two RF transmit field (B1+) correction methods: (1) using an acquired B1+ map and (2) using a data-driven approach. Maps were generated with and without Gibb's ringing correction. The intra-/inter-subject coefficient of variation (CoV) of all maps in the gray and white matter, as well as in all anatomical regions of a fine-grained brain atlas, were compared between the different post-processing methods using Student's t -test. The intra-subject stability of the 1.6-mm MPM protocol is 2–3 times higher than for the standard 1-mm sequence and can be achieved in less than half the scan duration. Intra-subject variability for all four maps in white matter ranged from 1.2–5.3% and in gray matter from 1.8 to 9.2%. Bias-field correction using an acquired B1+ map significantly improved intra-subject variability of PD and R1 in the gray (42%) and white matter (54%) and correcting the raw images for the effect of Gibb's ringing further improved intra-subject variability in all maps in the gray (11%) and white matter (10%). Combining Gibb's ringing correction and bias field correction using acquired B1+ maps provides excellent stability of the 7-min MPM sequence with 1.6 mm resolution suitable for the clinical routine. [ABSTRACT FROM AUTHOR]

Background: Psychological stress can influence the severity of multiple sclerosis (MS), but little is known about neurobiological factors potentially counteracting these effects. Objective: To identify gray matter (GM) brain regions related to relaxation after stress exposure in persons with MS (PwMS). Methods: 36 PwMS and 21 healthy controls (HCs) reported their feeling of relaxation during a mild stress task. These markers were related to regional GM volumes, heart rate, and depressive symptoms. Results: Relaxation was differentially linked to heart rate in both groups (t = 2.20, p = 0.017), i.e., both markers were only related in HCs. Relaxation was positively linked to depressive symptoms across all participants (t = 1.99, p = 0.045) although this link differed weakly between groups (t = 1.62, p = 0.108). Primarily, the volume in medial temporal gyrus was negatively linked to relaxation in PwMS (t = −5.55, pfamily−wise−error(FWE)corrected = 0.018). A group-specific coupling of relaxation and GM volume was found in ventromedial prefrontal cortex (VMPFC) (t = −4.89, pFWE = 0.039). Conclusion: PwMS appear unable to integrate peripheral stress signals into their perception of relaxation. Together with the group-specific coupling of relaxation and VMPFC volume, a key area of the brain reward system for valuation of affectively relevant stimuli, this finding suggests a clinically relevant misinterpretation of stress-related affective stimuli in MS. [ABSTRACT FROM AUTHOR]

Aims: To explore differences in advanced brain magnetic resonance imaging (MRI) characteristics between myelin oligodendrocyte (MOG) immunoglobulin (IgG) and aquaporin-4 (AQP4) IgG seropositive (+) neuromyelitis optica spectrum disorders (NMOSD). Methods: 33 AQP4-IgG and 18 MOG-IgG seropositive NMOSD patients and 61 healthy control (HC) subjects were included. All 112 participants were scanned with the same standardized MRI-protocol on a 3-Tesla MRI-scanner. Brain volume and diffusion tensor imaging (DTI) parameters were assessed. Results: MOG-IgG+ patients showed reduced parallel diffusivity within white matter tracts compared to HC whereas AQP4-IgG+ showed no significant brain parenchymal damage in DTI analysis. AQP4-IgG+ patients showed reduced whole brain volumes and reduced volumes of several deep gray matter structures compared to HC whereas MOG-IgG+ patients did not show reduced brain or deep gray matter volumes compared to HC. Conclusions: Microstructural brain parenchymal damage in MOG-IgG+ patients was more pronounced than in AQP4-IgG+ patients, compared with HC, whereas normalized brain volume reduction was more severe in AQP4-IgG+ patients. Longitudinal imaging studies are warranted to further investigate this trend in NMOSD. Our results suggest that MOG-IgG+ and AQP4-IgG+ NMOSD patients differ in cerebral MRI characteristics. Advanced MRI analysis did not help to differentiate between MOG-IgG+ and AQP4-IgG+ patients in our study. [ABSTRACT FROM AUTHOR]