Validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in the Russian Population.

OBJECTIVE: Cognitive dysfunction is common in multiple sclerosis (MS). The Brief International Cognitive Assessment for MS (BICAMS) battery of tests has been suggested as a measure for the evaluation of the cognitive status of MS patients. This study aims to validate the BICAMS battery in the Russian population of MS patients. METHODS: Age- and sex-matched MS patients (n = 98) and healthy individuals (n = 86) were included in the study. Symbol Digit Modalities Test (SDMT), California Verbal Learning Test, 2nd edition (CVLT-II) and the Brief Visuospatial Memory Test - Revised (BVMT-R) were administered to all participants. The battery was readministered 1 month later to 44 MS patients to investigate the test-retest reliability. RESULTS: MS patients exhibited a significantly lower performance in testing with BICAMS than the control group in all three neuropsychological tests. Test-retest reliability was good for SDMT and CVLT-II (r = .82 and r = .85, respectively) and adequate for BVMT-R (r = .70). Based on the proposed criterion for impairment as z score below 1.5 SD the mean of the control group, we found that 34/98 (35%) of MS patients were found impaired at least in one cognitive domain. Patients with Expanded Disability Status Scale score ≥3.5 performed significantly worse than controls (SDMT, p < .0001; CVLT-II, p = .03; BVMT-R, p = .0004), while those with ≤3.0 scores did not. CONCLUSION: This study demonstrates that the BICAMS battery is a valid instrument to identify cognitive impairment in MS patients and it can be recommended for routine use in the Russian Federation.

COVID-19 Immunopathology and the Central Nervous System: Implication for Multiple Sclerosis and Other Autoimmune Diseases with Associated Demyelination.

In the frame of the coronavirus disease 2019 (COVID-19) pandemic, recent reports on SARS-CoV-2 potential neuroinvasion placed neurologists on increased alertness in order to assess early neurological manifestations and their potentially prognostic value for the COVID-19 disease. Moreover, the management of chronic neurological diseases, such as Multiple Sclerosis (MS), underwent guided modifications, such as an Extended Interval Dose (EID) of Disease-Modifying Treatment (DMT) administration, in order to minimize patients' exposure to the health system, thus reducing the risk of SARS-CoV-2 infection. In this review, we summarize existing evidence of key immune pathways that the SARS-CoV-2 modifies during COVID-19 and the relevant implication for MS and other autoimmune diseases with associated demyelination (such as Systemic lupus erythematosus and Antiphospholipid syndrome), including the context of potential neuroinvasion by SARS-Cov-2 and the alterations that DMT induces to the immune system. Moreover we hereby aim to provide an overview of the possible consequences that COVID-19 may carry for the Central Nervous System (CNS) in People with MS (PwMS) and other demyelinating diseases, which are likely to pose challenges for treating Neurologists with respect to the long-term disease management of these diseases.

Real-world study of efficacy, risk management and reasons for discontinuation of natalizumab for treatment of multiple sclerosis in Russia.

BACKGROUND: NTZ is approved in Russia for the treatment of highly active relapsing remitting multiple sclerosis and is reimbursed via federal budget program. However, no data about NTZ treatment in Russia and the effect of federal reimbursement have been performed so far. OBJECTIVE: To characterize the population of patients receiving natalizumab and assess the efficacy and risk-management plan (RMP) implementation of NTZ therapy in routine clinical practice in Russia. METHODS: We analyzed data for 334 patients, who received at least one infusion of NTZ. Relapse rate, MRI activity, NEDA-3 status after 2 years were assessed. Anti-JC virus antibodies status and RMP implementation were evaluated. Drop-out rate and reasons for therapy discontinuation were analyzed. RESULTS: Patients switched to natalizumab in Russia are mainly female (63%), with median EDSS score of 3.5 and high disease activity: 93% had at least 1 relapse and 58% had both T1Gd+ and new T2 lesion a year before therapy initiation. Introduction of federal reimbursement allowed patients with less relapses to start therapy with natalizumab. The only predictor of 6-month progression was EDSS score at the baseline of therapy (HR = 2.1375, 95%CI 1.0026-4.5570, p = 0.0492). 82% patients reached NEDA-3 at 24 month of therapy. 25% of patients discontinued NTZ for reasons: tolerability (14.5%), JCV antibody status (61%), and patient's decision (17%). RMP was implemented in only 36% patients. CONCLUSION: Natalizumab appeared to have high efficacy in Russian clinical practice. Federal reimbursement allowed less active patients to start natalizumab. More efforts should be done to improve RMP implementation.

Leptomeningeal Contrast Enhancement Is Associated with Disability Progression and Grey Matter Atrophy in Multiple Sclerosis.

Leptomeningeal contrast enhancement (LMCE) on magnetic resonance imaging (MRI) is a newly recognized possible biomarker in multiple sclerosis (MS), associated with MS progression and cortical atrophy. In this study, we aimed to assess the prevalence of LMCE foci and their impact on neurodegeneration and disability. Materials. 54 patients with MS were included in the study. LMCE were detected with a 3 Tesla scanner on postcontrast fluid-attenuated inversion-recovery (FLAIR) sequence. Expanded Disability Status Scale (EDSS) score, number of relapses during 5 years from MS onset, and number of contrast-enhancing lesions on T1 weighted MRI were counted. Results. LMCE was detected in 41% (22/54) of patients. LMCE-positive patients had longer disease duration (p = 0,0098) and higher EDSS score (p = 0,039), but not a higher relapse rate (p = 0,091). No association of LMCE with higher frequency of contrast-enhancing lesions on T1-weighted images was detected (p = 0,3842). Analysis of covariates, adjusted for age, sex, and disease duration, revealed a significant effect of LMCE on the cortex volume (p = 0.043, F = 2.529), the total grey matter volume (p = 0.043, F = 2.54), and total ventricular volume (p = 0.039, F = 2.605). Conclusions. LMCE was shown to be an independent and significant biomarker of grey matter atrophy and disability in MS.

Resilience and vulnerability are dose-dependently related to neonatal stressors in mice.

Early life experiences have been shown to adjust cognitive abilities, stress reactivity, fear responses and immune activity in adult mammals of many species. However, whereas severe stressors have been generally associated with the emergence of hypothalamic pituitary adreno-cortical (HPA)-mediated pathology, mild neonatal stressful experiences have been traditionally associated with 'positive' effects or resilience. External stressors stimulate the HPA axis to induce a corticosterone secretion in mouse dams, which, in turn is directly transmitted to the progeny through lactation. Such corticosteroid transfer may offer a unitary mechanism whereby early low corticosterone exposure may favor resilience in the offspring and high corticosterone increase vulnerability to pathology. In this study we further investigated this hypothesis by evaluating the long-term effects of a neonatal exposure to low (33 mg/l) and high (100 mg/l) doses of corticosterone during the first 10 days of life in outbred CD-1 mice through supplementation in the maternal drinking water. Offspring attentional set-shifting abilities, central neurotrophic regulation and levels of natural auto-antibodies (na-Abs) directed to serotonin (SERT) and dopamine (DAT) transporters were assessed in adulthood. While low levels of neonatal corticosterone improved adult cognitive abilities and increased na-Abs levels directed to SERT, high doses of neonatal corticosterone reduced hippocampal BDNF levels and na-Abs directed to DAT. These findings confirm and extend our previous findings, supporting the view that both adaptive plasticity and pathological outcomes in adulthood may depend on circulating neonatal corticosterone levels and that these effects follow a U-shaped profile.

Autoantibodies against opioid or glutamate receptors are associated with changes in morphine reward and physical dependence in mice.

BACKGROUND: Possible interactions between nervous and immune systems during opioid addiction remain elusive. Recombinant mu-delta opioid receptors (MDOR) and the glutamate receptor 1 (GluR1) subunit of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors are involved in acute and chronic effects of morphine. Elevated levels of autoantibodies (aAbs) to these receptors were demonstrated in heroin human addicts and in animal models. This study characterized the role of aAbs to these receptors in behavioral modulations recruited during opioid tolerance and sensitization. METHODS AND FINDINGS: Male CD-1 mice, immunized with either MDOR or GluR1 peptide fragments (80 microg intraperitoneal (i.p.)), were examined for spontaneous behavior and response to morphine (5 mg/kg i.p.). Spontaneous home-cage activity, novelty-induced self-grooming and morphine-induced hyperactivity were higher in GluR1 mice compared to Vehicle subjects, whereas MDOR immunization was associated with an increased morphine-induced conditioned place preference. In response to escalating doses of morphine (from 10 to 60 mg/kg i.p., twice daily) and naloxone-precipitated withdrawal (1 mg/kg subcutaneous), GluR1 mice exhibited a more marked stereotyped sniffing behavior and less body tremors compared to Vehicle subjects, whereas less sniffing and teeth chattering were found in MDOR mice. The expected downregulation of mu receptor binding sites, induced by chronic morphine in vehicle subjects, was completely absent following MDOR immunization. CONCLUSIONS: These findings indicate an altered response to morphine-related reinforcing and aversive effects in MDOR mice and altered coping with the environment in GluR1 mice. Circulating aAbs to specific neuroreceptors may alter the response to opiates and play a role as determinants of vulnerability to opiate addiction.

Specific changes in levels of autoantibodies to glutamate and opiate receptors induced by morphine administration in rats.

Several groups of brain receptors are involved in the mechanisms underlying the development of opiate addiction, but the interactions occurring between these neuroreceptors and the immune system, including potential autoimmune responses, remain poorly understood. We studied in rats the effects of repeated administration of different psychotropic drugs on serum levels of autoantibodies (aAbs) to the mu delta-opiate receptor (MDOR), as well as to the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) GluR1 and to the N-methyl-D-aspartate (NMDA) NR2 subunits of the glutamate receptor, as analyzed by ELISA. We found that repeated administration of morphine significantly elevated aAbs levels to MDOR and to the AMPA GluR1 subunit, but not to the NMDA NR2 subunit. In contrast, a similar regimen of a psychostimulant drug, such as D-amphetamine, or a commonly abused substance, such as nicotine, had no effect on these aAbs levels. A nonspecific elevating effect on aAbs to the brain structural protein S100B was observed for all drugs tested versus controls. These observations support the hypothesis that, following opiate administration, specific interactions between nervous and immune systems occur. Therefore, together with further investigations on their potential functional consequences, we propose a thorough exploration of aAbs to MDOR and to AMPA GluR1 subunit as early biomarkers signaling opiate addiction.