Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.
ObjectivesCentral nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM).Methods12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects.ResultsClinical symptoms were depression (more pronounced in DM2), excessive daytime sleepiness (more pronounced in DM1), reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio-frontal and primary somato-sensory WM was affected.Significant structural-functional correlations of morphological MRI findings (global volumetry and VBM) with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex.ConclusionGM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes to cognitive impairment, depression and daytime sleepiness, partly indicating involvement of complex neuronal networks.
Remote health assessments that gather real-world data (RWD) outside of clinic settings require a clear understanding of appropriate methods for data collection, quality assessment, analysis and interpretation. Here, we examine the performance and limitations of smartphones in collecting RWD in the remote mPower observational study of Parkinson's Disease (PD). Within the first six months of study commencement, 960 participants had enrolled and performed at least 5 self-administered active PD symptom assessments (speeded tapping, gait/balance, phonation, or memory). Task performance, especially speeded tapping, was predictive of self-reported PD status (AUC=0.8) and correlated with in-clinic evaluation of disease severity (r =0.71; p<1.8×10 -6 ) when compared with motor MDS-UPDRS). Although remote assessment requires careful consideration for accurate interpretation of RWD, our results support the use of smartphones and wearables in objective and personalized disease assessments.RWD offers the opportunity to improve our understanding and management of health and disease outside of the clinical setting. 1 An increasingly popular method for collecting RWD is the use of remote digital assessments that allow frequent sampling and have been used to aid in the diagnosis, treatment, and monitoring of multiple conditions, including atrial fibrillation and diabetes. 2,3 When used in population-based studies, remote assessment can increase understanding of heterogeneity in disease manifestation, the Bas Bloem currently serves as Editor-in-Chief for the Journal of Parkinson's disease, serves on the editorial board of Practical Neurology and Digital Biomarkers, has received honoraria from serving on the scientific advisory board for Zambon, Biogen, UCB and Walk with Path, has
et al. Alemtuzumab versus interferon beta 1a as fi rst-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012; 380: 1819−28.
The ongoing Coronavirus Disease 2019 (COVID-19) pandemic is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is occasionally associated with manifold diseases of the central nervous system (CNS). We sought to present the neuroimaging features of such CNS involvement. In addition, we sought to identify typical neuroimaging patterns that could indicate possible COVID-19-associated neurological manifestations. METHODS: In this systematic literature review, typical neuroimaging features of cerebrovascular diseases and inflammatory processes associated with COVID-19 were analyzed. Reports presenting individual patient data were included in further quantitative analysis with descriptive statistics. RESULTS: We identified 115 studies reporting a total of 954 COVID-19 patients with associated neurological manifestations and neuroimaging alterations. A total of 95 (82.6%) of the identified studies were single case reports or case series, whereas 660 (69.2%) of the reported cases included individual information and were thus included in descriptive statistical analysis. Ischemia with neuroimaging patterns of large vessel occlusion event was revealed in 59.9% of ischemic stroke patients, whereas 69.2% of patients with intracerebral hemorrhage exhibited bleeding in a location that was not associated with hypertension. Callosal and/or juxtacortical location was identified in 58.7% of cerebral microbleed positive images. Features of hemorrhagic necrotizing encephalitis were detected in 28.8% of patients with meningo-/encephalitis. CONCLUSIONS: Manifold CNS involvement is increasingly reported in COVID-19 patients. Typical and atypical neuroimaging features have been observed in some disease entities, so that familiarity with these imaging patterns appears reasonable and may assist clinicians in the differential diagnosis of COVID-19 CNS manifestations.
IMPORTANCE Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.OBJECTIVE To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.DESIGN, PARTICIPANTS, AND SETTING Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.INTERVENTIONS Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. MAIN OUTCOMES AND MEASURESThe primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. RESULTSBased on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine 11.1 [95% CI,] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, −0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).CONCLUSIONS AND RELEVANCE Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.
Myotonic dystrophies (DMs) are clinically similar but distinct multisystemic diseases related to different repeat expansion mutations. CNS involvement is one important aspect of both, myotonic dystrophy type 1 and type 2 (DM1, DM2). Transcran ial sonography (TCS) has become a reliable diagnostic tool in the evaluation of several CNS disorders. The aim of this study was to evaluate TCS-findings in DM-patients in correlation with their clinical status. Thirty-one DM-patients (DM1 = 17; DM2 = 14) were examined clinically and sonographically by independent physicians. Echogenicities of basal ganglia and mesencephalic regions were assessed according to the examination protocol for extrapyramidal disorders using a Toshiba Aplio(®) XG ultrasound system. TCS abnormalities were correlated to clinical findings and secondly compared to 31 controls. Ventricle diameters were additionally compared to 3T-MRI volumetry. Nine patients (29 %) showed hyperechogenicity of substantia nigra. Mesencephalic raphe was hypoechogenic in nine (29 %) DM-patients and was more frequently in DM1 patients (p = 0.021). Width of third ventricle was significantly larger in the patient group (p = 0.021) and correlated with MRI-based volumetry (R (2) = 0.756). Pathological raphe signal was observed mainly in patients suffering from daytime sleepiness (sensitivity = 42.1 %, specificity = 88.9 %, p = 0,044), while alterations did not correlate with symptoms of depression. As a novel finding, a relation between mesencephalic raphe echogenicity and excessive daytime sleepiness could be identified in our DM-patients. An alteration of serotonergic raphe structures might be involved in the pathogenesis of hypersomnia in DM. TCS allows for measurement of third ventricle enlargement as a feasible bedside test.
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