Lesion Frequency Distribution Maps of Traumatic Axonal Injury on Early Magnetic Resonance Imaging After Moderate and Severe Traumatic Brain Injury and Associations to 12 Months Outcome.

Traumatic axonal injury (TAI) is a common finding on magnetic resonance imaging (MRI) in patients with moderate-severe traumatic brain injury (TBI), and the burden of TAI is associated with outcome in this patient group. Lesion mapping offers a way to combine imaging findings from numerous individual patients into common lesion maps where the findings from a whole patient cohort can be assessed. The aim of this study was to evaluate the spatial distribution of TAI lesions on different MRI sequences and its associations to outcome with use of lesion mapping. Included prospectively were 269 patients (8-70 years) with moderate or severe TBI and MRI within six weeks after injury. The TAI lesions were evaluated and manually segmented on fluid-attenuated inversed recovery (FLAIR), diffusion weighted imaging (DWI), and either T2* gradient echo (T2*GRE) or susceptibility weighted imaging (SWI). The segmentations were registered to the Montreal Neurological Institute space and combined to lesion frequency distribution maps. Outcome was assessed with Glasgow Outcome Scale Extended (GOSE) score at 12 months. The frequency and distribution of TAI was assessed qualitatively by visual reading. Univariable associations to outcome were assessed qualitatively by visual reading and also quantitatively with use of voxel-based lesion-symptom mapping (VLSM). The highest frequency of TAI was found in the posterior half of corpus callosum. The frequency of TAI was higher in the frontal and temporal lobes than in the parietal and occipital lobes, and in the upper parts of the brainstem than in the lower. At the group level, all voxels in mesencephalon had TAI on FLAIR. The patients with poorest outcome (GOSE scores ≤4) had higher frequencies of TAI. On VLSM, poor outcome was associated with TAI lesions bilaterally in the splenium, the right side of tectum, tegmental mesencephalon, and pons. In conclusion, we found higher frequency of TAI in posterior corpus callosum, and TAI in splenium, mesencephalon, and pons were associated with poor outcome. If lesion frequency distribution maps containing outcome information based on imaging findings from numerous patients in the future can be compared with the imaging findings from individual patients, it would offer a new tool in the clinical workup and outcome prediction of the patient with TBI.

Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis.

BACKGROUND: Natalizumab was not shown to modify disability in progressive multiple sclerosis (MS). This matched observational study compared the effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) with natalizumab in progressive MS. METHODS: Patients with primary/secondary progressive MS from seven AHSCT MS centres and the MSBase registry, treated with AHSCT or natalizumab, were matched on a propensity score derived from sex, age, Expanded Disability Status Scale (EDSS), number of relapses 12/24 months before baseline, time from MS onset, the most effective prior therapy and country. The pairwise-censored groups were compared on hazards of 6-month confirmed EDSS worsening and improvement, relapses and annualised relapse rates (ARRs), using Andersen-Gill proportional hazards models and conditional negative binomial model. RESULTS: 39 patients treated with AHSCT (37 with secondary progressive MS, mean age 37 years, EDSS 5.7, 28% with recent disability progression, ARR 0.54 during the preceding year) were matched with 65 patients treated with natalizumab. The study found no evidence for difference in hazards of confirmed EDSS worsening (HR 1.49, 95% CI 0.70 to 3.14) and improvement (HR 1.50, 95% CI 0.22 to 10.29) between AHSCT and natalizumab over up to 4 years. The relapse activity was also similar while treated with AHSCT and natalizumab (ARR: mean±SD 0.08±0.28 vs 0.08±0.25; HR 1.05, 95% CI 0.39 to 2.82). In the AHSCT group, 3 patients experienced febrile neutropenia during mobilisation, 9 patients experienced serum sickness, 6 patients required intensive care unit admission and 36 patients experienced complications after discharge. No treatment-related deaths were reported. CONCLUSION: This study does not support the use of AHSCT to control disability in progressive MS with advanced disability and low relapse activity.

Autologous hematopoietic stem cell transplantation for multiple sclerosis: Long-term follow-up data from Norway.

BACKGROUND: Autologous hematopoietic stem cell transplantation (HSCT) is a potent treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate long-term outcomes of HSCT in MS. METHODS: National retrospective single-center observational study of patients with aggressive RRMS that underwent HSCT in Norway from January 2015 to January 2018. Criteria for receiving HSCT included at least two clinical relapses the last year while on disease modifying treatment (DMT). RESULTS: In total, 29 patients, with a mean follow-up time of 70 months (standard deviation:14.3), were evaluated. Twenty patients (69%) had sustained no evidence of disease activity (NEDA-3) status, 24 (83%) were relapse-free, 23 (79%) free of magnetic resonance imaging (MRI) activity, and 26 (90%) free of progression. Number of patients working full-time increased from 1 (3%), before HSCT, to 10 (33%) after 2 years and 15 (52%) after 5 years. CONCLUSION: HSCT offers long-term disease-free survival with successively increasing work participation in patients with aggressive MS resistant to DMTs.

Healthcare utilization and costs associated with autologous haematopoietic stem cell transplantation in Norwegian patients with relapsing remitting multiple sclerosis.

Multiple sclerosis (MS) patients experience long-term deterioration of neurological function, reduced quality of life, long-lasting treatment cycles, and an increased risk of early workability loss imposing an economic burden to society. Autologous haematopoietic stem cell transplantation (AHSCT) has shown promising treatment effects for relapsing remitting MS (RRMS). This study employs a micro-costing approach to estimate healthcare utilization and costs associated with AHSCT in Norwegian RRMS patients. Patient-level data were extracted from medical journals of 30 RRMS patients receiving AHSCT treatment at Haukeland University Hospital in the period from January 2015 to January 2018. The time horizon for the analysis was from the pretransplant screening until one year after AHSCT. A correlation was found between patient body weight and total healthcare cost. The average total healthcare cost of AHSCT for RRMS patients was estimated to EUR 66 304 (95% CI: EUR 63 598 - EUR 69 010) including costs associated with the pre-AHSCT period, AHSCT treatment phases and one-year follow-up. The majority of the costs, EUR 64 329, occurred during the treatment phase and within the first 100 days after AHSCT. The results indicate that long-term healthcare cost savings may be achieved using AHSCT in selected patients with aggressive RRMS. This is due to the high costs of most used disease modifying treatments. Further research including long-term clinical data is needed to determine the cost-effectiveness of this treatment.

An Association of Chitinase-3 Like-Protein-1 With Neuronal Deterioration in Multiple Sclerosis.

Elevated levels of Chitinase-3-like protein-1 (CHI3L1) in cerebrospinal fluid have previously been linked to inflammatory activity and disease progression in multiple sclerosis (MS) patients. This study aimed to investigate the presence of CHI3L1 in the brains of MS patients and in the cuprizone model in mice (CPZ), a model of toxic/metabolic demyelination and remyelination in different brain areas. In MS gray matter (GM), CHI3L1 was detected primarily in astrocytes and in a subset of pyramidal neurons. In neurons, CHI3L1 immunopositivity was associated with lipofuscin-like substance accumulation, a sign of cellular aging that can lead to cell death. The density of CHI3L1-positive neurons was found to be significantly higher in normal-appearing MS GM tissue compared to that of control subjects (p = .014). In MS white matter (WM), CHI3L1 was detected in astrocytes located within lesion areas, as well as in perivascular normal-appearing areas and in phagocytic cells from the initial phases of lesion development. In the CPZ model, the density of CHI3L1-positive cells was strongly associated with microglial activation in the WM and choroid plexus inflammation. Compared to controls, CHI3L1 immunopositivity in WM was increased from an early phase of CPZ exposure. In the GM, CHI3L1 immunopositivity increased later in the CPZ exposure phase, particularly in the deep GM region. These results indicate that CHI3L1 is associated with neuronal deterioration, pre-lesion pathology, along with inflammation in MS.

The neuroprotective potential of mesenchymal stem cells from bone marrow and human exfoliated deciduous teeth in a murine model of demyelination.

INTRODUCTION: Multiple sclerosis (MS) is characterized by chronic inflammation, demyelination, and axonal degeneration within the central nervous system (CNS), for which there is no current treatment available with the ability to promote neuroprotection or remyelination. Some aspects of the progressive form of MS are displayed in the murine cuprizone model, where demyelination is induced by the innate immune system without major involvement of the adaptive immune system. Mesenchymal stem cells (MSCs) are multipotent cells with immunomodulatory and neuroprotective potential. In this study, we aimed to assess the neuroprotective potential of MSCs from bone marrow (BM-MSCs) and stem cells from human exfoliated deciduous teeth (SHED) in the cuprizone model. METHODS: Human BM-MSCs and SHED were isolated and characterized. Nine-week-old female C57BL/6 mice were randomized to receive either human BM-MSCs, human SHED or saline intraperitoneally. Treatments were administered on day -1, 14 and 21. Outcomes included levels of local demyelination and inflammation, and were assessed with immunohistochemistry and histology. RESULTS: BM-MSCs were associated with increased myelin content and reduced microglial activation whereas mice treated with SHED showed reduced microglial and astroglial activation. There were no differences between treatment groups in numbers of mature oligodendrocytes or axonal injury. MSCs were identified in the demyelinated corpus callosum in 40% of the cuprizone mice in both the BM-MSC and SHED group. CONCLUSION: Our results suggest a neuroprotective effect of MSCs in a toxic MS model, with demyelination mediated by the innate immune system.

Trajectories of occupational physical activity and risk of later-life mild cognitive impairment and dementia: the HUNT4 70+ study.

Background: High levels of occupational physical activity (PA) have been linked to an increased risk of dementia. We assessed the association of trajectories of occupational PA at ages 33-65 with risk of dementia and mild cognitive impairment (MCI) at ages 70+. Methods: We included 7005 participants (49.8% were women, 3488/7005) from the HUNT4 70+ Study. Group-based trajectory modelling was used to identify four trajectories of occupational PA based on national registry data from 1960 to 2014: stable low (30.9%, 2162/7005), increasing then decreasing (8.9%, 625/7005), stable intermediate (25.1%, 1755/7005), and stable high (35.2%, 2463/7005). Dementia and MCI were clinically assessed in 2017-2019. We performed adjusted multinomial regression to estimate relative risk ratios (RRR) with 95% confidence intervals (CI) for dementia and MCI. Findings: 902 participants were diagnosed with dementia and 2407 were diagnosed with MCI. Absolute unadjusted risks for dementia and MCI were 8.8% (95% CI: 7.6-10.0) and 27.4% (25.5-29.3), respectively, for those with a stable low PA trajectory, 8.2% (6.0-10.4) and 33.3% (29.6-37.0) for those with increasing, then decreasing PA; while they were 16.0% (14.3-17.7) and 35% (32.8-37.2) for those with stable intermediate, and 15.4% (14.0-16.8) and 40.2% (38.3-42.1) for those with stable high PA trajectories. In the adjusted model, participants with a stable high trajectory had a higher risk of dementia (RRR 1.34, 1.04-1.73) and MCI (1.80, 1.54-2.11), whereas participants with a stable intermediate trajectory had a higher risk of MCI (1.36, 1.15-1.61) compared to the stable low trajectory. While not statistically significant, participants with increasing then decreasing occupational PA had a 24% lower risk of dementia and 18% higher risk of MCI than the stable low PA group. Interpretation: Consistently working in an occupation with intermediate or high occupational PA was linked to an increased risk of cognitive impairment, indicating the importance of developing strategies for individuals in physically demanding occupations to prevent cognitive impairment. Funding: This work was supported by the National Institutes of Health (R01AG069109-01) and the Research Council of Norway (296297, 262700, 288083).

Association between patient-reported cognitive function and location of glioblastoma.

Objective cognitive function in patients with glioblastoma may depend on tumor location. Less is known about the potential impact of tumor location on cognitive function from the patients' perspective. This study aimed to investigate the association between patient-reported cognitive function and the location of glioblastoma using voxel-based lesion-symptom mapping. Patient-reported cognitive function was assessed with the European Organisation for Research and Treatment (EORTC) QLQ-C30 cognitive function subscale preoperatively and 1 month postoperatively. Semi-automatic tumor segmentations from preoperative MRI images with the corresponding EORTC QLQ-C30 cognitive function score were registered to a standardized brain template. Student's pooled-variance t-test was used to compare mean patient-reported cognitive function scores between those with and without tumors in each voxel. Both preoperative brain maps (n = 162) and postoperative maps of changes (n = 99) were developed. Glioblastomas around the superior part of the left lateral ventricle, the left lateral part of the thalamus, the left caudate nucleus, and a portion of the left internal capsule were significantly associated with reduced preoperative patient-reported cognitive function. However, no voxels were significantly associated with postoperative change in patient-reported cognitive function assessed 1 month postoperatively. There seems to be an anatomical relation between tumor location and patient-reported cognitive function before surgery, with the left hemisphere being the dominant from the patients' perspective.

Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis.

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Retirement age and disability status as pathways to later-life cognitive impairment: Evidence from the Norwegian HUNT Study linked with Norwegian population registers.

BACKGROUND: Research shows that retirement age is associated with later-life cognition but has not sufficiently distinguished between retirement pathways. We examined how retirement age was associated with later-life dementia and mild cognitive impairment (MCI) for people who retired via the disability pathway (received a disability pension prior to old-age pension eligibility) and those who retired via the standard pathway. METHODS: The study sample comprised 7210 participants from the Norwegian Trøndelag Health Study (HUNT4 70+, 2017-2019) who had worked for at least one year in 1967-2019, worked until age 55+, and retired before HUNT4. Dementia and MCI were clinically assessed in HUNT4 70+ when participants were aged 69-85 years. Historical data on participants' retirement age and pathway were retrieved from population registers. We used multinomial regression to assess the dementia/MCI risk for women and men retiring via the disability pathway, or early (<67 years), on-time (age 67, old-age pension eligibility) or late (age 68+) via the standard pathway. RESULTS: In our study sample, 9.5% had dementia, 35.3% had MCI, and 28.1% retired via the disability pathway. The disability retirement group had an elevated risk of dementia compared to the on-time standard retirement group (relative risk ratio [RRR]: 1.64, 95% CI 1.14-2.37 for women, 1.70, 95% CI 1.17-2.48 for men). MCI risk was lower among men who retired late versus on-time (RRR, 0.76, 95% CI 0.61-0.95). CONCLUSION: Disability retirees should be monitored more closely, and preventive policies should be considered to minimize the dementia risk observed among this group of retirees.

Predictors of hospitalization due to infection in rituximab-treated MS patients.

BACKGROUND: Rituximab is extensively used off-label to treat multiple sclerosis (MS), and long-term vigilance for adverse events is needed. This study was conducted to determine frequencies and predictors of hematological adverse events, including hypogammaglobulinemia, severe lymphopenia, neutropenia, and infections leading to hospitalization. METHODS: This retrospective cohort study included all patients with MS initiating rituximab treatment at Haukeland University Hospital between January 1st, 2017, and July 1st, 2021. Patients were followed by clinical monitoring and repeated blood sampling every six months. Clinical outcomes and laboratory results were retrieved from the Norwegian MS Registry and Biobank and the patient administrative system at Haukeland University Hospital. RESULTS: Five hundred and fifty-six patients were included, 515 with relapsing-remitting MS (RRMS) and 41 with progressive MS. Overall, 33 patients (5.9%) experienced 56 episodes of infections requiring hospital admission. Sixty patients (10.8%) had confirmed hypogammaglobulinemia, 17 (3.1%) had confirmed severe lymphopenia, and 10 (1.8%) had confirmed severe neutropenia. Predictors of infection requiring hospital admission were progressive MS (adjusted OR (aOR): 4.81; 95%CI: 1.25-18.48), duration of treatment with rituximab (aOR: 1.52; 95%CI: 1.11-2.09) and confirmed severe lymphopenia (aOR: 13.58; 95%CI: 3.41-54.06) and neutropenia (aOR: 13.40; 95%CI: 2.93-61.25). Of the hematological abnormalities, only hypogammaglobulinemia was associated with treatment duration (aOR: 1.35; 95%CI: 1.09-1.69). CONCLUSION: The risk of hospitalization due to infection is associated with time on rituximab treatment, in patients with lympho- or neutropenia, and in patients with primary progressive MS. We observed a time-dependent decline in IgG values, in contrast to neutrophil and lymphocyte count, suggesting a cumulative dose-dependent response. These predictors can assist clinicians in assessing and monitoring MS patients receiving rituximab.

Hearing impairment and risk of dementia in The HUNT Study (HUNT4 70+): a Norwegian cohort study.

Background: Hearing impairment is strongly associated with future dementia. No studies have reported objectively measured hearing impairment in a cohort with a long period of follow-up (>20 years), and few have reported follow-up over 10 years. Hence, there is a need for high quality studies with sufficient follow-up time and data to account for reverse causality and confounding. We aimed to address this knowledge gap. Methods: This cohort study used individual participant data from The Trøndelag Health Study (HUNT) in Norway. All current residents aged at least 20 years in the former Norwegian Nord-Trøndelag County were invited to participate in four decennial surveys: HUNT1 (1984-1986), HUNT2 (1995-1997), HUNT3 (2006-2008), and HUNT4 (2017-2019) with individuals aged at least 70 years included in a substudy, known as HUNT4 70+. Here, we report the findings of this substudy. HUNT4 70+ comprised 7135 participants who were assessed for dementia using the Diagnostic and Statistical Manual of Mental Disorders 5 criteria and who had audiometry between 1996 and 1998. The primary objective was to investigate, with gold standard audiometric testing and dementia diagnostic assessment, whether hearing impairment was an independent risk factor for all-cause dementia. The secondary objective was to investigate if a risk also applied to Alzheimer dementia and non-Alzheimer dementia. We analysed the association using Poisson regression and adjusted for confounders. This study is registered with ClinicalTrials.gov (NCT04284384). Findings: At baseline, 1058 (15%) individuals had acquired hearing impairment with a hearing threshold of at least 25 decibel (dB) and, at follow-up, 1089 (15%) had dementia. In the total group, people with hearing impairment had a relative risk (RR) 1.04 (95% confidence interval (CI) 1.00-1.09) per 10 dB increase in hearing thresholds. For individuals younger than 85 years at follow-up the RR was 1.12 (95% CI 1.05-1.21). Associations between hearing impairment and Alzheimer dementia and non-Alzheimer dementia were similar. There was no association for individuals aged at least 85 years. Interpretation: We found a moderate association between objectively measured hearing impairment and dementia in the younger age group (<85 years). The findings of no association in the older age group (≥85 years) might be due to the competing risk of death. The present study adds to the literature showing that acquired hearing impairment is a risk for dementias over a period which is too long for reverse causation, and with thorough consideration of confounders. Further research is needed to investigate associations between the different aetiologies of hearing loss and dementia subtypes, and risk differences for sexes. Funding: The Norwegian National Centre for Ageing and Health with a grant from Health South-East.

Breastfeeding and treatment for multiple sclerosis. / Amming og behandling av multippel sklerose.

Monoclonal antibody therapy is effective for multiple sclerosis, and only small amounts of antibodies are transferred to breast milk. Even though the approved product descriptions advise against breastfeeding during medicinal treatment, several of the most effective MS drugs are compatible with breastfeeding.

Safety of breast feeding during rituximab treatment in multiple sclerosis.

BACKGROUND: There are limited data on the safety of breast feeding during rituximab therapy. Our objective is to determine exposure from breast feeding and biological effects of rituximab in breastfed infants. METHODS: In our case series of six mother-infant pairs, the nursing mothers with relapsing-remitting multiple sclerosis received rituximab during breast feeding. As part of clinical follow-up, six serial breast milk samples, and blood samples from both mothers and infants, were collected and analysed. RESULTS: The median average rituximab concentration (Cavg) in breast milk was 0.04 µg/mL and the estimated relative infant dose (RID) was 0.07%. The highest measured concentration of rituximab in the breast milk samples was 0.25 µg/mL, giving an estimated RID of 0.26%.All infant serum rituximab concentrations were below 0.01 µg/mL. The CD19 +B cell count values were within the 10th- 90th percentiles of reported normal ranges in healthy infants. CONCLUSIONS: We found minimal transfer of rituximab into breast milk and could not reliably detect levels of rituximab in infant serum. B cell counts in infants were unaffected.

Serum neurofilament as a predictor of 10-year grey matter atrophy and clinical disability in multiple sclerosis: a longitudinal study.

BACKGROUND: The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear. OBJECTIVE: Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years. METHODS: 85 patients, originally enrolled in a multicentre, randomised trial of ω-3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer. RESULTS: Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (ß=-0.399, p=0.040) and deep (ß=-0.556, p=0.010) GM volume, lower mean cortical thickness (ß=-0.581, p=0.010) and higher T2 lesion count (ß=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (ß=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression. CONCLUSION: Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions.

Safety and Clinical Efficacy of Mesenchymal Stem Cell Treatment in Traumatic Spinal Cord Injury, Multiple Sclerosis and Ischemic Stroke - A Systematic Review and Meta-Analysis.

Background: Mesenchymal stem cells (MSCs) is an attractive candidate in regenerative research and clinical trials have assessed their therapeutic potential in different neurological conditions with disparate etiologies. In this systematic review, we aimed to assess safety and clinical effect of MSC treatment in traumatic spinal cord injury (TSCI), multiple sclerosis (MS) and ischemic stroke (IS). Methods: A systematic search was performed 2021-12-10 in MEDLINE, EMBASE, Web of Science and Cochrane where clinical studies assessing MSC treatment in TSCI, MS or IS were included. Studies without control group were excluded for efficacy analysis, but included in the safety analysis. For efficacy, AIS score, EDSS score and mRS were used as clinical endpoints and assessed in a meta-analysis using the random effects model. Findings: Of 5,548 identified records, 54 studies were included. Twenty-six studies assessed MSC treatment in TSCI, 14 in MS and nine in IS, of which seven, seven and five studies were controlled, respectively. There were seven serious adverse events (SAEs), of which four were related to the surgical procedure and included one death due to complications following the implantation of MSCs. Three SAEs were considered directly related to the MSC treatment and all these had a transient course. In TSCI, a meta-analysis showed no difference in conversion from AIS A to C and a trend toward more patients treated with MSCs improving from AIS A to B as compared to controls (p = 0.05). A subgroup analysis performed per protocol, showed more MSC treated patients improving from AIS A to C in studies including patients within 8 weeks after injury (p = 0.04). In MS and IS, there were no significant differences in clinical outcomes between MSC treated patients and controls as measured by EDSS and mRS, respectively. Interpretation: MSC-treatment is safe in patients with TSCI, MS and IS, although surgical implantation of MSC led to one fatal outcome in TSCI. There was no clear clinical benefit of MSC treatment, but this is not necessarily a proof of inefficacy due to the low number of controlled studies. Future studies assessing efficacy of MSC treatment should aim to do this in randomized, controlled studies.

The Effect of Smoking on Long-term Gray Matter Atrophy and Clinical Disability in Patients with Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS). METHODS: We included 85 treatment-naive patients with RRMS with recent inflammatory disease activity who participated in a 10-year follow-up visit after a multicenter clinical trial of 24 months. Smoking status was decided for each patient by 2 separate definitions: by serum cotinine levels measured regularly for the first 2 years of the follow-up (during the clinical trial) and by retrospective patient self-reporting. At the 10-year follow-up visit, clinical tests were repeated, and brain atrophy measures were obtained from MRI using FreeSurfer. Differences in clinical and MRI measurements at the 10-year follow-up between smokers and nonsmokers were investigated by 2-sample t tests or Mann-Whitney tests and linear mixed-effect regression models. All analyses were conducted separately for each definition of smoking status. RESULTS: After 10 years, smoking (defined by serum cotinine levels) was associated with lower total white matter volume (ß = -21.74, p = 0.039) and higher logT2 lesion volume (ß = 0.22, p = 0.011). When defining smoking status by patient self-reporting, the repeated analyses found an additional association with lower deep gray matter volume (ß = -2.35, p = 0.049), and smoking was also associated with a higher score (higher walking impairment) on the log timed 25-foot walk test (ß = 0.050, p = 0.039) after 10 years and a larger decrease in paced auditory serial addition test (attention) scores (ß = -3.58, p = 0.029). DISCUSSION: Smoking was associated with brain atrophy and disability progression 10 years later in patients with RRMS. The findings imply that patients should be advised and offered aid in smoking cessation shortly after diagnosis, to prevent long-term disability progression.

Impact of previous disease-modifying treatment on safety and efficacy in patients with MS treated with AHSCT.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is a highly effective treatment for multiple sclerosis (MS). The impact of previous long-lasting disease-modifying treatments (DMT) for safety and efficacy of AHSCT is unknown. OBJECTIVE: To explore whether previous DMTs with long-lasting effects on the immune system (anti-CD20 therapy, alemtuzumab and cladribine) affect treatment-related complications, long-term outcome and risk of new MS disease activity in patients treated with AHSCT. METHODS: Retrospective observational study of 104 relapsing remitting patients with MS treated by AHSCT in Sweden and Norway from 2011 to 2021, grouped according to the last DMT used ≤6 months prior to AHSCT. The primary outcomes were early AHSCT-related complications (mortality, neutropenic fever and hospitalisation length), long-term complications (secondary autoimmunity) and proportion of patients with No Evidence of Disease Activity (NEDA-3 status): no new relapses, no MRI activity and no disease progression during the follow-up. RESULTS: The mean follow-up time was 39.5 months (range 1-95). Neutropenic fever was a common AHSCT-related complication affecting 69 (66%) patients. There was no treatment-related mortality. During the follow-up period, 20 patients (19%) were diagnosed with autoimmunity. Occurrence of neutropenic fever, hospitalisation length or secondary autoimmunity did not vary dependent on the last DMT used prior to AHSCT. A total of 84 patients (81%) achieved NEDA-3 status, including all patients (100%) using rituximab, alemtuzumab or cladribine before AHSCT. CONCLUSION: This study provides level 4 evidence that AHSCT in patients previously treated with alemtuzumab, cladribine or rituximab is safe and efficacious.

Relationship Between White Matter Lesions and Gray Matter Atrophy in Multiple Sclerosis: A Systematic Review.

BACKGROUND AND OBJECTIVES: There is currently no consensus about the extent of gray matter (GM) atrophy that can be attributed to secondary changes after white matter (WM) lesions or the temporal and spatial relationships between the 2 phenomena. Elucidating this interplay will broaden the understanding of the combined inflammatory and neurodegenerative pathophysiology of multiple sclerosis (MS), and separating atrophic changes due to primary and secondary neurodegenerative mechanisms will then be pivotal to properly evaluate treatment effects, especially if these treatments target the different processes individually. To untangle these complex pathologic mechanisms, this systematic review provides an essential first step: an objective and comprehensive overview of the existing in vivo knowledge of the relationship between brain WM lesions and GM atrophy in patients diagnosed with MS. The overall aim was to clarify the extent to which WM lesions are associated with both global and regional GM atrophy and how this may differ in the different disease subtypes. METHODS: We searched MEDLINE (through PubMed) and Embase for reports containing direct associations between brain GM and WM lesion measures obtained by conventional MRI sequences in patients with clinically isolated syndrome and MS. No restriction was applied for publication date. The quality and risk of bias in included studies were evaluated with the Quality Assessment Tool for observational cohort and cross-sectional studies (NIH, Bethesda, MA). Qualitative and descriptive analyses were performed. RESULTS: A total of 90 articles were included. WM lesion volumes were related mostly to global, cortical and deep GM volumes, and those significant associations were almost without exception negative, indicating that higher WM lesion volumes were associated with lower GM volumes or lower cortical thicknesses. The most consistent relationship between WM lesions and GM atrophy was seen in early (relapsing) disease and less so in progressive MS. DISCUSSION: The findings suggest that GM neurodegeneration is mostly secondary to damage in the WM during early disease stages while becoming more detached and dominated by other, possibly primary neurodegenerative disease mechanisms in progressive MS.

The effect of gadolinium-based contrast-agents on automated brain atrophy measurements by FreeSurfer in patients with multiple sclerosis.

OBJECTIVE: To determine whether reliable brain atrophy measures can be obtained from post-contrast 3D T1-weighted images in patients with multiple sclerosis (MS) using FreeSurfer. METHODS: Twenty-two patients with MS were included, in which 3D T1-weighted MR images were obtained during the same scanner visit, with the same acquisition protocol, before and after administration of gadolinium-based contrast agents (GBCAs). Two FreeSurfer versions (v.6.0.1 and v.7.1.1.) were applied to calculate grey matter (GM) and white matter (WM) volumes and global and regional cortical thickness. The consistency between measures obtained in pre- and post-contrast images was assessed by intra-class correlation coefficient (ICC), the difference was investigated by paired t-tests, and the mean percentage increase or decrease was calculated for total WM and GM matter volume, total deep GM and thalamus volume, and mean cortical thickness. RESULTS: Good to excellent reliability was found between all investigated measures, with ICC ranging from 0.926 to 0.996, all p values < 0.001. GM volumes and cortical thickness measurements were significantly higher in post-contrast images by 3.1 to 17.4%, while total WM volume decreased significantly by 1.7% (all p values < 0.001). CONCLUSION: The consistency between values obtained from pre- and post-contrast images was excellent, suggesting it may be possible to extract reliable brain atrophy measurements from T1-weighted images acquired after administration of GBCAs, using FreeSurfer. However, absolute values were systematically different between pre- and post-contrast images, meaning that such images should not be compared directly. Potential systematic effects, possibly dependent on GBCA dose or the delay time after contrast injection, should be investigated. TRIAL REGISTRATION: Clinical trials.gov. identifier: NCT00360906. KEY POINTS: • The influence of gadolinium-based contrast agents (GBCAs) on atrophy measurements is still largely unknown and challenges the use of a considerable source of historical and prospective real-world data. • In 22 patients with multiple sclerosis, the consistency between brain atrophy measurements obtained from pre- and post-contrast images was excellent, suggesting it may be possible to extract reliable atrophy measurements in T1-weighted images acquired after administration of GBCAs, using FreeSurfer. • Absolute values were systematically different between pre- and post-contrast images, meaning that such images should not be compared directly, and measurements extracted from certain regions (e.g., the temporal pole) should be interpreted with caution.