1These authors contributed equally to this study.Abbreviations used: AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionate; BDNF, brain-derived neurotrophic factor; CMS, chronic mild stress; NAc, nucleus accumbens; PFC, prefrontal cortex; VTA, ventral tegmental area. AbstractExposure to chronic mild stress (CMS) is known to induce anhedonia in adult animals, and is associated with induction of depression in humans. However, the behavioral effects of CMS in young animals have not yet been characterized, and little is known about the long-term neurochemical effects of CMS in either young or adult animals. Here, we found that CMS induces anhedonia in adult but not in young animals, as measured by a set of behavioral paradigms. Furthermore, while CMS decreased neurogenesis and levels of brainderived neurotrophic factor (BDNF) in the hippocampus of adult animals, it increased these parameters in young animals. We also found that CMS altered a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor GluR1 subunit levels in the hippocampus and the nucleus accumbens of adult, but not young animals. Finally, no significant differences were observed between the effects of CMS on circadian corticosterone levels in the different age groups. The substantially different neurochemical effects chronic stress exerts in young and adult animals may explain the behavioral resilience to such stress young animals possess.

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Background and purpose Although the COVID‐19 vaccines are currently recommended for people with multiple sclerosis (MS), the fact that they were not specifically tested in people with MS raises uncertainty regarding their safety in this population. The purpose of this study was to report real‐life safety data of the BNT162b2 COVID‐19 vaccine in a cohort of MS patients. Methods An anonymous survey was distributed to 425 MS patients. Participants were asked general demographic and disease‐related questions and specific questions regarding the safety profile of the COVID‐19 vaccine. Results Of the 425 MS patients, 262 completed the questionnaire. The median (range) participant age was 42 (22–79) years, 199 participants were women (75.9%), and 66 participants (25.2%) had associated comorbidities. A total of 198 participants (75.6%) were treated with disease‐modifying therapies. In all, 239 participants (91.2% of the responders) had received the BNT162b2 COVID‐19 vaccine. Of these, 182 (76.1%) were aged <55 years, and 57 (23.9%) were aged >55 years. Adverse events were reported by 136 participants (56.9%; 52.5% of those aged <55 years and 40.3% of those aged >55 years; p = 0.1517) and 36 participants (15.1%) reported new or worsening neurological symptoms following the vaccination, the most frequent being sensory disturbances (21 participants, 58.3%). Most symptoms occurred within the first 24 h after vaccination and resolved within 3 days. A total of 28 participants (77.8%) did not require any medication to treat their symptoms. Conclusions This survey indicates an overall favorable safety profile of the BNT162b2 vaccine in people with MS. These data should be confirmed in further prospective, large‐scale studies.

IMPORTANCE Recent studies suggest that maintenance intravenous immunoglobulin (IVIG) may be an effective treatment to prevent relapses in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD); however, most of these studies had pediatric cohorts, and few studies have evaluated IVIG in adult patients.OBJECTIVE To determine the association of maintenance IVIG with the prevention of disease relapse in a large adult cohort of patients with MOGAD. DESIGN, SETTING, AND PARTICIPANTSThis was a retrospective cohort study conducted from January 1, 2010, to October 31, 2021. Patients were recruited from 14 hospitals in 9 countries and were included in the analysis if they (1) had a history of 1 or more central nervous system demyelinating attacks consistent with MOGAD, (2) had MOG-IgG seropositivity tested by cell-based assay, and (3) were age 18 years or older when starting IVIG treatment. These patients were retrospectively evaluated for a history of maintenance IVIG treatment. EXPOSURES Maintenance IVIG.MAIN OUTCOMES AND MEASURES Relapse rates while receiving maintenance IVIG compared with before initiation of therapy. RESULTSOf the 876 adult patients initially identified with MOGAD, 59 (median [range] age, 36 [18-69] years; 33 women [56%]) were treated with maintenance IVIG. IVIG was initiated as first-line immunotherapy in 15 patients (25%) and as second-line therapy in 37 patients (63%) owing to failure of prior immunotherapy and in 7 patients (12%) owing to intolerance to prior immunotherapy. The median (range) annualized relapse rate before IVIG treatment was 1.4 (0-6.1), compared with a median (range) annualized relapse rate while receiving IVIG of 0 (0-3) (t 108 = 7.14; P < .001). Twenty patients (34%) had at least 1 relapse while receiving IVIG with a median (range) time to first relapse of 1 (0.03-4.8) years, and 17 patients (29%) were treated with concomitant maintenance immunotherapy. Only 5 of 29 patients (17%) who received 1 g/kg of IVIG every 4 weeks or more experienced disease relapse compared with 15 of 30 patients (50%) treated with lower or less frequent dosing (hazard ratio, 3.31; 95% CI, 1.19-9.09; P = .02). At final follow-up, 52 patients (88%) were still receiving maintenance IVIG with a median (range) duration of 1.7 (0.5-9.9) years of therapy. Seven of 59 patients (12%) discontinued IVIG therapy: 4 (57%) for inefficacy, 2 (29%) for adverse effects, and 1 (14%) for a trial not receiving therapy after a period of disease inactivity.CONCLUSIONS AND RELEVANCE Results of this retrospective, multicenter, cohort study of adult patients with MOGAD suggest that maintenance IVIG was associated with a reduction in disease relapse. Less frequent and lower dosing of IVIG may be associated with treatment failure. Future prospective randomized clinical trials are warranted to confirm these findings.

Among patients with Parkinson's disease (PD), a wide range of non-motor symptoms (NMS) are evident. We assessed markers of NMS and explored their behavioral correlates with the tremor-dominant (TD) and postural instability gait difficulty (PIGD) subtypes. 110 non-demented patients with PD were evaluated and stratified into the PIGD and TD subtypes and, using stricter criteria, into predominant subgroups: p-PIGD (n = 31) and p-TD (n = 32). Non-motor signs that were assessed included cognitive function (pen and paper and a computerized battery), autonomic function (NMSQest and SCOPA-AUT), mood, and sleep. Health-related quality of life was evaluated using the PDQ-39. The p-PIGD subgroup had a higher score on the NMSQest (p = 0.033) and a higher score (i.e., worse) on the PDQ-39 (p-PIGD: 26.28 ± 12.47; p-TD: 16.93 ± 12.22; p = 0.004), compared to the p-TD subgroup, while these measures did not differ in the larger PIGD and TD group. The p-PIGD subgroup used more sleep medications compared to the p-TD subgroup (1.0 ± 1.39 vs. 0.41 ± 0.94, p = 0.05, respectively). Most cognitive scores were similar in both subgroups; however, the visuospatial components of the Montreal Cognitive Assessment and the computerized catch game were significantly worse among the p-PIGD subgroup. Mild associations were found between certain non-motor symptoms, but not cognitive function, and the PIGD score. Non-demented patients from the PIGD subtype experience more non-motor symptoms and poorer quality of life compared to the TD subtype. These findings suggest that the clinical management of non-motor and motor symptoms in patients with PD may be enhanced by a personalized approach.

Although the COVID-19 vaccines are currently recommended for people with myasthenia gravis (MG), there is no data regarding the safety of the vaccines in this population. In order to investigate the real-life safety data of the BNT162b2 COVID-19 vaccine in people with MG, an anonymous survey was distributed to 142 MG patients. Fifty-six MG patients completed the questionnaire. The median age was 53 years (range 23-83 years); 35 (62.5%) were males, and 25 (44.6%) had associated comorbidities. Thirty-seven participants (66.1%) were treated with immunotherapies. Fifty-five participants (98.2% of the responders) received the BNT162b2 COVID-19 vaccine. Of these, 32 (58.2%) were < 55 years old, and 23 (41.8%) were > 55 years old. Adverse events were more common in patients younger than 55 years old (46.9% Vs. 17.4%; p=0.0428). Eight participants (14.5%) reported worsening neurological symptoms following the vaccination. Three of those who reported worsening of neurological symptoms (37.5%) required additional treatment. Most events occurred within the first few days after vaccination and resolved within a few weeks. This survey indicates an overall favorable safety and tolerability profile of the BNT162b2 vaccine in people with MG. Additional prospective, large-scale studies are warranted to confirm these findings.

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ObjectiveTo describe the WFS1 c.1672C>T; p.R558C missense variant, found in 1.34% of Ashkenazi Jews, that has a relatively mild phenotype and to use computational normal mode analysis (NMA) to explain the genotype-phenotype relationship.MethodsThe clinical, laboratory, and genetic features of 8 homozygotes were collected. A model of the wolframin protein was constructed, and NMA was used to simulate the effect of the variant on protein thermodynamics.ResultsMean age at Wolfram syndrome (WS) diagnosis among homozygotes was 30 years; diabetes (7/8) was diagnosed at mean age 19 years (15–21 years), and bilateral optic atrophy (with MRI evidence of optic/chiasm atrophy) (6/8) at mean age 29 years (15–48 years). The oldest patient (62 years) also had gait difficulties, memory problems, parietal and cerebellar atrophy, and white matter hyperintense lesions. All retained functional vision with independent ambulation and self-care; none had diabetes insipidus or hearing loss. The p.R558C variant caused less impairment of protein entropy than WFS1 variants associated with a more severe phenotype.ConclusionsThe p.R558C variant causes a milder, late-onset phenotype of WS. We report a structural model of wolframin protein based on empirical functional studies and use NMA modeling to show a genotype-phenotype correlation across all homozygotes. Clinicians should be alert to this condition in patients with juvenile diabetes and patients of any age with a combination of diabetes and optic atrophy. Computational NMA has potential benefit for prediction of the genotype-phenotype relationship.