Temporal and spatial progression of microstructural cerebral degeneration in ALS: A multicentre longitudinal diffusion tensor imaging study.

OBJECTIVE: The corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS. METHODS: The study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses. RESULTS: FA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts. CONCLUSIONS: Progressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.

Mismatch between clinically defined classification of ALS stage and the burden of cerebral pathology.

This study aimed to investigate the clinical stratification of amyotrophic lateral sclerosis (ALS) patients in relation to in vivo cerebral degeneration. One hundred forty-nine ALS patients and one hundred forty-four healthy controls (HCs) were recruited from the Canadian ALS Neuroimaging Consortium (CALSNIC). Texture analysis was performed on T1-weighted scans to extract the texture feature "autocorrelation" (autoc), an imaging biomarker of cerebral degeneration. Patients were stratified at baseline into early and advanced disease stages based on criteria adapted from ALS clinical trials and the King's College staging system, as well as into slow and fast progressors (disease progression rates, DPR). Patients had increased autoc in the internal capsule. These changes extended beyond the internal capsule in early-stage patients (clinical trial-based criteria), fast progressors, and in advanced-stage patients (King's staging criteria). Longitudinal increases in autoc were observed in the postcentral gyrus, corticospinal tract, posterior cingulate cortex, and putamen; whereas decreases were observed in corpus callosum, caudate, central opercular cortex, and frontotemporal areas. Both longitudinal increases and decreases of autoc were observed in non-overlapping regions within insula and precentral gyrus. Within-criteria comparisons of autoc revealed more pronounced changes at baseline and longitudinally in early- (clinical trial-based criteria) and advanced-stage (King's staging criteria) patients and fast progressors. In summary, comparative patterns of baseline and longitudinal progression in cerebral degeneration are dependent on sub-group selection criteria, with clinical trial-based stratification insufficiently characterizing disease stage based on pathological cerebral burden.

A Study on the Incidence and Prevalence of 5q Spinal Muscular Atrophy in Canada Using Multiple Data Sources.

OBJECTIVES: Spinal muscular atrophy (SMA) is a leading genetic cause of infant death and represents a significant burden of care. An improved understanding of the epidemiology of SMA in Canada may help inform strategies to improve the standard of care for individuals living with SMA. METHODS: We employed a multisource approach to estimate the minimal incidence and prevalence of 5q SMA and to gain greater insight into recent clinical practices and treatment trends for the Canadian SMA population. Data sources included the Canadian Paediatric Surveillance Program (CPSP), Canadian Neuromuscular Disease Registry (CNDR), and molecular genetics laboratories in Canada. RESULTS: The estimated annual minimum incidence of 5q SMA was 4.38, 3.44, and 7.99 cases per 100,000 live births in 2020 and 2021, based on CPSP, CNDR, and molecular genetics laboratories data, respectively, representing approximately 1 in 21,472 births (range 12,516-29,070) in Canada. SMA prevalence was estimated to be 0.85 per 100,000 persons aged 0-79 years. Delay in diagnosis exists across all SMA subtypes. Most common presenting symptoms were delayed milestones, hypotonia, and muscle weakness. Nusinersen was the most common disease-modifying treatment received. Most patients utilized multidisciplinary clinics for management of SMA. CONCLUSION: This study provides data on the annual minimum incidence of pediatric 5q SMA in Canada. Recent therapeutic advances and newborn screening have the potential to drastically alter the natural history of SMA. Findings underline the importance of ongoing surveillance of the epidemiology and long-term health outcomes of SMA in the Canadian population.

SF2Former: Amyotrophic lateral sclerosis identification from multi-center MRI data using spatial and frequency fusion transformer.

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 SF2Former, 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.

Motor cortex functional connectivity is associated with underlying neurochemistry in ALS.

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.

Rate of speech decline in individuals with amyotrophic lateral sclerosis.

Although speech declines rapidly in some individuals with amyotrophic lateral sclerosis (ALS), longitudinal changes in speech have rarely been characterized. The study objectives were to model the rate of decline in speaking rate and speech intelligibility as a function of disease onset site, sex, and age at onset in 166 individuals with ALS; and estimate time to speech loss from symptom onset. We also examined the association between clinical (speaking rate/intelligibility) measures and patient-reported measures of ALS progression (ALSFRS-R). Speech measures declined faster in the bulbar-onset group than in the spinal-onset group. The rate of decline was not significantly affected by sex and age. Functional speech was still maintained at 60 months since disease onset for most patients with spinal onset. However, the time to speech loss was 23 months based on speaking rate < 120 (w/m) and 32 months based on speech intelligibility < 85% in individuals with ALS-bulbar onset. Speech measures were more responsive to functional decline than were the patient-reported measures. The findings of this study will inform future work directed toward improving speech prognosis in ALS, which is critical for determining the appropriate timing of interventions, providing appropriate counseling for patients, and evaluating functional changes during clinical trials.

Gold Coast criteria expand clinical trial eligibility in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Consensus criteria to formalize the diagnosis of amyotrophic lateral sclerosis (ALS) and refine clinical trial populations have evolved. The recently proposed Gold Coast consensus criteria are intended to simplify use and increase sensitivity. We aimed to evaluate the potential impact of these criteria on clinical trial eligibility. METHODS: We performed a single-center, retrospective study of people diagnosed with ALS between 2016 and 2021 to determine the numbers of those meeting Gold Coast, revised El Escorial (rEEC) criteria, and Awaji criteria. We identified the proportion of those who would have been eligible for participation in three major ALS clinical trials if Gold Coast were used in place of rEEC definite/probable criteria. (rEEC D/P). RESULTS: Two hundred six people with ALS were included in our study. 48.5% met Gold Coast criteria but not rEEC D/P. Using the Gold Coast criteria would result in higher rates of clinical trial eligibility after other inclusion criteria were met: 95.2% vs 42.5% (P < .001) in a phase III study of riluzole; 100% vs 31.0% (P = .002) in a phase III study of edaravone; and 95.6% vs 45.3% (P < .001) in an ongoing phase III study of sodium phenylbutyrate and taurursodiol. The sensitivity of the Gold Coast criteria (96.1%; 95% confidence interval [CI], 92.2%-98.2%) was significantly higher than that of rEEC D/P (47.6%; 95% CI, 40.6%-54.6%; for difference, χ2  = 117.6; P < .001). DISCUSSION: Until robust biomarkers are available to diagnose ALS, consensus diagnostic criteria remain necessary. Gold Coast criteria would expand research and clinical trial eligibility and improve external validity of clinical trial results.

Functional alterations in large-scale resting-state networks of amyotrophic lateral sclerosis: A multi-site study across Canada and the United States.

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.

Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. METHODS: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. RESULTS: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. DISCUSSION: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.

Defining cognitive impairment in amyotrophic lateral sclerosis: an evaluation of empirical approaches.

Objective: Amyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized primarily by motor neuron degeneration, but may be accompanied by cognitive dysfunction. Statistically appropriate criteria for establishing cognitive impairment (CI) in ALS are lacking. We evaluate quantile regression (QR), that accounts for age and education, relative to a traditional two standard deviation (SD) cutoff for defining CI. Methods: QR of cross-sectional data from a multi-center North American Control (NAC) cohort of 269 healthy adults was used to model the 5th percentile of cognitive scores on the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). The QR approach was compared to traditional two SD cutoff approach using the same NAC cohort (2SD-NAC) and to existing UK-based normative data derived using the 2SD approach (2SD-UK) to assess the impact of cohort selection and statistical model in identifying CI in 182 ALS patients. Results: QR-NAC models revealed that age and education impact cognitive performance on the ECAS. Based on QR-NAC normative cutoffs, the frequency of CI in the 182 PENN ALS patients was 15.9% for ALS specific, 12.6% for ALS nonspecific, and 15.4% for ECAS total. This frequency of CI is substantially more conservative in comparison to the 2SD-UK (20.3%-34.6%) and modestly more conservative to the 2SD-NAC (14.3%-16.5%) approaches for estimating CI. Conclusions: The choice of normative cohort has a substantial impact and choice of statistical method a modest impact on defining CI in ALS. This report establishes normative ECAS thresholds to identify whether ALS patients in the North American population have CI.

Validating Automatic Diadochokinesis Analysis Methods Across Dysarthria Severity and Syllable Task in Amyotrophic Lateral Sclerosis.

PURPOSE: Oral diadochokinesis (DDK) is a standard dysarthria assessment task. To extract automatic and semi-automatic DDK measurements, numerous DDK analysis algorithms based on acoustic signal processing are available, including amplitude based, spectral based, and hybrid. However, these algorithms have been predominantly validated in individuals with no perceptible to mild dysarthria. The behavior of these algorithms across dysarthria severity is largely unknown. Likewise, these algorithms have not been tested equally for various syllable types. The goal of this study was to evaluate the performance of five common DDK algorithms as a function of dysarthria severity, considering syllable types. METHOD: We analyzed 282 DDK recordings of /ba/, /pa/, and /ta/ from 145 participants with amyotrophic lateral sclerosis. Recordings were stratified into mild, moderate, or severe dysarthria groups based on individual performance on the Speech Intelligibility Test. Analysis included manual and automatic estimation of the number of syllables, DDK rate, and cycle-to-cycle temporal variability (cTV). Validation metrics included Bland-Altman mixed-effects limits of agreement between manual and automatic syllable counts, recall and precision between manual and automatic syllable boundary detection, and Kendall's tau-b correlations between manual and algorithm-detected DDK rate and cTV. RESULTS: The amplitude-based algorithm (absolute energy) yielded the strongest correlations with manual analysis across all severity groups for DDK rate (τ b = 0.7-0.84) and cTV (τ b = 0.7-0.84) and the narrowest limits of agreement (-5.92 to 7.12 syllable difference). Moreover, this algorithm also provided the highest mean recall and precision across severity groups for /ba/ and /pa/, but with significantly more variation for/ta/. CONCLUSIONS: Algorithms based on signal energy analysis appeared to be the most robust for DDK analysis across dysarthria severity and syllable types; however, it remains prone to error against severe dysarthria and alveolar syllable context. Further development is needed to address this important issue.

Distinct patterns of progressive gray and white matter degeneration in amyotrophic lateral sclerosis.

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 (T0 ). 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 T0 and Tmax (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 Tmax than at T0 . 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.

Progressive Neurochemical Abnormalities in Cognitive and Motor Subgroups of Amyotrophic Lateral Sclerosis: A Prospective Multicenter Study.

OBJECTIVE: To evaluate progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) by assessing alterations in N-acetylaspartate (NAA) ratios in the motor and prefrontal cortex within clinical subgroups of ALS. METHODS: Seventy-six patients with ALS and 59 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium. Participants underwent serial clinical evaluations and magnetic resonance spectroscopy at baseline and 4 and 8 months using a harmonized protocol across 5 centers. NAA ratios were quantified in the motor cortex and prefrontal cortex. Patients were stratified into subgroups based on disease progression rate, upper motor neuron (UMN) signs, and cognitive status. Linear mixed models were used for baseline and longitudinal comparisons of NAA metabolite ratios. RESULTS: Patients with ALS had reduced NAA ratios in the motor cortex at baseline (p < 0.001). Ratios were lower in those with more rapid disease progression and greater UMN signs (p < 0.05). A longitudinal decline in NAA ratios was observed in the motor cortex in the rapidly progressing (p < 0.01) and high UMN burden (p < 0.01) cohorts. The severity of UMN signs did not change significantly over time. NAA ratios were reduced in the prefrontal cortex only in cognitively impaired patients (p < 0.05); prefrontal cortex metabolites did not change over time. CONCLUSIONS: Progressive degeneration of the motor cortex in ALS is associated with more aggressive clinical presentations. These findings provide biological evidence of variable spatial and temporal cerebral degeneration linked to the disease heterogeneity of ALS. The use of standardized imaging protocols may have a role in clinical trials for patient selection or subgrouping. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that MRS NAA metabolite ratios of the motor cortex are associated with more rapid disease progression and greater UMN signs in patients with ALS. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02405182.

Highly Elevated Prevalence of Spinobulbar Muscular Atrophy in Indigenous Communities in Canada Due to a Founder Effect.

OBJECTIVE: Spinobulbar muscular atrophy (SBMA) is an X-linked adult-onset neuromuscular disorder that causes progressive weakness and androgen insensitivity in hemizygous males. This condition is reported to be extremely rare, but has higher prevalence in certain populations due to multiple founder effects. Anecdotal observations of a higher prevalence of SBMA in patients of Indigenous descent in Saskatchewan led us to perform this study, to estimate the disease prevalence, and to attempt to identify a founder effect. METHODS: For our prevalence estimation, we identified patients with confirmed SBMA diagnosis from the Saskatoon neuromuscular clinic database for comparison with population data available from Statistics Canada. For our haplotype analysis, participants with SBMA were recruited from 2 neuromuscular clinics, as well as 5 control participants. Clinical data were collected, as well as a DNA sample using saliva kits. We performed targeted quantification of DXS1194, DXS1111, DXS135, and DXS1125 microsatellite repeats and the AR GGC repeat to attempt to identify a disease haplotype and compare it with prior studies. RESULTS: We estimate the prevalence of SBMA among persons of Indigenous descent in Saskatchewan as 14.7 per 100,000 population. Although we believe that this is an underestimate, this still appears to be the highest population prevalence for SBMA in the world. A total of 21 participants were recruited for the haplotype study, and we identified a unique haplotype that was shared among 13 participants with Indigenous ancestry. A second shared haplotype was identified in 2 participants, which may represent a second founder haplotype, but this would need to be confirmed with future studies. CONCLUSIONS: We describe a very high prevalence of SBMA in western Canadians of Indigenous descent, which appears to predominantly be due to a founder effect. This necessitates further studies of SBMA in these populations to comprehensively ascertain the disease prevalence and allow appropriate allocation of resources to support individuals living with this chronic disease.

Core Outcome Sets for Medium-Chain Acyl-CoA Dehydrogenase Deficiency and Phenylketonuria.

BACKGROUND: Evidence to guide treatment of pediatric medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency and phenylketonuria (PKU) is fragmented because of large variability in outcome selection and measurement. Our goal was to develop core outcome sets (COSs) for these diseases to facilitate meaningful future evidence generation and enhance the capacity to compare and synthesize findings across studies. METHODS: Parents and/or caregivers, health professionals, and health policy advisors completed a Delphi survey and participated in a consensus workshop to select core outcomes from candidate lists of outcomes for MCAD deficiency and PKU. Delphi participants rated the importance of outcomes on a nine-point scale (1-3: not important, 4-6: important but not critical, 7-9: critical). Candidate outcomes were progressively narrowed down over 3 survey rounds. At the workshop, participants evaluated the remaining candidate outcomes using an adapted nominal technique, open discussion, and voting. After the workshop, we finalized the COSs and recommended measurement instruments for each outcome. RESULTS: There were 85, 61, and 53 participants across 3 Delphi rounds, respectively. The candidate core outcome lists were narrowed down to 20 outcomes per disease to be discussed at the consensus workshop. Voting by 18 workshop participants led to COSs composed of 8 and 9 outcomes for MCAD deficiency and PKU, respectively, with measurement recommendations. CONCLUSIONS: These are the first known pediatric COSs for MCAD deficiency and PKU. Adoption in future studies will help to ensure best use of limited research resources to ultimately improve care for children with these rare diseases.

A Canadian Adult Spinal Muscular Atrophy Outcome Measures Toolkit: Results of a National Consensus using a Modified Delphi Method.

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.

Utility of Neuropathy Screening for Wild-Type Transthyretin Amyloidosis Patients.

BACKGROUND: Wild-type transthyretin amyloidosis (wtATTR) is an important cause of heart failure (HF); however, the prevalence and clinical significance of neurologic complications remains uncertain. METHODS: This analysis reports findings from a single-centre experience of routine neuropathy screening at the time of wtATTR diagnosis by nerve conduction studies and neurologist assessment, compared with age-matched controls. RESULTS: Forty-one wtATTR patients were included, 39 (95%) males, mean age 78.4 ± 7.7 years, 22 (54%) New York Heart Association (NYHA) class III-IV HF, along with 15 age-matched controls (mean age 77.1 ± 4.2 years, 80% male). Twenty-one (51%) wtATTR patients were diagnosed with polyneuropathy, 15 (37%) with spinal stenosis, 36 (88%) with carpal tunnel syndrome (CTS) and 14 (34%) with ulnar neuropathy. Comparison diagnoses among controls were 1 (7%), 0, 1 (7%) and 3 (20%), respectively. Among patients with NYHA class III-IV HF, 16 (73%) had polyneuropathy compared with 5 (26%) with class I-II (p < 0.01), odds ratio of 7.5 (95% confidence interval 1.9-29.9). After neuropathy screening, 19 (46%) patients were offered neurologic therapy and/or additional diagnostic evaluation. This included CTS release surgery (16, 39%), neuropathic pain medication (3, 7%), nerve block (1, 2%), wrist splinting (2, 5%) and foot care (1, 2%). Spine imaging was performed for 3 (7%) patients, and deltoid muscle and sural nerve biopsy for 1 (2%) patient. CONCLUSIONS: Screening of wtATTR patients for neurologic complications resulted in a management change for nearly half. CTS, polyneuropathy and ulnar neuropathy were common. This approach warrants consideration as part of routine assessment for newly diagnosed wtATTR patients.

Neuroanatomical associations of the Edinburgh cognitive and Behavioural ALS screen (ECAS).

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.

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS.

OBJECTIVE: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).