The ability to chronically monitor neuronal activity in the living brain is essential for understanding the organization and function of the nervous system. The genetically encoded green fluorescent ...protein-based calcium sensor GCaMP provides a powerful tool for detecting calcium transients in neuronal somata, processes, and synapses that are triggered by neuronal activities. Here we report the generation and characterization of transgenic mice that express improved GCaMPs in various neuronal subpopulations under the control of the Thy1 promoter. In vitro and in vivo studies show that calcium transients induced by spontaneous and stimulus-evoked neuronal activities can be readily detected at the level of individual cells and synapses in acute brain slices, as well as chronically in awake, behaving animals. These GCaMP transgenic mice allow investigation of activity patterns in defined neuronal populations in the living brain and will greatly facilitate dissecting complex structural and functional relationships of neural networks.
► Thy1-GCaMP2.2c and Thy1-GCaMP3 transgenic lines were generated ► Spontaneous and evoked calcium transients can be detected in acute brain slices ► Calcium transients can be detected in dendrites and spines in vivo ► Calcium transients can be detected in neuronal populations in vivo
Chen et al. generate transgenic mice expressing genetically encoded calcium sensors and demonstrate the utility of these mice in optically monitoring neuronal activity in vivo.
ObjectiveTo directly compare the efficacy of natalizumab and fingolimod in patients with active relapsing-remitting multiple sclerosis.MethodsThis phase 4, randomised, rater- and sponsor-blinded, ...prospective, parallel-group, clinic-based head-to-head study was conducted at 43 sites in nine countries. Patients were randomised (1:1) to intravenous natalizumab 300 mg every 4 weeks or oral fingolimod 0.5 mg once daily for ≤52 weeks. Enrolment-related early study termination precluded assessment of the primary endpoint (evolution of new on-treatment gadolinium-enhancing (Gd+) lesions to persistent black holes). Unplanned exploratory analyses of secondary endpoints evaluated the effects of treatment on the development of new T1 Gd+ lesions and new/newly enlarging T2 lesions, lesion volumes and relapse outcomes.ResultsThe intent-to-treat population comprised 108 patients (natalizumab, n=54; fingolimod, n=54); 63 completed ≥24 weeks of treatment. Due to the limited numbers of events and patients at risk, MRI and relapse outcomes were reported over up to 24 and 36 weeks, respectively. The mean number of new T1 Gd+ lesions was numerically lower with natalizumab than with fingolimod by 4 weeks; accumulation rates were 0.02 and 0.09 per week, respectively, over 24 weeks (p=0.004). The cumulative probability of developing ≥1 lesion at 24 weeks was 40.7% with natalizumab versus 58.0% with fingolimod (HR=0.60; 95% CI 0.31–1.16; p=0.126); the corresponding probabilities for ≥2 lesions were 11.5% vs 48.5% (HR=0.25; 95% CI 0.09–0.68; p=0.007). No significant between-group differences were observed for the other MRI outcomes at 24 weeks. The cumulative probability of relapse over follow-up was 1.9% with natalizumab versus 22.3% with fingolimod (HR=0.08; 95% CI 0.01–0.64; p=0.017). Adverse events were consistent with known safety profiles.ConclusionsThese results suggest that natalizumab is more efficacious than fingolimod in reducing multiple sclerosis relapses and T1 Gd+ lesion accumulation in patients with active disease.Trial registration numbersNCT02342704; EUCTR2013-004622-29-IT; Post-results.
Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy disease-modifying therapy (DMT) ...is of clinical relevance.
Evaluate long-term clinical outcomes in patients with MS who initiated treatment with either natalizumab or a BRACETD therapy (interferon beta, glatiramer acetate, teriflunomide, or dimethyl fumarate).
This retrospective analysis utilized data from MSBase to create a matched population allowing comparison of first-line natalizumab to first-line BRACETD.
This study included patients who initiated treatment either with natalizumab or a BRACETD DMT within 1 year of MS diagnosis and continued treatment for ⩾6 months, after which patients could switch DMTs or discontinue treatment. Patients had a minimum follow-up time of ⩾60 months from initiation. A subgroup analysis compared the natalizumab group to patients in the BRACETD group who escalated therapy after 6 months. Outcomes included unadjusted annualized relapse rates (ARRs), time-to-first relapse, time-to-first confirmed disability improvement (CDI), and time-to-first confirmed disability worsening (CDW).
After 1:1 propensity score matching, 355 BRACETD patients were matched to 355 natalizumab patients. Patients initiating natalizumab were less likely to experience a relapse over the duration of follow-up, with ARRs 95% confidence interval (CI) of 0.080 (0.070-0.092) for natalizumab patients and 0.191 (0.178-0.205) for BRACETD patients (
< 0.0001). A Cox regression model of time-to-first relapse showed a reduced risk of relapse for natalizumab patients hazard ratio (95% CI) of 0.52 (0.42-0.65);
< 0.001 and a more favorable time-to-first CDI. The risk of CDW was similar between groups. The subgroup analysis showed an increased relapse risk as well as a significantly higher risk of CDW for BRACETD patients.
Early initiation of natalizumab produced long-term benefits in relapse outcomes in comparison with BRACETD, regardless of a subsequent escalation in therapy.
Background:
Extended interval dosing of natalizumab is associated with significantly lower progressive multifocal leukoencephalopathy risk compared with every-4-week (Q4W) dosing in patients with ...relapsing-remitting multiple sclerosis. Previous studies have suggested that natalizumab effectiveness is maintained in patients who switch from Q4W to extended interval dosing but have been limited by a lack of well-matched patient cohorts.
Methods:
Tysabri Observational Program (TOP) data as of November 2019 were used to identify patients with relapsing-remitting multiple sclerosis treated with natalizumab Q4W and those with a single physician-indicated dosing change from Q4W to every-6-week (Q6W) dosing after ⩾1 year of Q4W treatment. Patients were propensity score matched at the time of the switch from Q4W to Q6W dosing. Clinical outcomes (annualized relapse rate and probability of remaining relapse free or free of 24-week confirmed disability worsening) and safety outcomes were assessed for the two cohorts.
Results:
This study included 219 pairs of propensity score–matched Q6W and Q4W patients. Annualized relapse rates were similar for Q6W (0.150) and Q4W (0.157) patients. The probability of remaining relapse free hazard ratio = 1.243 (95% confidence interval = 0.819–1.888); p = 0.307 and of remaining free of 24-week confirmed disability worsening hazard ratio = 0.786 (95% confidence interval = 0.284–2.176); p = 0.644 did not differ significantly between Q6W and Q4W patients. Summarized safety results for the matched Q6W and Q4W patients are also presented.
Conclusion:
These real-world findings in well-matched patient cohorts from TOP demonstrate that natalizumab effectiveness is maintained in patients who switch to Q6W dosing after ⩾1 year of Q4W dosing.
ClinicalTrials.gov identifier:
NCT00493298
ObjectiveSlowly expanding lesions (SELs), a subgroup of chronic white matter lesions that gradually expand over time, have been shown to predict disability accumulation in primary progressive ...multiple sclerosis (MS) disease. However, the relationships between SELs, acute lesion activity (ALA), overall chronic lesion activity (CLA) and disability progression are not well understood. In this study, we examined the ASCEND phase III clinical trial, which compared natalizumab with placebo in secondary progressive MS (SPMS).MethodsPatients with complete imaging datasets between baseline and week 108 (N=600) were analysed for SEL prevalence (the number and volume of SELs), disability progression, ALA (assessed by gadolinium-enhancing lesions and new T2-hyperintense lesions) and CLA (assessed by T1-hypointense lesion volume increase within baseline T2-non-enhancing lesions identified as SELs and non-SELs).ResultsCLA in both SELs and non-SELs was greater in patients with SPMS with confirmed disability progression than in those with no progression. In the complete absence of ALA at baseline and on study, SEL prevalence was significantly lower, while CLA within non-SELs remained associated with disability progression. Natalizumab decreased SEL prevalence and CLA in SELs and non-SELs compared with placebo.ConclusionsThis study shows that CLA in patients with SPMS is decreased but persists in the absence of ALA and is associated with disability progression, highlighting the need for therapeutics targeting all mechanisms of CLA, including smouldering inflammation and neurodegeneration.Trial registration numberNCT01416181.
Abstract Objectives Compare relapse clinical severity, post-relapse residual disability, and the probability of confirmed complete recovery from relapse between patients who relapsed during ...natalizumab ( n =183/627 29%) and placebo ( n =176/315 56%) treatments in the AFFIRM trial. Methods In this post-hoc analysis, relapse clinical severity and residual disability were defined by change in Expanded Disability Status Scale (EDSS) score occurring between pre-relapse and at-relapse assessment and between pre-relapse and post-relapse assessment, respectively. Patients were considered completely recovered from relapse when their post-relapse EDSS score was less than or equal to their pre-relapse EDSS score, and this was maintained for 12 or 24 weeks. Results At relapse, an increase in EDSS score of ≥0.5 points occurred in 71% of natalizumab and 84% of placebo patients ( P =0.0088); an increase of ≥1.0 point occurred in 49% of natalizumab and 61% of placebo patients ( P =0.0349) (mean increase in EDSS at relapse: natalizumab=0.77; placebo=1.09; P =0.0044). After relapse, residual disability of ≥0.5 EDSS points remained in 31% of natalizumab and 45% of placebo patients ( P =0.0136) (mean post-relapse residual EDSS increase: natalizumab=0.06; placebo=0.28; P =0.0170). In patients with an increase in EDSS of ≥0.5 or ≥1.0 during relapse, natalizumab increased the probability of 12-week confirmed complete recovery from relapse by 55% (hazard ratio HR=1.554; P =0.0161) and 67% (HR=1.673; P =0.0319) compared to placebo, respectively. Conclusions In AFFIRM, natalizumab treatment decreased the clinical severity of relapses and improved recovery from disability induced by relapses. These beneficial effects would limit the step-wise accumulation of disability.
...we did not exclude this patient from the primary endpoint analyses for two reasons: the prespecified statistical analysis plan made no allowances for patient exclusion, and a possible multiple ...sclerosis origin of the T2 lesions at week 48 could not be ruled out on the basis of the lesion characteristics. Because this patient contributed to analyses under both the primary and secondary estimands, we provide reanalysis of both results. The results of our analyses of these exploratory endpoints were presented at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis.2 These results show that there were no differences in MRI volumetric measures between the two dosing groups in NOVA and help provide a more complete understanding of the effectiveness of 6-week dosing of natalizumab for the treatment of patients with relapsing-remitting multiple sclerosis.
The hippocampus is one of only two regions in the adult brain where neurons are generated in significant numbers throughout the lifetime of the animal. Numerous studies have demonstrated that these ...adult-born neurons are essential for optimal cognitive function with unimpaired memory formation and retrieval. The extent to which adult-born neurons survive through an early “critical period” and become integrated into functional networks has been shown to depend on the richness of stimulation they receive during these formative stages. The dentate gyrus in the hippocampus – home of the adult-born neurons – receives extensive cholinergic innervation, and newly generated neurons in the adult hippocampus express substantial numbers of both major types of neuronal nicotinic acetylcholine receptors. Early studies indicated that nicotinic signaling may be important for the development of adult-born neurons: repeated exposure to nicotine impaired their long-term survival. Recent studies with mutant mice lacking either one of the two major nicotinic receptor subtypes demonstrate that receptor loss results in fewer adult-born neurons surviving the critical period and becoming integrated into neural networks. The key nicotinic receptor mediating the largest effects is one that has a high relative permeability to calcium. In view of this feature, it may not be surprising that excessive exposure to nicotine can have detrimental effects on survival and maturation of adult-born neurons in the dentate; these same receptors appear to be key. The results pose serious challenges for therapeutic strategies targeting an individual class of nicotinic receptors for global treatment in the recipient.
Previous estimates of risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis receiving natalizumab were stratified by three risk factors: anti-John Cunningham ...virus (JCV) antibodies in serum, previous immunosuppressant use, and treatment duration, which were estimated using population-based assumptions. We aimed to calculate PML risk estimates from patient-level risk-factor data and to stratify risk by concentrations of anti-JCV antibody in serum (anti-JCV antibody index).
Data on natalizumab-treated patients were pooled from four large, observational, open-label studies: STRATIFY-2, STRATA, TOP, and TYGRIS. Data were analysed with and without imputation for missing values of anti-JCV antibody status and previous immunosuppressant use. For anti-JCV antibody-positive patients in this pooled cohort, cumulative PML risk with or without previous immunosuppressant use was estimated using Kaplan-Meier analysis. Annual PML risks (per 12 natalizumab infusions) for patients without PML in the preceding year were estimated using conditional probability based on the life table method. For anti-JCV antibody-positive patients without previous immunosuppressant use, risk estimates were further stratified using a probability distribution for anti-JCV antibody index values, separately for patients with or without PML. Anti-JCV antibody index cutoffs were selected via sensitivity and specificity assessments for identifying PML cases in an index cohort.
156 (<1%) of 37 249 patients in the pooled cohort had PML. We imputed missing values on anti-JCV antibody status (3912 patients) and on previous immunosuppresant use (544 patients) using a multiple imputation method. For anti-JCV antibody-negative patients (n=13 996), estimated PML risk was less than 0·07 per 1000 patients (95% CI 0·00–0·40). In anti-JCV antibody-positive patients (n=21 696), estimated cumulative PML probability over 6 years (72 infusions of natalizumab) was 2·7% (95% CI 1·8–4·0) in patients with previous immunosuppressant use and 1·7% (1·4–2·1) in those without. In patients without previous immunosuppressant use (n=18 616), estimated annual PML risks per 1000 patients, conditional on having no PML before that year, ranged from 0·01 (0·00–0·03) in year 1 (1–12 infusions) to 0·6 (0·0–1·5) in year 6 (61–72 infusions) for people with an index of 0·9 or less; from 0·1 (0·0–0·2) in year 1 to 3·0 (0·2–5·8) in year 6 for those with an index of more than 0·9 up to and including 1·5; and from 0·2 (0·0–0·5) in year 1 to 10·0 (5·6–14·4) in year 6 for those with an index of more than 1·5.
Our risk estimates calculated from patient-level clinical data allow individualised annual prediction of risk of PML in patients receiving natalizumab for multiple sclerosis, supporting yearly benefit–risk re-evaluation in clinical practice. Further, our estimates are generally consistent with previously calculated estimates. Incorporating anti-JCV antibody index allows further risk stratification for anti-JCV antibody-positive patients who have not previously taken immunosuppressants.
Biogen.
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