Amyotrophic Lateral Sclerosis Cases Research Articles

Case-control study of environmental toxins and risk of amyotrophic lateral sclerosis involving the national ALS registry

Objective Neurotoxic chemicals are suggested in the etiology of amyotrophic lateral sclerosis (ALS). We examined the association of environmental and occupational risk factors including persistent organochlorine pesticides (OCPs) and ALS risk among cases from the Centers for Disease Control and Prevention National ALS Registry and age, sex, and county-matched controls. Methods Participants completed a risk factor survey and provided a blood sample for OCP measurement. ALS cases were confirmed through the Registry. Conditional logistic regression assessed associations between ALS and risk factors including OCP levels. Results 243 matched case-control pairs (61.7% male, mean [SD] age = 62.9 [10.1]) were included. Fifteen of the 29 OCPs examined had sufficient detectable levels for analysis. Modest correlations of self-reported years of exposure to residential pesticide mixtures and OCP serum levels were found (p<.001). Moreover, occupational exposure to lead including soldering and welding with lead/metal dust and use of lead paint/gasoline were significantly related to ALS risk (OR = 1.77, 95% CI: 1.11-2.83). Avocational gardening was a significant risk factor for ALS (OR = 1.57, 95% CI: 1.04-2.37). ALS risk increased for each 10 ng/g of α-Endosulfan (OR = 1.42, 95% CI: 1.14-1.77) and oxychlordane (OR = 1.24, 95% CI: 1.01-1.53). Heptachlor (detectable vs. nondetectable) was also associated with ALS risk (OR = 3.57, 95% CI: 1.50-8.52). Conclusion This national case-control study revealed both survey and serum levels of OCPs as risk factors for ALS. Despite the United States banning many OCPs in the 1970s and 1980s, their use abroad and long half-lives continue to exert possible neurotoxic health effects.

Incidence of amyotrophic lateral sclerosis before and during the COVID-19 pandemic: evidence from an 8-year population-based study in Central Italy based on healthcare utilization databases

Background Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder with a high multidimensional burden, with an obscure etiopathogenesis. Methods We designed a longitudinal, population-based study of people residing in Central Italy (Marche Region) who were beneficiaries of the National Health System. People with an unprecedented ALS hospitalization (335.20 ICD-9 CM) or tagged with an ALS exemption between 2014 and 2021 were considered incident cases. ALS cases residing in the region for <3 years or with an active ALS exemption or hospitalized for ALS before 2014 were excluded. We used secondary sources to identify new ALS diagnoses. The regional referral center for ALS’s database was used to test the accuracy of secondary sources in detecting cases. ALS mean incidence was compared to that reported in similar studies conducted in Italy. The incidence rate trend adjusted by sex and age was evaluated using the Poisson regression model. Results We detected 425 new ALS cases (median age: 70y) in the 2014–2021 period, with a mean incidence of 3.5:100,000 py (95%CI: 3.2–3.8; M:F = 1.2), similar to that reported in similar studies conducted in Italy. No trend was observed during 2014–2019. After including 2020–2021 in the model, we observed a mean decrease in incidence of 5.8% (95% CI 2.0%; 9.5%, p = 0.003). Conclusion We show a decrease in the incidence rate of ALS in Marche, during the 2014–2021 period, as a possible outcome of a delayed neurological assessment and diagnosis during the pandemic. An ad hoc developed identification algorithm, based on healthcare utilization databases, is a valuable tool to assess the health impact of global contingencies.

Edaravone counteracts redox and metabolic disruptions in an emerging zebrafish model of sporadic ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the death of motor neurons leads to loss of muscle function. Additionally, cognitive and circadian disruptions are common in ALS patients, contributing to disease progression and burden. Most ALS cases are sporadic, and environmental exposures contribute to their aetiology. However, animal models of these sporadic ALS cases are scarce. The small vertebrate zebrafish is a leading organism to model neurodegenerative diseases; previous studies have proposed bisphenol A (BPA) or β-methylamino-l-alanine (BMAA) exposure to model sporadic ALS in zebrafish, damaging motor neurons and altering motor responses. Here we characterise the face and predictive validity of sporadic ALS models, showing their potential for the mechanistic study of ALS drugs. We phenotypically characterise the BPA and BMAA-induced models, going beyond motor activity and motor axon morphology, to include circadian, redox, proteostasis, and metabolomic phenotypes, and assessing their predictive validity for ALS modelling. BPA or BMAA exposure induced concentration-dependent activity impairments. Also, exposure to BPA but not BMAA induced motor axonopathy and circadian alterations in zebrafish larvae. Our further study of the BPA model revealed loss of habituation to repetitive startles, increased oxidative damage, endoplasmic reticulum (ER) stress, and metabolome abnormalities. The BPA-induced model shows predictive validity, since the approved ALS drug edaravone counteracted BPA-induced motor phenotypes, ER stress, and metabolic disruptions. Overall, BPA exposure is a promising model of ALS-related redox and ER imbalances, contributing to fulfil an unmet need for validated sporadic ALS models.

Incidence of amyotrophic lateral sclerosis in Chile

Objective This study aimed to estimate amyotrophic lateral sclerosis (ALS) incidence and survival rates in the Metropolitan region of Chile. Methods We conducted a cohort study of ALS cases in the Metropolitan Region from 2016 to 2019. A total of 219 ALS patients were recruited from Corporación ELA-Chile registry, in collaboration with neurologists from Sociedad de Neurología, Psiquiatría y Neurocirugía de Chile. We calculated incidence rates by sex and age and determined median survival from onset and diagnosis. Survival analysis used the Kaplan–Meier statistic, estimating hazard ratios for age, sex, time from symptom onset and from diagnosis using a Weibull regression model. All analyses were done using R 4.1.0. Results Overall, ALS diagnosis incidence was 0.97 cases per 100,000 inhabitants, peaking in the 70–79 age group and declining thereafter. The male-to-female ratio was 1.23. The median time to death from diagnosis was 2.3 years (95% confidence interval [CI]: 1.9–2.5), and from the first symptom, it was 3.1 years (95% CI: 2.8–3.5). Conclusions This is the first population-based study reporting ALS incidence and survival rates in Chile’s Metropolitan region. Incidence resembled other Latin American studies. Median survival from diagnosis and from the first symptom were in line with previous findings. Our results corroborated lower ALS rates in Latin America, consistent with prior research.

Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS

The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS.

Genetic and in silico analysis of Indian sporadic young onset patient with amyotrophic lateral sclerosis

Background Amyotrophic lateral sclerosis (ALS) is an old onset devastating neurodegenerative disorder. Young-onset ALS cases especially sporadic ones who are between 25 and 45 years are rarely affected by the disease. Despite the identification of numerous candidate genes associated with ALS, the etiology of the disease remains elusive due to extreme genetic and phenotypic variability. The advent of affordable whole exome sequencing (WES) has opened new avenues for unraveling the disease’s pathophysiology better. Methods and results We aimed to determine the genetic basis of an Indian-origin, young onset sporadic ALS patient with very rapid deterioration of the disease course without any cognitive decline who was screened for mutations in major ALS candidate genes by WES. Variants detected were reconfirmed by Sanger sequencing. The clinicopathological features were investigated and two heterozygous missense variants were identified: R452W, not previously associated with ALS, present in one of the four conserved C terminal domains in ANXA11 and R208W in SIGMAR1, respectively. Both of these variants were predicted to be damaging by pathogenicity prediction tools and various in silico methods. Conclusion Our study revealed two potentially pathogenic variants in two ALS candidate genes. The genetic makeup of ALS patients from India has been the subject of a few prior studies, but none of them examined ANXA11 and SIGMAR1 genes so far. These results establish the framework for additional research into the pathogenic processes behind these variations that result in sporadic ALS disease and further our understanding of the genetic makeup of Indian ALS patients.

Medication use and risk of amyotrophic lateral sclerosis: using machine learning for an exposome-wide screen of a large clinical database

Background Accumulating evidence suggests that non-genetic factors have important etiologic roles in amyotrophic lateral sclerosis (ALS), yet identification of specific culprit factors has been challenging. Many medications target biological pathways implicated in ALS pathogenesis, and screening large pharmacologic datasets for signals could greatly accelerate the identification of risk-modulating pharmacologic factors for ALS. Method We conducted a high-dimensional screening of patients’ history of medication use and ALS risk using an advanced machine learning approach based on gradient-boosted decision trees coupled with Bayesian model optimization and repeated data sampling. Clinical and medication dispensing data were obtained from a large Israeli health fund for 501 ALS cases and 4,998 matched controls using a lag period of 3 or 5 years prior to ALS diagnosis for ascertaining medication exposure. Results Of over 1,000 different medication classes, we identified 8 classes that were consistently associated with increased ALS risk across independently trained models, where most are indicated for control of symptoms implicated in ALS. Some suggestive protective effects were also observed, notably for vitamin E. Discussion Our results indicate that use of certain medications well before the typically recognized prodromal period was associated with ALS risk. This could result because these medications increase ALS risk or could indicate that ALS symptoms can manifest well before suggested prodromal periods. The results also provide further evidence that vitamin E may be a protective factor for ALS. Targeted studies should be performed to elucidate the possible pathophysiological mechanisms while providing insights for therapeutics design.

Novel Pathogenic Variants Leading to Sporadic Amyotrophic Lateral Sclerosis in Greek Patients.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease that affects motor neurons, leading to paralysis and death usually 3-5 years after the onset of symptoms. The investigation of both sporadic and familial ALS highlighted four main genes that contribute to the pathogenesis of the disease: SOD1, FUS, TARDBP and C9orf72. This study aims to provide a comprehensive investigation of genetic variants found in SOD1, FUS and TARDBP genes in Greek sporadic ALS (sALS) cases. Our sequencing analysis of the coding regions of the abovementioned genes that include the majority of the variants that lead to ALS in 32 sALS patients and 3 healthy relatives revealed 6 variants in SOD1, 19 variants in FUS and 37 variants in TARDBP, of which the SOD1 p.D90A and the FUS c.*356G>A (rs886051940) variants have been previously associated with ALS, while two novel nonsense pathogenic variants were also identified, namely FUS p.R241* and TDP-43 p.Y214*. Our study contributes to the worldwide effort toward clarifying the genetic basis of sALS to better understand the disease's molecular pathology.

Microglial ferroptotic stress causes non-cell autonomous neuronal death

BackgroundFerroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.MethodsTo elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1G37R mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo.ResultsWe found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1G37R mouse model where treatment with a CNS-permeant ferroptosis inhibitor, CuII(atsm), ameliorated these markers and was neuroprotective.ConclusionsBy showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.Graphical

Incidence and prevalence of Amyotrophic Lateral Sclerosis in three Italian Regions: a study based on health administrative databases.

to estimate Amyotrophic Lateral Sclerosis (ALS) incidence and prevalence in three Italian Regions (Lazio, Tuscany, and Umbria), using health administrative databases. retrospective population-based study. ALS patients residing in Lazio, Umbria, and Tuscany were identified through an algorithm based on three different administrative databases: hospital discharge records, exemptions from health care co-payment, and emergency departments (study period 2014-2019). Crude, age- and gender-specific prevalence were calculated on 31.12.2019 and incidence rates of ALS were standardised by region, year, and gender between 2014-2019. Using a clinical dataset available in the Lazio Region, the proportion of individuals residing in the region correctly identified as ALS cases by the algorithm were calculated. prevalence and incidence rates. a total of 1,031 ALS patients (>=18 years) were identified: 408 cases in Tuscany, 546 in Lazio, and 77 in Umbria. ALS standardised prevalence (per 100,000) was similar among regions: 12.31 in Tuscany, 11.52 in Lazio, and 9.90 in Umbria. The 5-year crude rates were higher in men, and in people aged 65-79 years. Among 310 patients included in the clinical dataset, 263 (84.8%) were correctly identified by the algorithm based on health administrative databases. ALS prevalence and incidence in three Central Italy Regions are rather similar, but slightly higher than those previously reported. This finding is plausible, given that previous results relate to at least ten years ago and evidenced increasing trends. Overall, the results of this paper encourage the use of administrative data to produce occurrence estimates, useful to both epidemiological surveillance and research and healthcare policies.

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS.

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, "S-XL6," was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A's in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS.

Using an expanded algorithm to estimate prevalence of amyotrophic lateral sclerosis in U.S. and UK.

There is an increasing need to better understand the burden of amyotrophic lateral sclerosis (ALS) using real-world data (RWD). However, identifying ALS cases using RWD presents several challenges due to the rarity of ALS and the differences in database coding systems. MarketScan claims, and the UK Clinical Practice Research Datalink (CPRD) databases were searched for diagnosis codes of ALS or MND, the only drugs approved for treating ALS (riluzole and edaravone) and clinical visits with 12-month enrolment prior to 1 January 2011. The main algorithm required ≥ 1 ALS diagnosis code together with prescriptions or clinical visits. We expanded the existing algorithm to identify unspecific (possible) ALS group that had codes for motor neuron disease (MND) and the ALS drugs. The study period was from 1 January 2011 until 31 December 2020. We identified 16,246 patients with ≥ 1 ALS code in Marketscan (denominator n = 85,279,619), yet only 184 were found in the UK CPRD (denominator n = 21,318,589). Using the main algorithm 9,433 ALS patients were included in MarketScan, with a prevalence ranged between 4.5 per 100,000 in 2019 and 6.2 in 2015. In MarketScan, 3,658 (4.3 per 100,000) had ≥ 1 MND code and the ALS drug codes (possible cases). In CPRD, 47.9% of 2,785 patients with ≥ 1 MND code had a prescription for riluzole (6.3 per 100,000), regarded as possible ALS cases. The expanded algorithm enabled the identification of a large population with ALS, or possible ALS, and the estimation of ALS prevalence in MarketScan and CPRD.

DNA methylome, R-loop and clinical exome profiling of patients with sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the death of motor neurons, the aetiology of which is essentially unknown. Here, we present an integrative epigenomic study in blood samples from seven clinically characterised sporadic ALS patients to elucidate molecular factors associated with the disease. We used clinical exome sequencing (CES) to study DNA variants, DNA-RNA hybrid immunoprecipitation sequencing (DRIP-seq) to assess R-loop distribution, and reduced representation bisulfite sequencing (RRBS) to examine DNA methylation changes. The above datasets were combined to create a comprehensive repository of genetic and epigenetic changes associated with the ALS cases studied. This repository is well-suited to unveil new correlations within individual patients and across the entire patient cohort. The molecular attributes described here are expected to guide further mechanistic studies on ALS, shedding light on the underlying genetic causes and facilitating the development of new epigenetic therapies to combat this life-threatening disease.

Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.

Persistence of Kii amyotrophic lateral sclerosis after the 2000s and its characteristic aging-related tau astrogliopathy.

Kii amyotrophic lateral sclerosis (ALS) is a unique disease that occurs in the southern portion of the Kii Peninsula and exhibits a dual pathology of TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy and tauopathy. The incidence of ALS in this region was very high in the 1960s, briefly decreased through the 1980s, but began increasing again after 2000 with a change of high-concentration geographic foci. It is unclear, however, whether the unique pathological features have changed along with the incidence changes. This study analyzed postmortem specimens from neuropathologically confirmed Kii ALS cases from the 1970s (n = 4) and those after 1999 (n = 12) from the southern Kii Peninsula or outside of the area. Our results confirm the continued occurrence of Kii ALS after 2000 in the southern Kii Peninsula and the preservation of disease-specific neuronal tau pathology, including the widespread occurrence throughout the brain and spinal cord, sparse neuropil threads, and predominance in superficial layers. Furthermore, we assessed the glial tau pathology of Kii and non-Kii ALS in accordance with the aging-related tau astrogliopathy classification method for the first time and detected a unique brainstem predominant appearance of gray matter aging-related tau astrogliopathy in Kii ALS cases, which may provide clues to pathogenetic mechanisms.

Epidemiology of amyotrophic lateral sclerosis in the Krasnoyarsk region

Background. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes paralysis of muscles due to degeneration of motor neurons. According to available data, the incidence of ALS in different regions of the world is from 0.6 to 3.8 per 100,000 population per year. Data obtained during the study of the epidemiology of ALS at the regional level can be used in planning medical resources, in particular, calculating the necessary respiratory equipment and funds for nutritional support.Aim. Clinical and epidemiological analysis of ALS cases registered in the Krasnoyarsk region for the period 2018–2022.Materials and methods. A clinical and epidemiological analysis of ALS cases registered in the Krasnoyarsk region from 2018 to 2022 was conducted. To do this, we used data from the specialized office of neuromuscular pathology of the Regional Clinical Hospital in Krasnoyarsk and the Krasnoyarsk Regional Medical Information and Analytical Center. Diagnosis verification was carried out in accordance with the generally accepted El Escorial and Gold Coast criteria. The functional state and degree of neurological deficit were assessed using the ALS-FRS-R scale.Results. Over the period from 2018 to 2022, 78 cases of ALS were registered. The incidence rate was 0.54 cases per 100,000 population per year. In 2022, the prevalence rate was 1.16 cases per 100 thousand population. The time from symptom onset to diagnosis of the disease ranged from 4 to 57 months, with the average time to diagnosis being 17 months. Most patients were diagnosed with ALS when their ALS-FRS-R score decreased by 7–11 points. The division of patients into groups of rapid, moderate, and slow diagnostic correlates with life expectancy. Patients who are diagnosed quickly have a higher rate of disease progression, which results in a low life expectancy.Conclusion. The creation of specialized centers will improve the diagnosis and management of patients with ALS and plan the costs of palliative care. The increase in the incidence and detection of ALS emphasizes the need to develop new approaches to the treatment and rehabilitation of patients with ALS.

A case of amyotrophic lateral sclerosis managed by tracheostomy and invasive ventilation in which air leaks occurred at the cuff

The patient was a 64-year-old woman who had been diagnosed with amyotrophic lateral sclerosis 8 years ago, and had been under artificial ventilation with tracheotomy for 6 years. Computed tomography indicated a dilated tracheal diameter of 29.6 ‍mm at the cuff, and a high cuff pressure of 80 ‍cmH2O. An adjustable flange tracheostomy tube with an optional length setting was used to extend the effective length by 28 ‍mm. A previously evident air leak disappeared with the change in cuff level, and cuff pressure decreased to 25 ‍cmH2O. X-ray images indicated a reduction in the size of the previous cuff area. Tracheal dilatation due to improper management of cuff pressure is a contributing factor to air leakage at the cuff area, and using an adjustable flange tracheostomy tube in an effort to resolve such air leaks is a valid option.

Amyotrophic lateral sclerosis associated with a new pathogenic variant of the ERBB4 gene

Amyotrophic lateral sclerosis (ALS) is a sporadic disease in most of the cases; in 10-15% of cases genetic forms are recorded. A genetic form of ALS associated with the mutation in the ERBB4 gene (ALS19) has been reported in 2013. A protein encoded by the ERBB4 is probably involved in ubiquitous component of the pathogenesis of ALS. We present a case of ALS associated with a new pathogenic variant of the ERBB4 gene, with early bulbar onset and slow progression of the disease within 10 years.

Drug Screening and Validation Targeting TDP-43 Proteinopathy for Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) stands as a rare, yet severely debilitating disorder marked by the deterioration of motor neurons (MNs) within the brain and spinal cord, which is accompanied by degenerated corticobulbar/corticospinal tracts and denervation in skeletal muscles. Despite ongoing research efforts, ALS remains incurable, attributed to its intricate pathogenic mechanisms. A notable feature in the pathology of ALS is the prevalence of TAR DNA-binding protein 43 (TDP-43) proteinopathy, detected in approximately 97% of ALS cases, underscoring its significance in the disease's progression. As a result, strategies targeting the aberrant TDP-43 protein have garnered attention as a potential avenue for ALS therapy. This review delves into the existing drug screening systems aimed at TDP-43 proteinopathy and the models employed for drug efficacy validation. It also explores the hurdles encountered in the quest to develop potent medications against TDP-43 proteinopathy, offering insights into the intricacies of drug discovery and development for ALS. Through this comprehensive analysis, the review sheds light on the critical aspects of identifying and advancing therapeutic solutions for ALS.

Premorbid lipid levels and long-term risk of ALS—a population-based cohort study

Objective To assess the temporal relationship between premorbid lipid levels and long-term amyotrophic lateral sclerosis (ALS) risk. Methods From Norwegian cardiovascular health surveys (1974–2003), we collected information on total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose, and other cardiovascular risk factors. ALS incidence and mortality were identified through validated Norwegian health registries. The relation between premorbid lipid levels and ALS risk was assessed by Cox regression models. Results Out of 640,066 study participants (51.5% females), 974 individuals (43.5% females) developed ALS. Mean follow-up time was 23.7 (SD 7.1) years among ALS cases. One mmol/l increase in LDL-C was associated with 6% increase in risk for ALS (hazard ratio 1.06 [95% CI: 1.01–1.09]). Higher levels of TC and TG were also associated with increased ALS risk, but only within the last 6–7 years prior to ALS diagnosis or death. No association between HDL-C and ALS risk was found. Adjusting for body mass index, birth cohort, smoking, and physical activity did not alter the results. Conclusions Higher levels of LDL-C are associated with increased ALS risk over 40 years later, compatible with a causal relationship. The temporal relationship between TG, TC, and ALS risk suggests that increased levels of these lipid biomarkers represent consequences of ALS.