Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive. AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms. MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L = 5.46 mg/ml, SSP-M = 10.92 mg/ml or SSP-H = 16.38 mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin & Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1G93A NSC-34 cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway. RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1ß mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-ß mRNA, but also the levels of cGAS and STING protein in hSOD1G93A NSC-34 cells. CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.

Investigating the impact of socioeconomic status on amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the gradual death of motor neurons in the brain and spinal cord, leading to fatal paralysis. Socioeconomic status (SES) is a measure of an individual's shared economic and social status, which has been shown to have an association with health outcomes. Understanding the impact of SES on health conditions is crucial, as it can influence and be influenced by health-related variables. The role of socioeconomic status in influencing the risk and progression of ALS has not been established, and understanding the various factors that impact ALS is important in developing strategies for treatment and prevention. To investigate this relationship, we recruited 413 participants with definite, probable, or possible ALS according to the El Escorial criteria, from three tertiary centers in London, Sheffield, and Birmingham. Logistic regression was used to examine the association between case-control status, socioeconomic criteria, and ALS risk. Linear regression was used to examine the association between age of onset and socioeconomic variables. Two sensitivity analyses were performed, one using an alternative occupational classifier, and the other using Mendelian Randomization analysis to examine association. There was no significant relationship between any variables and ALS risk. We found an inverse relationship between mean lifetime salary and age of ALS onset (Beta = -0.157, p = 0.011), but no effect of education or occupation on the age of onset. The finding was confirmed in both sensitivity analyses and in Mendelian Randomization. We find that a higher salary is associated with a younger age of ALS onset taking into account sex, occupation, years of education, and clinical presentation.

Initiation of noninvasive ventilation in patients with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Noninvasive ventilation (NIV) has been shown to improve survival and symptom burden in patients with amyotrophic lateral sclerosis (ALS). However, limited data exist regarding the clinical and physiological parameters at the time of NIV initiation. This study aimed to describe the clinical characteristics and respiratory physiological markers in a cohort of ALS patients with chronic respiratory failure. METHODS: This is a single-center retrospective cohort study of patients with ALS assessed for NIV initiation between February 2012 and January 2021. NIV was initiated based on insurance eligibility criteria: daytime hypercapnia, defined by partial pressure of carbon dioxide (PaCO2) >45 mm Hg using diurnal transcutaneous CO2 (TcCO2) as a surrogate, a maximal inspiratory pressure (MIP) <60 cmH2O or forced vital capacity (FVC) <50% predicted normal. RESULTS: We identified 335 patients with ALS and chronic respiratory failure referred to an outpatient home ventilation clinic for NIV initiation. The mean age was 64 years ±11; 151 (45%) were female, 326 (97%) were white, and 100 (29%) had bulbar-onset ALS. At the time of NIV initiation, the mean FVC was 64% ± 19%, the mean MIP; 41 cmH2O ± 17, and diurnal TcCO2; 40 ± 6 mmHg. The most common reasons for NIV initiation were MIP <60 cmH2O (58%) and multiple concomitant indications (28%). Within 1 year of NIV initiation, 126 (37%) patients were deceased. DISCUSSION: We found that impairment in inspiratory force was the most common reason for NIV initiation and often preceded significant declines in FVC.

Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs.

A hexanucleotide (G4C2) repeat expansion (HRE) within intron one of C9ORF72 is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9ORF72 haploinsufficiency, formation of RNA foci, and production of dipeptide repeat (DPR) proteins have been proposed as mechanisms of disease. Here, we report the first example of disease-modifying siRNAs for C9ORF72 driven ALS/FTD. Using a combination of reporter assay and primary cortical neurons derived from a C9-ALS/FTD mouse model, we screened a panel of more than 150 fully chemically stabilized siRNAs targeting different C9ORF72 transcriptional variants. We demonstrate the lack of correlation between siRNA efficacy in reporter assay versus native environment; repeat-containing C9ORF72 mRNA variants are found to preferentially localize to the nucleus, and thus C9ORF72 mRNA accessibility and intracellular localization have a dominant impact on functional RNAi. Using a C9-ALS/FTD mouse model, we demonstrate that divalent siRNAs targeting C9ORF72 mRNA variants specifically or non-selectively reduce the expression of C9ORF72 mRNA and significantly reduce DPR proteins. Interestingly, siRNA silencing all C9ORF72 mRNA transcripts was more effective in removing intranuclear mRNA aggregates than targeting only HRE-containing C9ORF72 mRNA transcripts. Combined, these data support RNAi-based degradation of C9ORF72 as a potential therapeutic paradigm.

Longitudinal analysis of glymphatic function in amyotrophic lateral sclerosis and primary lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central in the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we perform a longitudinal analysis of glymphatic function in ALS and compare it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analyzed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate), and white matter hyperintensity (WMH) burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared to PLS and control participants across all three time points. There was no association with clinical factors, however the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis.

Improving prediction models of amyotrophic lateral sclerosis (ALS) using polygenic, pre-existing conditions, and survey-based risk scores in the UK Biobank.

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function, and a cure for this devastating disease remains elusive. This study aimed to identify pre-disposing genetic, phenotypic, and exposure-related factors for amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential. METHODS: Utilizing data from the UK (United Kingdom) Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates. RESULTS: Both PRSs modestly predicted ALS diagnosis but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1 year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved the prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a fourfold higher ALS risk (95% CI [2.04, 7.73]) versus those in the 40%-60% range. DISCUSSION: By leveraging UK Biobank data, our study uncovers pre-disposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.

TwinF interface inhibitor FP802 prevents retinal ganglion cell loss in a mouse model of amyotrophic lateral sclerosis.

Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1G93A, we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1G93A mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention.

Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS. METHODS: A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications. RESULTS: Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L = 1.07, 95%CI:1.02-1.12; I 2 =18%) and lower HDL-c (HRper mmol/L = 0.83, 95%CI:0.74-0.94; I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW = 1.085, 95%:CI 1.008-1.168, pFDR = 0.0406), total cholesterol (ORIVW = 1.081, 95%:CI 1.013-1.154, pFDR = 0.0458) and apolipoprotein B (ORIVW = 1.104, 95%:CI 1.041-1.171, pFDR = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW = 1.424, 95%CI 1.072-1.829, pFDR = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759-0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387-0.874, pFDR = 0.0362). CONCLUSION: These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.

ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. Currently mutations in > 40 genes have been linked to ALS, but the contribution of many genes and genetic mutations to the ALS pathogenic process remains poorly understood. Therefore, we first performed comparative interactome analyses of five recently discovered ALS-associated proteins (C21ORF2, KIF5A, NEK1, TBK1, and TUBA4A) which highlighted many novel binding partners, and both unique and shared interactors. The analysis further identified C21ORF2 as a strongly connected protein. The role of C21ORF2 in neurons and in the nervous system, and of ALS-associated C21ORF2 variants is largely unknown. Therefore, we combined human iPSC-derived motor neurons with other models and different molecular cell biological approaches to characterize the potential pathogenic effects of C21ORF2 mutations in ALS. First, our data show C21ORF2 expression in ALS-relevant mouse and human neurons, such as spinal and cortical motor neurons. Further, the prominent ALS-associated variant C21ORF2-V58L caused increased apoptosis in mouse neurons and movement defects in zebrafish embryos. iPSC-derived motor neurons from C21ORF2-V58L-ALS patients, but not isogenic controls, show increased apoptosis, and changes in DNA damage response, mitochondria and neuronal excitability. In addition, C21ORF2-V58L induced post-transcriptional downregulation of NEK1, an ALS-associated protein implicated in apoptosis and DDR. In all, our study defines the pathogenic molecular and cellular effects of ALS-associated C21ORF2 mutations and implicates impaired post-transcriptional regulation of NEK1 downstream of mutant C21ORF72 in ALS.

Different patterns of structural network impairments in two amyotrophic lateral sclerosis subtypes driven by 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging.

The structural network damages in amyotrophic lateral sclerosis patients are evident but contradictory due to the high heterogeneity of the disease. We hypothesized that patterns of structural network impairments would be different in amyotrophic lateral sclerosis subtypes by a data-driven method using 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging. The data of positron emission tomography, structural MRI and diffusion tensor imaging in fifty patients with amyotrophic lateral sclerosis and 23 healthy controls were collected by a 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid. Two amyotrophic lateral sclerosis subtypes were identified as the optimal cluster based on grey matter volume and standardized uptake value ratio. Network metrics at the global, local and connection levels were compared to explore the impaired patterns of structural networks in the identified subtypes. Compared with healthy controls, the two amyotrophic lateral sclerosis subtypes displayed a pattern of a locally impaired structural network centralized in the sensorimotor network and a pattern of an extensively impaired structural network in the whole brain. When comparing the two amyotrophic lateral sclerosis subgroups by a support vector machine classifier based on the decreases in nodal efficiency of structural network, the individualized network scores were obtained in every amyotrophic lateral sclerosis patient and demonstrated a positive correlation with disease severity. We clustered two amyotrophic lateral sclerosis subtypes by a data-driven method, which encompassed different patterns of structural network impairments. Our results imply that amyotrophic lateral sclerosis may possess the intrinsic damaged pattern of white matter network and thus provide a latent direction for stratification in clinical research.

The cross-sectional area of the median nerve: An independent prognostic biomarker in amyotrophic lateral sclerosis.

INTRODUCTION: Ultrasound changes in the cross-sectional area of the median nerve (CSAmn) could be of interest as biomarkers in patients with amyotrophic lateral sclerosis (ALS). METHODS: Eighty-four ALS patients (51 men [60.7%]; mean 62.0 [SD 11.46] years old) and forty-six controls (27 men [58.7%]; mean 59.9 [SD 8.08] years old) of two different cohorts were recruited between September 2013 and February 2018. The CSAmn was measured bilaterally in each cohort, by two different examiners with two different ultrasound machines (one in each cohort). Its association with clinical variables (disease duration, muscle strength, disability, progression rate and tracheostomy-free survival) was assessed. RESULTS: The CSAmn was smaller in patients than in controls, and the study cohort did not influence its values. A mild correlation between the strength of the wrist flexor and the CSAmn was found. In the multivariable analysis, the probability of this association being true was 90%. In the cox regression, both a faster progression rate and a larger CSAmn independently predicted poor survival (HR=4.29, [Cr.I95%: 2.71-6.80], p<0.001; and HR=1.14, [Cr.I95%: 1.03-1.25], p=0.01), after adjusting by age, body mass index, bulbar onset, and diagnostic delay. CONCLUSIONS: The CSAmn is an easy to assess biomarker that seems reliable and reproducible. Our data also suggest that it could act as a progression and prognostic biomarker in ALS patients. Longitudinal studies with repeated measures are warranted to confirm its usefulness in the clinical practice.

Impact of SARS-CoV-2 infection and COVID-19 pandemic on the morbidity and mortality of amyotrophic lateral sclerosis patients in Valencia, Spain.

BACKGROUND AND PURPOSE: The purpose was to describe the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization for coronavirus disease 2019 (COVID-19) and related death and to assess the impact of the pandemic in the survival of amyotrophic lateral sclerosis (ALS) patients. METHODS: The risk of SARS-CoV-2 infection, hospitalization for COVID-19 and related death was assessed in ALS patients alive between March 2020 and July 2022. To evaluate its impact in the overall survival of ALS patients, the survival of patients who died before and during the pandemic was compared. RESULTS: Amongst 263 ALS patients alive during the pandemic, 62 got infected during the study period (infection rate 14.34 per 100 person-years). Most infections (68%) occurred during the sixth wave (November 2021 to January 2022) and most patients (67%) were vaccinated at the time of infection. The hospitalization rate due to COVID-19 was 4.16 per 100 person-years. The multivariable model confirmed non-invasive ventilation (NIV) use prior to infection as a risk factor for hospitalization (odds ratio [OR] = 7.96, p = 0.003) and COVID-19 vaccination as a protective factor (OR = 0.093, p = 0.025) independent of age, sex and gastrostomy. Within 30 days after infection, 7% of non-ventilated patients started NIV and five patients (8.06%) died, of whom four were previously ventilated. The median survival of ALS patients was similar before and during the pandemic and no effect was found in the Cox regression model (hazard ratio 1.02, p = 0.89). CONCLUSIONS: This study shows a high risk of severe COVID-19 amongst ALS patients requiring NIV. Nevertheless, the pandemic showed no impact in the overall survival of ALS patients, probably due to a high vaccination rate and an adequate access to healthcare resources.

Prevalence and motor-functional correlates of frontotemporal-spectrum disorders in a large cohort of non-demented ALS patients.

BACKGROUND: This study aimed at (1) delivering generalizable estimates of the prevalence of frontotemporal-spectrum disorders (FTSDs) in non-demented ALS patients and (2) exploring their motor-functional correlates. METHODS: N = 808 ALS patients without FTD were assessed for motor-functional outcomes-i.e., disease duration, severity (ALSFRS-R), progression rate (ΔFS), and stage (King's and Milano-Torino-MiToS-systems)-cognition-via the cognitive section of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-via the ECAS-Carer Interview. Neuropsychological phenotypes were retrieved via Strong's revised criteria-i.e., ALS cognitively and behaviourally normal (ALScbn) or cognitively and/or behaviourally impaired (ALSci/bi/cbi). RESULTS: Defective ECAS-Total performances were detected in ~ 29% of patients, with the ECAS-Executive being failed by the highest number of patients (~ 30%), followed by the ECAS-Language, -Fluency, and -Memory (~ 15-17%) and -Visuospatial (~ %8). Apathy was the most frequent behavioural change (~ 28%), followed by loss of sympathy/empathy (~ 13%); remaining symptoms were reported in < 4% of patients. The distribution of Strong's classifications was as follows: ALScbn: 46.7%; ALSci/bi/cbi: 22.9%/20.0%/10.4%. Multinomial regressions on Strong's classifications revealed that lower ALSFRS-R scores were associated with a higher probability of ALSbi and ALScbi classifications (p ≤ .008). Higher King's and MiToS stages were associated with a higher probability of ALSbi classification (p ≤ .031). CONCLUSIONS: FTSDs affect ~ 50% of non-demented ALS patients, with cognitive deficits being as frequent as behavioural changes. A higher degree of motor-functional involvement is associated with worse behavioural outcomes-with this link being weaker for cognitive deficits.

Comparative analysis of in situ and ex situ postmortem brain MRI: Evaluating volumetry, DTI, and relaxometry.

PURPOSE: To compare postmortem in situ with ex situ MRI parameters, including volumetry, diffusion tensor imaging (DTI), and relaxometry for assessing methodology-induced alterations, which is a crucial prerequisite when performing MRI biomarker validation. METHODS: MRI whole-brain scans of five deceased patients with amyotrophic lateral sclerosis were performed at 3 T. In situ scans were conducted within 32 h after death (SD 18 h), and ex situ scans after brain extraction and 3 months of formalin fixation. The imaging protocol included MP2RAGE, DTI, and multi-contrast spin-echo and multi-echo gradient-echo sequences. Volumetry, fractional anisotropy, mean diffusivity, T1, T2, and T 2 * $$ {T}_2^{\ast } $$ have been assessed for specific brain regions. RESULTS: When comparing ex situ to in situ values, the following results were obtained. Deep gray matter as well as the thalamus and the hippocampus showed a reduced volume. Fractional anisotropy was reduced in the cortex and the whole brain. Mean diffusivity was decreased in white matter and deep gray matter. T1 and T2 were reduced in all investigated structures, whereas T 2 * $$ {T}_2^{\ast } $$ was increased in the cortex. CONCLUSION: The results of this study show that the volumes and MRI parameters of several brain regions are potentially affected by tissue extraction and subsequent formalin fixation, suggesting that methodological alterations are present in ex situ MRI. To avoid overlap of indistinguishable methodological and disease-related changes, we recommend performing in situ postmortem MRI as an additional intermediate step for in vivo MRI biomarker validation.

A scoping review of the role of managed entry agreements in upcoming drugs for amyotrophic lateral sclerosis: learning from the case of spinal muscular atrophy.

Introduction: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure for amyotrophic lateral sclerosis (ALS). The clinical and economic uncertainty surrounding innovative treatments for rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). The aim of this study was to review whether models of MEAs in SMA could be extrapolated to ALS. Methods: We performed a scoping review with information on MEAs on SMA in Web of Science (WOS), PubMed, Lyfegen Library, the National Institute for Health and Care Excellence (NICE), and the Canadian Agency for Drugs and Technologies in Health (CADTH). Results: We found 45 results in WOS and PubMed. After an initial survey, 10 were reviewed to assess eligibility, and three were selected. We obtained 44 results from Lyfegen Library, and three results each from NICE and CADTH. Conclusion: The main objective of MEAs is to reduce uncertainty in the financing of drugs with a high budgetary impact and clinical concerns, as is the case with drugs for SMA and ALS. While the information available on MEAs in SMA is scarce, some conceptual models are publicly available. MEAs for long-term treatments for SMA could be used for the design of MEAs in ALS because of their similarities in economic and clinical uncertainty.

Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.

Disrupted copper availability in the central nervous system (CNS) is implicated as a significant feature of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Solute carrier family 31 member 1 (Slc31a1; Ctr1) governs copper uptake in mammalian cells and mutations affecting Slc31a1 are associated with severe neurological abnormalities. Here, we examined the impact of decreased CNS copper caused by ubiquitous heterozygosity for functional Slc31a1 on spinal cord motor neurons in Slc31a1+/- mice. Congruent with the CNS being relatively susceptible to disrupted copper availability, brain and spinal cord tissue from Slc31a1+/- mice contained significantly less copper than wild-type littermates, even though copper levels in other tissues were unaffected. Slc31a1+/- mice had less spinal cord α-motor neurons compared to wild-type littermates, but they did not develop any overt physical signs of motor impairment. By contrast, ALS model SOD1G37R mice had fewer α-motor neurons than control mice and exhibited clear signs of motor function impairment. With the expression of Slc31a1 notwithstanding, spinal cord expression of genes related to copper handling revealed only minor differences between Slc31a1+/- and wild-type mice. This contrasted with SOD1G37R mice where changes in the expression of copper handling genes were pronounced. Similarly, the expression of genes related to toxic glial activation was unchanged in spinal cords from Slc31a1+/- mice but highly upregulated in SOD1G37R mice. Together, results from the Slc31a1+/- mice and SOD1G37R mice indicate that although depleted CNS copper has a significant impact on spinal cord motor neuron numbers, the manifestation of overt ALS-like motor impairment requires additional factors.

Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model.

Neuroinflammation is a miscreant in accelerating progression of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, treatments targeting neuroinflammation alone have led to disappointing results in clinical trials. Both neuronal and non-neuronal cell types have been implicated in the pathogenesis of ALS, and multiple studies have shown correction of each cell type has beneficial effects on disease outcome. Previously, we shown that AAV9-mediated superoxide dismutase 1 (SOD1) suppression in motor neurons and astrocytes significantly improves motor function and extends survival in ALS mouse models. Despite neuron and astrocyte correction, ALS mice still succumb to death with microgliosis observed in endpoint tissue. Therefore, we hypothesized that the optimal therapeutic approach will target and simultaneously correct motor neurons, astrocytes, and microglia. Here, we developed a novel approach to indirectly target microglia with galectin-1 (Gal1) and combined this with our previously established AAV9.SOD1.short hairpin RNA treatment. We show Gal1 conditioning of SOD1 G93A microglia decreases inflammatory markers and rescues motor neuron death in vitro. When paired with SOD1 downregulation, we found a synergistic effect of combination treatment in vivo and show a significant extension of survival of SOD1 G93A mice over SOD1 suppression alone. These results highlight the importance of targeting inflammatory microglia as a critical component in future therapeutic development.

C9orf72 repeat expansions in Wakayama: One potential cause of amyotrophic lateral sclerosis in the Kii Peninsula, Japan.

A cluster of cases of amyotrophic lateral sclerosis (ALS) exists in the southern part of the Kii Peninsula in Japan. Although both genetic and environmental factors are thought to be causative, the critical cause of this cluster has not been identified. C9orf72 is the most common genetic factor in both familial and sporadic C9orf72-related ALS in people of European ancestry, but it is rare among Japanese populations. However, a previous report revealed that the frequency of C9orf72-related ALS was significantly higher in the cluster area. We evaluated the proportion of C9orf72 hexanucleotide repeat expansions in 99 cases of ALS diagnosed in Wakayama Prefecture, including the cluster area, by using repeat-primed polymerase chain reaction and fluorescence fragment length analysis. We found that 2 of the 99 patients (0 % of those with familial ALS and 2.4 % of those with sporadic ALS) had hexanucleotide repeat expansions in C9orf72, and long-read sequencing revealed that these expansions were causative. No expansions were observed among 90 patients with Parkinson's disease or among 90 healthy controls. Haplotype analysis with long-read sequencing data revealed that the two patients with repeat expansions shared the common haplotype with that previously reported in Finnish patients with C9orf72-related ALS, which suggests a founder effect. C9orf72 was thought to be a rare causative gene in Japan, but this study revealed that it may be relatively common in Wakayama Prefecture.

Effects of COVID-19 on motor neuron disease mortality in the United States: a population-based cross-sectional study.

BACKGROUND: In March 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) to be a pandemic, stating that those with underlying health conditions are most susceptible, including motor neuron disease (MND). OBJECTIVE: To examine the effect the COVID-19 pandemic had on deaths from MND in the United States. METHODS: Death certificate data for all MND deaths aged 20 years and older were analyzed from 2017 to 2019 (pre-COVID), then expanded to include 2020 and 2021 (COVID) deaths to evaluate if COVID-19 impacted MND deaths. RESULTS: The average number of MND deaths documented during the COVID-19 years was 8009, up from 7485 MND deaths pre-COVID. The age-adjusted mortality rate among the non-Hispanic population increased during COVID to 2.78 per 100,000 persons (95% CI = 2.73-2.82) from 1.81 (95% CI = 1.78-1.84). The Hispanic population also saw an increase in mortality rate during COVID (1.61, 95% CI = 1.51-1.71) compared with pre-COVID (1.10, 95% CI = 1.03-1.17). Decedent's home as a place of death also saw a mortality rate increase during COVID (1.51, 95% CI = 1.48-1.54) compared with pre-COVID (1.30, 95% CI = 1.27-1.32). For the Hispanic population, the rate peaked at 80-84 years pre-COVID, but for the COVID years, the rate peaked earlier, at 75-79 years. CONCLUSION: The total number of MND deaths was greater during COVID than in the preceding years. The analysis suggests there might have been a consequence of circumstances surrounding the global pandemic and the associated restrictions.

Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions.

Short tandem repeat expansions in the human genome are overrepresented in a variety of neurological disorders. It was recently shown that huntingtin (HTT) repeat expansions with full penetrance, i.e. 40 or more CAG repeats, which normally cause Huntington's disease (HD), are overrepresented in patients with amyotrophic lateral sclerosis (ALS). Whether patients carrying HTT repeat expansions with reduced penetrance, (36-39 CAG repeats), or alleles with intermediate penetrance, (27-35 CAG repeats), have an increased risk of ALS has not yet been investigated. Here, we examined the role of HTT repeat expansions in a motor neuron disease (MND) cohort, searched for expanded HTT alleles, and investigated correlations with phenotype and neuropathology. MND patients harboring C9ORF72 hexanucleotide repeat expansions (HREs) were included, to investigate whether HTT repeat expansions were more common in this group. We found a high prevalence of intermediate (range 5.63%-6.61%) and reduced penetrance (range 0.57%-0.66%) HTT gene expansions in this cohort compared to other populations of European ancestry, but no differences between the MND cohort and the control cohort were observed, regardless of C9ORF72HRE status. Upon autopsy of three patients with intermediate or reduced penetrance HTT alleles, huntingtin inclusions were observed in the caudate nucleus and frontal lobe, but no significant somatic mosaicism was detected in different parts of the nervous system. Thus, we demonstrate, for the first time, huntingtin inclusions in individuals with MND and intermediate and reduced penetrance HTT repeat expansions but more clinicopathological investigations are needed to further understand the impact of HTT gene expansion-related pleiotropy.