T cell subset composition differs between blood and cerebrospinal fluid in amyotrophic lateral sclerosis.

Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS) and is often assessed through biological samples. Due to the easier access, peripheral blood is more commonly phenotyped instead of cerebrospinal fluid (CSF) or affected tissues in ALS. Here, using flow cytometry, we compared the composition of T cell subsets in blood and CSF in ALS patients. We found consistent but weak correlations between blood and CSF for all T cell subsets examined. This finding implies that blood and CSF offer complementary information when characterizing T cell immunity in ALS and blood may not be used as a surrogate for CSF.

International network for ALS research and care (INARC).

The International Network for Amyotrophic Lateral Sclerosis (ALS) Research and Care (INARC) was founded in 2022. INARC's main goals are to offer a platform dedicated to staff members for ALS clinics and research teams who are not physicians. By nurturing experience and expertise exchanges to improve problem solving skills, the ultimate goal is to increase the standard ALS care and research. This brief report aims to describe the formation of INARC, the 2023 INARC meeting, as well as to report topics discussed, lessons learned and challenges raised by INARC members.

ECAS correlation with metabolic alterations on FDG-PET imaging in ALS.

Background: Cognitive impairment is observed in up to 50% of patients with amyotrophic lateral sclerosis (ALS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is an ALS-specific multi-domain screening tool. Few studies have examined the relationship between ECAS scores and [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) findings. Objective: To assess the relationship between ECAS scores and glucose metabolism patterns on [18F]FDG -PET images in ALS. Methods: We collected [18F]FDG-PET images from 65 patients with ALS and 39 healthy controls. ECAS scores were collected on all patients and we calculated the correlation to [18F]FDG-PET in order to investigate the potential links between cognition and glucose metabolism. Results: We observed hypometabolism in the frontal cortex, insula, and limbic system, together with hypermetabolism in the cerebellum in patients with ALS compared to controls. A lower ECAS total score was associated with lower glucose metabolism in the right orbitofrontal gyrus and higher glucose metabolism in lateral occipital, medial occipital, and cerebellar regions, among patients with ALS. Similar results, although less widespread, were observed in the analyses of ECAS ALS-specific scores. Conclusions: The metabolic patterns in [18F]FDG -PET show that changes in the glucose metabolism of corresponding areas are related to cognitive dysfunction in ALS, and can be detected using the ECAS.

Repeated cognitive assessments show stable function over time in patients with ALS.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multisystem disorder with not only motor symptoms but also extra-motor features including cognitive impairment. The most common cognitive profile observed in patients with ALS includes deficits in executive function, language, and social cognition. However, longitudinal studies on cognitive changes over time in ALS are sparse. We aimed to investigate the presence and nature of cognitive impairment at the time of ALS diagnosis and its association with survival as well as explore longitudinal cognitive change. METHOD: Patients (n = 216) were recruited at the Karolinska University Hospital in Stockholm, Sweden. Follow-up visits (n = 307 in total) were performed every 6 months. Cognitive impairment was assessed using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and/or Montreal Cognitive Assessment (MoCA). RESULTS: Cognitive impairment was observed in 38% of the patients at the time of ALS diagnosis, and the majority of these patients had deficits in executive function and/or language. Patients with cognitive impairment at the time of diagnosis had a more rapid decline in ALSFRS-R at 12- and 18-months follow-up, and a shorter survival. Cognitive function was stable during the first 2 years after diagnosis, and did not follow the trajectories of decline in motor functions. CONCLUSION: Cognitive impairment in ALS was associated with a faster decline of motor functions, and shorter survival. However, cognitive function did not deteriorate over time. Cognitive assessment is essential for the patients and caregivers to understand the phenotypic expression of ALS.

Lifestyle and medical conditions in relation to ALS risk and progression-an introduction to the Swedish ALSrisc Study.

BACKGROUND: This study was an introduction to the Swedish ALSrisc Study and explored the association of lifestyle and medical conditions, with risk and progression of amyotrophic lateral sclerosis (ALS). METHODS: We included 265 newly diagnosed ALS patients during 2016-2022 in Stockholm and 207 ALS-free siblings and partners of the patients as controls. Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment. Patients were followed from diagnosis until death, invasive ventilation, or November 30, 2022. RESULTS: Higher BMI at recruitment was associated with lower risk for ALS (OR 0.89, 95%CI 0.83-0.95), especially among those diagnosed after 65 years. One unit increase in the average BMI during the 3 decades before diagnosis was associated with a lower risk for ALS (OR 0.94, 95%CI 0.89-0.99). Diabetes was associated with lower risk of ALS (OR 0.38, 95%CI 0.16-0.90), while hypercholesterolemia was associated with higher risk of ALS (OR 2.10, 95%CI 1.13-3.90). Higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95%CI 0.84-0.98), while the highest level of smoking exposure (in pack-years) (HR 1.90, 95%CI 1.20-3.00), hypercholesterolemia (HR 1.84, 95%CI 1.06-3.19), and hypertension (HR 1.76, 95%CI 1.03-3.01) were associated with higher risk of death, following ALS diagnosis. CONCLUSIONS: Higher BMI and diabetes were associated with lower risk of ALS. Higher BMI was associated with lower risk of death, whereas smoking (especially in high pack-years), hypercholesterolemia, and hypertension were associated with higher risk of death after ALS diagnosis.

The usage of population and disease registries as pre-screening tools for clinical trials, a systematic review.

OBJECTIVE: This systematic review aims to outline the use of population and disease registries for clinical trial pre-screening. MATERIALS AND METHODS: The search was conducted in the time period of January 2014 to December 2022 in three databases: MEDLINE, Embase, and Web of Science Core Collection. References were screened using the Rayyan software, firstly based on titles and abstracts only, and secondly through full text review. Quality of the included studies was assessed using the List of Included Studies and quality Assurance in Review tool, enabling inclusion of publications of only moderate to high quality. RESULTS: The search originally identified 1430 citations, but only 24 studies were included, reporting the use of population and/or disease registries for trial pre-screening. Nine disease domains were represented, with 54% of studies using registries based in the USA, and 62.5% of the studies using national registries. Half of the studies reported usage for drug trials, and over 478,679 patients were identified through registries in this review. Main advantages of the pre-screening methodology were reduced financial burden and time reduction. DISCUSSION AND CONCLUSION: The use of registries for trial pre-screening increases reproducibility of the pre-screening process across trials and sites, allowing for implementation and improvement of a quality assurance process. Pre-screening strategies seem under-reported, and we encourage more trials to use and describe their pre-screening processes, as there is a need for standardized methodological guidelines.

Motor band sign is specific for amyotrophic lateral sclerosis and corresponds to motor symptoms.

OBJECTIVE: Magnetic resonance imaging can detect neurodegenerative iron accumulation in the motor cortex, called the motor band sign. This study aims to evaluate its sensitivity/specificity and correlations to symptomatology, biomarkers, and clinical outcome in amyotrophic lateral sclerosis. METHODS: This prospective study consecutively enrolled 114 persons with amyotrophic lateral sclerosis and 79 mimics referred to Karolinska University Hospital, and also 31 healthy controls. All underwent 3-Tesla brain susceptibility-weighted imaging. Three raters independently assessed motor cortex susceptibility with total and regional motor band scores. Survival was evaluated at a median of 34.2 months after the imaging. RESULTS: The motor band sign identified amyotrophic lateral sclerosis with a sensitivity of 59.6% and a specificity of 91.1% versus mimics and 96.8% versus controls. Higher motor band scores were more common with genetic risk factors (p = 0.032), especially with C9orf72 mutation, and were associated with higher neurofilament light levels (std. ß 0.22, p = 0.019). Regional scores correlated strongly with focal symptoms (medial region vs. gross motor dysfunction, std. ß -0.64, p = 0.001; intermediate region vs. fine motor dysfunction, std. ß -0.51, p = 0.031; lateral region vs. bulbar symptoms std. ß -0.71, p < 0.001). There were no associations with cognition, progression rate, or survival. INTERPRETATION: In a real-life clinical setting, the motor band sign has high specificity but relatively low sensitivity for identifying amyotrophic lateral sclerosis. Associations with genetic risk factors, neurofilament levels and somatotopic correspondence to focal motor weakness suggest that the motor band sign could be a suitable biomarker for diagnostics and clinical trials in amyotrophic lateral sclerosis.

Increased incidence of motor neuron disease in Sweden: a population-based study during 2002-2021.

BACKGROUND: Motor neuron diseases (MND), with amyotrophic lateral sclerosis constituting most cases, are rare conditions of unknown etiology. There have been reports of an increase in incidence during the latter half of the twentieth century in various Western countries, including Sweden. This study provides updated data on the incidence of MND in Sweden during the last 20 years. METHODS: Data was obtained from the Swedish National Patient Register on individuals diagnosed with MND from 2002 to 2021 and analysed in relation to group level data for the entire Swedish population. Incidence rates were calculated and presented in relation to year, age, sex, and region. RESULTS: In the early 2000s, there was a crude incidence rate of 3.5-3.7 per 100,000 person-years, which then increased to 4.0-4.6 from 2008 onward. Age standardization to the starting year (2002) partially mitigated this increase. The incidence rate was greater among men compared to women and was highest within the age range of 70 to 84 years. There were indications of a higher incidence rate in the northernmost parts of the country, although the difference was not statistically significant. CONCLUSIONS: The incidence rate of MND in Sweden now seems to have surpassed 4 cases per 100,000 person-years. This is higher when compared to both other European countries and previous Swedish studies. It remains to be determined if this increase reflects an actual increasing incidence of MND in Sweden or is due to other factors such as better registry coverage.

Neurodegenerative biomarkers outperform neuroinflammatory biomarkers in amyotrophic lateral sclerosis.

OBJECTIVE: To describe the diagnostic and prognostic performance, and longitudinal trajectories, of potential biomarkers of neuroaxonal degeneration and neuroinflammation in amyotrophic lateral sclerosis (ALS). METHODS: This case-control study included 192 incident ALS patients, 42 ALS mimics, 114 neurological controls, and 117 healthy controls from Stockholm, Sweden. Forty-four ALS patients provided repeated measurements. We assessed biomarkers of (1)neuroaxonal degeneration: neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in cerebrospinal fluid (CSF) and NfL in serum, and (2)neuroinflammation: chitotriosidase-1 (CHIT1) and monocyte chemoattractant protein 1 (MCP-1) in CSF. To evaluate diagnostic performance, we calculated the area under the curve (AUC). To estimate prognostic performance, we applied quantile regression and Cox regression. We used linear regression models with robust standard errors to assess temporal changes over time. RESULTS: Neurofilaments performed better at differentiating ALS patients from mimics (AUC: pNfH 0.92, CSF NfL 0.86, serum NfL 0.91) than neuroinflammatory biomarkers (AUC: CHIT1 0.71, MCP-1 0.56). Combining biomarkers did not improve diagnostic performance. Similarly, neurofilaments performed better than neuroinflammatory biomarkers at predicting functional decline and survival. The stratified analysis revealed differences according to the site of onset: in bulbar patients, neurofilaments and CHIT1 performed worse at predicting survival and correlations were lower between biomarkers. Finally, in bulbar patients, neurofilaments and CHIT1 increased longitudinally but were stable in spinal patients. CONCLUSIONS: Biomarkers of neuroaxonal degeneration displayed better diagnostic and prognostic value compared with neuroinflammatory biomarkers. However, in contrast to spinal patients, in bulbar patients neurofilaments and CHIT1 performed worse at predicting survival and seemed to increase over time.

Validation of elevated levels of interleukin-8 in the cerebrospinal fluid, and discovery of new biomarkers in patients with GBS and CIDP using a proximity extension assay.

Background: Biomarkers for diagnosis of inflammatory neuropathies, assessment of prognosis, and treatment response are lacking. Methods: CSF and EDTA plasma from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), healthy controls (HC) and disease controls were analyzed with Olink multiplex proximity extension assay (PEA) from two independent cohorts. Levels of interleukin-8 (IL8) were further analyzed with ELISA in patients with GBS, CIDP, paraproteinemia-related demyelinating polyneuropathy (PDN), multifocal motor neuropathy (MMN), HC and disease controls. ROC analysis was performed. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) score. Results: In CSF, multiplex PEA analysis revealed up-regulation of IL8 in GBS compared to CIDP and HC respectively, and CIDP compared to HC. In addition, levels of IL2RA were upregulated in GBS compared to both HC and CIDP, SELE in GBS compared to HC, and ITGAM, IL6, and NRP1 in GBS compared to CIDP. In plasma, levels of MMP3, THBD and ITGAM were upregulated in CIDP compared to HC. Validation of multiplex IL8 results using ELISA, revealed increased levels of IL8 in CSF in patients with GBS and CIDP versus HC and non-inflammatory polyneuropathies (NIP) respectively, as well as in PDN versus NIP and HC. Levels of IL8 in CSF correlated with impairment in the acute phase of GBS as well as outcome at 6-months follow up. Conclusion: IL8 in CSF is validated as a diagnostic biomarker in GBS and CIDP, and a prognostic biomarker in GBS. Multiplex PEA hereby identifies several potential biomarkers in GBS and CIDP.

Biomarkers in amyotrophic lateral sclerosis: current status and future prospects.

Disease heterogeneity in amyotrophic lateral sclerosis poses a substantial challenge in drug development. Categorization based on clinical features alone can help us predict the disease course and survival, but quantitative measures are also needed that can enhance the sensitivity of the clinical categorization. In this Review, we describe the emerging landscape of diagnostic, categorical and pharmacodynamic biomarkers in amyotrophic lateral sclerosis and their place in the rapidly evolving landscape of new therapeutics. Fluid-based markers from cerebrospinal fluid, blood and urine are emerging as useful diagnostic, pharmacodynamic and predictive biomarkers. Combinations of imaging measures have the potential to provide important diagnostic and prognostic information, and neurophysiological methods, including various electromyography-based measures and quantitative EEG-magnetoencephalography-evoked responses and corticomuscular coherence, are generating useful diagnostic, categorical and prognostic markers. Although none of these biomarker technologies has been fully incorporated into clinical practice or clinical trials as a primary outcome measure, strong evidence is accumulating to support their clinical utility.

A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS-R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration. RESULTS: In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% confidence interval = -1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed. CONCLUSIONS: Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.

Validity and reliability measures of the Swedish Karolinska version of the Edinburgh Cognitive and Behavioral ALS Screen (SK-ECAS).

OBJECTIVE: Cognitive and behavioral impairment is observed in up to 50% of patients with amyotrophic lateral sclerosis (ALS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a 5-domain screening tool customized for quick cognitive screening in patients with ALS. Although the ECAS is available in Swedish at the Karolinska University Hospital (SK-ECAS), it has not yet been validated in Sweden stressing the need to assess validity and reliability of the SK-ECAS Version A. METHODS: The study included 176 patients with ALS or other motor neuron disease diagnosed between September 2017 and October 2021 at the Karolinska ALS Clinical Research Center in Stockholm, Sweden, and 35 age-matched healthy control subjects. SK-ECAS was validated against the Montreal Cognitive Assessment (MoCA) and optimal cutoffs, receiver operating characteristic (ROC) curve and area under the curve (AUC) were calculated. RESULTS: We identified an optimal cutoff of 108 for the SK-ECAS total score and 82 for the SK-ECAS ALS-specific score to detect cognitive impairment. The SK-ECAS showed good performance in indicating abnormal cognition with an AUC of 0.73 for SK-ECAS ALS-specific score and 0.77 for SK-ECAS total score. There was good internal consistency with a Cronbach's alpha of 0.79. CONCLUSIONS: This study demonstrates good validity and reliability indices for SK-ECAS Version A for the detection of cognitive impairment in newly diagnosed ALS patients.

PRECISION ALS-an integrated pan European patient data platform for ALS.

Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative condition. Despite significant advances in pre-clinical models that enhance understanding of disease pathobiology, translation of candidate drugs to effective human therapies has been disappointing. There is increasing recognition of the need for a precision medicine approach toward drug development, as many failures in translation can be attributed in part to disease heterogeneity in humans. PRECISION-ALS is an academic industry collaboration between clinicians, Computer Scientists, Information engineers, technologists, data scientists and industry partners that will address the key clinical, computational, data science and technology associated research questions to generate a sustainable precision medicine based approach toward new drug development. Using extant and prospectively collected population based clinical data across nine European sites, PRECISION-ALS provides a General Data Protection Regulation (GDPR) compliant framework that seamlessly collects, processes and analyses research-quality multimodal and multi-sourced clinical, patient and caregiver journey, digitally acquired data through remote monitoring, imaging, neuro-electric-signaling, genomic and biomarker datasets using machine learning and artificial intelligence. PRECISION-ALS represents a first-in-kind modular transferable pan-European ICT framework for ALS that can be easily adapted to other regions that face similar precision medicine related challenges in multimodal data collection and analysis.

COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success.

Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS).Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial.Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort.Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS).

Diagnostic delay in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease, and the time from symptom onset to diagnosis remains long. With the advent of disease-modifying treatments, the need to identify and diagnose ALS in a timely fashion has never been greater. METHODS: We reviewed the literature to define the severity of ALS diagnostic delay, the various factors that contribute to this delay (including patient and physician factors), and the role that site of symptom onset plays in a patient's diagnostic journey. RESULTS: Diagnostic delay is influenced by general practitioners' lack of recognition of ALS due to disease rarity and heterogenous presentations. As a result, patients are referred to non-neurologists, have unnecessary diagnostic testing, and may ultimately be misdiagnosed. Patient factors include their illness behavior-which impacts diagnostic delay-and their site of symptom onset. Limb-onset patients have the greatest diagnostic delay because they are frequently misdiagnosed with degenerative spine disease or peripheral neuropathy. CONCLUSION: Prompt ALS diagnosis results in more effective clinical management, with earlier access to disease-modifying therapies, multidisciplinary care, and, if desired, clinical trial involvement. Due to lack of commercially available ALS biomarkers, alternative strategies to identify and triage patients who likely have ALS must be employed. Several diagnostic tools have been developed to encourage general practitioners to consider ALS and make an urgent referral to ALS specialists, bypassing unnecessary referrals to non-neurologists and unnecessary diagnostic workup.

FDG-PET shows weak correlation between focal motor weakness and brain metabolic alterations in ALS.

Objective: Amyotrophic lateral sclerosis (ALS) is a clinically heterogenous disease, typically presenting with focal motor weakness that eventually generalizes. Weather there is a correlation between focal motor weakness and metabolic alterations in specific areas of the brain has not been thoroughly explored. This study aims to systematically investigate this by using fluorodeoxyglucose-positron emission tomography (FDG-PET), including longitudinal imaging. Methods: This observational imaging study included 131 ALS patients diagnosed and examined with FDG-PET at the ALS Clinical Research Center at the Karolinska University Hospital in Stockholm, Sweden. Thirteen ALS patients had a second scan and were analyzed longitudinally. The findings were compared to 39 healthy controls examined at the University Medical Center of Gröningen, the Netherlands. Results: There was a general pattern of brain metabolic alterations consistent with previously reported findings in ALS, namely hypometabolism in frontal regions and hypermetabolism in posterior regions. A higher symptom burden was associated with increased hypometabolism and decreased hypermetabolism. However, there was no clear correlation between focal motor weakness and specific metabolic alterations, neither when analyzing focal motor weakness with concomitant upper motor neuron signs or when including all focal motor weakness. Longitudinal FDG-PET imaging showed inconsistent results with little correlation between progression of motor weakness and metabolic alterations. Conclusion: Our results support the disease model of ALS as a diffuse process since no clear correlation was seen between focal motor weakness and specific metabolic alterations. However, there is need for further research on a larger number of patients, particularly including longitudinal imaging.

UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the UNC13A gene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in UNC13A lead to the inclusion of a cryptic exon in UNC13A messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of UNC13A leads to impaired neurotransmission. Recent discoveries have identified UNC13A as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in UNC13A cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering UNC13A is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of UNC13A as a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.

Dying from ALS in Sweden: clinical status, setting, and symptoms.

OBJECTIVES: This retrospective cohort study aims to provide a comprehensive account of death in Swedish patients with ALS, including clinical status preceding death, the death setting, as well as symptoms. METHODS: The study presents detailed information on a cohort of patients with ALS from Stockholm, Sweden, deceased in 2018-2020. In addition, selected information is presented on a larger complementary cohort of ALS patients from all regions of Sweden deceased in 2011-2020. Data were obtained from patient medical records, the Swedish Motor Neuron Disease Quality Registry, and the Swedish Quality Registry of Palliative Care. RESULTS: Ninety-three patients were included in the main cohort and 2224 patients in the complementary cohort. In the main cohort, there was a slow decline in weight and motor function during the 12 months preceding death. Most (93.4%) anticipated/prolonged deaths occurred in a palliative care unit, at home, or in an assisted living facility while 44.8% of precipitous deaths occurred in a hospital ward. Next of kin or health care staff were present at death for most patients (78.7%). In the final week of life, 41.1% experienced at least one symptom (either pain, anxiety, confusion, or dyspnea) that was only partially relieved or not at all. CONCLUSION: The majority of patients died in their own homes or at a palliative unit in the presence of next of kin and most symptoms were adequately managed. This paper might be used in educating patients, next of kin as well as health professionals, decreasing uncertainty surrounding the end of life.

The path to diagnosis in ALS: delay, referrals, alternate diagnoses, and clinical progression.

Objective: To provide a detailed and differentiated description of the path to receiving the correct amyotrophic lateral sclerosis (ALS) diagnosis, including delay times, referrals, alternate diagnoses, and clinical progression.Methods: Medical records until the date of ALS diagnosis were reviewed and linked to the Swedish Motor Neuron Disease Quality Registry.Results: The study included 353 Stockholm ALS patients diagnosed in 2016-2021. Patients were divided into four groups: 117 (33.1%) with lower extremity (LE), 85 (24.1%) with upper extremity (UE), 136 (38.5%) with bulbar, and 15 (4.2%) with respiratory onset. The time from onset to diagnosis was 16.0 (9.4-27.5) months in LE, 12.9 (8.8-17.8) months in UE, 11.7 (7.4-16.0) months in bulbar, and 8.3 (4.7-15.6) months in respiratory onset. Patients with UE or LE onset were often referred to orthopedics or a spinal/hand surgery clinic (29.3% for LE and 41.8% for UE), while bulbar patients were more frequently referred to ENT (66.3%). For those with LE or UE onset, the most common alternate diagnosis was spinal/foraminal stenosis whereas myasthenia gravis and stroke were more common for bulbar onset patients. For the respiratory group, cardiopulmonary diagnoses predominated. The proportion of all patients in King's stage 3 or 4 increased from 11.3% to 46.1% from the initial health care visit to diagnosis.Conclusions: There was great variation in the path to ALS diagnosis according to the onset clinical phenotype. In all groups, the diagnostic delay and clinical progression was substantial. We identified subgroups where the delay was the longest and might be reduced.