Within-person fluctuations over three years in depression, anxiety, fatigue, and health-related quality of life in multiple sclerosis.

BACKGROUND: Longitudinal studies of health-related quality of life (HRQoL) in multiple sclerosis (MS) are limited. Most have examined average changes within the population, rather than dynamic changes within individuals. OBJECTIVE: To assess the between- and within-individual association between depression, anxiety, fatigue, cognition, physical functioning, and physical comorbidities and HRQoL. METHODS: Adults with MS underwent physical and cognitive assessments and reported symptoms of fatigue (Daily Fatigue Impact Scale), depression and anxiety (Hospital Anxiety and Depression Scale (HADS)), and HRQoL (RAND-36) annually (n = 4 visits). We evaluated associations of elevated symptoms of anxiety (HADS-A) and depression (HADS-D), fatigue, physical function (timed-walk and nine-hole peg test), cognitive function and comorbidity count with physical (PCS-36) and mental (MCS-36) HRQoL using multivariable linear models-estimating between-person and within-person effects. RESULTS: Of 255 participants with MS enrolled, 81.6% were women. After adjustment, within-person increases in depression and fatigue were associated with decreases in physical HRQoL. Increases in depression, anxiety, and comorbidity count were associated with decreases in mental HRQoL. CONCLUSIONS: Within-person increases in symptoms of depression, anxiety and fatigue, and comorbidity count are associated with HRQoL decreases among adults with MS, highlighting the potential magnitude of individual benefit of intervention for these symptoms.

Use of Benzodiazepines and Z-Drugs in Inflammatory Bowel Disease.

INTRODUCTION: We estimated the incidence and prevalence of benzodiazepine and Z-drug (separately and jointly as BZD) use in the inflammatory bowel disease (IBD) population compared with matched controls without IBD and examined the association of mood/anxiety disorders (M/ADs) with the use of BZD from 1997 to 2017. METHODS: Using administrative data from Manitoba, Canada, we identified 5,741 persons with incident IBD who were matched in a 1:5 ratio to controls on sex, birth year, and region. Validated case definitions were used to identify M/AD. Dispensations of BZD were identified. Multivariable generalized linear models were used to assess the association between IBD, M/AD, and BZD use. RESULTS: In 2016, the incident age/sex-standardized benzodiazepine use rates per 1,000 were 28.06 (95% confidence interval [CI] 26.41-29.81) in the IBD cohort and 16.83 (95% CI 16.28-17.39) in controls (adjusted rate ratio = 1.69 [95% CI 1.56-1.79]). Benzodiazepine incidence rates were higher for women with IBD than men, but the RR between cases and controls were similar for men and women. The incident age/sex-standardized Z-drug use rate per 1,000 was 21.07 (95% CI 19.69-22.41) in the IBD cohort. This was 1.87-fold higher than in controls (95% CI 1.73-2.01). In 2017, approximately 20% of persons with IBD used benzodiazepines and 20% used Z-drugs. There was a subadditive effect of both benzodiazepine and Z-drug uses between IBD and M/AD after adjusting for covariates. DISCUSSION: The use of BZD is more common in people with IBD than in population controls. Strategies to reduce the use of BZDs in persons with IBD and to offer alternative management strategies for M/ADs, sleep disorders, and other symptomatic concerns are needed.

Childhood Maltreatment and Psychiatric Comorbidity in Immune-Mediated Inflammatory Disorders.

OBJECTIVE: To determine whether childhood maltreatment is associated with immune-mediated inflammatory disorders (IMIDs; multiple sclerosis [MS], inflammatory bowel disease [IBD], and rheumatoid arthritis [RA]). We further aimed to determine the relationship between maltreatment and psychiatric comorbidity in IMIDs and whether these relationships differed across IMID. METHODS: Six hundred eighty-one participants (MS, 232; IBD, 216; RA, 130; healthy controls, 103) completed a structured psychiatric interview to identify psychiatric disorders, and the Childhood Trauma Questionnaire to evaluate five types of maltreatment: emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. We evaluated associations between maltreatment, IMID, and psychiatric comorbidity using multivariable logistic regression models. RESULTS: The prevalence of having ≥1 maltreatment was similar across IMID but higher than in controls (MS, 63.8%; IBD, 61.6%; RA, 62.3%; healthy controls, 45.6%). Emotional abuse was associated with having an IMID (adjusted odds ratio [aOR] = 2.37; 1.15-4.89). In the sex-specific analysis, this association was only present in women. History of childhood maltreatment was associated with a lifetime diagnosis of a psychiatric disorder in the IMID cohort (OR = 2.24; 1.58-3.16), but this association did not differ across diseases. In those with IMID, total types of maltreatments (aOR = 1.36; 1.17-1.59) and emotional abuse (aOR = 2.64; 1.66-4.21) were associated with psychiatric comorbidity. CONCLUSIONS: Childhood maltreatment is more common in IMID than in a healthy population and is associated with psychiatric comorbidity. Given the high burden of psychiatric disorders in the IMID population, clinicians should be aware of the contribution of maltreatment and the potential need for trauma-informed care strategies.

Anxiety and depression affect performance on the symbol digit modalities test over time in MS and other immune disorders.

BACKGROUND: Longitudinal studies assessing depression and anxiety effects on cognition in multiple sclerosis (MS) are limited. OBJECTIVE: We tested whether within-person fluctuations in symptoms of depression or anxiety over time affect cognition in persons with MS, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and a lifetime history of depression/anxiety disorders (DEP/ANX) but without an immune-mediated inflammatory diseases (IMID). METHODS: We followed participants (MS: 255, IBD: 247, RA: 154, and DEP/ANX: 306) for 3 years. Annually, they completed the hospital anxiety and depression scale (HADS) and cognitive tests including the symbol digit modalities test (SDMT). We evaluated associations of elevated symptoms (scores ⩾ 11) of anxiety (HADS-A) and depression (HADS-D) with SDMT z-scores using multivariable linear models-estimating between-person and within-person effects. RESULTS: Participants with MS performed worse on the SDMT than participants in the DEP/ANX cohort (ß = -0.68; 95% CI: -0.88, -0.48). Participants with elevated HADS-A scores performed worse on the SDMT than those without elevated scores (ß = -0.43; 95% CI: -0.65, -0.21), particularly those with RA. Time-varying within-person elevations in depressive symptoms were associated with worse SDMT performance (ß = -0.12; 95% CI: -0.21, -0.021). CONCLUSIONS: Across persons, elevated symptoms of anxiety adversely affected information processing. Elevated symptoms of depression within-persons over time were associated with declines in information processing speed.

Effect of mood and anxiety disorders on health care utilization in multiple sclerosis.

BACKGROUND: Little is known about the effects of changes in the presence or absence of psychiatric disorders on health care utilization in multiple sclerosis (MS). OBJECTIVE: To evaluate the association between "active" mood and anxiety disorders (MAD) and health care utilization in MS. METHODS: Using administrative data from Manitoba, Canada, we identified 4748 persons with MS and 24,154 persons without MS matched on sex, birth year, and region. Using multivariable general linear models, we evaluated the within-person and between-person effects of any "active" MAD on annual physician visits, hospital days, and number of drug classes dispensed in the following year. RESULTS: Annually, the MS cohort had an additional two physician visits, two drug classes, and nearly two more hospital days versus the matched cohort. Individuals with any MAD had more physician visits, had hospital days, and used more drug classes than individuals without a MAD. Within individuals, having an "active" MAD was associated with more utilization for all outcomes than not having an "active" MAD, but the magnitude of this effect was much smaller for visits and drugs than the between-person effect. CONCLUSION: Within individuals with MS, changes in MAD activity are associated with changes in health services use.

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

BACKGROUND: On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. METHODS: During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]). RESULTS: A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. CONCLUSIONS: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).

Canadian Expert Panel Recommendations for MRI Use in MS Diagnosis and Monitoring.

BACKGROUND: A definitive diagnosis of multiple sclerosis (MS), as distinct from a clinically isolated syndrome, requires one of two conditions: a second clinical attack or particular magnetic resonance imaging (MRI) findings as defined by the McDonald criteria. MRI is also important after a diagnosis is made as a means of monitoring subclinical disease activity. While a standardized protocol for diagnostic and follow-up MRI has been developed by the Consortium of Multiple Sclerosis Centres, acceptance and implementation in Canada have been suboptimal. METHODS: To improve diagnosis, monitoring, and management of a clinically isolated syndrome and MS, a Canadian expert panel created consensus recommendations about the appropriate application of the 2010 McDonald criteria in routine practice, strategies to improve adherence to the standardized Consortium of Multiple Sclerosis Centres MRI protocol, and methods for ensuring effective communication among health care practitioners, in particular referring physicians, neurologists, and radiologists. RESULTS: This article presents eight consensus statements developed by the expert panel, along with the rationale underlying the recommendations and commentaries on how to prioritize resource use within the Canadian healthcare system. CONCLUSIONS: The expert panel calls on neurologists and radiologists in Canada to incorporate the McDonald criteria, the Consortium of Multiple Sclerosis Centres MRI protocol, and other guidance given in this consensus presentation into their practices. By improving communication and general awareness of best practices for MRI use in MS diagnosis and monitoring, we can improve patient care across Canada by providing timely diagnosis, informed management decisions, and better continuity of care.

Low-Field (64mT) Portable MRI for Rapid Point-of-Care Diagnosis of DIS in Patients Presenting with Optic Neuritis.

BACKGROUND AND PURPOSE: Low-field 64mT portable brain MRI (pMRI) has recently shown diagnostic promise for MS. This study aimed to evaluate the utility of pMRI in assessing dissemination in space (DIS) in patients presenting with optic neuritis and determine whether deploying pMRI in the MS clinic can shorten the time from symptom onset to MRI. MATERIALS AND METHODS: Newly diagnosed optic neuritis patients referred to a tertiary academic MS center from July 2022 to January 2024 underwent both point-of-care pMRI and subsequent conventional 3T MRI (cMRI). Images were evaluated for periventricular (PV), juxtacortical (JC) and infratentorial (IT) lesions. DIS was determined on brain MRI per 2017 McDonald criteria. Test characteristics were computed using cMRI as the reference. Interrater and intermodality agreement between pMRI and cMRI were evaluated using Cohen's kappa. Time from symptom onset to pMRI and cMRI during the study period was compared to the preceding 1.5 years before pMRI implementation using Kruskal-Wallis with post-hoc Dunn's tests. RESULTS: Twenty patients (median age: 32.5 [IQR, 28-40]; 80% females) were included, of whom 9 (45%) and 5 (25%) had DIS on cMRI and pMRI, respectively. Median time interval between pMRI and cMRI was 7 days (IQR, 3.5-12.5). Interrater agreement was very good for PV (95%, κ=0.89), and good for JC and IT lesions (90%, κ=0.69 for both). Intermodality agreement was good for PV (90%, κ=0.80) and JC (85%, κ=0.63), and moderate for IT lesions (75%, κ=0.42) and DIS (80%, κ=0.58). pMRI had a sensitivity of 56% and specificity of 100% for DIS.The median time from symptom onset to pMRI was significantly shorter (8.5 days [IQR 7-12]) compared to the interval to cMRI before pMRI deployment (21 days [IQR 8-49], n=50) and after pMRI deployment (15 days [IQR 12-29], n=30) (both p<0.01). Time from symptom onset to cMRI in those periods was not significantly different (p=0.29). CONCLUSIONS: In optic neuritis patients, pMRI exhibited moderate concordance, moderate sensitivity and high specificity for DIS compared to cMRI. Its integration into the MS clinic reduced the time from symptom onset to MRI. Further studies are warranted to evaluate the role of pMRI in expediting early MS diagnosis and as an imaging tool in resource-limited settings. ABBREVIATIONS: pMRI = portable MRI; cMRI = conventional MRI; pwMS = patients with MS; PV = periventricular; JC= juxtacortical; IT = infratentorial; DIS = dissemination in space.

Incidence and prevalence of multiple sclerosis in Europe: a systematic review.

BACKGROUND: Multiple sclerosis (MS) is the most common cause of neurological disability in young adults worldwide and approximately half of those affected are in Europe. The assessment of differential incidence and prevalence across populations can reveal spatial, temporal and demographic patterns which are important for identifying genetic and environmental factors contributing to MS. However, study methodologies vary and the quality of the methods can influence the estimates. This study aimed to systematically review European studies of incidence and prevalence of MS and to provide a quantitative assessment of their methodological quality. METHODS: A comprehensive literature search was performed to obtain all original population-based studies of MS incidence and prevalence in European populations conducted and published between January 1985 and January 2011. Only peer-reviewed full-text articles published in English or French were included. All abstracts were screened for eligibility and two trained reviewers abstracted the data and graded the quality of each study using a tool specifically designed for this study. RESULTS: There were 123 studies that met the inclusion criteria. The study estimates were highly heterogeneous, even within regions or countries. Quality was generally higher in the more recent studies, which also tended to use current diagnostic criteria. Prevalence and incidence estimates tended to be higher in the more recent studies and were higher in the Nordic countries and in northern regions of the British Isles. With rare exceptions, prevalence and incidence estimates were higher in women with ratios as high as 3:1. Few studies examined ethnicity. Epidemiological data at the national level was uncommon and there were marked geographical disparities in available data, with large areas of Europe unrepresented and other regions well-represented in the literature. Only 37% of the studies provided standardized estimates. CONCLUSIONS: Despite the breadth of the literature on the epidemiology of MS in Europe, inter-study comparisons are hampered by the lack of standardization. Further research should focus on regions not yet studied and the evaluation of ethnic differences in MS prevalence and incidence. National-level studies using current diagnostic criteria, validated case definitions and similar age- and sex-standardization would allow better geographical comparisons.

Multiple sclerosis disease-modifying therapy prescribing patterns in Ontario.

BACKGROUND: Differences in Multiple sclerosis (MS) disease-modifying therapy (DMT) prescribing patterns between different groups of neurologists have not been explored. OBJECTIVE: To examine concentrations of prescribing patterns and to assess if MS-specialists use a broader range of DMTs relative to general neurologists. METHODS: We conducted a cross-sectional study using administrative claims databases in Ontario, Canada to link neurologists to 2009 DMT prescription data. MS specialization was defined using both practice location and prescription patterns. Lorenz curves and Gini coefficients were constructed to examine prescribing patterns, separating neurologist characteristics dichotomously and separating Avonex from the other standard DMTs (Betaseron, Rebif and Copaxone). Gini coefficient 95% confidence intervals (CIs) were derived using jack-knife statistical techniques. RESULTS: Prescriptions were highly concentrated with 12% of Ontario neurologists prescribing 80% of DMTs. There was a trend towards Avonex being more commonly prescribed relative to the other DMTs. When MS specialization was defined by DMT prescribing, high-volume prescribing neurologists showed a broader range of DMT prescribing (Gini 0.38-0.44) in comparison to low-volume prescribers (Gini 0.57-0.66). CONCLUSIONS: The majority of DMTs are prescribed by a small subset of neurologists. High-volume prescribing MS-specialists show more variability in DMT use while low-volume prescribers tend to individually focus on a narrower range of DMTs.

Pain and participation in social activities in people with relapsing remitting and progressive multiple sclerosis.

Background: Differences in pain between subtypes of multiple sclerosis are understudied. Objective: To compare the prevalence of pain, and the association between pain and: (a) pain interference and (b) social participation in people with relapsing-remitting multiple sclerosis and progressive multiple sclerosis. Methods: Participants completed the McGill Pain Questionnaire Short-Form-2, Pain Effects Scale and Ability to Participate in Social Roles and Activities-V2.0 questionnaires. We tested the association between multiple sclerosis subtype, pain severity, and pain interference/social participation using quantile regression. Results: Of 231 participants (relapsing-remitting multiple sclerosis: 161, progressive multiple sclerosis: 70), 82.3% were women. The prevalence of pain was 95.2%, of more than mild pain was 38.1%, and of pain-related limitations was 87%; there were no differences between multiple sclerosis subtypes. Compared to participants with relapsing-remitting multiple sclerosis, those with progressive multiple sclerosis reported higher pain interference (mean (standard deviation) Pain Effects Scale; progressive multiple sclerosis: 15[6.0] vs relapsing-remitting multiple sclerosis: 13[5], p = 0.039) and lower social participation (Ability to Participate in Social Roles and Activities T-scores 45[9.0] vs 48.3[8.9], p = 0.011). However, on multivariable analysis accounting for age, physical disability, mood/anxiety and fatigue, multiple sclerosis subtype was not associated with differences in pain interference or social participation. Conclusions: Pain was nearly ubiquitous. Over one-third of individuals with relapsing-remitting multiple sclerosis and progressive multiple sclerosis reported pronounced pain, although this did not differ by multiple sclerosis subtype.

Assessment of differential item functioning of the PHQ-9, HADS-D and PROMIS-depression scales in persons with and without multiple sclerosis.

OBJECTIVE: We tested for the presence of differential item functioning (DIF) in commonly used measures of depressive symptoms, in people with multiple sclerosis (MS) versus people with a psychiatric disorder without MS. METHODS: Participants included individuals with MS, or with a lifetime history of a depressive or anxiety disorder (Dep/Anx) but no immune-mediated inflammatory disease. Participants completed the Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), and the Patient Reported Outcome Measurement Information System (PROMIS)-Depression. We assessed unidimensionality of the measures using factor analysis. We evaluated DIF using logistic regression, with and without adjustment for age, gender and body mass index (BMI). RESULTS: We included 555 participants (MS: 252, Dep/Anx: 303). Factor analysis showed that each depression symptom measure had acceptable evidence of unidimensionality. In unadjusted analyses comparing the MS versus Dep/Anx groups we identified multiple items with evidence of DIF, but few items showed DIF effects that were large enough to be clinically meaningful. We observed non-uniform DIF for one PHQ-9 item, and three HADS-D items. We also observed DIF with respect to gender (one HADS-D item), and BMI (one PHQ-9 item). For the MS versus Dep/Anx groups, we no longer observed DIF post-adjustment for age, gender and BMI. On unadjusted and adjusted analyses, we did not observe DIF for any PROMIS-D item. CONCLUSION: Our findings suggest that DIF exists for the PHQ-9 and HADS-D with respect to gender and BMI in clinical samples that include people with MS whereas DIF was not observed for the PROMIS-Depression scale.

Well-being and flourishing mental health in adults with inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis in Manitoba, Canada: a cross-sectional study.

OBJECTIVES: Among people with immune-mediated inflammatory disease (IMID), including multiple sclerosis (MS), inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) most research has focused on mental illness rather than on mental health. We assessed dimensions of mental health among persons with IMID and compared them across IMID. We also evaluated demographic and clinical characteristics associated with flourishing mental health. DESIGN: Participants: Adults with an IMID (MS, 239; IBD, 225; RA 134; total 598) who were participating in a cohort study. SETTING: Tertiary care centre in Manitoba, Canada. PRIMARY OUTCOME MEASURE: Participants completed the Mental Health Continuum Short-Form (MHC-SF), which measures emotional, psychological and social well-being, and identifies flourishing mental health. This outcome was added midway through the study on the advice of the patient advisory group. Depression, anxiety, pain, fatigue and physical function were also assessed. RESULTS: Total MHC-SF and subscale scores were similar across IMID groups. Nearly 60% of participants were considered to have flourishing mental health, with similar proportions across disease types (MS 56.5%; IBD 58.7%; RA 59%, p=0.95). Older age was associated with a 2% increased odds of flourishing mental health per year of age (OR 1.02; 95% CI: 1.01 to 1.04). Clinically meaningful elevations in anxiety (OR 0.25; 95% CI: 0.12 to 0.51) and depressive symptoms (OR 0.074; 95% CI: 0.009 to 0.61) were associated with lower odds. Higher levels of pain, anxiety and depressive symptoms were associated with lower total Mental Health Continuum scores at the 50th quantile. CONCLUSIONS: Over half of people with MS, IBD and RA reported flourishing mental health, with levels similar across the disease groups. Interventions targeting symptoms of depression and anxiety, and upper limb impairments, as well as resilience training may help a higher proportion of the IMID population achieve flourishing mental health.

Vascular comorbidity is associated with decreased cognitive functioning in inflammatory bowel disease.

Reports of cognitive impairment in inflammatory bowel disease (IBD) have been mixed. IBD and cardiovascular disease are often co-morbid, yet it remains unknown whether vascular comorbidity confers a risk for decreased cognitive functioning, as observed in other populations. Participants with IBD were recruited from a longitudinal study of immune-mediated disease. Participants were administered a standardized neuropsychological test protocol, evaluating information processing speed, verbal learning and memory, visual learning and memory, and verbal fluency/executive function. Cognitive test scores were standardized using local regression-based norms, adjusting for age, sex, and education. Vascular risk was calculated using a modified Framingham Risk Score (FRS). We tested the association between FRS and cognitive test scores using a quantile regression model, adjusting for IBD type. Of 84 IBD participants, 54 had ulcerative colitis and 30 had Crohn's disease; mean (SD) age was 53.36 (13.95) years, and a high proportion were females (n = 58). As the risk score (FRS) increased, participants demonstrated lower performance in information processing speed (ß = - 0.12; 95% CI - 0.24, - 0.006) and verbal learning (ß = - 0.14; 95% CI - 0.28, - 0.01) at the 50th percentile. After adjusting for IBD type and disease activity, higher FRS remained associated with lower information processing speed (ß = - 0.14; 95% CI - 0.27, - 0.065). Vascular comorbidity is associated with lower cognitive functioning in persons with IBD, particularly in the area of information processing speed. These findings suggest that prevention, identification, and treatment of vascular comorbidity in IBD may play a critical role for improving functional outcomes in IBD.

Differences in resting state functional connectivity relative to multiple sclerosis and impaired information processing speed.

Background: Fifty-one percent of individuals with multiple sclerosis (MS) develop cognitive impairment (CI) in information processing speed (IPS). Although IPS scores are associated with health and well-being, neural changes that underlie IPS impairments in MS are not understood. Resting state fMRI can provide insight into brain function changes underlying impairment in persons with MS. Objectives: We aimed to assess functional connectivity (FC) differences in (i) persons with MS compared to healthy controls (HC), (ii) persons with both MS and CI (MS-CI) compared to HC, (iii) persons with MS that are cognitively preserved (MS-CP) compared to HC, (iv) MS-CI compared to MS-CP, and (v) in relation to cognition within the MS group. Methods: We included 107 participants with MS (age 49.5 ± 12.9, 82% women), and 94 controls (age 37.9 ± 15.4, 66% women). Each participant was administered the Symbol Digit Modalities Test (SDMT) and underwent a resting state fMRI scan. The MS-CI group was created by applying a z-score cut-off of ≤-1.5 to locally normalized SDMT scores. The MS-CP group was created by applying a z-score of ≥0. Control groups (HCMS-CI and HCMS-CP) were based on the nearest age-matched HC participants. A whole-brain ROI-to-ROI analysis was performed followed by specific contrasts and a regression analysis. Results: Individuals with MS showed FC differences compared to HC that involved the cerebellum, visual and language-associated brain regions, and the thalamus, hippocampus, and basal ganglia. The MS-CI showed FC differences compared to HCMS-CI that involved the cerebellum, visual and language-associated areas, thalamus, and caudate. SDMT scores were correlated with FC between the cerebellum and lateral occipital cortex in MS. No differences were observed between the MS-CP and HCMS-CP or MS-CI and MS-CP groups. Conclusion: Our findings emphasize FC changes of cerebellar, visual, and language-associated areas in persons with MS. These differences were apparent for (i) all MS participants compared to HC, (ii) MS-CI subgroup and their matched controls, and (iii) the association between FC and SDMT scores within the MS group. Our findings strongly suggest that future work that examines the associations between FC and IPS impairments in MS should focus on the involvement of these regions.

Vascular Disease Is Associated With Differences in Brain Structure and Lower Cognitive Functioning in Inflammatory Bowel Disease: A Cross-Sectional Study.

BACKGROUND: Vascular disease and cognitive impairment have been increasingly documented in inflammatory bowel disease (IBD), and both have been individually correlated with changes in brain structure. This study aimed to determine if both macro- and microstructural brain changes are prevalent in IBD and whether alterations in brain structure mediate the relationship between vascular disease and cognitive functioning. METHODS: Eighty-four IBD participants underwent multimodal magnetic resonance imaging. Volumetric and mean diffusivity measures of the thalamus, hippocampus, normal-appearing white matter, and white matter lesions were converted to age- and sex-adjusted z scores. Vascular comorbidity was assessed using a modified Framingham Risk Score and cognition was assessed using a battery of neuropsychological tests. Test scores were standardized using local regression-based norms. We generated summary statistics for the magnetic resonance imaging metrics and cognitive tests, and these were examined using canonical correlation analysis and linear regression modeling. RESULTS: Greater vascular comorbidity was negatively correlated with thalamic, normal-appearing white matter, and white matter lesion volumes. Higher Framingham Risk Score were also correlated with lower processing speed, learning and memory, and verbal fluency. Increased vascular comorbidity was predictive of poorer cognitive functioning, and this effect was almost entirely mediated (94.76%) by differences in brain structure. CONCLUSIONS: Vascular comorbidity is associated with deleterious effects on brain structure and lower cognitive functioning in IBD. These findings suggest that proper identification and treatment of vascular disease is essential to the overall management of IBD, and that certain brain areas may serve as critical targets for predicting the response to therapeutic interventions.

Vascular disease is associated with decreased cognitive performance in persons with inflammatory bowel disease, and this is mainly driven by changes in the brain, including both gray matter and white matter regions.

Development of an indicator of smoking status for people with multiple sclerosis in administrative data.

BACKGROUND: Administrative data lack health behavior information. METHODS: We developed an administrative case definition for past or current ('ever smoking') in 1320 individuals with MS from Manitoba, Canada. Candidate indicators for 'ever smoked' included smoking cessation medications, and diagnosis codes for tobacco use and chronic obstructive pulmonary disease, using variable lookback periods. RESULTS: When compared to self-reported smoking status, the case definition incorporating all indicators over a lifetime lookback period had a sensitivity of 31.98%, and positive predictive value of 78.26%. CONCLUSION: This smoking status definition could only partially control for confounding due to smoking because of the low sensitivity.

High or increasing serum NfL is predictive of impending multiple sclerosis relapses.

BACKGROUND: One-off serum levels of neurofilament light chain (sNfL) is an established predictor of emerging disease activity in multiple sclerosis (MS). However, the importance of longitudinal increases in sNfL is yet to be enumerated, an important consideration as this test is translated for serial monitoring. Glial Fibrillary Acidic Protein (sGFAP) is another biomarker of predictive interest. Our objective was to assess the association between longitudinal changes sNfL and prediction of future relapses, as well as a possible role for sGFAP. METHODS: Participants with active MS were prospectively monitored for one year as part of a clinical trial testing mesenchymal stem cells. Visits every three months or less included clinical assessments, MRI scans and serum draws. sNfL and sGFAP concentrations were quantified with Single Molecule Array immunoassay. We used Kaplan-Meier estimates and Anderson-Gill Cox regression models with and without adjustment for age, sex, disease subtype, disease duration and expanded disability status score (EDSS) to estimate the rate of relapse predicted by baseline and longitudinal changes in biomarker. RESULTS: 58 Canadian and Italian participants with MS were enrolled in this study. Higher baseline sNfL was future relapse (Log-rank p = 0.0068), MRI lesions (p=0.0096), composite-relapse associated worsening (p=0.01) and progression independent of relapse activity (p=0.0096). Conversely, baseline sGFAP was only weakly associated with MRI lesions (0.044). Cross-sectional analyses of baseline sNfL revealed that a two-fold difference in baseline sNfL, e.g. from 10 to 20 pg/mL, was associated with a 2.3-fold increased risk of relapse during follow-up (95% confidence interval 1.65-3.17). Longitudinally, a two-fold increase in sNfL level from the first measurement was associated with an additional 1.46 times increased risk of relapse (1.07-2.00). The impact of longitudinal increases in sNfL on the risk of relapse were most pronounced for patients with lower baseline values of sNfL (<10 pg/mL: HR = 1.54, 1.06-2.24). These associations remained significant after adjustment for potential confounders. CONCLUSION: We enumerate the risk of relapse associated with dynamic changes in sNfL. Both baseline and longitudinal change in sNfL may help identify patients who would benefit from early treatment optimisation. TRIAL REGISTRATIONS: Canada:NCT02239393, Italy:NCT01854957&EudraCT, 2011-001295-19 CLASSIFICATION OF EVIDENCE: This study provides class 1 evidence that high baseline and longitudinal increases in sNfL are predictive of impending relapses in patients with active MS.

Depressive symptom trajectories and polygenic risk scores in individuals with an immune-mediated inflammatory disease.

OBJECTIVE: To develop group-based trajectories of depressive symptoms in immune-mediated inflammatory disease (IMID) to understand their evolution and identify any associated factors, with the overall goal of identifying those at highest risk of higher depressive symptom burden. METHOD: 922 participants had an IMID or anxiety/depression. The PHQ-9 was administered at four visits, and polygenic risk scores (PRS) for major depressive disorder, depressive symptoms, and body mass index (BMI) were generated. Group-based trajectory modelling of PHQ-9 scores estimated distinct trajectories. Regression tested whether specific factors were associated with the trajectories. Mediation analyses assessed whether IMID mediated the association between BMI PRS and trajectories. RESULTS: Three trajectories were identified. Regression demonstrated those in Group 3 ('high symptoms') had significantly higher PRS for the three traits, compared to Group 1 ('minimal symptoms') (OR: 1.34-1.66, P < 0.01). Stratified analyses in the IMID subgroup revealed an increased effect for BMI PRS in Group 3 (OR: 2.31, P < 0.001), in contrast, BMI PRS was no longer associated in the non-IMID sample. No significant indirect effect of BMI PRS on depressive symptoms trajectories was identified via IMID. CONCLUSIONS: A significant association between polygenicity and PHQ-9 trajectories supports a role for genetic inheritance in the variability in depressive symptoms in IMID.