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The primary objective of this study was to determine if speech and pause measures obtained using a passage reading task and timing measures from a monosyllabic diadochokinesis (DDK) task differ across speakers of Canadian French diagnosed with amyotrophic lateral sclerosis (ALS) presenting with and without bulbar symptoms, and healthy controls. The secondary objective was to determine if these measures can reflect the severity of bulbar symptoms. A total of 29 Canadian French speakers with ALS (classified as bulbar symptomatic [n = 14] or pre-symptomatic [n = 15]) and 17 age-matched healthy controls completed a passage reading task and a monosyllabic DDK task (/pa/ and /ta/), for up to three follow-up visits. Measures of speaking rate, total duration, speech duration, and pause events were extracted from the passage reading recordings using a semi-automated speech and pause analysis procedure. Manual analysis of DDK recordings provided measures of DDK rate and variability. Group comparisons revealed significant differences (p = <.05) between the symptomatic group and the pre-symptomatic and control groups for all passage measures and DDK rates. Only the DDK rate in /ta/ differentiated the pre-symptomatic and control groups. Repeated measures correlations revealed moderate correlations (rrm = > 0.40; p = < 0.05) between passage measures of total duration, speaking rate, speech duration, and number of pauses, and ALSFRS-R total and bulbar scores, as well as between DDK rate and ALSFRS-R total score. Speech and pause measures in passage and timing measures in monosyllabic DDK tasks might be suitable for monitoring bulbar functional symptoms in French speakers with ALS, but more work is required to identify which measures are sensitive to the earliest stages of the disease. [ABSTRACT FROM AUTHOR]

The absence of disease modifying treatments for amyotrophic lateral sclerosis (ALS) is in large part a consequence of its complexity and heterogeneity. Deep clinical and biological phenotyping of people living with ALS would assist in the development of effective treatments and target specific biomarkers to monitor disease progression and inform on treatment efficacy. The objective of this paper is to present the Comprehensive Analysis Platform To Understand Remedy and Eliminate ALS (CAPTURE ALS), an open and translational platform for the scientific community currently in development. CAPTURE ALS is a Canadian-based platform designed to include participants' voices in its development and through execution. Standardized methods will be used to longitudinally characterize ALS patients and healthy controls through deep clinical phenotyping, neuroimaging, neurocognitive and speech assessments, genotyping and multisource biospecimen collection. This effort plugs into complementary Canadian and international initiatives to share common resources. Here, we describe in detail the infrastructure, operating procedures, and long-term vision of CAPTURE ALS to facilitate and accelerate translational ALS research in Canada and beyond. [ABSTRACT FROM AUTHOR]

Purpose: The genetic etiology of amyotrophic lateral sclerosis (ALS) includes few rare, large-effect variants and potentially many common, small-effect variants per case. The genetic risk liability for ALS might require a threshold comprised of a certain amount of variants. Here, we tested the degree to which risk for ALS was affected by rare variants in ALS genes, polygenic risk score, or both., Methods: 335 ALS cases and 356 controls from Québec, Canada were concurrently tested by microarray genotyping and targeted sequencing of ALS genes known at the time of study inception. ALS genome-wide association studies summary statistics were used to estimate an ALS polygenic risk score (PRS). Cases and controls were subdivided into rare-variant heterozygotes and non-heterozygotes., Results: Risk for ALS was significantly associated with PRS and rare variants independently in a logistic regression model. Although ALS PRS predicted a small amount of ALS risk overall, the effect was most pronounced between ALS cases and controls that were not heterozygous for a rare variant in the ALS genes surveyed., Conclusion: Both PRS and rare variants in ALS genes impact risk for ALS. PRS for ALS is most informative when rare variants are not observed in ALS genes., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by motor neuron degeneration. Significant research has begun to establish brain magnetic resonance imaging (MRI) as a potential biomarker to diagnose and monitor the state of the disease. Deep learning has emerged as a prominent class of machine learning algorithms in computer vision and has shown successful applications in various medical image analysis tasks. However, deep learning methods applied to neuroimaging have not achieved superior performance in classifying ALS patients from healthy controls due to insignificant structural changes correlated with pathological features. Thus, a critical challenge in deep models is to identify discriminative features from limited training data. To address this challenge, this study introduces a framework called SF 2 Former, which leverages the power of the vision transformer architecture to distinguish ALS subjects from the control group by exploiting the long-range relationships among image features. Additionally, spatial and frequency domain information is combined to enhance the network's performance, as MRI scans are initially captured in the frequency domain and then converted to the spatial domain. The proposed framework is trained using a series of consecutive coronal slices and utilizes pre-trained weights from ImageNet through transfer learning. Finally, a majority voting scheme is employed on the coronal slices of each subject to generate the final classification decision. The proposed architecture is extensively evaluated with multi-modal neuroimaging data (i.e., T1-weighted, R2*, FLAIR) using two well-organized versions of the Canadian ALS Neuroimaging Consortium (CALSNIC) multi-center datasets. The experimental results demonstrate the superiority of the proposed strategy in terms of classification accuracy compared to several popular deep learning-based techniques., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The complement system is a tightly controlled signaling network that plays a role in innate immune surveillance. However, abnormal signaling through this pathway contributes to tissue damage in several inflammatory, autoimmune, and degenerative diseases. Myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) have complement dysfunction at the core of pathogenesis, providing a strong rationale for therapeutic targeting of complement components. The purpose of this paper is to briefly review the role of complement activation in the pathogenesis of MG and NMOSD, to discuss the rationale and evidence for complement inhibition as a method to manage these diseases, and to provide a Canadian perspective on the use of complement inhibition therapy through real-world cases of MG and NMOSD.

Objective: To identify structural and neurochemical properties that underlie functional connectivity impairments of the primary motor cortex (PMC) and how these relate to clinical findings in amyotrophic lateral sclerosis (ALS)., Methods: 52 patients with ALS and 52 healthy controls, matched for age and sex, were enrolled from 5 centres across Canada for the Canadian ALS Neuroimaging Consortium study. Resting-state functional MRI, diffusion tensor imaging and magnetic resonance spectroscopy data were acquired. Functional connectivity maps, diffusion metrics and neurometabolite ratios were obtained from the analyses of the acquired multimodal data. A clinical assessment of foot tapping (frequency) was performed to examine upper motor neuron function in all participants., Results: Compared with healthy controls, the primary motor cortex in ALS showed reduced functional connectivity with sensory (T=5.21), frontal (T=3.70), temporal (T=3.80), putaminal (T=4.03) and adjacent motor (T=4.60) regions. In the primary motor cortex, N-acetyl aspartate (NAA, a neuronal marker) ratios and diffusion metrics (mean, axial and radial diffusivity, fractional anisotropy (FA)) were altered. Within the ALS cohort, foot tapping frequency correlated with NAA (r=0.347) and white matter FA (r=0.537). NAA levels showed associations with disturbed functional connectivity of the motor cortex., Conclusion: In vivo neurochemistry may represent an effective imaging marker of impaired motor cortex functional connectivity in ALS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder characterized by progressive degeneration of upper motor neurons and lower motor neurons, and frontotemporal regions resulting in impaired bulbar, limb, and cognitive function. Magnetic resonance imaging studies have reported cortical and subcortical brain involvement in the pathophysiology of ALS. The present study investigates the functional integrity of resting-state networks (RSNs) and their importance in ALS. Intra- and inter-network resting-state functional connectivity (Rs-FC) was examined using an independent component analysis approach in a large multi-center cohort. A total of 235 subjects (120 ALS patients; 115 healthy controls (HC) were recruited across North America through the Canadian ALS Neuroimaging Consortium (CALSNIC). Intra-network and inter-network Rs-FC was evaluated by the FSL-MELODIC and FSLNets software packages. As compared to HC, ALS patients displayed higher intra-network Rs-FC in the sensorimotor, default mode, right and left fronto-parietal, and orbitofrontal RSNs, and in previously undescribed networks including auditory, dorsal attention, basal ganglia, medial temporal, ventral streams, and cerebellum which negatively correlated with disease severity. Furthermore, ALS patients displayed higher inter-network Rs-FC between the orbitofrontal and basal ganglia RSNs which negatively correlated with cognitive impairment. In summary, in ALS there is an increase in intra- and inter-network functional connectivity of RSNs underpinning both motor and cognitive impairment. Moreover, the large multi-center CALSNIC dataset permitted the exploration of RSNs in unprecedented detail, revealing previously undescribed network involvement in ALS., Competing Interests: NO authors have competing interests

Objective: To understand current genetic testing practices at Canadian ALS clinics. Methods: An online survey and phone interviews, with clinicians practicing in 27 ALS clinics in Canada, were employed to collect data. Quantitative and qualitative analyses were conducted. Results: Ninety-three percent (25/27) of ALS clinics in Canada are routinely ordering genetic testing for familial ALS, while 33% (9/27) of clinics are routinely ordering genetic testing for sporadic ALS. Barriers to genetic testing include a perceived lack of an impact on treatment plan, difficulty in obtaining approvals, primarily from provincial Ministries of Health, and limited access to genetic counseling. Predictive testing practices were found to be the most variable across the country. The average wait time for a symptomatic patient living with ALS to see a genetic counselor in Canada is 10 months (range 0-36 months). Conclusions: Access to genetic testing, and testing practices, vary greatly across Canadian ALS clinics. There may be patients with a monogenetic etiology to their ALS who are not being identified given that genetic testing for patients diagnosed with ALS is not routinely performed at all clinics. This study highlights potential inequities for patients with ALS that can arise from variability in health care delivery across jurisdictions, in a federally-funded, but provincially-regulated, health care system. Clinical trials for both symptomatic ALS patients and pre-symptomatic ALS gene carriers are ongoing, and ALS clinicians in Canada are motivated to improve access to genetic testing for ALS.

Progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) remains poorly understood. Here, three-dimensional (3D) texture analysis was used to study longitudinal gray and white matter cerebral degeneration in ALS from routine T1-weighted magnetic resonance imaging (MRI). Participants were included from the Canadian ALS Neuroimaging Consortium (CALSNIC) who underwent up to three clinical assessments and MRI at four-month intervals, up to 8 months after baseline (T 0 ). Three-dimensional maps of the texture feature autocorrelation were computed from T1-weighted images. One hundred and nineteen controls and 137 ALS patients were included, with 81 controls and 84 ALS patients returning for at least one follow-up. At baseline, texture changes in ALS patients were detected in the motor cortex, corticospinal tract, insular cortex, and bilateral frontal and temporal white matter compared to controls. Longitudinal comparison of texture maps between T 0 and T max (last follow-up visit) within ALS patients showed progressive texture alterations in the temporal white matter, insula, and internal capsule. Additionally, when compared to controls, ALS patients had greater texture changes in the frontal and temporal structures at T max than at T 0 . In subgroup analysis, slow progressing ALS patients had greater progressive texture change in the internal capsule than the fast progressing patients. Contrastingly, fast progressing patients had greater progressive texture changes in the precentral gyrus. These findings suggest that the characteristic longitudinal gray matter pathology in ALS is the progressive involvement of frontotemporal regions rather than a worsening pathology within the motor cortex, and that phenotypic variability is associated with distinct progressive spatial pathology., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Cognitive impairment is now recognized in a subset of patients with amyotrophic lateral sclerosis (ALS). The objective of the study was to identify group differences and neuroanatomical correlates of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) in participants ALS. Fifty-three ALS patients and 43 healthy controls recruited as a part of our multicentre study (CALSNIC) were administered the ECAS and underwent an MRI scan. Voxel-based morphometry and tract based spatial statistics (TBSS) was performed to identify structural changes and associations with impaired ECAS scores. Lower performance in the ECAS verbal fluency and executive domains were noted in ALS patients as compared to controls (p < 0.01). Extensive white matter degeneration was noted in the corticospinal tract in all ALS patients, while ALS patients with impaired verbal fluency or executive domains (ALS-exi, n = 22), displayed additional degeneration in the corpus callosum, cingulum and superior longitudinal fasciculus as compared to controls (p < 0.05, TFCE corrected). Mild grey matter changes and associations with ECAS verbal fluency or executive performance were noted at lenient statistical thresholds (p < 0.001, uncorrected). Executive impairment was detected using the ECAS in our multicentre sample of Canadian ALS patients. White matter degeneration in motor regions was revealed in ALS patients with extensive spread to frontal regions in the ALS-exi sub-group. Mild associations between ECAS verbal fluency, executive function scores and MRI metrics suggest that reduced performance may be associated with widespread structural integrity., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Spinal Muscular Atrophy (SMA) is a rare disease that affects 1 in 11 000 live births. Recent developments in SMA treatments have included new disease-modifying therapies that require high quality data to inform decisions around initiation and continuation of therapy. In Canada, there are no nationally agreed upon outcome measures (OM) used in adult SMA. Standardization of OM is essential to obtain high quality data that is comparable among neuromuscular clinics., Objective: To develop a recommended toolkit and timing of OM for assessment of adults with SMA., Methods: A modified delphi method consisting of 2 virtual voting rounds followed by a virtual conference was utilized with a panel of expert clinicians treating adult SMA across Canada., Results: A consensus-derived toolkit of 8 OM was developed across three domains of function, with an additional 3 optional measures. Optimal assessment frequency is 12 months for most patients regardless of therapeutic access, while patients in their first year of receiving disease-modifying therapy should be assessed more frequently., Conclusions: The implementation of the consensus-derived OM toolkit will improve monitoring and assessment of adult SMA patients, and enrich the quality of real-world evidence. Regular updates to the toolkit must be considered as new evidence becomes available.

Background: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population., Methods: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials., Results: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner., Conclusion: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.

Amyotrophic lateral sclerosis (ALS) is characterized primarily by motor neuron but also frontotemporal lobar degeneration. Although the cerebellum is involved in both motor and cognitive functions, little is known of its role in ALS. We targeted the dentate nucleus (DN) in the cerebellum and the associated white matter fibers tracts connecting the DN to the rest of the brain using multimodal imaging techniques to examine the cerebellar structural and functional connectivity patterns in ALS patients and hypothesized that the DN is implicated in the pathophysiology of ALS. A cohort of 127 participants (56 healthy subjects (HS); 71 ALS patients) were recruited across Canada through the Canadian ALS Neuroimaging Consortium (CALSNIC). Resting state functional MRI, diffusion tensor imaging (DTI), and 3D weighted T1 structural images were acquired on a 3-tesla scanner. The DN in the cerebellum was used as a seed to evaluate the whole brain cerebral resting-state functional connectivity (rsFC). The superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP) and inferior cerebellar peduncle (ICP) were used as a region of interest in DTI to evaluate the structural integrity of the DN with the cortex and brain stem. Cerebellar volumetric analysis was done to examine the lobular and DN grey matter (GM) changes in ALS patients. Lastly, an association between DN rsFC and structural alterations were explored. DN rsFC was reduced with cerebrum (supplementary motor area, precentral gyrus, frontal, posterior parietal, temporal), lobule IV, and brain stem, and increased with parieto-occipital region. DN rsFC and white matter (WM) diffusivity alterations at SCP, MCP, and ICP were accompanied by correlations with ALSFRS-R. There were no DN volumetric changes. Notably, DN rsFC correlated with WM abnormalities at superior cerebellar peduncle. The DN plays a pathophysiological role in ALS. Impaired rsFC is likely due to the observed cerebellar peduncular WM damage given the lack of GM atrophy of the DN. This study demonstrates altered cerebellar rsFC connectivity with motor and extra-motor regions in ALS, and impaired rsFC is likely due to the observed cerebellar peduncular WM damage given the lack of GM atrophy of the DN. The correlation between the altered DN connectivity, and the behavioral data support the hypothesis that the DN plays a pathophysiological role in ALS., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Gradient-based texture analysis methods have become popular in computer vision and image processing and has many applications including medical image analysis. This motivates us to develop a texture feature extraction method to discriminate Amyotrophic Lateral Sclerosis (ALS) patients from controls. But, the lack of data in ALS research is a major constraint and can be mitigated by using data from multiple centers. However, multi-center data gives some other challenges such as differing scanner parameters and variation in intensity of the medical images, which motivate the development of the proposed method. To investigate these challenges, we propose a gradient-based texture feature extraction method called Modified Co-occurrence Histograms of Oriented Gradients (M-CoHOG) to extract texture features from 2D Magnetic Resonance Images (MRI). We also propose a new feature-normalization technique before feeding the normalized M-CoHOG features into an ensemble of classifiers, which can accommodate for variation of data from different centers. ALS datasets from four different centers are used in the experiments. We analyze the classification accuracy of single center data as well as that arising from multiple centers. It is observed that the extracted texture features from downsampled images are more significant in distinguishing between patients and controls. Moreover, using an ensemble of classifiers shows improvement in classification accuracy over a single classifier in multi-center data. The proposed method outperforms the state-of-the-art methods by a significant margin., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: As declining respiratory muscle function commonly leads to disability and death in amyotrophic lateral sclerosis (ALS), respiratory measurements such as slow vital capacity (SVC) may predict disease progression. This study evaluated the relationship between SVC and symptoms measured by the revised ALS Functional Rating Scale (ALSFRS-R)., Methods: About 453 ALS placebo-treated patients from the EMPOWER trial (NCT01281189) were evaluated. Correlations between %predicted SVC and individual respiratory ALSFRS-R subdomain items, respiratory subdomain score (maximum score of 12), and total ALSFRS-R score (maximum score of 48) were evaluated using the Pearson correlation coefficient. Pearson's chi-squared test was used to evaluate changes from baseline to week 48 in ALSFRS-R respiratory symptom and respiratory subdomain scores in patients with baseline %predicted SVC above/below the median at baseline and with more slowly/more rapidly decreasing %predicted SVC., Results: The %predicted SVC showed significant correlations with dyspnea, orthopnoea, respiratory insufficiency, respiratory subdomain score, and total ALSFRS-R score (all p < 0.0001). Patients with baseline SVC values < median were significantly more likely than those with baseline SVC ≥ median to have a change in total ALSFRS-R respiratory subdomain score from 12 to <12 (40.9% vs. 30.2%, p = 0.0358) and from ≥10 to <10 (41.6% vs. 24.4%, p = 0.0005). Additionally, patients with smaller declines in SVC over time were significantly more likely to have smaller decreases in their respiratory subdomain scores (p < 0.0001)., Conclusions: The higher correlation between %predicted SVC and specific ALSFRS-R symptom scores in patients with rapidly versus more slowly progressing disease reinforces the importance of continually monitoring respiratory function throughout the disease course.

Background: Patient registries represent an important method of organizing "real world" patient information for clinical and research purposes. Registries can facilitate clinical trial planning and recruitment and are particularly useful in this regard for uncommon and rare diseases. Neuromuscular diseases (NMDs) are individually rare but in aggregate have a significant prevalence. In Canada, information on NMDs is lacking. Barriers to performing Canadian multicentre NMD research exist which can be overcome by a comprehensive and collaborative NMD registry., Methods: We describe the objectives, design, feasibility and initial recruitment results for the Canadian Neuromuscular Disease Registry (CNDR)., Results: The CNDR is a clinic-based registry which launched nationally in June 2011, incorporates paediatric and adult neuromuscular clinics in British Columbia, Alberta, Ontario, Quebec, New Brunswick and Nova Scotia and, as of December 2012, has recruited 1161 patients from 12 provinces and territories. Complete medical datasets have been captured on 460 "index disease" patients. Another 618 "non-index" patients have been recruited with capture of physician-confirmed diagnosis and contact information. We have demonstrated the feasibility of blended clinic and central office-based recruitment. "Index disease" patients recruited at the time of writing include 253 with Duchenne and Becker muscular dystrophy, 161 with myotonic dystrophy, and 71 with ALS., Conclusions: The CNDR is a new nationwide registry of patients with NMDs that represents an important advance in Canadian neuromuscular disease research capacity. It provides an innovative platform for organizing patient information to facilitate clinical research and to expedite translation of recent laboratory findings into human studies.