Longitudinal analysis of cerebral aqueduct flow measures: multiple sclerosis flow changes driven by brain atrophy

Paired serum and cerebrospinal fluid (CSF) specimens from 30 multiple sclerosis (MS) patients and 30 patients with other neurological diseases (ONDs) were analyzed for the presence of immune complexes (ICs). With each of the 4 tests used, ICs were found more frequently in sera from both MS and OND patients than in sera from healthy blood donors. IC-positivity for MS and OND patient CSF varied from 10-33% and from 10-17% in different tests. The number of IC-positive sera or CSF in MS patients did not differ significantly from those in OND patients. For both MS and OND patients, the positivity pattern for serum and CSF specimens in each IC test was essentially unique. Furthermore, because several CSF IC-positive and serum IC-negative paired specimens were found, intrathecal IC formation may be independent of IC formation in peripheral blood. The presence of ICs in serum or CSF did not correlate with the clinical status of or laboratory data on the MS patients, nor was a correlation found with the diagnosis of the OND patients. In total, these results suggest that the presence or absence of ICs in MS or OND patients may simply reflect changes in the immunological regulation of individual patients.

<h3>Objective:</h3> To describe oral hygiene habits in MS and NMOSD patients from Argentina and evaluate the oral health-related quality of life, and its possible association with IST and other relevant clinical factors. <h3>Background:</h3> Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory diseases of the central nervous system. Most MS and NMOSD patients are on immunosuppressive treatment (IST), leading to an increased risk of infections, including those of odontogenic origin. There is scarce evidence on oral health-related quality of life in these patients. <h3>Design/Methods:</h3> A cross-sectional study was conducted using an Oral Health Impact Profile test (OHIP-14) in 202 MS, 36 NMOSD patients, and 167 controls (HC; non-MS, non-NMOSD and without any IST). We retrospectively reviewed the medical records, and demographic, clinical/paraclinical data and treatments were evaluated. Higher OHIP-14 scores are related to a poorer state of oral health. <h3>Results:</h3> A total of 405 individuals were included. NMOSD patients had a significantly worse performance in functional limitation and handicap domains of the OHIP-14 score compared with MS and HC. HC scored significantly higher in psychological discomfort than MS. No differences in the frequency of dental hygiene were found between groups. MS and NMOSD patients had worse subjective perception of their oral health and fewer odontological visits than HC within the last year. MS patients on active disease modifying treatment were independently associated with higher total OHIP-14 score (β 5.90, 95%CI 1.96–9.84, p=0.003) in our linear regression model. <h3>Conclusions:</h3> This study showed that MS and NMOSD patients may be vulnerable regarding their oral health. Using DMT in MS patients was a predictor of poor state of oral health. Patient-reported OHIP-14 scores provide comprehensive additional information in clinical practice. <b>Disclosure:</b> Veronica A. Tkachuk has nothing to disclose. Dr. Aguirre has nothing to disclose. Dr. Cao has nothing to disclose. Dr. Nadur has nothing to disclose. Dr. Isa has nothing to disclose. Mrs. Balbuena has nothing to disclose. Miss Perachino has nothing to disclose. Edgar Carnero Contentti has nothing to disclose.

Fibroblast growth factor-2 levels are elevated in the cerebrospinal fluid of multiple sclerosis patients

BackgroundThe presence of Blood-Brain Barrier (BBB) dysfunction is defined by albumin quotient (QALB) and characterize a group of Multiple Sclerosis (MS) patients at clinical onset. We evaluated the concentration in cerebrospinal fluid (CSF) of 87 cytokines, to better characterize the CSF inflammatory pattern in presence of BBB damage. Materials and MethodIn an exploratory cohort, CSF cytokines were evaluated by means of Multiplex technology (Bio-Plex Pro-Human Cytokine, GF and Diabetes 27-Plex Panel, Bio-Plex Pro-Human Chemokines 40-Plex Panel, Bio-Plex Pro-Human Inflammation Assays 37-Plex Panel) in a cohort of Other Not Inflammatory Neurological Disorders (ONIND) and in cohort of patients with MS, stratified according to BBB damage into QALB+ and QALB− MS patients. In the validation cohort, we evaluated the relevant molecules in a cohort of MS patients, stratified again into QALB+ and QALB−, including also Neurofilament Light (NfL) and Chitinase 3-like 1 (CHI3L1) CSF concentration. ResultsWhile MIP-1α, CXCL-13, and CCL-22 CSF concentrations were higher in both MS groups compared to ONIND, in QALB+ MS CSF concentrations of CXCL-9 (17.85 ± 4.69 pg/mL), CXCL-10 (476.5 ± 324.3 pg/mL), and IL-16 (96.08 ± 86.17 pg/mL) were higher than in QALB− MS (8.98 ± 5368 pg/mL, p < 0.005, 281.0 ± 180.9 pg/mL, p < 0.05, and 47.35 ± 36.87 pg/mL, p < 0.005, respectively) and ONIND (8.98 ± 5368 pg/mlL, p < 0.005, 281.0 ± 180.9 pg/mL, p < 0.005, and 47.35 ± 36.87 pg/mL, p < 0.001, respectively). A strong correlation was observed between CXCL-9 and CXCL-10 in all MS groups (all r>0.75, all p < 0.001). In the validation cohort again CXCL-10 CSF concentration were higher in QALB+ MS than in QALB− MS (94.25 ± 64.75 vs 153.8 ± 99.52, p < 0.05), while no difference was observed in serum. CSF NfL (1642 ± 1963 vs 3231 ± 3492 pg/mL, p < 0.05) and CHI3L1 (183.9 ± 86.62 vs 262 ± 137.5 ng/mL, p < 0.05) were increased in QALB+ MS. ConclusionsBBB damage in MS is linked to a specific CSF cytokines pattern (CXCL-9, CXCL-10, IL-16), that are also involved in astrocyte-microglia interaction. To what extent their continuous production in the CNS may mark a more severe disease course merits to be investigated.

Ventricular cerebrospinal fluid (CSF) flow has bi-directional flow profiles synchronized with cardiac pulsation. The increase in CSF stroke volume through the aqueduct (flow pathway between the third and fourth ventricle) is believed to be a biomarker of idiopathic normal pressure hydrocephalus (iNPH). However, several studies have reported that CSF stroke volume varies considerably even in healthy populations. To explore these variations from a fluid mechanics perspective, this study analyzed CSF flow characteristics in healthy individuals using magnetic resonance imaging (MRI)-based computational simulations. MRI data from 47 healthy subjects were acquired, and the maximum Reynolds number of the CSF flow through the aqueduct and the degree of CSF mixing were evaluated. Results showed that the Reynolds number of the CSF flow through the aqueduct was 28.6 ± 13.3, and the limited variation suggested fluid mechanical similarities of CSF flow characteristics in the healthy population. A positive correlation between CSF flow mixing and the Reynolds number was observed in both healthy populations and iNPH patients. These findings demonstrate that CSF flow through the aqueduct, especially in healthy populations, can be well characterized by examining fluid mechanical similarities.Graphical

Evaluation of total, ceruloplasmin-associated and type II ferroxidase activities in serum and cerebrospinal fluid of multiple sclerosis patients

Introduction: Body fluid biomarkers for clinical subtyping and monitoring of disease progression are of considerable interest in multiple sclerosis (MS). Proteomics tools are optimal for the unbiased simultaneous detection of large series of peptides and proteins. Objectives: To identify novel candidate biomarkers discriminating patients with MS from patients with other neurological diseases (OND), and for subtyping of relapsing–remitting (RR), secondary progressive (SP) and primary progressive (PP) MS patients using a high-throughput MALDI-TOF-based mass spectrometry method. Methods: Paired cerebrospinal fluid (CSF) and serum samples of 41 RRMS, 30 SPMS, 13 PPMS patients and 25 patients with OND were analysed. Results: Out of a total of 100 detected peptides in CSF and 200 peptides in serum, 11 peptides were differentially regulated in serum and two in CSF between patients with MS and the OND control group. Eleven peptides were differentially regulated in both serum and CSF between relapse-onset MS and PPMS patients. Lastly, four peptides were differentially regulated in serum and two in CSF between RRMS and SPMS patients. Specific peaks regulated in MS were tentatively identified as fragments of secretogranin III and complement C3. The peak intensity of the CSF peptide ion with m/z value 8607.7 correlated to atrophy (r = −0.27, p < 0.005), black hole volumes (r = 0.31, p < 0.008) and total lesion load (r = 0.34, p < 0.003). A serum peptide with m/z value of 872.4 elevated in SPMS correlated to Expanded Disability Status Scale (r = 0.341, p < 0.005) and atrophy (r = −0.286, p < 0.028). Conclusions: Using high-throughput body fluid profiling by MALDI-TOF mass spectrometry, small proteins and peptides were detected as promising candidate biomarkers for diagnosis and disease progression of MS.

BackgroundNationwide surveys conducted in Japan over the past thirty years have revealed a four-fold increase in the estimated number of multiple sclerosis (MS) patients, a decrease in the age at onset, and successive increases in patients with conventional MS, which shows an involvement of multiple sites in the central nervous system, including the cerebrum and cerebellum. We aimed to clarify whether genetic and infectious backgrounds correlate to distinct disease phenotypes of MS in Japanese patients.Methodology/Principal FindingsWe analyzed HLA-DRB1 and -DPB1 alleles, and IgG antibodies specific for Helicobacter pylori, Chlamydia pneumoniae, varicella zoster virus, and Epstein-Barr virus nuclear antigen (EBNA) in 145 MS patients and 367 healthy controls (HCs). Frequencies of DRB1*0405 and DPB1*0301 were significantly higher, and DRB1*0901 and DPB1*0401 significantly lower, in MS patients as compared with HCs. MS patients with DRB1*0405 had a significantly earlier age of onset and lower Progression Index than patients without this allele. The proportion and absolute number of patients with DRB1*0405 successively increased with advancing year of birth. In MS patients without DRB1*0405, the frequency of the DRB1*1501 allele was significantly higher, while the DRB1*0901 allele was significantly lower, compared with HCs. Furthermore, DRB1*0405-negative MS patients were significantly more likely to be positive for EBNA antibodies compared with HCs.ConclusionsOur study suggests that MS patients harboring DRB1*0405, a genetic risk factor for MS in the Japanese population, have a younger age at onset and a relatively benign disease course, while DRB1*0405-negative MS patients have features similar to Western-type MS in terms of association with Epstein-Barr virus infection and DRB1*1501. The recent increase of MS in young Japanese people may be caused, in part, by an increase in DRB1*0405-positive MS patients.

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Cerebrospinal fluid kynurenines in multiple sclerosis; relation to disease course and neurocognitive symptoms

To investigate rapid cerebrospinal fluid (CSF) dynamics in infants in relation to respiration and cardiac cycle. CSF-flow signals were detected in 35 of 526 consecutive infants (22 male and 13 female infants, aged 1-30 days) who underwent 140 color flow and pulsed Doppler ultrasonographic studies at the cerebral aqueduct. In infants with spontaneous CSF flow, Doppler spectrum and respiratory signal or electrocardiogram were recorded simultaneously. In 64 examinations performed in 20 infants, CSF flow was induced by abdominal pressure change only. Among 76 examinations performed in 15 infants, CSF flow was synchronous to spontaneous respiration in 28 examinations, to mechanical ventilation in nine, to the cardiac cycle in 15, and to both respiratory and heart rates in 24. Respiration-modulated CSF flow predominates in infants without significant intracranial disease. Pulsation or CSF solely or mainly synchronous to the cardiac cycle is associated with conditions causing increased intracranial pressure.

Objective This study compares the nutritional status and physical activity levels of relapsing-remitting multiple sclerosis (RRMS) patients and healthy people. Method The study included 120 participants: 60 multiple sclerosis (MS) patients and 60 controls. RRMS diagnoses were made based on the 2017 McDonald criteria. The food intake frequency questionnaire was administered to the participants, their threeday food intake records were collected, their activity levels were determined, and anthropometric measurements were made. The differences between the groups were analyzed using the Mann–Whitney U test and Pearson's exact chi-squared test. Results The participants with MS (46.7%) had a significantly lower rate of shopping for their own food compared to the control group (68.3%) (p = 0.002). The MS group (3.3%) had a lower rate of intake of green leafy vegetables 5 times weekly or more frequently than the control group (20.0%) (p < 0.05); and the control group (35.0%) had a higher consumption rate of pastry more than 1 to 2 times monthly than the MS group (13.3%) (p < 0.05). The participants with MS had a higher intake of fiber, insoluble fiber, and omega 3 fatty acid than the control group (p < 0.05). Expanded Disability Status Scale (EDSS) scores indicates that a positive correlation was found between daily intake of fiber and insoluble fiber (p < 0.05). The patients with MS in the inactive group had a higher EDSS median [2.00(0.00 –5.00)] than the minimal active group [1.25(0.00 –4.00)] (p = 0.034). Conclusion With the increase in disability in MS patients, their physical activity levels decrease and it becomes difficult for them to shop on their own. In addition, the consumption frequency of green leafy vegetables, which take time to prepare and a source of fiber, is also decreasing. It has been shown that fiber intake decreases when the disability increase. Therefore, preventing the progression of disability in MS patients is very important in ensuring diversity in food consumption.

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.

Background: Epstein-Barr virus (EBV), a common human lymphotropic herpes virus infecting over 95% of the overall individuals. Strong evidence from recent research that EBV is a contributing factor in multiple sclerosis (MS). The exact mechanism by which EBV might exacerbate MS in risk groups is unknown. Objectives: To determine plasma levels of Autophagy-related proteins 5 (ATG5) and Epstein-Barr virus nuclear antigen1 (EBNA1) IgG. Additionally, assessing EBV DNA load in MS patients in relation to disease activity. Also, studying the relation between EBV DNA burden and the plasma levels of ATG5 and EBNA1 IgG in MS patients. Methodology: The study was conducted on 23 relapsing remitting MS (RRMS) patients in active attack, 23 RRMS patients' in-between attacks and 23 healthy controls. Enzyme-linked immunosorbent assay (ELISA) method was used to measure the amount of ATG5 and EBNA1 IgG in plasma. Real-time polymerase chain reaction (real-time PCR) was used to assess the EBV DNA load in peripheral blood mononuclear cells (PBMCs). Results: No statistically significant difference in ATG5 or EBNA1 IgG level between MS patients and healthy controls. However, all MS patients (100%) were EBNA1 IgG positive while 91.3% of the control group were EBNA1 IgG positive. EBV DNA load did not show statistically significant difference between MS patients and healthy controls. Significant positive correlation between EBV DNA load and ATG5 plasma level in MS patients in between attacks, P value =0.019. Conclusion: ATG5 levels and EBV DNA load could be utilized to predict disease-related activities in predisposed individuals or MS patients.

Monoaminergic network dysfunction is thought to underpin depression in multiple sclerosis (MS) patients. However, longitudinal studies are lacking. Here, we investigated the association between development of depressive symptoms in MS and changes of resting-state functional connectivity (RS FC) within monoaminergic networks. Forty-nine MS patients without depression [Montgomery-Asberg Depression Scale (MADRS) ≤ 9] and 27 healthy controls underwent clinical and 3.0T RS FC assessment at baseline and after a median follow-up of 1.6years (interquartile range 1.0-2.1years). Monoamine-related RS FC was derived by independent component analysis, constrained to PET atlases for dopamine, noradrenaline and serotonin transporters. Longitudinal changes of RS FC within monoaminergic networks and their correlations with MADRS scores were assessed. At baseline, MS patients showed decreased RS FC vs healthy controls in all PET-guided monoaminergic networks in frontal, cingulate and cerebellar cortices, and increased RS FC in parieto-occipital regions. Fourteen (29%) MS patients developed depressive symptoms (MADRS > 9) at follow-up (D-MS) and exhibited widespread RS FC decrease over time in the PET-guided dopamine network, mainly in orbitofrontal, occipital, anterior cingulate and precuneal cortices compared to patients who did not develop depressive symptoms. In D-MS, decreased RS FC over time was also observed in parahippocampal and occipital regions of the PET-guided noradrenaline network. Decreased RS FC over time in dopamine and noradrenaline PET-guided networks correlated with concomitant increased MADRS scores (r = range - 0.65/- 0.61, p < 0.001). The development of depressive symptoms in MS patients was associated with specific RS FC changes within the dopamine and noradrenaline networks.