Propionic acid promotes neurite recovery in damaged multiple sclerosis neurons.

Neurodegeneration in the autoimmune disease multiple sclerosis still poses a major therapeutic challenge. Effective drugs that target the inflammation can only partially reduce accumulation of neurological deficits and conversion to progressive disease forms. Diet and the associated gut microbiome are currently being discussed as crucial environmental risk factors that determine disease onset and subsequent progression. In people with multiple sclerosis, supplementation of the short-chain fatty acid propionic acid, as a microbial metabolite derived from the fermentation of a high-fiber diet, has previously been shown to regulate inflammation accompanied by neuroprotective properties. We set out to determine whether the neuroprotective impact of propionic acid is a direct mode of action of short-chain fatty acids on CNS neurons. We analysed neurite recovery in the presence of the short-chain fatty acid propionic acid and butyric acid in a reverse-translational disease-in-a-dish model of human-induced primary neurons differentiated from people with multiple sclerosis-derived induced pluripotent stem cells. We found that recovery of damaged neurites is induced by propionic acid and butyric acid. We could also show that administration of butyric acid is able to enhance propionic acid-associated neurite recovery. Whole-cell proteome analysis of induced primary neurons following recovery in the presence of propionic acid revealed abundant changes of protein groups that are associated with the chromatin assembly, translational, and metabolic processes. We further present evidence that these alterations in the chromatin assembly were associated with inhibition of histone deacetylase class I/II following both propionic acid and butyric acid treatment, mediated by free fatty acid receptor signalling. While neurite recovery in the presence of propionic acid is promoted by activation of the anti-oxidative response, administration of butyric acid increases neuronal ATP synthesis in people with multiple sclerosis-specific induced primary neurons.

Early postpartum treatment strategies and early postpartum relapses in women with active multiple sclerosis.

BACKGROUND: Relapse risk after delivery is increased in women with active multiple sclerosis (MS), the best strategy to reduce it is unknown. We aimed to assess the association of four different postpartum strategies with relapses during the first 6 months post partum. METHODS: This cohort study includes data prospectively collected through structured telephone interviews from the German Multiple Sclerosis and Pregnancy Registry. Pregnancies with active MS (fingolimod or natalizumab treatment OR relapse within 1 year before pregnancy) and postpartum follow-up of ≥6 months were included. We compared four strategies: (1) intention to breastfeed exclusively without disease-modifying therapy (DMT) (exclusive breast feeding ≥2 months or switching to non-exclusive/weaning within 2 weeks after a relapse during the first 2 months), (2) early treatment with natalizumab/fingolimod and (3) other DMT initiated within 6 weeks post partum before a relapse. If women did not or only partially breastfed, or started DMT≤6 weeks after delivery after a relapse or later, we assumed (4) no-DMT-no-exclusive- breastfeeding-strategy. Main outcome was time to postpartum MS relapses. RESULTS: In 867 women with 911 pregnancies, most (n=416) intended to breastfeed exclusively or had no-DMT-no-exclusive-breastfeeding-strategy (n=290); fewer started fingolimod (n=38), natalizumab (n=74) or another DMT (n=93) early. Recurrent time-to-event analysis showed a statistically significant reduction in relapse hazard only with the natalizumab/fingolimod-strategy as of months 3-4 post partum compared with intention-to-breastfeed-exclusively-strategy. The very early relapse risk was highest in no-DMT-no-exclusive-breastfeeding-strategy. CONCLUSION: In active MS, an early postpartum treatment strategy should be determined well before delivery. Natalizumab/fingolimod-strategy reduced postpartum relapse hazard from month 3, but none diminished the early postpartum relapse hazard.

Multiple Sclerosis Disease Activity and Disability Following Cessation of Fingolimod for Pregnancy.

BACKGROUND AND OBJECTIVE: Discontinuation of fingolimod ≥2 months before pregnancy is recommended to minimize potential teratogenicity. The magnitude of MS pregnancy relapse risk, particularly severe relapses, after fingolimod cessation is unclear, as is whether this risk is reduced by pregnancy or modifiable factors. METHODS: Pregnancies who stopped fingolimod treatment within 1 year before or during pregnancy were identified from the German MS and Pregnancy Registry. Data were collected through structured telephone-administered questionnaires and neurologists' notes. Severe relapses were defined as a ≥2.0 increase in Expanded Disability Status Scale (EDSS) or new or worsening relapse-related ambulatory impairment. Women who continued to meet this definition 1 year postpartum were classified as reaching the Severe Relapse Disability Composite Score (SRDCS). Multivariable models accounting for measures of disease severity and repeated events were used. RESULTS: Of the 213 pregnancies among 201 women (mean age at pregnancy onset 32 years) identified, 56.81% (n = 121) discontinued fingolimod after conception. Relapses during pregnancy (31.46%) and the postpartum year (44.60%) were common. Nine pregnancies had a severe relapse during pregnancy and additional 3 during the postpartum year. One year postpartum, 11 of these (6.32% of n = 174 with complete EDSS information) reached the SRDCS. Adjusted relapse rates during pregnancy were slightly higher compared with the year before pregnancy (relapse rate ratio = 1.24, 95% CI 0.91-1.68). Neither exclusive breastfeeding nor resuming fingolimod within 4 weeks of delivery were associated with a reduced risk of postpartum relapses. Most pregnancies relapsed during the first 3 months postpartum (n = 55/204, 26.96%). DISCUSSION: Relapses during pregnancy after fingolimod cessation are common. Approximately 6% of women will retain clinically meaningful disability from these pregnancy-related, fingolimod cessation relapses 1 year postpartum. This information should be shared with women on fingolimod desiring pregnancy, and optimizing MS treatment with nonteratogenic approaches should be discussed.

Evaluation of the non-auditory neurocognitive test MoCA-HI for hearing-impaired.

Background: Since hearing loss and cognitive decline often co-occur among older adults, a cognitive screening test suitable for hearing-impaired people is of high clinical relevance. We report the first evaluation of a German language version of the Montreal Cognitive Assessment-Hearing Impaired version (MoCA-HI). Objective: The aim of the present study was to compare cognitively healthy participants with and without hearing loss, to examine the impact of age, sex, educational level and degree of hearing impairment on the German MoCA-HI performance, and to develop normative data. Material and methods: The German MoCA-HI was tested in 94 participants with normal or mild hearing impairment (group 1: 4PTA ≤ 40 dB on the better hearing ear) and 81 participants with moderate to profound hearing loss (group 2: 4PTA > 40 dB on the better hearing ear). Additionally, all participants performed the standard MoCA (version 8.2). Results: No significant group difference between group 1 and 2 was found in the MoCA-HI total score (p = 0.05). In contrast, group 1 performed significantly better than group 2 on the standard MoCA (p < 0.001). There was no difference between the MoCA and the MoCA-HI performance in group 1 (p = 0.12), whereas individuals of group 2 performed significantly better on the MoCA-HI than on the standard MoCA (p < 0.001). Test-retest reliability of the MoCA-HI was high (p < 0.001). Higher age (p < 0.001), male sex (p = 0.009) and lower education (p < 0.001) were associated with a lower overall MoCA-HI score. Based on the demographic data normative data were developed by a regression-based approach. Conclusion: The MoCA-HI is a cognitive screening test which is suitable for people with hearing impairment.

Multiple Sclerosis Disease Activity and Disability Following Discontinuation of Natalizumab for Pregnancy.

Importance: The magnitude of risk of pregnancy-related multiple sclerosis relapses, particularly severe relapses, following natalizumab cessation is unclear, as is whether this risk is reduced by pregnancy or other modifiable factors. Objective: To determine the association of early natalizumab withdrawal before or during pregnancy with risk of severe relapses and relapse-related disability. Design, Setting, and Participants: This prospective cohort study used data from the German Multiple Sclerosis and Pregnancy Registry, which enrolled participants between November 2006 and February 2018. Data were collected through structured telephone-administered questionnaires and review of neurologists' notes. Registry patients who stopped natalizumab treatment within the 2 years before or in the first trimester of pregnancy were included in this analysis. Data were analyzed between January and November 2021. Exposures: Cessation of natalizumab before pregnancy or until the first trimester. Main Outcomes and Measures: Severe and significant relapse-related disability was defined as at least a 2.0-point increase on the expanded disability status scale or new or worsening relapse-related ambulatory impairment. Multivariable models accounting for measures of disease severity and repeated events were used. Results: The cohort comprised 255 women with 274 pregnancies (mean [SD] age at pregnancy onset, 31.25 [4.27] years) who stopped natalizumab before pregnancy (n = 85; median time before last menstrual period, 14.29 weeks [IQR, 3.14-42.43 weeks]) or in the first trimester (n = 189). During pregnancy and the postpartum year, relapses were reported in 183 pregnancies (66.78%), severe relapses in 44 pregnancies (16.05%), and potentially life-threatening relapses in 3 pregnancies (1.10%). One year post partum, significant relapse-related disability was accrued in 29 pregnancies (10.58%). Relapses during pregnancy (n = 109; 39.78%) and in the postpartum period (n = 135; 49.27%) were common. Pregnancy (as a time-dependent covariate) was not associated with a reduced relapse risk (adjusted HR, 0.90; 95% CI, 0.64-1.27). Neither exclusive breastfeeding (adjusted HR, 1.34; 95% CI, 0.86-2.10) nor restarting natalizumab within 4 weeks post partum (adjusted HR, 1.06; 95% CI, 0.48-2.36) were associated with a reduced risk of early postpartum relapses 6 months after delivery. However, the relapse rate ratio during 12 months post partum was lower (0.49; 95% CI, 0.28-0.86) when natalizumab was restarted in the first 4 weeks after birth. Conclusions and Relevance: This cohort study's finding suggest that 10% of women may retain clinically meaningful disability from pregnancy-related natalizumab cessation relapses 1 year post partum. This information should be shared with women on natalizumab who desire pregnancy to weigh the high risk of pregnancy-related relapses and disability to the partly uncertain risks of continuing natalizumab throughout pregnancy or switching to depleting agents before conception.