Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer's disease astrocytes.

Abnormalities in cellular metabolism are seen early in Alzheimer's disease (AD). Astrocyte support for neuronal function has a high metabolic demand, and astrocyte glucose metabolism plays a key role in encoding memory. This indicates that astrocyte metabolic dysfunction might be an early event in the development of AD. In this paper we interrogate glycolytic and mitochondrial functional changes and mitochondrial structural alterations in patients' astrocytes derived with a highly efficient direct conversion protocol. In astrocytes derived from patients with sporadic (sAD) and familial AD (fAD) we identified reductions in extracellular lactate, total cellular ATP and an increase in mitochondrial reactive oxygen species. sAD and fAD astrocytes displayed significant reductions in mitochondrial spare respiratory capacity, have altered mitochondrial membrane potential and a stressed mitochondrial network. A reduction in glycolytic reserve and glycolytic capacity is seen. Interestingly, glycolytic reserve, mitochondrial spare respiratory capacity and extracellular lactate levels correlated positively with neuropsychological tests of episodic memory affected early in AD. We identified a deficit in the glycolytic enzyme hexokinase 1 (HK1), and correcting this deficit improved the metabolic phenotype in sAD not fAD astrocytes. Importantly, the amount of HK1 at the mitochondria was shown to be reduced in sAD astrocytes, and not in fAD astrocytes. Overexpression of HK1 in sAD astrocytes increases mitochondrial HK1 levels. In fAD astrocytes HK1 levels were unaltered at the mitochondria after overexpression. This study highlights a clear metabolic deficit in AD patient-derived astrocytes and indicates how HK1, with its roles in both oxidative phosphorylation and glycolysis, contributes to this.

New developments in the diagnosis and management of motor neuron disease.

INTRODUCTION: Motor neuron disease (MND) is a devastating neurodegenerative disease characterized by progressive muscle weakness. SOURCES OF DATA: PubMed, MEDLINE, and Cochrane databases were searched for articles to March 2024. Searches involved the terms 'motor neuron disease' or 'amyotrophic lateral sclerosis' and 'epidemiology', 'diagnosis', 'clinical', 'genetic', 'management', 'treatment', or 'trial'. AREAS OF AGREEMENT: Evidence-based management involves riluzole, multidisciplinary care, provision of noninvasive ventilation and gastrostomy, and symptomatic treatments. Tofersen should be offered to treat SOD1-MND. AREAS OF CONTROVERSY: Edaravone and Relyvrio are approved treatments in the USA, but insufficient evidence was found to support approval in the UK and Europe. GROWING POINTS: The discovery of neurofilaments as MND biomarkers, growth of platform trials and development of novel therapies provide optimism for more powerful neuroprotective therapies. AREAS TIMELY FOR DEVELOPING RESEARCH: Further work should focus on the elucidation of environmental causes of MND, gene-environment interactions, and advanced cellular models of disease.

Post-hospitalisation COVID-19 cognitive deficits at one year are global and associated with elevated brain injury markers and grey matter volume reduction.

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers, and reduced anterior cingulate cortex volume one year after COVID-19. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies.

In Vivo Raman Spectroscopy of Muscle Is Highly Sensitive for Detection of Healthy Muscle and Highly Specific for Detection of Disease.

Raman spectroscopy of muscle provides a molecular fingerprint to identify the disease. Previous work has demonstrated effectiveness in differentiating between two groups of equal sizes (e.g., healthy vs disease) but imbalanced multiclass scenarios are more common in medicine. We performed in vivo Raman spectroscopy in a total of 151 mice across four different histopathologies (healthy, acute myopathy, chronic myopathy, neurogenic), with variable numbers in each (class "imbalance"). Using hierarchical modeling and synthetic data generation, we demonstrate high sensitivity (94%) for detection of healthy muscle and high specificity (≥97%) for disease. Further, we demonstrate the potential for unique biomarker development by demonstrating variations in the protein structure across different pathologies. The findings demonstrate the potential of Raman spectroscopy to provide accurate disease identification and unique molecular insights.

RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy.

OBJECTIVE: Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models. METHODS: A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD. RESULTS: Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish. INTERPRETATION: The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024.

predicTTE: An accessible and optimal tool for time-to-event prediction in neurological diseases.

Time-to-event prediction is a key task for biological discovery, experimental medicine, and clinical care. This is particularly true for neurological diseases where development of reliable biomarkers is often limited by difficulty visualising and sampling relevant cell and molecular pathobiology. To date, much work has relied on Cox regression because of ease-of-use, despite evidence that this model includes incorrect assumptions. We have implemented a set of deep learning and spline models for time-to-event modelling within a fully customizable 'app' and accompanying online portal, both of which can be used for any time-to-event analysis in any disease by a non-expert user. Our online portal includes capacity for end-users including patients, Neurology clinicians, and researchers, to access and perform predictions using a trained model, and to contribute new data for model improvement, all within a data-secure environment. We demonstrate a pipeline for use of our app with three use-cases including imputation of missing data, hyperparameter tuning, model training and independent validation. We show that predictions are optimal for use in downstream applications such as genetic discovery, biomarker interpretation, and personalised choice of medication. We demonstrate the efficiency of an ensemble configuration, including focused training of a deep learning model. We have optimised a pipeline for imputation of missing data in combination with time-to-event prediction models. Overall, we provide a powerful and accessible tool to develop, access and share time-to-event prediction models; all software and tutorials are available at www.predictte.org.

Understanding resilience: Lifestyle-based behavioral predictors of mental health and well-being in community-dwelling older adults during the COVID-19 pandemic.

BACKGROUND: Changes in sleep, physical activity and mental health were observed in older adults during early stages of the COVID-19 pandemic. Here we describe effects of the COVID-19 pandemic on older adult mental health, wellbeing, and lifestyle behaviors and explore predictors of better mid-pandemic mental health and wellbeing. METHODS: Participants in the Adult Changes in Thought study completed measures of lifestyle behaviors (e.g., sleep, physical activity) and mental health and wellbeing both pre-pandemic during regular study visits and mid-pandemic via a one-time survey. We used paired t-tests to compare differences in these measures pre- vs. mid-pandemic. Using multivariate linear regression, we further explored demographic, health, and lifestyle predictors of pandemic depressive symptoms, social support, and fatigue. We additionally qualitatively coded free text data from the mid-pandemic survey for related comments. RESULTS: Participants (N = 896) reported significant changes in mental health and lifestyle behaviors at pre-pandemic vs. mid-pandemic measurements (p < 0.0001). Qualitative findings supported these behavioral and wellbeing changes. Being male, never smoking, and lower pre-pandemic computer time and sleep disturbance were significantly associated with lower pandemic depressive symptoms. Being partnered, female, never smoking, and lower pre-pandemic sleep disturbance were associated with higher pandemic social support. Pre-pandemic employment, more walking, less computer time, and less sleep disturbance were associated with less pandemic fatigue. Participant comments supported these quantitative findings, highlighting gender differences in pandemic mental health, changes in computer usage and physical activity during the pandemic, the value of spousal social support, and links between sleep disturbance and mental health and wellbeing. Qualitative findings also revealed additional factors, such as stresses from personal and family health situations and the country's concurrent political environment, that impacted mental health and wellbeing. CONCLUSIONS: Several demographic, health, and lifestyle behaviors appeared to buffer the effects of the COVID-19 pandemic and may be key sources of resilience. Interventions and public health measures targeting men and unpartnered individuals could promote social support resilience, and intervening on modifiable behaviors like sleep quality, physical activity and sedentary activities like computer time may promote resilience to fatigue and depressive symptoms during future community stressor events. Further research into these relationships is warranted.

Tumor cell-directed STING agonist antibody-drug conjugates induce type III interferons and anti-tumor innate immune responses.

Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro, in vivo (in female mice), and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore, STINGa ADCs induce type III interferons, which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs.

A systematic review of immunosuppressive protocols used in AAV gene therapy for monogenic disorders.

The emergence of adeno-associated virus (AAV)-based gene therapy has brought hope to patients with severe monogenic disorders. However, immune responses to AAV vectors and transgene products present challenges that require effective immunosuppressive strategies. This systematic review focuses on the immunosuppressive protocols used in 38 clinical trials and 35 real-world studies, considering a range of monogenic diseases, AAV serotypes, and administration routes. The review underscores the need for a deeper understanding of immunosuppressive regimens to enhance the safety and effectiveness of AAV-based gene therapy. Characterizing the immunological responses associated with various gene therapy treatments is crucial for optimizing treatment protocols and ensuring the safety and efficacy of forthcoming gene therapy interventions. Further research and understanding of the impact of immunosuppression on disease, therapy, and route of administration will contribute to the development of more effective and safer gene therapy approaches in the future.

Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study.

BACKGROUND: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS. METHODS: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed. FINDINGS: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator. INTERPRETATION: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS. FUNDING: Biogen.

Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.

Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.

Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.

OBJECTIVE: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. METHODS: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case-control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data. RESULTS: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13-9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14-1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18-1.77, pMadsen-Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86-4.37, pMadsen-Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation. INTERPRETATION: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.

A Randomized Trial of Choice Architecture and Mailed Colorectal Cancer Screening Outreach in a Community Health Setting.

BACKGROUND & AIMS: Mailed outreach for colorectal cancer (CRC) screening increases uptake but it is unclear how to offer the choice of testing. We evaluated if the active choice between colonoscopy and fecal immunochemical test (FIT), or FIT alone, increased response compared with colonoscopy alone. METHODS: This pragmatic, randomized, controlled trial at a community health center included patients between ages 50 and 74 who were not up to date with CRC screening. Patients were randomized 1:1:1 to the following: (1) colonoscopy only, (2) active choice of colonoscopy or FIT, or (3) FIT only. Patients received an outreach letter with instructions for testing (colonoscopy referral and/or an enclosed FIT kit), a reminder letter at 2 months, and another reminder at 3 to 5 months via text message or automated voice recording. The primary outcome was CRC screening completion within 6 months. RESULTS: Among 738 patients in the final analysis, the mean age was 58.7 years (SD, 6.2 y); 48.6% were insured by Medicaid and 24.3% were insured by Medicare; and 71.7% were White, 16.9% were Black, and 7.3% were Hispanic/Latino. At 6 months, 5.6% (95% CI, 2.8-8.5) completed screening in the colonoscopy-only arm, 12.8% (95% CI, 8.6-17.0) in the active-choice arm, and 11.3% (95% CI, 7.4-15.3) in the FIT-only arm. Compared with colonoscopy only, there was a significant increase in screening in active choice (absolute difference, 7.1%; 95% CI, 2.0-12.2; P = .006) and FIT only (absolute difference, 5.7%; 95% CI, 0.8-10.6; P = .02). CONCLUSIONS: Both choice of testing and FIT alone increased response and may align with patient preferences. TRIAL REGISTRATION: clinicaltrials.gov NCT04711473.

A Principled Approach to Characterize and Analyze Partially Observed Confounder Data from Electronic Health Records.

Objective: Partially observed confounder data pose challenges to the statistical analysis of electronic health records (EHR) and systematic assessments of potentially underlying missingness mechanisms are lacking. We aimed to provide a principled approach to empirically characterize missing data processes and investigate performance of analytic methods. Methods: Three empirical sub-cohorts of diabetic SGLT2 or DPP4-inhibitor initiators with complete information on HbA1c, BMI and smoking as confounders of interest (COI) formed the basis of data simulation under a plasmode framework. A true null treatment effect, including the COI in the outcome generation model, and four missingness mechanisms for the COI were simulated: completely at random (MCAR), at random (MAR), and two not at random (MNAR) mechanisms, where missingness was dependent on an unmeasured confounder and on the value of the COI itself. We evaluated the ability of three groups of diagnostics to differentiate between mechanisms: 1)-differences in characteristics between patients with or without the observed COI (using averaged standardized mean differences [ASMD]), 2)-predictive ability of the missingness indicator based on observed covariates, and 3)-association of the missingness indicator with the outcome. We then compared analytic methods including "complete case", inverse probability weighting, single and multiple imputation in their ability to recover true treatment effects. Results: The diagnostics successfully identified characteristic patterns of simulated missingness mechanisms. For MAR, but not MCAR, the patient characteristics showed substantial differences (median ASMD 0.20 vs 0.05) and consequently, discrimination of the prediction models for missingness was also higher (0.59 vs 0.50). For MNAR, but not MAR or MCAR, missingness was significantly associated with the outcome even in models adjusting for other observed covariates. Comparing analytic methods, multiple imputation using a random forest algorithm resulted in the lowest root-mean-squared-error. Conclusion: Principled diagnostics provided reliable insights into missingness mechanisms. When assumptions allow, multiple imputation with nonparametric models could help reduce bias.

Historic Cognitive Function Trajectories as Predictors of Sedentary Behavior and Physical Activity in Older Adults.

BACKGROUND: We examined whether trajectories of cognitive function over 10 years predict later-life physical activity (PA), sedentary time (ST), and sleep. METHODS: Participants were from the Adult Changes in Thought (ACT) cohort study. We included 611 ACT participants who wore accelerometers and had 3+ measures of cognition in the 10 years prior to accelerometer wear. The Cognitive Assessment Screening Instrument (CASI) measured cognition and was scored using item-response theory (IRT). activPAL and ActiGraph accelerometers worn over 7 days measured ST and PA outcomes. Self-reported time in bed and sleep quality measured sleep outcomes. Analyses used growth mixture modeling to classify CASI-IRT scores into latent groups and examine associations with PA, ST, and sleep including demographic and health covariates. RESULTS: Participants (Mean age = 80.3 (6.5) years, 90.3% White, 57.1% female, 29.3% had less than 16 years of education) fell into 3 latent trajectory groups: average stable CASI (56.1%), high stable CASI (34.0%), and declining CASI (9.8%). The declining group had 16 minutes less stepping time (95% confidence interval [95% CI]: 0.6, 31.4), 1 517 fewer steps per day (95% CI: 138, 2 896), and 16.3 minutes per day less moderate-to-vigorous PA (95% CI: 1.3, 31.3) compared to the average stable group. There were no associations between CASI trajectory and sedentary or sleep outcomes. CONCLUSIONS: Declining cognition predicted lower PA providing some evidence of a reverse relationship between PA and cognition in older adults. However, this conclusion is limited by having outcomes at only one time point, a nonrepresentative sample, self-reported sleep outcomes, and using a global cognition measure.

Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.

Current neuroprotective therapies and future prospects for motor neuron disease.

Four medications with neuroprotective disease-modifying effects are now in use for motor neuron disease (MND). With FDA approvals for tofersen, relyvrio and edaravone in just the past year, 2022 ended a quarter of a century when riluzole was the sole such drug to offer to patients. The acceleration of approvals may mean we are witnessing the beginning of a step-change in how MND can be treated. Improvements in understanding underlying disease biology has led to more therapies being developed to target specific and multiple disease mechanisms. Consideration for how the pipeline of new therapeutic agents coming through in clinical and preclinical development can be more effectively evaluated with biomarkers, advances in patient stratification and clinical trial design pave the way for more successful translation for this archetypal complex neurodegenerative disease. While it must be cautioned that only slowed rates of progression have so far been demonstrated, pre-empting rapid neurodegeneration by using neurofilament biomarkers to signal when to treat, as is currently being trialled with tofersen, may be more effective for patients with known genetic predisposition to MND. Early intervention with personalized medicines could mean that for some patients at least, in future we may be able to substantially treat what is considered by many to be one of the most distressing diseases in medicine.