Multiple sclerosis and environmental risk factors: a case-control study in Iran

Studies have shown an increase in the incidence of MS in Iran. The aim of our study was to evaluate the relationship between environmental exposure and MS in Iran. This case-control study was conducted on 660 MS patients and 421 controls. Many environmental factors are compared between the two groups. Our findings demonstrated that prematurity ([OR = 4.99 (95% CI 1.34–18.68), P = 0.017]), history of measles and mumps ([OR = 1.60 (95% CI 1.05–2.45), P = 0.029; OR = 1.85 (95% CI 1.22–2.78), P = 0.003, respectively]), breast feeding [OR = 2.90 (95% CI 1.49–5.65), P = 0.002], head trauma in childhood ([OR = 8.21 (95% CI 1.56–43.06), P = 0.013]), vaccination in adulthood ([OR = 4.57 (95% CI 1.14–18.41), P = 0.032, respectively]), migraine ([OR = 3.50 (95% CI 1.61–7.59), P = 0.002]), family history of MS, IBD, migraine, and collagen vascular diseases ([OR = 2.73 (95% CI 1.56–4.78), P < 0.001], [OR = 3.14 (95% CI 1.460–6.78), P = 0.004; OR = 3.18 (95% CI 1.83–5.53), P < 0.001; OR = 1.81 (95% CI 1.03–3.20), P = 0.040, respectively]), stressful events ([OR = 32.57 (95% CI 17.21–61.64), P < 0.001]), and microwave exposure ([OR = 3.55 (95% CI 2.24–5.63), P ≤0.001]) were more in the MS group. Sun exposure ([OR = 0.09 (95% CI 0.02–0.38), P = 0.001]), dairy and calcium consumption ([OR = 0.44 (95% CI 0.27–0.71), P = 0.001]), diabetes mellitus ([OR = 0.11 (95% CI 0.01–00.99), P = 0.049], and complete vaccination during childhood appeared to decreased MS risk. Our results investigated many risk factors and protective factors in Iran.     

Brain volume loss is present in Japanese multiple sclerosis patients with no evidence of disease activity

No evidence of disease activity-3 (NEDA-3), defined as absence of clinical relapse, disability progression, and brain magnetic resonance imaging (MRI) activity, has emerged as the therapeutic target of disease-modifying therapy for multiple sclerosis (MS). However, recent studies have revealed that NEDA-3 might not be sufficient to prevent cognitive deterioration and predict long-term disability. In addition to NEDA-3, brain atrophy has recently been recognized as a pivotal biomarker that is closely associated to disability in patients with MS. This retrospective observational study included 22 Japanese MS patients with relatively mild disease (median expanded disability status scale?=?1.75). Fifteen patients (68%) received disease-modifying therapy (DMT), including interferon (IFN)-β (n =?6), IFN-β, or azathioprine followed by fingolimod (n =?4), fingolimod (n =?4), and IFN-β followed by natalizumab (n =?1). It revealed that 14 (64.6%) patients achieved NEDA-3 in the 2-year observational period. However, nine (64.3%) of the patients with NEDA-3 were revealed to have a significant BVL, defined as ≥?0.4% per year. Importantly, these nine patients included all patients receiving IFN-β therapy (n =?6), whereas patients without BVL included none of these patients. Conversely, patients treated with fingolimod following IFN-β did not have significant BVL. These results indicate that evaluation of NEDA-4 is encouraged especially in patients with IFN-β therapy in MS clinical practice in Japan although Japanese MS patients have generally been thought to possess a milder disease including brain atrophy compared to their Western counterparts.     

A multicenter,observational, prospective study of self- and parent-reported quality of life in adolescent multiple sclerosis patients self-administering interferon-β1a using RebiSmart™—the FUTURE study

Besides the impact of disease per se, the use of immunomodulatory therapies in adolescents with relapsing-remitting multiple sclerosis (RRMS) may have an effect on quality of life (QL). The FUTURE (Quality of liFe in adolescent sUbjecTs affected by mUltiple sclerosis treated with immunomodulatoRy agEnt using self-injecting device) study was designed to evaluate the changes in QL of Italian adolescents with RRMS receiving treatment with IFN-β1a (Rebif; 22 μg), administered subcutaneously three times weekly using the RebiSmart? electronic autoinjection device over a 52-week period. Fifty adolescents with RRMS were enrolled and 40 completed the study. Changes from baseline to end of treatment (EoT) in adolescent self-reported and parent-reported QL were assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL), which has been validated for use in pediatric MS and for which an Italian version is available. The adolescent self-reported total PedsQL4.0 score and all of its subscales tended to increase from baseline to EoT, the only exception being “Emotional functioning.” In parent-reported measures, the total PedsQL4.0 score increased significantly from baseline to EoT (+ 5.27 points, p = 0.041). Significant increases were also evident for parent-reported “Psychosocial health summary score” (+ 5.90 points; p = 0.015) and “School functioning” (+ 7.84 points; p = 0.029). Our results indicate that adolescents with RRMS using the electronic injection device RebiSmart? for self-administration of Rebif® can experience long-term improvements in QL.     

Expression Analysis of Long Non-coding RNAs in the Blood of Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS) with multiple genetic and environmental risk factors. Long non-coding RNAs (lncRNAs) have been recently reported to participate in the regulation of immune responses. Consequently, aberrant expression of lncRNAs has been suggested as an underlying cause of MS. In the present study, we evaluated the expression of three lncRNAs with putative roles in the regulation of immune response, namely TNF-α and heterogeneous nuclear ribonucleoprotein L (THRIL), Fas cell surface death receptor- antisense 1 (FAS-AS1), and plasmacytoma variant translocation 1 (PVT1) in circulating blood cells of 50 Iranian relapsing–remitting multiple sclerosis (RRMS) patients compared with healthy subjects by means of quantitative real-time polymerase chain reaction (PCR). We detected a significant downregulation of PVT1 and FAS-AS1 expressions in RRMS patients while a significant upregulation of THRIL in patients compared with controls (P < 0.001). Correlation analyses between lncRNA expression levels and clinical data of MS patients revealed no significant correlation between lncRNAs expression levels and Expanded Disability Status Scale (EDSS), a moderate correlation between PVT1 expression levels and duration of the disorder and no significant correlation between lncRNAs expression levels and age at onset. In addition, we demonstrated correlations between the expression levels of PVT1 and THRIL as well as expression levels of THRIL and FAS-AS1 in RRMS patients. In brief, we have demonstrated dysregulation of three lncRNAs in MS patients. Further studies are needed to explore the exact mechanisms by which these lncRNAs participate in regulation of immune responses.     

Early elevated levels of soluble triggering receptor expressed on myeloid cells-1 in subarachnoid hemorrhage patients

Early brain injury (EBI) contributes to poor prognosis of subarachnoid hemorrhage (SAH). This study aimed to clarify whether triggering receptor expressed on myeloid cells-1 (TREM-1) was implicated in the inflammatory mechanisms of EBI. The cerebrospinal fluid (CSF) levels of soluble TREM-1 (sTREM-1), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) as well as plasma levels of white blood cells (WBC) count and C-reactive protein in 17 SAH patients at early stage (within the EBI period) and 9 volunteers were observed. Also World Federation of Neurosurgical Societies (WFNS) scale of SAH patients was calculated on admission. Compared to controls, increased CSF levels of sTREM-1 (t = 5.66, P < 0.001), TNF-α (t = 5.41, P < 0.001) and IL-6 (t = 2.98, P = 0.007) as well as elevated plasma WBC counts (t = 7.61, P < 0.001) and C-reactive protein levels (t = 3.91, P = 0.001) were found in SAH patients. Considering the increased WBC counts in SAH group, covariate analysis was also performed when comparing patients’ sTREM-1 levels with respect to controls and no obvious difference was found (F = 0.982, P = 0.332). For SAH group, early CSF concentrations of sTREM-1 were correlated with those of both TNF-α (r = 0.582, P = 0.014) and IL-6 (r = 0.593, P = 0.012). Also the CSF sTREM-1 levels were positively correlated with WBC counts (r = 0.629, P = 0.007) and C-reactive protein levels (r = 0.804, P < 0.001) as well as WFNS scale (r = 0.835, P < 0.001). This study showed an early increased sTREM-1 CSF level in SAH patients, which correlated with inflammation intensity post-SAH and clinical severity, indicating that TREM-1 may participate in the inflammatory mechanisms of EBI.     

Natalizumab reduces serum pro-angiogenic activity in MS patients

Angiogenesis has been implicated in the pathobiology of multiple sclerosis (MS). Osteopontin exerts a pro-angiogenetic effect and is increased in body fluid of MS patients. To evaluate the effect of 1 year natalizumab treatment on serum pro-angiogenic activity and on plasma osteopontin levels in relapsing (RR) MS patients. Ten RRMS patients scheduled for natalizumab treatment were enrolled and evaluated at baseline and after 1-year natalizumab treatment. Pro-angiogenic activity was assessed by a chick embryo chorioallantoic membrane assay (CAM), osteopontin levels were evaluated by an enzyme-linked immunosorbent assay. Plasma and serum samples of 10 treatment-naïve RRMS and 10 healthy controls (HCs) were used as controls of baseline evaluations. Both treatment-naïve and natalizumab scheduled RRMS patients had higher baseline vessel density (22.0?±?3.9 and 22.5?±?2.6, p?<?0.0001) and higher osteopontin levels (65.7?±?24.3 ng/ml and 65.9?±?16.6 ng/ml, p?=?0.019 and p?=?0.029, respectively) than HCs (9.0?±?2.2; 48.5?±?7.8 ng/ml, respectively). Baseline osteopontin levels and vessel density were significantly correlated (rs?=?0.373, p?=?0.043). After 1 year of treatment, the number of vessels and the osteopontin levels, were significantly reduced (11.9?±?2.1, p?<?0.005; 49.3?±?20.0 ng/ml, p?=?0.028). Our results suggest that natalizumab could exert its anti-inflammatory properties also by inhibiting the angiogenetic mechanisms in RRMS patients.     

Exercise Addiction and Psychophysiological Health in Korean Collegiate Students

This study was carried out with collegiate students who took part in an exercise program for 1 year. An exercise addiction (EA) questionnaire was used to classify EA and non-EA (NEA) groups. Exercise dependence (ED), compulsive exercise (CE), and obligatory exercise (OE) questionnaires were used to validate the EA results. A total of 38 male and 37 female college students were selected as the subjects for this study to investigate the effects of EA on psychophysiological health. The psychophysiological health variables were composed of depression, stress, body composition, and muscular joint health. This study showed that EA was significantly associated with ED (r = 0.746; P = 0.001), CE (r = 0.644; P = 0.001), and OE (r = 0.731; P = 0.001), respectively. Although there were no significant differences between EA groups and NEA groups for both males and females on depression (Z = ? 0.813; P = 0.416 and Z = ? 0.148; P = 0.882, respectively), physical stress (Z = ? 0.777; P = 0.437 and Z = ?0.074; P = 0.941, respectively), and emotional stress (Z = ? 1.035; P = 0.300 and Z = ? 0.573; P = 0.567, respectively), the elbow and knee joint functions of EA males were significantly higher compared with those of NEA males. However, the variables of body composition in EA females were not significantly different from those of NEA females. Being addicted to exercise for 1 year resulted in negative effects on the psychological health in both genders, while it had a negative effect on physical health for women only.     

The Validation Study of Neurofilament Heavy Chain and 8-hydroxy-2′-deoxyguanosine as Plasma Biomarkers of Clinical/Paraclinical Activity in First and Relapsing-Remitting Demyelination Acute Attacks

Although current evidence mainly suggests immunopathogenesis of demyelination and neurodegeneration in multiple sclerosis (MS), there are results which document the importance of other factors, such as oxidative stress and its mediated injuries. The oxidative stress intensity in axonal damage during acute demyelination is little known. We performed this study as a cross-sectional biomarker validation study in order to evaluate the parameters of axonal damage (phosphorylated neurofilaments heavy chain (pNF-H)) and oxidative stress (8-hydroxy-2′-deoxyguanosine (8-OHdG)) in plasma of patients with initial and relapsing-remitting demyelination attacks, defined as clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RRMS); and the correlations between these parameters and biological (index of blood brain barrier (BBB) permeability), clinical (index of disease progression), and radiological (T₁-Gd-enhancing lesion volume) activities of disease. Both parameters were increased in CIS and RRMS compared to control subjects (p < 0.05). The positive correlations were observed between 8-OHdG values and index of BBB permeability, clinical severity of disease, and demyelinated brain lesion volume, in CIS group (r > 0.50; p < 0.05). Similar correlations were obtained between pNF-H values and the above parameters, as well as the index of disease progression, in RRMS group (r > 0.30; p < 0.05). There was a significant correlation between values of 8-OHdG and pNF-H only in CIS group, r = 0.52, p < 0.05. While the plasma values of 8-OHdG reflect the degree of acute demyelination in CIS, pNF-H values reflect that in RRMS. The obtained results must be reevaluated in similar prospective studies related to their prognostic values.     

Capturing saccades in multiple sclerosis with a digitized test of rapid number naming

The King–Devick (K–D) test of rapid number naming is a visual performance measure that captures saccadic eye movements. Patients with multiple sclerosis (MS) have slowed K–D test times associated with neurologic disability and reduced quality of life. We assessed eye movements during the K–D test to identify characteristics associated with slowed times. Participants performed a computerized K–D test with video-oculography. The 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and its 10-Item Neuro-Ophthalmic Supplement measured vision-specific quality of life (VSQOL). Among 25 participants with MS (age 37 ± 10 years, range 20–59) and 42 controls (age 33 ± 9 years, range 19–54), MS was associated with significantly longer (worse) K–D times (58.2 ± 19.8 vs. 43.8 ± 8.6 s, P = 0.001, linear regression models, accounting for age). In MS, test times were slower among patients with higher (worse) Expanded Disability Status Scale scores (P = 0.01). Average inter-saccadic intervals (ISI) were significantly longer in MS participants compared to controls (362 ± 103 vs. 286 ± 50 ms, P = 0.001), and were highly associated with prolonged K–D times in MS (P = 0.006). MS participants generated greater numbers of saccades (P = 0.007). VSQOL scores were reduced in MS patients with longer (worse) K–D times (P = 0.04–0.001) and longer ISI (P = 0.002–0.001). Patients with MS have slowed K–D times that may be attributable to prolonged ISI and greater numbers of saccades. The K–D test and its requisite eye movements capture VSQOL and make rapid number naming a strong candidate efferent visual performance measure in MS.     

Relevance of early cervical cord volume loss in the disease evolution of clinically isolated syndrome and early multiple sclerosis: a 2-year follow-up study

Upper cervical cord area (UCCA) atrophy is a prognostic marker for clinical progression in longstanding multiple sclerosis (MS). The objectives of the study were to quantify UCCA atrophy and evaluate its impact in clinically isolated syndrome (CIS) and relapsing–remitting MS (RRMS); to compare converting CIS patients with stable CIS, and to study changes of UCCA and brain white matter (WM) and grey matter (GM) at 2-year follow-up. 110 therapy-naive patients including 53 CIS [6 ± 6 months after symptom onset (SO)] and 57 early RRMS (SO: 12 ± 9 months) underwent sagittal 3D-T1w brain MR (3T). Mean UCCA (C1–C3 level), WM and GM, disability status (EDSS), pyramidal and sensory functional scores, motoric fatigue were assessed at baseline (BL), 12 and 24 months. Volumes were compared with 34 age- and gender-matched healthy controls to assess atrophy. RRMS (78.1 ± 8.7 mm², p = 0.011) and converting CIS (77.3 ± 8.0 mm², p = 0.046) presented with baseline UCCA atrophy, when compared with controls (82.7 ± 5.2 mm²), but not stable CIS (82.6 ± 7.4 mm², p = 0.998). Baseline WM was reduced in RRMS (509.3 ± 25.7 ml vs. controls: 528.4 ± 24.1 ml, p = 0.032). Baseline UCCA correlated negative with muscular weakness and fatigability in all patients and RRMS. EDSS exceeding 3 was associated with lower baseline UCCA. Longitudinal atrophy rates were higher in UCCA than in brain volumes. Early cervical cord atrophy in CIS and RRMS was confirmed and may represent a potential new risk marker for conversion from CIS to MS. Baseline atrophy and atrophy change rates were higher in UCCA compared to WM and GM, suggesting that cervical cord volumetry might become an additional MRI marker relevant in future clinical studies in CIS and early MS.     

Insular multiple sclerosis lesions are associated with erectile dysfunction

Erectile function (EF) is frequently compromised in men with multiple sclerosis (MS). Functional neuroimaging in healthy men identified a network of brain areas, such as the insula, visual and somatosensory association areas, cingulate gyrus, prefrontal cortex, as well as subcortical regions, contributing to EF. This study intended to determine associations between EF deterioration during MS and cerebral MS-associated lesion sites. In 31 men with MS (mean age 38.2 ± 11.2 years), we evaluated MS-related EF deterioration by comparing scores of the 5-item International Index of Erectile Function-5 questionnaire (IIEF5) at the time of study and retrospectively, 3 months prior to MS diagnosis, by calculating score differences as DeltaIIEF5 (DeltaIIEF5 score < 0 indicated EF deterioration). To assess the impact of confounding factors of EF, patient age, disease duration, disease severity, depressiveness, bladder and bowel symptoms, and total cerebral MS lesion volume were correlated with DeltaIIEF5 scores (Spearman rank correlation) and compared between patients with and without EF deterioration (t tests or Mann–Whitney U test). MS lesions were assessed on T2-weighted magnetic resonance imaging (MRI; 1.5 or 3 T). We determined the lesion overlap (prevalence of identical lesion sites among patients), subtracted lesion overlaps in patients without EF deterioration from overlaps in patients with EF deterioration, and compared DeltaIIEF5 scores voxel-wise between patients with and without lesions in a given voxel (t test; significance: p < 0.05). In 14 patients (45.2%), DeltaIIEF5 scores indicated EF deterioration. DeltaIIEF5 scores were not associated with age (ρ = 0.06; p = 0.74), disease duration (ρ = 0.26; p = 0.15), disease severity (ρ = ? 0.19; p = 0.31), depressiveness (ρ = 0.07; p = 0.72), bladder symptoms (ρ = ? 0.11; p = 0.57), bowel symptoms (ρ = 0.17; p = 0.37), and total lesion volume (ρ = ? 0.13; p = 0.47). The voxel-wise analysis showed associations between EF deterioration and MS lesions primarily in the bilateral, and predominantly left juxtacortical insular region. In conclusion, MS lesions particularly in the left insular region, which is activated with sexual arousal, contribute to erectile dysfunction.     

Persistence to oral disease-modifying therapies in multiple sclerosis patients

Dimethyl fumarate (DMF), fingolimod (FTY) and teriflunomide (TFN) are oral disease-modifying therapies (DMTs) approved for relapsing–remitting multiple sclerosis (RRMS) whose efficacy and tolerability have been separately assessed in phase III trials. Conversely, little evidence exists about their head-to-head comparison. The aim of the study was to evaluate the 1-year persistence to DMF, FTY and TFN in patients with RRMS. Patients affected by RRMS who started treatment with DMF, FTY or TFN were identified. The study end-point was 12-month drug persistence as time to discontinuation and proportion of patients who discontinued medication within 1-year. A total of 307 patients were included (DMF = 114, FTY = 129, TFN = 64). The mean times to discontinuation were 144 (84), 189 (72) and 138 (120) days in the DMF, FTY and TFN cohorts (p = 0.036). At 12-month, the proportion of patients discontinuing medication was lower for subjects taking FTY (9.8%) compared with those starting DMF (21.9%) and TFN (23.6%) (p = 0.020). Compared to FTY cohort, DMF [_adjOR = 3.26 (1.38–7.70); p = 0.007] and TFN [_adjOR = 2.89 (1.10–7.63); p = 0.032] treated patients were more likely to have discontinued their drug at 1-year since initiation. In patients with RRMS, FTY was associated with a better persistence profile as compared to DMF and TFN.     

The BRAIN test: a keyboard-tapping test to assess disability and clinical features of multiple sclerosis

Background

The BRadykinesia Akinesia INcordination (BRAIN) test is an online keyboard-tapping test previously validated as a sensitive tool for detecting signs of Parkinson’s disease.

Objectives

To determine whether the BRAIN test can measure disability in MS and identify the presence of pyramidal or cerebellar dysfunction.

Methods

Kinesia scores (KS, number of key taps in 30 s), akinesia times (AT, mean dwell time on each key) and incoordination scores (IS, variance of travelling time between keys) were calculated in 39 MS patients. These were correlated against the Expanded Disability Status Scale (EDSS) scores, pyramidal and cerebellar functional system scores and 9-hole peg test scores.

Results

EDSS correlated with KS (r = ? 0.594, p < 0.001), AT (r = 0.464, p = 0.003) and IS (r = 0.423, p = 0.007). 9-HPT scores strongly correlated with KS (r = 0.926, p < 0.001). Pyramidal scores correlated with KS (r = ? 0.517, p < 0.001). Cerebellar scores correlated with KS (r = ? 0.665, p < 0.001), AT (r = 0.567, p < 0.001) and IS (r = 0.546, p = 0.007). Receiver operating characteristic curves demonstrate that KS can distinguish between the presence or absence of pyramidal and cerebellar dysfunction with area under curve 0.840 (p < 0.001) and 0.829 (p < 0.001), respectively.

Conclusions

The BRAIN test can remotely measure disability in MS. Specific scores differ according to the presence and severity of pyramidal or extrapyramidal dysfunction. It demonstrates huge potential in monitoring disease progression in clinical trials.

     

Factors Associated with Thrombolysis Outcome in Ischemic Stroke Patients with Atrial Fibrillation

The outcome of early intravenous thrombolysis for ischemic stroke in patients with atrial fibrillation (AF) is worse than that without thrombosis. How to increase the efficacy of intravenous thrombolysis for AF-related ischemic stroke remains largely unknown. In this study, we investigated factors that influence the effect of intravenous thrombolysis in these patients. Our results showed that thrombolysis was independently associated with a favorable outcome (P < 0.001) and did not influence the mortality of AF-related ischemic stroke, although it increased the risk of hemorrhage within 24 h after treatment. Risk factors for a poor outcome at admission were: heart failure (P = 0.045); high systolic pressure (P = 0.039); high blood glucose (P = 0.030); and a high National Institutes of Health Stroke Scale (NIHSS) score (P < 0.001). Moreover, high systolic pressure at admission (P = 0.007), high blood glucose (P = 0.027), and a high NIHSS score (P < 0.001) were independent risk factors for mortality at 3 months. Besides thrombolysis, a high NIHSS score (P = 0.006) and warfarin taken within 48 h before stroke onset (P = 0.032) were also independent risk factors for symptomatic hemorrhage within 24 h after treatment. Ischemic stroke patients with AF benefited from intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 h after stroke.     

Circulating insulin-like growth factor 1 and insulin-like growth factor binding protein-3 level in Alzheimer’s disease: a meta-analysis

It has been reported that the associations between circulating insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) and Alzheimer’s disease (AD) are controversial. Thus, present meta-analysis was carried out to confirm the probable associations. We searched “PubMed”, “Springer” and “Medline” databases using the term (“insulin-like growth factor-1” or “IGF-1” or “insulin-like growth factor binding protein-3” or “IGFBP-3”) and (“Alzheimer’s disease”) until April 2016. Furthermore, standard mean differences (SMDs) were calculated. A total of seven reports involving 1342 percipients were pooled. SMDs were ?0.25 (P = 0.22) and ?0.33 (P = 0.08) for IGF-1 and IGFBP-3, respectively. Furthermore, the circulating IGF-1 levels in AD patients were lower than controls when studies with the difference of mean age ≤1 year (SMD ?0.57, P = 0.007) or 2 years (SMD ?0.58, P = 0.02) or difference of mean MMSE scores ≤10 scores (SMD ?0.94, P < 0.00001), or studies from Europe (SMD ?0.89, P < 0.00001) were excluded. In addition, the circulating IGFBP-3 levels in AD patients were lower than controls when studies with the difference of mean age ≤2 years (SMD ?0.62, P = 0.006) or difference of mean MMSE scores ≤6 scores (SMD ?0.48, P = 0.0004), 7 scores (SMD ?0.58, P = 0.02), or 8 scores (SMD ?0.80, P = 0.03) were excluded. Even though no significant difference of circulating IGF-1 and IGFBP-3 levels in AD patients comparing with controls was found in present meta-analysis, the current study provided the evidence that the circulating IGF-1 and IGFBP-3 level in AD patients were influenced by the difference of mean age as well as MMSE scores. Furthermore, circulating IGFBP-3 levels in AD patients may be decreased earlier than IGF-1.     

<Emphasis Type="Italic">TLR4</Emphasis> polymorphisms affect stroke risk and inflammatory response in Chinese ischemic stroke patients

This study aimed to evaluate the association of the toll-like receptor 4 (TLR4) polymorphisms rs1927914, rs10759932, and rs11536889 with susceptibility to ischemic stroke (IS) and the serum levels of inflammatory cytokines. A total of 816 IS patients and 816 control subjects were genotyped using Sequenom MassARRAY technology. The serum levels of interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNFα) were measured by enzyme-linked immunosorbent assay. rs1927914 was significantly associated with male IS patients in the additive model [odds ratio (OR) = 0.81; 95% confidence interval (CI) = 0.67–0.99; P = 0.039] and in the allele model (OR = 0.81; 95% CI = 0.66–0.99; P = 0.037). In the dominant model, rs10759932 was significantly associated with the serum TNFα level of the male IS patients [regression coefficient (β) = 0.15; 95% CI = 0.01–0.29; P _adj = 0.042]. This polymorphism was also correlated with the serum IL-8 level of female IS patients in the additive model (β = 0.24; 95% CI = 0.25–0.43; P _adj = 0.021) and in the recessive model (β = 0.65; 95% CI = 0.11–1.11; P _adj = 0.026). The TLR4 gene rs1927914 polymorphism was associated with susceptibility to IS in males. Moreover, the rs10759932 polymorphism may affect inflammatory response in IS patients.     

Cognitive dysfunction in adult patients with neuromyelitis optica: a systematic review and meta-analysis

The objective of this study was to investigate cognitive dysfunction in 24–60-year-old neuromyelitis optica (NMO) patients, demographically matched healthy subjects, and MS patients. We conducted a comprehensive literature review of the PubMed, Medline, EMBASE, CNKI, Wan Fang Date, Web of Science, and Cochrane Library databases from inception to May 2016 for case–control studies that reported cognitive test scores in NMO patients, healthy subjects, and MS patients. Outcome measures were cognitive function evaluations, including performance on attention, language, memory, information processing speed, and executive function tests. The meta-analysis included eight studies. NMO patients performed significantly worse on attention (P < 0.00001), language (P = 0.00008), memory (P = 0.00004), information processing speed (P < 0.00001), and executive function tests (P = 0.00009) than healthy subjects. There were no significant differences in performance between NMO patients and MS patients on these tests. This meta-analysis indicates that NMO patients aged 24–60 years have significantly worse cognitive performance than demographically matched healthy subjects. However, this was comparable to the performance of demographically matched MS patients. There is a need for further rigorous randomized controlled trials with focus on elucidating the underlying mechanism of cognitive dysfunction in NMO patients.     

Sympathetic cardiovascular and sudomotor functions are frequently affected in early multiple sclerosis

Objective

The aim of this study was to determine the prevalence of autonomic dysfunction using the composite autonomic scoring scale (CASS) and heart rate variability (HRV) in patients with clinically isolated syndrome (CIS) and to correlate autonomic dysfunction with other measures of MS disease activity.

Methods

CASS, HRV and plasma catecholamines during supine and tilted phase were performed in 104 CIS patients. MRI findings were analyzed for total number of lesions and the presence of brainstem and cervical spinal cord lesions.

Results

Autonomic dysfunction (CASS >1) was present in 59.8 % of patients, parasympathetic dysfunction in 5 %, sympathetic in 42.6 % and sudomotor in 32.7 % of patients. Patients with autonomic dysfunction on CASS had lower level of norepinephrine in the supine position compared to patients without autonomic dysfunction (1.06 ± 0.53 vs. 1.37 ± 0.86, p = 0.048). The CASS score showed positive correlation with s-HF (r = 0.226, p = 0.031), s-SDNN (r = 0.221, p = 0.035), t-HF (r = 0.225, p = 0.032), and t-HFnu (r = 0.216, p = 0.04), and a negative correlation with t-LF/HF (r = ?0.218, p = 0.038). More patients with MRI brainstem lesions had a positive adrenergic index (p = 0.038). Patients with MRI brainstem lesions also had a lower t-SDNN (26.2 ± 14.2 vs. 32 ± 13.3, p = 0.036) and a lower t-LF (median 415.0 vs. 575.5, p = 0.018) compared to patients without these lesions. Patients with adrenergic index ≥1 had a significantly higher standing heart rate compared to patients with an adrenergic index of 0 (96 ± 13.5 vs. 90 ± 12, p = 0.032).

Conclusion

Autonomic (primarily sympathetic) dysfunction is present in a large proportion of early MS patients and it seems to be related to brainstem involvement.

     

Olfactory bulb volume predicts therapeutic outcome in major depression disorder

The volume of the olfactory bulb (OB) is strongly reduced in patients with major depressive disorder (MDD) and this group exhibits markedly decreased olfactory function. It has been suggested that olfactory input is important for maintaining balance in limbic neurocircuits. The aim of our study was to investigate whether reduced OB volume is associated with response to therapy in MDD. Twenty-four inpatients (all women, age 21–49 years, mean 38?±?10 years SD) with MDD and 36 healthy controls (all women, age 20–52 years, mean 36?±?10 years SD) underwent structural MRI. OB volume was compared between responders (N?=?13) and non-responders (N?=?11) to psychotherapy. Retest of OB volume was performed about 6 months after the end of therapy in nine of the patients. Therapy responders exhibited no significant difference in OB volume compared to healthy controls. However, average OB volume of non-responders was 23 % smaller compared to responders (p?=?.0011). Furthermore, OB volume was correlated with the change of depression severity (r?=?.46, p?=?.024). Volume of the OB did not change in the course of therapy. OB volume may be a biological vulnerability factor for the occurrence and/or maintenance of depression, at least in women.