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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder involving loss of upper and lower motor neurons, with most cases ending in death within 3-5 years of onset. Several molecular and cellular pathways have been identified to cause ALS; however, treatments to stop or reverse disease progression are yet to be found. Riluzole, a neuroprotective agent offering only a modest survival benefit, has long been the sole disease-modifying therapy for ALS. Edaravone, which demonstrated statistically significant slowing of ALS disease progression, is gaining approval in an increasing number of countries since its first approval in 2015. Sodium phenylbutyrate and taurursodiol (PB-TURSO) was conditionally approved in Canada in 2022, having shown significant slowing of disease progression and prolonged survival. Most clinical trials have focused on testing small molecules affecting common cellular pathways in ALS: targeting glutamatergic, apoptotic, inflammatory, and oxidative stress mechanisms among others. More recently, clinical trials utilizing stem cell transplantation and other biologics have emerged. This rich and ever-growing pipeline of investigational products, along with innovative clinical trial designs, collaborative trial networks, and an engaged ALS community', provide renewed hope to finding a cure for ALS. This article reviews existing ALS therapies and the current clinical drug development pipeline.

BACKGROUND AND PURPOSE There is a relative paucity of data regarding long-term outcomes and treatment-related complications in women of childbearing age with cerebral venous sinus thrombosis (CVST). We sought to determine whether outcomes differ in women of childbearing age with versus without postpartum CVST. METHODS We retrospectively analysed 373 non-pregnant females of childbearing age (18-45 years) included in the multicenter observational Anticoagulation in the Treatment of Cerebral Venous Thrombosis study (ACTION-CVT). Comparisons were made between postpartum (first 12 weeks from delivery, n=38 [10.2%]) versus non-postpartum women (n=335 [89.8%]). The primary outcomes of interest were one-year risk of all-cause death, venous thromboembolism (VTE) recurrence, and major hemorrhage (i.e., new or worsening intracranial hemorrhage or major extracranial hemorrhage). Secondary outcomes were the discharge disposition and modified Rankin Scale (mRS) score at discharge and 90 days. RESULTS Postpartum status was associated with greater risk of seizures (42.1% versus 20.9%, p=0.003), venous infarction (47.4% versus 29.5%, p=0.025), intracranial hemorrhage (55.3% versus 36.1%, p=0.022), and requirement for neurosurgical treatment (13.2% versus 3.6%, p=0.021). There was no significant association with one year all cause death (N=373 HR=1.35, 95%-CI=0.15-11.87, p=0.784), VTE recurrence (N=373, HR=1.27, 95%-CI=0.45-3.59, p=0.648), major hemorrhage (N=373, HR=1.36, 95%-CI=0.46-4.0, p=0.581) as well as excellent (mRS[0-1]: OR=1.58, 95%-CI=0.4-7.1, p=0.554) and good (mRS[0-2]: OR=0.92, 95%-CI=0.2-4.27, p=0.918) 90-day mRS. Results were similar after adjustment for potential confounders. CONCLUSIONS Although CVST in the 12-week postpartum period was more frequently associated with early complications, 90-day functional disability and one-year outcomes were similar to women with CVST unrelated to pregnancy.

Patient reported outcome measures (PROMs) can provide researchers with a direct view of patients’ experiences. They are becoming increasingly important tools for evaluating clinical care and research outcomes. There has been little data on the application of PROMs to amyotrophic lateral sclerosis (ALS) care. The objective of this study was to examine the feasibility of PROM collection in an academic ALS clinic and to measure correlations between PROMs and standard ALS clinical outcome measures. PROMs were gathered from tablet-based surveys offered to adult patients in the waiting room, prior to ALS outpatient clinic visits. They included a demographic section and two validated surveys: the patient reported outcome measurement information system (PROMIS-10), which generates physical health and mental health subscores, and the quality of life in neurological disorders-fatigue subscale (NeuroQoL-fatigue). The ALS functional rating scale-revised (ALSFRS-R) and other ALS measures were collected by clinic staff as part of routine clinical care. PROMIS-10 physical and mental health scores correlated positively with the ALSFRS-R score (physical: R = 0.85, p

Background: Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons resulting in progressive paralysis and death, typically within 3–5 years. Although the heritability of ALS is about 60%, only about 11% is explained by common gene variants, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication and shorten naturally with age. Gender and age are risk factors for ALS and also associated with telomere length. We, therefore, investigated telomere length in ALS. Methods: We estimated telomere length by applying a bioinformatics analysis to whole genome sequence data of leukocyte-derived DNA from people with ALS and age and gender-matched matched controls in a UK population. We tested the association of telomere length with ALS and ALS survival. Results: There were 1241 people with ALSand 335 controls. The median age for ALS was 62.5 years and for controls, 60.1 years, with a male–female ratio of 62:38. Accounting for age and sex, there was a 9% increase of telomere length in ALS compared to matched controls. Those with longer telomeres had a 16% increase in median survival. Of nine SNPs associated with telomere length, two were also associated with ALS: rs8105767 near the ZNF208 gene (p = 1.29 × 10 −4 ) and rs6772228 (p = 0.001), which is in an intron for the PXK gene. Conclusions: Longer telomeres in leukocyte-derived DNA are associated with ALS, and with increased survival in those with ALS.

Objective: Clinical stages in amyotrophic lateral sclerosis (ALS) can be measured using a simple system based on the number of CNS regions involved and requirement for gastrostomy or noninvasive ventilation (NIV). We aimed to design a standard operating procedure (SOP) to define the standardized use and application of the King’s staging system. Methods: We designed a SOP for the King’s staging system. We wrote case vignettes representative of ALS patients at different disease stages. During two workshops, we taught health care professionals how to use the SOP, then asked them to stage the vignettes using the SOP. We measured the extent to which SOP staging corresponded with correct clinical stage. Results: The reliability of staging using the SOP was excellent, with a Spearman’s Rank coefficient of 0.95 (p

Patient reported outcome measures (PROMs) can provide researchers with a direct view of patients' experiences. They are becoming increasingly important tools for evaluating clinical care and research outcomes. There has been little data on the application of PROMs to amyotrophic lateral sclerosis (ALS) care. The objective of this study was to examine the feasibility of PROM collection in an academic ALS clinic and to measure correlations between PROMs and standard ALS clinical outcome measures.PROMs were gathered from tablet-based surveys offered to adult patients in the waiting room, prior to ALS outpatient clinic visits. They included a demographic section and two validated surveys: the patient reported outcome measurement information system (PROMIS-10), which generates physical health and mental health subscores, and the quality of life in neurological disorders-fatigue subscale (NeuroQoL-fatigue). The ALS functional rating scale-revised (ALSFRS-R) and other ALS measures were collected by clinic staff as part of routine clinical care.PROMIS-10 physical and mental health scores correlated positively with the ALSFRS-R score (physical: R = 0.85, p 0.001; mental: R = 0.58, p = 0.02). NeuroQoL-fatigue scores were inversely correlated with the ALSFRS-R scores-higher fatigue correlated with lower function (R = - 0.72, p = 0.004).Collection of PROMs is feasible in the context of routine ALS care. PROM scores are highly correlated with validated ALS outcome measures.

Highlights • Conditioning-induced increase of phospho-αCaMKII in area CA3 is age-dependent. • Aging increases the ratio of phosphor/total αCaMKII in area CA3. • Conditioning-induced decrease of αCaMKII in lateral amygdala is age-dependent. • Aging does not impact on αCaMKII in central and basolateral amygdala., The hippocampus and amygdala are essential brain regions responsible for contextual fear conditioning (CFC). The autophosphorylation of alpha calcium-calmodulin kinase II (αCaMKII) at threonine-286 (T286) is a critical step implicated in long-term potentiation (LTP), learning and memory. However, the changes in αCaMKII levels with aging and training in associated brain regions are not fully understood. Here, we studied how aging and training affect the levels of phosphorylated (T286) and proportion of phosphorylated:total αCaMKII in the hippocampus and amygdala. Young and aged mice, naïve (untrained) and trained in CFC, were analysed by immunohistochemistry for the levels of total and phosphorylated αCaMKII in the hippocampus and amygdala. We found that two hours after CFC training, young mice exhibited a higher level of phosphorylated and increased ratio of phosphorylated:total αCaMKII in hippocampal CA3 stratum radiatum. Furthermore, aged untrained mice showed a higher ratio of phosphorylated:total αCaMKII in the CA3 region of the hippocampus when compared to the young untrained group. No effect of training or aging were seen in the central, lateral and basolateral amygdala regions, for both phosphorylated and ratio of phosphorylated:total αCaMKII. These results show that aging impairs the training-induced upregulation of autophosphorylated (T286) αCaMKII in the CA3 stratum radiatum of the hippocampus. This indicates that distinct age-related mechanisms underlie CFC that may rely more heavily on NMDA receptor-dependent plasticity in young age.