Association Between Early-Life and Premorbid Measurements of Body Composition and Risk of Motor Neuron Disease: A Prospective Cohort Study in the UK Biobank.

OBJECTIVE: The objective of this study was to investigate the association between developmental and premorbid body composition measurements and the risk of motor neuron disease (MND). METHODS: We performed a cohort study in the UK Biobank to assess the association of developmental body metrics and premorbid body composition measures (using 28 measurements and 7 patterns of body composition) with the risk of MND. Among participants with longitudinal measures, we compared the changes in body composition over time between individuals who later developed MND and those who remained free of MND. RESULTS: Among the 412,691 individuals included in this study, 549 people received an MND diagnosis during the follow-up visit. Higher birth weight was associated with an increased risk of MND among individuals born over 4 kg (hazard ratio [HR] per kg increase = 2.21, 95% confidence interval [CI] = 1.38-3.55), and taller adult height was associated with an increased risk of MND (HR per 5 cm increase = 1.10, 95% CI = 1.03-1.17). We observed that measures of elevated fat mass were associated with a lower risk of MND more than 5 years before diagnosis. A higher "leg-dominant fat distribution" pattern was associated with an increased risk whereas higher "muscle strength" was associated with a reduced risk of MND 5 years before diagnosis. Longitudinal analyses indicated a faster decline in measures of fat mass and muscle strength, as well as a shift in fat distribution from arm to leg dominant, among individuals who later developed MND, compared with others. INTERPRETATION: Body composition at early and middle age may be indicative of the risk of MND development. ANN NEUROL 2024.

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.

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.

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.

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.

Hospital-treated infections in early- and mid-life and risk of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis: A nationwide nested case-control study in Sweden.

BACKGROUND: Experimental observations have suggested a role of infection in the etiology of neurodegenerative disease. In human studies, however, it is difficult to disentangle whether infection is a risk factor or rather a comorbidity or secondary event of neurodegenerative disease. To this end, we examined the risk of 3 most common neurodegenerative diseases in relation to previous inpatient or outpatient episodes of hospital-treated infections. METHODS AND FINDINGS: We performed a nested case-control study based on several national registers in Sweden. Cases were individuals newly diagnosed with Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) during 1970 to 2016 in Sweden, identified from the National Patient Register. For each case, 5 controls individually matched to the case on sex and year of birth were randomly selected from the general population. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for potential confounders, including sex, year of birth, area of residence, educational attainment, family history of neurodegenerative disease, and Charlson comorbidity index. Infections experienced within 5 years before diagnosis of neurodegenerative disease were excluded to reduce the influence of surveillance bias and reverse causation. The analysis included 291,941 AD cases (median age at diagnosis: 76.2 years; male: 46.6%), 103,919 PD cases (74.3; 55.1%), and 10,161 ALS cases (69.3; 56.8%). A hospital-treated infection 5 or more years earlier was associated with an increased risk of AD (OR = 1.16, 95% CI: 1.15 to 1.18, P < 0.001) and PD (OR = 1.04, 95% CI: 1.02 to 1.06, P < 0.001). Similar results were observed for bacterial, viral, and other infections and among different sites of infection including gastrointestinal and genitourinary infections. Multiple infections before age 40 conveyed the greatest risk of AD (OR = 2.62, 95% CI: 2.52 to 2.72, P < 0.001) and PD (OR = 1.41, 95% CI: 1.29 to 1.53, P < 0.001). The associations were primarily due to AD and PD diagnosed before 60 years (OR = 1.93, 95% CI: 1.89 to 1.98 for AD, P < 0.001; OR = 1.29, 95% CI: 1.22 to 1.36 for PD, P < 0.001), whereas no association was found for those diagnosed at 60 years or older (OR = 1.00, 95% CI: 0.98 to 1.01 for AD, P = 0.508; OR = 1.01, 95% CI: 0.99 to 1.03 for PD, P = 0.382). No association was observed for ALS (OR = 0.97, 95% CI: 0.92 to 1.03, P = 0.384), regardless of age at diagnosis. Excluding infections experienced within 10 years before diagnosis of neurodegenerative disease confirmed these findings. Study limitations include the potential misclassification of hospital-treated infections and neurodegenerative diseases due to incomplete coverage of the National Patient Register, as well as the residual confounding from unmeasured risk or protective factors for neurodegenerative diseases. CONCLUSIONS: Hospital-treated infections, especially in early- and mid-life, were associated with an increased risk of AD and PD, primarily among AD and PD cases diagnosed before 60 years. These findings suggest that infectious events may be a trigger or amplifier of a preexisting disease process, leading to clinical onset of neurodegenerative disease at a relatively early age. However, due to the observational nature of the study, these results do not formally prove a causal link.

Medication use and risk of amyotrophic lateral sclerosis-a systematic review.

BACKGROUND: Studying whether medications act as potential risk factors for amyotrophic lateral sclerosis (ALS) can contribute to the understanding of disease etiology as well as the identification of novel therapeutic targets. Therefore, we conducted a systematic review to summarize the existing evidence on the association between medication use and the subsequent ALS risk. METHODS: A systematic review was conducted in Medline, Embase, and Web of Science from the date of database establishment to December 10, 2021. References of identified articles were further searched for additional relevant articles. Studies were included if (1) published in English, (2) explored medication use as exposure and development of ALS as outcome, and (3) the design was a human observational study. Clinical trials, reviews, comments, editorials, and case reports were excluded. Quality assessment was performed using a pre-validated tool for non-randomized studies, the Newcastle-Ottawa Assessment Scale (NOS). RESULTS: Of the 4760 studies identified, 25 articles, including 13 case-control studies, five nested case-control studies, six cohort studies, and one retrospective chart review, were included in the review. Among these studies, there were 22 distinct study populations that included 171,407 patients with ALS, seven classes of medication examined, and 23 studies with a NOS ≥ 5. There was a general lack of agreement between studies on the associations of cholesterol-lowering drugs, anti-inflammatory drugs, immunosuppressants, antibiotics, oral contraceptives (OCs) or hormone replacement therapy (HRT), antihypertensive drugs, antidiabetics, and drugs for psychiatric and neurological disorders with the subsequent risk of ALS. However, it appeared that statins, aspirin, OCs/HRT, antihypertensives, and antidiabetics were unlikely related to a higher risk of ALS. The positive associations noted for antibiotics, antidepressants, and skeletal muscle relaxants might be attributable to prodromal symptoms of ALS. CONCLUSIONS: There is currently no strong evidence to link any medication use with ALS risk.

Military service and related risk factors for amyotrophic lateral sclerosis.

BACKGROUND: The cause of amyotrophic lateral sclerosis (ALS) is unknown, but occupations have been explored as a potential proxy measure of risk. There is a substantial body of literature connecting military service to ALS. We aimed to summarize and assess the quality of this evidence. METHODS: Systematic review of the literature, including observational studies which explored one of the following exposures: general military service (army, air force, marines, or navy); or specific exposures associated with military service measured among military personnel. The outcome of interest was ALS incidence, which could include onset, diagnosis, or death from ALS. RESULTS: A total of 2642 articles were screened. Following exclusion, 19 articles remained for inclusion in the systematic review, including 1 meta-analysis and 18 original observational studies. Most studies were of moderate quality. In general, the relationship between military service was suggestive of an increased risk, particularly among Gulf War and WWII veterans. Exposure to pesticides (including Agent Orange) certain chemicals (exhaust, burning agents), heavy metals, and head trauma appeared to increase the risk of ALS among military personnel. CONCLUSIONS: There is a possible association between military service and the subsequent development of ALS; however, the evidence was limited. Studies were generally hindered by small sample sizes and inadequate follow-up time. Future studies should endeavor to objectively measure specific exposures, or combinations thereof, associated with military service, as this will be of vital importance in implementing preventative strategies into military organizations.

Peripheral immune biomarkers and neurodegenerative diseases: A prospective cohort study with 20 years of follow-up.

OBJECTIVE: To assess the associations of several blood immune biomarkers with the future risks of amyotrophic lateral sclerosis and Parkinson disease in a prospective cohort study with 20 years of follow-up. METHODS: The Swedish Apolipoprotein-Related Mortality Risk study is a longitudinal cohort study including 812,073 participants with repeated blood biomarker measurements between 1985 and 1996 and a follow-up until 2011. Using a Cox model, we first estimated hazard ratios of amyotrophic lateral sclerosis and Parkinson disease in relation to leukocytes, immunoglobulin G, haptoglobin, and uric acid. We further described the temporal changes of these biomarkers during the 20 years prior to the diagnosis of these diseases. RESULTS: A total of 585 incident cases of amyotrophic lateral sclerosis and 3,769 incident cases of Parkinson disease were identified during the follow-up. Increasing concentrations of leukocytes, haptoglobin, and uric acid were associated with a lower risk of Parkinson disease. No statistically significant association was, however, noted between the studied biomarkers and amyotrophic lateral sclerosis. Parkinson disease patients appeared to have lower levels of leukocytes and haptoglobin between 20 and 10 years before diagnosis and lower levels of uric acid during the 20 years before diagnosis, compared to controls, although statistically significant differences were only noted during parts of the respective time intervals after multivariable adjustment. No clear differences were noted between patients with amyotrophic lateral sclerosis and controls. INTERPRETATION: If verified in studies of independent populations, our findings may suggest a different role of systemic inflammation on the risk of Parkinson disease compared to amyotrophic lateral sclerosis. ANN NEUROL 2019;86:913-926.

Complications and outcome of percutaneous endoscopic gastrostomy in a high-volume centre.

Introduction: Percutaneous endoscopic gastrostomy (PEG) is the method of choice for long-term enteral feeding for patients with swallowing disorders and normal gut function. There is limited data regarding the demographics and clinical characteristics of patients from whom PEG was removed. Patients and methods: We performed a retrospective analysis of all consecutive adult patients who underwent first placement of PEG between 1 August 2013 and 31 December 2015 at Karolinska University Hospital in Stockholm, Sweden. Results: In total, 495 PEG were inserted in 495 patients during the study period, 56% male, mean age at insertion 67 years (range 19-95). Most patients belonged to the neurologic group (52%), followed by the oncologic (32%), another diagnosis (9%) and trauma (7%). Major complications occurred in 10 (2.0%) patients. There were no differences in the age or BMI of patients with either minor or major complications but both parameters were risk factors in terms of survival. PEG was removed from 165 (33.3%) patients, most of them from the oncology group, due to the improvement of general status of patients after specific oncologic treatment. Conclusion: Increased age and low BMI were identified as risk factors for mortality but did not correspond with the rate of complications. Antibiotic prophylaxis with sulfamethoxazole and trimethoprim provides good protection for patients with PEG.

Blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms and risk of amyotrophic lateral sclerosis: A more than 20-year follow-up of the Swedish AMORIS cohort.

OBJECTIVE: To assess the associations of blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms with the future risk of amyotrophic lateral sclerosis (ALS). METHODS: In the Apolipoprotein-related MOrtality RISk study, we enrolled 636,132 men and women during 1985-1996 in Stockholm, Sweden, with measurements of serum glucose, total cholesterol, triglycerides, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I). Serum low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were either directly measured or calculated from total cholesterol, triglycerides, and apoA-I. The cohort was followed until the end of 2011. We used Cox models and mixed-effects models to, first, estimate the associations between these biomarkers and ALS incidence and, second, to assess the changes of these biomarkers during the 20 years before ALS diagnosis. RESULTS: One-unit increase of LDL-C (hazard ratio [HR] = 1.14; 95% confidence interval [CI] = 1.02-1.27), apoB (HR = 1.68; 95% CI = 1.17-2.42), and apoB/apoA-I ratio (HR = 1.90; 95% CI = 1.29-2.78) was associated with a higher incidence of ALS. High glucose level (≥6.11mmol/L) was associated with a lower incidence (HR = 0.62; 95% CI = 0.42-0.93), whereas high LDL-C/HDL-C (≥3.50; HR = 1.50; 95% CI = 1.15-1.96) and high apoB/apoA-I (≥0.90 for men, ≥0.8 for women; HR = 1.41; 95% CI = 1.04-1.90) ratios were associated with a higher incidence. During the 10 years before diagnosis, ALS patients had increasing levels of LDL-C, HDL-C, apoB, and apoA-I, whereas gradually decreasing levels of LDL-C/HDL-C and apoB/apoA-I ratios. INTERPRETATION: Alterations in the carbohydrate, lipid, and apolipoprotein metabolisms are associated with ALS risk and may serve as prodromal symptoms decades before ALS diagnosis. The imbalance between apoB and apoA-I as well as between LDL-C and HDL-C may be an etiological mechanism for ALS and needs to be further studied. Ann Neurol 2017;81:718-728.

Amyotrophic lateral sclerosis among cross-country skiers in Sweden.

A highly increased risk of amyotrophic lateral sclerosis (ALS) has been suggested among professional athletes. We aimed to examine whether long distance cross-country skiers have also a higher risk of ALS and whether the increased risk was modified by skiing performance. We followed 212,246 cross-country skiers in the Swedish Vasaloppet cohort and a random selection of 508,176 general Swedes not participating in the Vasaloppet during 1989-2010. The associations between cross-country skiing as well as skiing performance (i.e., type of race, finishing time and number of races) and the consequent risk of ALS were estimated through hazard ratios (HRs) derived from Cox model. During the study, 39 cases of ALS were ascertained among the skiers. The fastest skiers (100-150% of winner time) had more than fourfold risk of ALS (HR 4.31, 95% confidence interval [CI] 1.78-10.4), as compared to skiers that finished at >180% of winner time. Skiers who participated >4 races during this period had also a higher risk (HR 3.13, 95% CI 1.37-7.17) than those participated only one race. When compared to the non-skiers, the fastest skiers still had a higher risk (HR 2.08, 95% CI 1.12-3.84), as skiers who had >4 races (HR 1.88, 95% CI 1.05-3.35), but those finishing at >180% of winner time had a lower risk (HR 0.46, 95% CI 0.24-0.87). In conclusion, long distance cross-country skiing is associated with a higher risk of ALS, but only among the best skiers; recreational skiers appear to have a largely reduced risk.

A yeast functional screen predicts new candidate ALS disease genes.

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

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.

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.

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.

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.

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.