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Identifying a reliable biomarker may accelerate diagnosis of multiple sclerosis (MS) and lead to early management of the disease. Accumulating evidence suggest that cerebrospinal fluid (CSF) and peripheral blood concentration of osteopontin (OPN) may have diagnostic and prognostic value in MS. We conducted a systematic review and meta-analysis of studies that measured peripheral blood and CSF levels of OPN in MS patients and controls to evaluate the diagnostic potential of this biomarker better. We searched PubMed, Web of Science and Scopus databases to find articles that measured OPN concentration in peripheral blood and CSF samples from MS patients up to October 19, 2016. Q statistic tests and the I2 index were applied for heterogeneity assessment. If the I2 index was less than 40%, the fixed-effects model was used for meta-analysis. Random-effects meta-analysis was chosen if the I2 value was greater than 40%. After removal of duplicates, 918 articles were identified, and 27 of them fulfilled the inclusion criteria. We included 22 eligible studies in the final meta-analysis. MS patients, in general, had considerably higher levels of OPN in their CSF and blood when compared to all types of controls (p<0.05). When the comparisons were made between different subtypes of MS patients and controls, the results pointed to significantly higher levels of OPN in CSF of MS subgroups (p<0.05). All subtypes of MS patients, except CIS patients, had increased blood levels of OPN compared to controls (p<0.05). In the second set of meta-analyses, we compared the peripheral blood and CSF concentrations of OPN between MS patient subtypes. CIS patients had significantly lower levels of OPN both in their peripheral blood and CSF compared to patients with progressive subtypes of MS (p<0.05). CSF concentration of OPN was significantly higher among RRMS patients compared to the CIS patients and SPMS patients (P<0.05). Finally, patients with active MS had significantly higher OPN levels in their CSF compared to patients with stable disease (P = 0.007). The result of this study confirms that increased levels of OPN exist in CSF and peripheral blood of MS patients and strengthens the evidence regarding the clinical utility of OPN as a promising and validated biomarker for MS.

Recent literature suggests that markers of neuroaxonal damage, such as neurofilaments and tau protein, might serve as potential biomarkers for ALS. We conducted this systematic review and meta-analysis study to compare cerebrospinal fluid (CSF) and blood levels of total tau (t-tau), phosphorylated tau (p-tau), amyloid beta peptide 42 (Abeta-42), and neurofilaments in ALS patients and controls. A systematic search of Cochrane Library, PubMed, Embase, and ISI Web of Science was conducted on March 18, 2022, and updated on January 26, 2023. Observational studies that compared the concentrations of neurofilament light chain (NfL), neurofilament heavy chain (NFH), t-tau, p-tau, or Abeta-42 in CSF or peripheral blood of ALS patients and controls were included. Data from relevant studies were independently extracted and screened for quality using a standard tool, by at least two authors. Meta-analysis was conducted when a minimum of 3 studies reported the same biomarker within the same biofluid. A total of 100 studies were eligible for at least one meta-analysis. CSF and blood levels of NfL (standardized mean difference (SMD) [95% CI]; CSF: 1.46 [1.25–1.68]; blood: 1.35 [1.09–1.60]) and NFH (CSF: 1.32 [1.13–1.50], blood: 0.90 [0.58–1.22]) were significantly higher in ALS patients compared with controls. The pooled differences between ALS patients and controls were not significant for CSF t-tau, blood t-tau, and CSF Abeta-42, but CSF p-tau was lower in ALS patients (-0.27 [-0.47- -0.07]). Significantly decreased p-tau/t-tau ratios were found in ALS patients compared with controls (-0.84 [-1.16- -0.53]). Heterogeneity was considerable in most of our meta-analyses. CSF and blood neurofilament levels, as well as the CSF p-tau/t-tau ratio, might be potential candidates for improving ALS diagnosis. Further research is warranted to better understand the underlying mechanisms and the clinical implications of these biomarker alterations.

Background Amyotrophic lateral sclerosis (ALS) is a highly progressive and debilitating neurodegenerative disease, which usually leads to the death of affected individuals within a few years after the onset of symptoms. ALS is currently incurable and very little is known about its pathophysiology. Finding validated biomarkers will help us to advance our understanding of ALS etiology and find better strategies for early diagnosis and management of the disease. The main aim of the present systematic review is to evaluate the concentration of 11 frequently reported biomarkers for ALS in peripheral blood and CSF of patients diagnosed with ALS compared with controls. Methods This systematic review protocol has been established according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) 2015 guideline. We will include all types of observational studies with human subjects that investigated the concentrations of intended biomarkers (amyloid beta (Aβ-42), tau and phosphorylated tau (p-Tau), neurofilaments, S100β, cystatin C, progranulin (PGRN), glial fibrillary acidic protein (GFAP), monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), TAR DNA-binding protein-43 (TDP43), YKL-40, and CHIT1 in CSF or peripheral blood of ALS patients for initial assessment. Also, we will include case series with a minimum of 10 cases and clinical trials which have measured baseline biomarker levels. Case studies, case reports, reviews, letters, and animal and in vitro studies will be excluded. Multiple electronic databases including Cochrane Library, MEDLINE (PubMed), ISI Web of Science, and EMBASE will be searched to find all eligible articles published since 1980. No language restriction will be applied. All titles and abstracts retrieved by searching information sources will be evaluated independently by two authors against the eligibility criteria. The following information will be extracted from each included study by two independent authors: bibliographic details (first author, study title, year of publication, country), demographics and clinical information (number of patients and controls, type of ALS and controls, study design, age, gender, specimen, biomarkers levels, ALS functional rating scale Revised (ALSFRS-R), duration of disease), and measurements (method, value type, biomarkers levels). We will use the extracted mean and standard deviation (SD) of biomarkers concentrations to calculate the standardized mean difference (SMD) and 95% confidence intervals (CI). The primary outcome measures are the mean difference of biomarker levels between ALS patients and controls, different types of ALS, and ALS patients with genetic mutations. Discussion We will systematically review the literature and analyze studies of biomarker level in CSF and peripheral blood of patients with ALS and controls. The results will help us to identify biomarkers with possible diagnostic and prognostic value. Systematic review registration PROSPERO CRD42017078127

Objective. In this study, we aimed to evaluate the executive profile of juvenile myoclonic epilepsy (JME) patients using the Frontal Assessment Battery (FAB) as a bedside screening tool and investigate its association with seizure proximity, family history of epilepsy, and polytherapy/monotherapy with antiepileptic drugs (AEDs). Background. JME patients have deficits in various aspects of executive functions. FAB has proved to be a useful tool for evaluating executive functions in clinical settings. Methods. Thirty-one JME patients and 110 healthy controls (HCs) were enrolled in this study. The participants were assessed using six subsets of FAB, including conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. Results. Compared to HCs, JME patients showed lower scores in conceptualization, mental flexibility, programming, sensitivity to interference, and total FAB. The number of AEDs (polytherapy versus monotherapy) and duration of time since the last seizure had no significant effect on FAB scores in JME patients. We found significant associations between disease duration and conceptualization, mental flexibility, inhibitory control, and total FAB score only in JME patients with recent seizure. Finally, receiver operating characteristic (ROC) analysis showed area under the curve (AUC) of 0.971 (95% confidence interval (CI): 0.947–0.994) for FAB total score, 0.933 for conceptualization (95% CI: 0.973-894), and 0.836 for mental flexibility (95% CI: 0.921-751). Conclusions. In summary, JME patients had deficits in different aspects of executive functions. FAB is a useful clinical tool for evaluation of executive functions in JME patients.

In this study, we examined phenotypic features of human Wharton’s jelly mesenchymal stem cells-derived oligodendrocytes. We induced human WJMSCs to form OLs by signaling molecules including basic fibroblastic growth factor, platelet-derived growth factor-AA, and triiodothyronine hormone. Differentiated WJMSCs showed morphologic characteristics of an OL phenotype. Expression of surface markers and genes in oligodendrocyte precursor cells or OLs were analyzed by immunocytochemistry staining and real-time polymerase chain reaction, respectively. These results suggest that WJMSCs could be programmed to OLs and might provide a potential source for cell therapy in neurodegenerative disease.

The objective of present study was to assess the safety and efficacy of nanocurcumin as an anti-inflammatory and antioxidant agent in adults with amyotrophic lateral sclerosis (ALS). We conducted a 12-month, double-blind, randomized, placebo-controlled trial at a neurological referral center in Iran. Eligible patients with a definite or probable ALS diagnosis were randomly assigned to receive either nanocurcumin (80 mg daily) or placebo in a 1:1 ratio. A computerized random number generator was used to prepare the randomization list. All patients and research investigators were blinded to treatment allocation. The primary outcome was survival, and event was defined to be death or mechanical ventilation dependency. Analysis was by intention-to-treat and included all patients who received at least one dose of study drug. A total of 54 patients were randomized to receive either nanocurcumin (n = 27) or placebo (n = 27). After 12 months, events occurred in 1 patient (3.7%) in the nanocurcumin group and in 6 patients (22.2%) in the placebo group. Kaplan–Meier analysis revealed a significant difference between the study groups regarding their survival curves (p = 0.036). No significant between-group differences were observed for any other outcome measures. No serious adverse events or treatment-related deaths were detected. No patients withdrew as a result of drug adverse events. The results suggest that nanocurcumin is safe and might improve the probability of survival as an add-on treatment in patients with ALS, especially in those with existing bulbar symptoms. Future studies with larger sample sizes and of longer duration are needed to confirm these findings.

Background Dysregulation of cation-chloride cotransporters NKCC1 and KCC2 expression was shown to be related to drug-resistant epilepsy. Previous studies suggested that bumetanide, an inhibitor of NKCC1, might have antiepileptic effects. Objective The aim of this study was to investigate the safety and efficacy of bumetanide add-on therapy in patients with drug-resistant epilepsy and its relation to cation-chloride cotransporters NKCC1 and KCC2. Methods We conducted an open-label, single-arm clinical trial in drug-resistant temporal lobe epilepsy (TLE) patients. This study consisted of three phases: pretreatment (3 months), titration (3 weeks), and active treatment (6 months). During the pretreatment phase, the dose of antiepileptic drugs was stabilized, and bumetanide was then added at an initial dose of 0.5 mg/day, increasing by 0.5 mg/week until a target dose of 2 mg/day was achieved. Bumetanide treatment was then continued for 6 months. Seizure frequency and adverse events were assessed at every monthly visit. Blood samples were collected from patients and 12 healthy controls were used for polymerase chain reaction and Western blot analyses. Primary clinical outcomes were drug safety and change in seizure frequency. Changes in NKCC1 and KCC2 expression were the non-clinical endpoints. Results A total of 30 patients were enrolled, 27 of whom completed the study. The mean duration of epilepsy was 16.5 years. Median seizure frequency per month was 9 [interquartile range (IQR) 7–14.5] at baseline, 3.67 (IQR 1.84–6.17) at the first 3 months, and 2 (IQR 0.84–4.34) at the last 3 months ( p  < 0.001). Five adverse events were detected in six patients. The reported adverse events were anorexia in four patients, nausea and vomiting in two patients, and agitation, headache and increased seizure frequency in one patient each. The level of NKCC1 and KCC2 gene transcripts and KCC2 protein did not change significantly following treatment ( p  > 0.05); however, we observed a significant reduction in NKCC1 protein levels ( p  = 0.042). Conclusions Bumetanide might be an effective and relatively tolerable drug in patients with drug-resistant TLE. Downregulation of NKCC1 protein following bumetanide treatment may be responsible for its antiepileptic effects. Iranian Registry of Clinical Trials Identifier IRCT 201012115368N1.

BackgroundSleep disturbances are common non-motor symptoms of Parkinson’s disease (PD). We aimed to compare the safety and efficacy of trazodone with melatonin and clonazepam in patients with PD and sleep complaints.MethodsThis single-center, double-blind, randomized clinical trial was conducted on PD patients with subjective sleep complaints. Eligible patients were randomized 1:1:1 to receive melatonin 3 mg/day, clonazepam 1 mg/day, or trazodone 50 mg/day for 4 weeks. The primary outcome measure was the changes in Pittsburgh Sleep Quality Index (PSQI) scores. The mean change in Epworth Sleepiness Scale (ESS) and RBD screening questionnaire (RBDSQ) was considered as the secondary outcome measures.ResultsA total of 112 eligible patients were randomized and 93 participants, melatonin (n = 31), trazodone (n = 31), and clonazepam (n = 31), completed the study. There was a significant decrease in PSQI scores after 4 weeks of treatment in all groups. The mean changes of PSQI from baseline were similar among the treatment arms (P = 0.325). Mean changes of RBDSQ and ESS from baseline were significantly different between study arms (P < 0.05). Melatonin intake was associated with a higher decrease in RBDSQ score compared to trazodone (P = 0.011) and clonazepam (P = 0.004). Trazodone intake was associated with a higher decrease in ESS score compared to clonazepam (P = 0.010). Mild adverse events were reported in three patients in the clonazepam, two patients in the trazodone group, and none in the melatonin group.ConclusionsTrazodone 50 mg/day, clonazepam 1 mg/day, and melatonin 3 mg/day were all tolerable and effective in improving sleep quality in patients with PD.Trial registrationIranian Registry of Clinical Trials (registration number; IRCT20170821035819N2).

ObjectivesPoor sleep quality is more prevalent in patients with amyotrophic lateral sclerosis (ALS) than in healthy populations. The purpose of this study was to examine whether or not motor dysfunction at various distinct levels correlates with subjective sleep quality.MethodsPatients with ALS and controls were assessed using the Pittsburgh Sleep Quality Index (PSQI), ALS Functional Rating Scale Revised (ALSFRS-R), Beck Depression Inventory-II (BDI-II), and the Epworth Sleepiness Scale (ESS). The ALSFRS-R was used to obtain information on 12 different aspects of motor function in patients with ALS. We compared these data between the groups with poor and good sleep quality.ResultsA total of 92 patients with ALS and 92 age- and sex-matched controls entered the study. The global PSQI score was significantly higher in patients with ALS than in healthy subjects (5.5 ± 4.2 vs. 4.0 ± 2.8) and 44% of the patients with ALS had poor sleep quality (PSQI score > 5). The sleep duration, sleep efficiency, and sleep disturbances components were significantly worse in patients with ALS. Sleep quality (PSQI) score correlated with ALSFRS-R score, BDI-II score, and ESS score. Of the 12 ALSFRS-R functions, swallowing significantly affected sleep quality. Orthopnea, speech, salivation, dyspnea, and walking had a medium effect. In addition, turning in bed, climbing stairs, and dressing and hygiene were found to have a small effect on sleep quality among patients with ALS.ConclusionsNearly half of our patients had poor sleep quality related to disease severity, depression, and daytime sleepiness. Bulbar muscle dysfunction may be associated with sleep disturbances in individuals with ALS, particularly when swallowing is impaired. In addition, patients suffering from axial or lower limb muscle disruptions are likely to have trouble sleeping.

Background Cerebral small vessel disease (SVD) is characterized by white matter hyperintensities (WMH) and microstructural damage detectable via diffusion‐weighted imaging (DWI) parameters such as free water (FW) and fractional anisotropy (FA). Vascular risk factors contribute to white matter damage and cognitive decline. Despite the disproportionate burden of vascular risk factors among Hispanic/Latino individuals, their impact on white matter integrity remains underexplored in this population. We investigated the association between vascular risk factors and MRI measures of white matter changes (FW, FA, and WMH) in cognitively normal Hispanic/Latino adults. Method This study was conducted on 1,619 cognitively normal participants from the SOL‐INCA MRI sub‐study cohort of self‐identified Hispanic/Latino individuals, with complete MRI data. MRI data were acquired using standardized 3T protocols, and white matter integrity measures, including FW, FA, and WMH burden, were obtained. Linear regression models were conducted to assess the associations of vascular risk factors (hypertension, diabetes, total cholesterol ≥200 mg/dL, and ever‐smoking) and Hispanic/Latino heritage with white matter integrity measures, adjusting for age, sex, education, and field center. Result Analyses showed significant heritage‐based differences in FW and WMH, with Cuban and Puerto Rican participants having higher levels of FW and WMH as compared to Mexican participants (p <0.05). Hypertension and diabetes were associated with increased FW and WMH (p <0.001), and diabetes was associated with lower FA values (p <0.001). No significant interactions were observed between vascular risk factors and heritage except between smoking status and heritage for FW (p = 0.011) and FA (p = 0.010), where smoking status was associated with increased FW and decreased FA among Cuban and Puerto Rican and decreased FA values in Central or South American as compared with Mexican participants (p <0.05). Conclusion Our findings indicate heritage‐specific differences in white matter integrity not explained by differences in vascular risk factors. We hypothesize that other factors, such as genetic, cultural, and environmental influences, explain these differences.