Association of cerebrospinal inflammatory profile with radiological features in newly diagnosed treatment-naïve patients with multiple sclerosis.

Objective: Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Without reliable diagnostic biomarkers, the clinical and radiological heterogeneity of MS makes diagnosis difficult. Although magnetic resonance imaging (MRI) is a major diagnostic tool for MS, the association of MRI findings with the inflammatory profile in cerebrospinal fluid (CSF) has been insufficiently investigated. Therefore, we focused on CSF profile of MS patients and examined its association with MRI findings. Methods: Concentrations of 26 cytokines and chemokines were determined in CSF of 28 treatment-naïve MS patients and 12 disease-control patients with aquaporin-4 antibody-seropositive neuromyelitis optica spectrum disorder (NMOSD). Results: High levels of interleukin (IL)-6, IL-17A, B-cell activating factor (BAFF), a proliferation inducing ligand (APRIL), and CD40 ligand were correlated with the absence of at least one of the following three MRI findings in MS: an ovoid lesion, three or more periventricular lesions, and a nodular and/or ring-shaped contrast-enhancing lesion. The multivariate analysis revealed that elevated IL-17A was an independent predictor of absence of ovoid lesion and periventricular lesions less than three. MS patients were classified into a group with all three MRI findings (MS-full) and a group with less than three (MS-partial). The discriminant analysis model distinguished three groups: MS-full, MS-partial, and NMOSD, with 98% accuracy. Conclusion: The CSF inflammatory profile was associated with radiological findings of treatment-naïve MS. This result indicates the possible utility of combined CSF and MRI profiling in identifying different MS phenotypes related to the heterogeneity of underlying immune processes.

T cells from MS Patients with High Disease Severity Are Insensitive to an Immune-Suppressive Effect of Sulfatide.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Its early phase is characterized by a relapse-remitting disease course, followed by disability progression in the later stage. While chronic inflammation accompanied with degeneration is well-established as the key pathological feature, the pathogenesis of MS, particularly progressive MS, remains elusive. Sulfatide is a major glycolipid component of myelin, and previous studies in experimental autoimmune encephalomyelitis mouse models have demonstrated it to have immune-protective functions. Notably, sulfatide concentration is increased in the serum and cerebrospinal fluid of patients with MS, particularly those in a progressive disease course. Here, we show that the myelin-glycolipid sulfatide displays an ability to suppress the proliferation of polyclonally activated human T cells. Importantly, this suppressive effect was impaired in T cells obtained from MS patients having higher disability status. Therefore, it is plausible that progression of MS is associated with an escape from the immune-regulatory effect of sulfatide. Our study suggests that, although the precise mechanisms remain unrevealed, an escape of T cells from immunosuppression by sulfatide is associated with disease progression in the advanced stage. Further studies will provide novel insights into the pathogenesis of MS, particularly regarding disease progression, and help develop novel treatment strategies for this challenging disease.

Radiological and Laboratory Features of Multiple Sclerosis Patients With Immunosuppressive Therapy: A Multicenter Retrospective Study in Japan.

Background: Multiple sclerosis (MS) is a relapsing, inflammatory, and demyelinating disease of central nervous system showing marked clinical heterogeneity. Many factors might influence the choice of relapse prevention drug, and treatment response varies among patients. Despite the enlargement of disease-modifying drugs for MS (MS-DMDs), some patients have been treated with corticosteroid and/or immunosuppressant (CS/IS). Objective: To clarify the radiological and laboratory features of MS treated with CS/IS for relapse prevention. Methods: Clinical records including radiological and laboratory findings, and drugs used for relapse prevention were reviewed retrospectively. Results: Out of 92 consecutive MS patients, 25 (27%) were treated with CS/IS. The followings were observed less frequently in patients treated with CS/IS than in those with MS-DMDs: three or more periventricular lesions, ovoid lesions, subcortical lesions, typical contrast-enhancing lesions, negative for serum autoantibodies, and positive for oligoclonal bands in the cerebrospinal fluid. Multiple logistic regression analysis revealed that the absence of typical contrast-enhancing lesions and positivity for serum autoantibodies were independent factors associated with CS/IS prescription (odds ratio 25.027 and 14.537, respectively). Conclusion: In this cohort of Japanese patients clinically diagnosed with MS, radiological and serological findings atypical of MS were observed more frequently in patients treated with CS/IS than in those with MS-DMDs as a part of MS therapy. The absence of contrast-enhancing lesions typical of MS and positivity for serum autoantibodies were independent factors strongly associated with CS/IS use.

[Secondary Progressive Multiple Sclerosis].

Secondary progressive multiple sclerosis (SPMS) is defined by the slowly progressive deterioration of clinical symptoms independent of relapse, following the early relapsing-remitting disease course. Diagnosis of SPMS is challenging and usually retrospective because of the lack of reliable diagnostic tests. There is also a lack of reliable clinical symptoms other than gait disturbance, which are well evaluated in the clinical setting. The pathogenic mechanisms driving SPMS are poorly understood, and therapy for SPMS remains limited. It is assumed that the characteristic features of neurodegeneration observed in SPMS are caused by chronic inflammation with compartmentalized T and B cells from the periphery, glial and mitochondrial dysfunction, and other factors. Neuroprotective agents, promotion of remyelination, and immunological modifications may be key targets for novel treatment strategies.

Immune Skew of Circulating Follicular Helper T Cells Associates With Myasthenia Gravis Severity.

OBJECTIVE: To clarify functional alterations of follicular helper T cells (Tfh) in myasthenia gravis (MG) because Tfh play important roles in helping B cells generate antibody-producing cells. METHODS: A total of 24 immunotherapy-naive patients with anti-acetylcholine receptor (AchR) antibody-positive MG and 18 age-matched healthy subjects (HS) were enrolled. Samples from 6 patients were available for posttreatment analysis. Subsets of circulating Tfh (cTfh) and B cells were identified by flow cytometry analysis of surface molecules. Cytokine production by isolated cTfh subsets from 5 patients with MG and 5 HS was measured in vitro. Analysis was performed to examine the correlation between the frequency of cTfh subsets and that of plasmablasts and between cTfh subsets and the quantitative MG score. RESULTS: cTfh increased with elevated expression of inducible T-cell costimulator (ICOS) in patients with MG. cTfh shifted to Th2 and Th17 over Th1 in MG. ICOShighcTfh produced significantly higher levels of interleukin (IL)-21, IL-4, and IL-17A than ICOSlow cTfh only in patients with MG. The frequency of cTfh within CD4 T cells was more closely associated with disease severity than the serum anti-AchR antibody titer and frequency of plasmablasts within B cells. Abnormalities of cTfh were improved after immunotherapy in parallel with clinical improvement. CONCLUSIONS: Alternation of cTfh is a key feature in the development of MG and may become a biomarker for disease severity and therapeutic efficacy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the level of cTfh is associated with disease severity in patients with MG.

Altered features of monocytes in adult onset leukoencephalopathy with axonal spheroids and pigmented glia: A clue to the pathomechanism of microglial dyshomeostasis.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal-dominant type of leukoencephalopathy caused by gene mutation of colony stimulating factor 1 receptor, which is expressed mainly on monocyte lineage cells such as monocytes in the peripheral blood and microglia in the brain. Hence, microglial dysfunction is regarded as critical in the pathogenesis of ALSP. However, functional changes in these cells have not been elucidated. In this study, we report the phenotypic and functional alterations of monocytes in four patients with ALSP. Flow cytometric analysis revealed altered expression of antigen presentation- and migration-related molecules, an inflammatory shift in cytokine production and phagocytic impairment in ALSP monocytes. We speculate that the observed altered features of monocytes are mostly shared by microglial cells, leading to the clinical history and pathological characteristics of ALSP. Our analysis of PB monocytes provides novel insights into the pathogenesis of ALSP.

Signaling via toll-like receptor 4 and CD40 in B cells plays a regulatory role in the pathogenesis of multiple sclerosis through interleukin-10 production.

BACKGROUND: B cells play an important role in the development of multiple sclerosis (MS), but can also exhibit regulatory functions through IL-10 production. Toll-like receptors (TLR) and CD40 signaling are likely to be involved in this process. OBJECTIVE: To investigate the ability of MS B cells to produce IL-10 in response to TLR stimulation in the presence or absence of CD40 co-stimulation. METHODS: Peripheral blood mononuclear cells obtained from 34 MS patients and 24 matched healthy participants (HS) were stimulated through either TLR4 or TLR9 alone, or together with CD40. Intracellular cytokine production was analyzed by flow cytometry. RESULTS: The frequency of IL-10-producing cells in total B cells after either TLR9 or CD40 stimulation was significantly lower in MS than HS, regardless of disease phase. The frequency of IL-10 producing B cells after TLR4 stimulation did not differ significantly between HS and MS, regardless of disease phase. TLR4 and CD40 co-stimulation synergistically increased the frequency of IL-10-producing but not pro-inflammatory cytokine-producing B cells at MS relapse. This effect was observed in both CD27- naïve and CD27+ memory B cells. The frequency of IL-10-producing B cells following CD40 stimulation was significantly higher in interferon-ß responders than non-treated MS patients. Finally, we confirmed that the frequency of IL-10-producing B cells positively correlated with IL-10 production quantity by B cells using magnetic-isolated B cells. CONCLUSIONS: Cross-talk between TLR4 and CD40 signaling plays a crucial role in regulating IL-10 production by B cells during MS relapses, which may promote recovery from relapse. CD40 signaling in B cells is involved in the response to interferon-ß in MS. Collectively, TLR4 and CD40 signaling in B cells may provide a promising target for MS therapy.

The first Japanese case of leukodystrophy with ovarian failure arising from novel compound heterozygous AARS2 mutations.

Even now, only a portion of leukodystrophy patients are correctly diagnosed, though various causative genes have been identified. In the present report, we describe a case of adult-onset leukodystrophy in a woman with ovarian failure. By whole-exome sequencing, a compound heterozygous mutation consisting of NM_020745.3 (AARS2_v001):c.1145C>A and NM_020745.3 (AARS2_v001):c.2255+1G>A was identified. Neither of the mutations has been previously reported, and this is the first report of alanyl-transfer RNA synthetase 2 mutation in Asia. We anticipate that further studies of the molecular basis of leukodystrophy will provide insight into its pathogenesis and hopefully lead to sophisticated diagnostic and treatment strategies.

A case of variant biochemical phenotype of Niemann-Pick disease type C accompanying savant syndrome.

A 40-year-old man was referred to our hospital because of vertical supranuclear gaze palsy, frequent sudden loss of muscle tonus and ataxia for several years. He had a history of prolonged neonatal jaundice. He was given a diagnosis of autism in his childhood, followed by a diagnosis of schizophrenia in his teenage. He also developed a savant skill of calendar calculating. (123)I-IMP-SPECT showed decreased cerebral blood flow in the left frontotemporal lobe as often seen in savant syndrome. Although genetic analysis of NPC1 and NPC2 revealed no pathogenic mutation, filipin staining of cultured fibroblasts from his biopsied skin revealed a certain amount of intracellular cholesterol storage pattern, indicating a variant biochemical phenotype of Niemann-Pick disease type C (NPC). The diagnosis of adulthood onset NPC is difficult and challenging, especially for neurologists, because the symptoms and signs are not as clear as those in the classical childhood onset NPC and this subtype is not yet widely known. However, the diagnosis can be made by a combination of filipin staining of fibroblast and/or gene analysis. As a disease-specific therapy for NPC has been approved in Japan, the diagnosis of NPC is of significance.

Incidence and predictors of ischemic stroke during hospitalization for congestive heart failure.

Heart failure (HF) increases the risk of ischemic stroke. Data regarding the incidence and predictors of ischemic stroke during hospitalization for HF are limited. The study population of this retrospective cohort study consisted of patients with congestive HF, consecutively admitted to our center from October 2010 to April 2014. We excluded patients complicated with acute myocardial infarction, infective endocarditis, and takotsubo cardiomyopathy. We also excluded those with dialysis or mechanical circulatory support. We investigated the incidence of ischemic stroke during hospitalization for HF. Thereafter, we divided the patients without oral anticoagulants at admission into two groups: patients with ischemic stroke and those without it, and explored the predictors of ischemic stroke. A total of 558 patients (287 without atrial fibrillation (AF), 271 with AF) were enrolled. The mean age was 76.8 ± 12.3 years, and 244 patients (44 %) were female. The mean left-ventricular ejection fraction was 47.4 %. Oral anticoagulants were prescribed in 147 patients (8 without AF, 139 with AF). During hospitalization (median length 18 days), symptomatic ischemic stroke (excluding catheter-related) occurred in 15 patients (2.7 % of the total, 8 without AF, 7 with AF). Predictors significantly associated with increased risk of ischemic stroke in patients without oral anticoagulants were as follows; short-term increases in blood urea nitrogen after admission (at day 3; odds ratio (per 1 md/dl): 1.06, 95 % confidence interval (CI) 1.01-1.11, p = 0.02, and at day 7; odds ratio: 1.03, 95 % CI 1.00-1.07, p = 0.03, respectively), and previous stroke (odds ratio; 3.33, 95 % CI 1.01-11.00, p = 0.04). The incidence of ischemic stroke during hospitalization for HF was high, even in patients without AF. Previous stroke and short-term increases in blood urea nitrogen was significantly associated with the incidence of ischemic stroke.