No treatments exist for apathy in people with frontotemporal dementia. Previously, in a randomised double-blind, placebo-controlled, dose-finding study, intranasal oxytocin administration in people with frontotemporal dementia improved apathy ratings on the Neuropsychiatric Inventory over 1 week and, in a randomised, double-blind, placebo-controlled, crossover study, a single dose of 72 IU oxytocin increased blood-oxygen-level-dependent signal in limbic brain regions. We aimed to determine whether longer treatment with oxytocin improves apathy in people with frontotemporal dementia. We conducted a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b trial, enrolling participants from 11 expert frontotemporal dementia outpatient clinics across Canada and the USA. People aged 30-80 years with a diagnosis of probable frontotemporal dementia, a Neuropsychiatric Inventory apathy score of 2 or higher, a study partner who interacted with them for at least 3 h per day, and stable cognitive and behavioural medications for 30 days were eligible for inclusion. In stage 1, participants were randomly assigned (1:1:1:1:1:1) to one of three dose schedules (every day, every other day, and every third day) of 72 IU intranasal oxytocin or placebo and to the order they would received the intervention in the crossover; intranasal oxytocin or placebo were administered twice daily for 6 weeks, with a 6-week washout and then crossover to the other intervention. In stage 2, new participants were randomised (1:1) to the dose that had been determined as optimal in stage 1 or to placebo, with crossover as in stage 1. Randomisation used variable block sizes and was stratified by participant sex and Clinical Dementia Rating severity score. All kits of investigational product were identical and produced centrally, and all local teams, study staff, and participants were masked to treatment allocation and order. The primary outcome was difference in the change in Neuropsychiatric Inventory apathy scores for oxytocin versus placebo periods in the per-protocol population after 6 weeks of treatment. Safety was assessed at each visit via electrocardiogram, blood work, and collection of data on adverse events. This trial is registered at ClinicalTrials.gov (NCT03260920). Between Jan 31, 2018, and Dec 11, 2020, 70 patients were screened for stage 1 and 60 (86%) were enrolled. 45 (75%) completed both treatment periods of stage 1. 72 IU oxytocin every third day was the optimal dose schedule from stage 1 based on its Bayesian posterior probability (Pr(Best)=0·478). Between June 28, 2021, and Jan 31, 2023, 42 patients were screened for stage 2, and 34 (81%) were enrolled. 28 (82%) completed both treatment periods in stage 2. 38 (40%) of 94 participants were female and 56 (60%) were male (mean age 65·9 years, SD 8·2) Treatment with oxytocin every third day resulted in an improved Neuropsychiatric Inventory apathy score, with an estimated -1·32 points (95% CI -2·43 to -0·21) relative to placebo (one sided p=0·010). Two adverse events were reported in at least 5% of participants: upper respiratory tract infection (five [6%] of 78 participants on placebo and three [5%] on every third day at all doses of oxytocin) and headache (two [3%] participants on placebo, one [7%] of 15 participants on oxytocin every day, and two [4%] of 55 participants on oxytocin every third day). No adverse events were attributed to oxytocin treatment. Intranasal oxytocin given every third day was well tolerated and was associated with a small reduction in apathy in patients with frontotemporal dementia. Future trials might investigate intermittent dosing of more potent formulations than in this study, to establish whether larger effects are possible. Canadian Institutes of Health Research and Weston Foundation.

Given burdensome side-effects and long latency for efficacy with conventional agents, there is a continued need for generalised myasthenia gravis treatments that are safe and provide consistently sustained, long-term disease control. Nipocalimab, a neonatal Fc receptor blocker, was associated with dose-dependent reductions in total IgG and anti-acetylcholine receptor (AChR) antibodies and clinically meaningful improvements in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale in patients with generalised myasthenia gravis in a phase 2 study. We aimed to assess the safety and efficacy of nipocalimab in a phase 3 study. Vivacity-MG3 was a phase 3, randomised, double-blind, placebo-controlled, phase 3 study conducted at 81 outpatient centres with expertise in myasthenia gravis in 17 countries in Asia-Pacific, Europe, and North America. Adults (aged ≥18 years) with generalised myasthenia gravis inadequately controlled with standard-of-care therapy (MG-ADL score ≥6) were randomly assigned (1:1) to either nipocalimab (30 mg/kg loading dose then 15 mg/kg every 2 weeks for maintenance dosing) or placebo infusions every 2 weeks, added to standard-of-care therapy in both groups, for 24 weeks. Randomisation was stratified by antibody status, day 1 MG-ADL total score, and region. The sponsor, investigators, clinical raters, and participants were masked to treatment assignment. The primary endpoint was the difference between nipocalimab and placebo based on least-squares mean change from baseline in MG-ADL total score averaged over weeks 22, 23, and 24 in the intention-to-treat population of patients who were antibody-positive (for AChR, anti-muscle-specific tyrosine kinase [MuSK], or anti-low-density lipoprotein receptor-related protein 4 [LRP4]). Adverse events were assessed in patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT04951622; the double-blind phase is completed and an open-label extension phase is ongoing. Between July 15, 2021, and Nov 17, 2023, 199 patients were enrolled, and 196 patients received study drug (98 in the nipocalimab group and 98 in the placebo group); of these, 153 (77 in the nipocalimab group and 76 in the placebo group) were antibody-positive. The least-squares mean change in MG-ADL score from baseline to weeks 22, 23, and 24 was -4·70 (SE 0·329) in the nipocalimab group versus -3·25 (0·335) in the placebo group (difference -1·45 [95% CI -2·38 to -0·52]; p=0·0024). The incidence of adverse events was similar between groups (82 [84%] of 98 in both the nipocalimab and placebo groups), including infections (42 [43%] of 98 in the nipocalimab group and placebo group) and headache (14 [14%] of 98 in the nipocalimab group and 17 [17%] of 98 in the placebo group). Serious adverse events were reported for nine (9%) of 98 patients in the nipocalimab group and 14 (14%) of 98 patients in the placebo group, three of which had a fatal outcome (nipocalimab: myasthenic crisis; placebo: cardiac arrest and myocardial infarction). Results from the completed double-blind phase of Vivacity-MG3 support the role of nipocalimab, added to standard-of-care therapies, as a safe treatment for sustained disease control over 6 months for a broad population of patients with generalised myasthenia gravis who are antibody-positive. The ongoing open-label extension phase should provide longer term sustained safety and efficacy data with nipocalimab. Janssen Research & Development, LLC, a Johnson & Johnson company.

Autosomal dominant mutations in the gene encoding the DNA and RNA binding protein FUS are a cause of amyotrophic lateral sclerosis (ALS), and about 0·3-0·9% of patients with ALS are FUS mutation carriers. FUS-mutation-associated ALS (FUS-ALS) is characterised by early onset and rapid progression, compared with other forms of ALS. However, different pathogenic mutations in FUS can result in markedly different age at symptom onset and rate of disease progression. Most FUS mutations disrupt its nuclear localisation, leading to its cytoplasmic accumulation in the CNS. FUS also forms inclusions in around 5% of patients with the related neurodegenerative condition frontotemporal dementia. However, there are key differences between the two diseases at the genetic and neuropathological level, which suggest distinct pathogenic processes. Experimental models have uncovered potential pathogenic mechanisms in FUS-ALS and informed therapeutic strategies that are currently in development, including the silencing of FUS expression using an intrathecally administered antisense oligonucleotide.

The age-specific incidence of traumatic brain injury in older adults is rising in high-income countries, mainly due to an increase in the incidence of falls. The severity of traumatic brain injury in older adults can be underestimated because of a delay in the development of mass effect and symptoms of intracranial haemorrhage. Management and rehabilitation in older adults must consider comorbidities and frailty, the treatment of pre-existing disorders, the reduced potential for recovery, the likelihood of cognitive decline, and the avoidance of future falls. Older age is associated with worse outcomes after traumatic brain injury, but premorbid health is an important predictor and good outcomes are achievable. Although prognostication is uncertain, unsubstantiated nihilism (eg, early withdrawal decisions from the assumption that old age necessarily leads to poor outcomes) should be avoided. The absence of management recommendations for older adults highlights the need for stronger evidence to enhance prognostication. In the meantime, decision making should be multidisciplinary, transparent, personalised, and inclusive of patients and relatives.