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We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.

The misfolding, aggregation, and deposition of specific proteins is the key hallmark of most progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). ALS is characterized by the rapid and progressive degenerations of motor neurons in the spinal cord and motor cortex, resulting in paralysis of those who suffer from it. Pathologically, there are three major aggregating proteins associated with ALS, including TAR DNA-binding protein of 43kDa (TDP-43), superoxide dismutase-1 (SOD1), and fused in sarcoma (FUS). While there are ALS-associated mutations found in each of these proteins, the most prevalent aggregation pathology is that of wild-type TDP-43 (97% of cases), with the remaining split between mutant forms of SOD1 (~2%) and FUS (~1%). Considering the progressive nature of ALS and its association with the aggregation of specific proteins, a growing notion is that the spread of pathology and symptoms can be explained by a prion-like mechanism. Prion diseases are a group of highly infectious neurodegenerative disorders caused by the misfolding, aggregation, and spread of a transmissible conformer of prion protein (PrP). Pathogenic PrP is capable of converting healthy PrP into a toxic form through template-directed misfolding. Application of this finding to other neurodegenerative disorders, and in particular ALS, has revolutionized our understanding of cause and progression of these disorders. In this chapter, we first provide a background on ALS pathology and genetic origin. We then detail and discuss the evidence supporting a prion-like propagation of protein misfolding and aggregation in ALS with a particular focus on SOD1 and TDP-43 as these are the most well-established models in the field., (© 2020 Elsevier Inc. All rights reserved.)

Background: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative neurological disease with significant effects on quality of life. International studies continue to provide consistent incidence values, though complete case ascertainment remains a challenge. The Canadian population has been understudied, and there are currently no quantitative data on the incidence of ALS in British Columbia (BC). The objectives of this study were to determine the five-year incidence rates of ALS in BC and to characterize the demographic patterns of the disease., Methods: The capture-recapture method was employed to estimate ALS incidence over a five-year period (2010-2015). Two sources were used to identify ALS cases: one database from an ALS medical centre and another from a not-for-profit ALS organization., Results: During this time period, there were 690 incident cases within the two sources. The capture-recapture method estimated 57 unobserved cases, corresponding to a crude five-year incidence rate of 3.29 cases per 100,000 (CI 95%=3.05-3.53). The mean age of diagnosis was 64.6 (CI 95%=59.7-69.4), with 63.5 (CI 95%=56.9-70.1) for men and 65.7 (CI 95%=58.6-72.7) for women. There was a slight male preponderance in incidence, with a 1.05:1 ratio to females. Peak numbers in incidence occurred between the ages of 70 and 79., Conclusions: The incidence of ALS in BC was found to be consistent with international findings though nominally higher than that in other Canadian provinces to date.

Full length TrkC (TrkC-FL) is a receptor tyrosine kinase whose mRNA can be spliced to a truncated TrkC.T1 isoform lacking the kinase domain. Neurotrophin-3 (NT-3) activates TrkC-FL to maintain motor neuron health and function and TrkC.T1 to produce neurotoxic TNF-α; hence resulting in opposing pathways. In mouse and human ALS spinal cord, the reduction of miR-128 that destabilizes TrkC.T1 mRNA results in up-regulated TrkC.T1 and TNF-α in astrocytes. We exploited conformational differences to develop an agonistic mAb 2B7 that selectively activates TrkC-FL, to circumvent TrkC.T1 activation. In mouse ALS, 2B7 activates spinal cord TrkC-FL signals, improves spinal cord motor neuron phenotype and function, and significantly prolongs life-span. Our results elucidate biological paradoxes of receptor isoforms and their role in disease progression, validate the concept of selectively targeting conformational epitopes in naturally occurring isoforms, and may guide the development of pro-neuroprotective (TrkC-FL) and anti-neurotoxic (TrkC.T1) therapeutic strategies., Competing Interests: Patents protecting this work were filed by McGill University (MF, NC, and HUS, inventors).

Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open-reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we identified the C9ORF72 mutation in 17 familial (27.4%) and six sporadic (3.6%) cases. Patients with the mutation presented with typical motor features of ALS, although subjects with the C9ORF72 mutation had more frequent bulbar onset, compared to those without this mutation. Dementia was significantly more common in ALS patients and families with the C9ORF72 mutation and was usually early-onset FTD. There was striking clinical heterogeneity among the members of individual families with the mutation. The associated neuropathology was a combination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to TDP-43-immunoreactive pathology, a consistent and specific feature of cases with the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative inclusions in a variety of neuroanatomical regions, such as the cerebellar cortex. These findings support the C9ORF72 mutation as an important newly recognized cause of ALS, provide a more detailed characterization of the associated clinical and pathological features and further demonstrate the clinical and molecular overlap between ALS and FTD.

Mutations in the fused in sarcoma (FUS) gene have recently been found to cause familial amyotrophic lateral sclerosis (FALS). We screened FUS in a cohort of 200 ALS patients [32 FALS and 168 sporadic ALS (SALS)]. In one FALS proband, we identified a mutation (p.R521C) that was also present in her affected daughter. Their clinical phenotype was remarkably similar and atypical of classic ALS, with symmetric proximal pelvic and pectoral weakness. Distal weakness and upper motor neuron features only developed late. Neuropathological examination demonstrated FUS-immunoreactive neuronal and glial inclusions in the spinal cord and many extramotor regions, but no TDP-43 pathology. We also identified a novel mutation (p.G187S) in one SALS patient. Overall, FUS mutations accounted for 3% of our non-SOD1, non-TARDBP FALS cases and 0.6% of SALS. This study demonstrates that the phenotype with FUS mutations extends beyond classical ALS cases. Our findings suggest there are specific clinicogenetic correlations and provide the first detailed neuropathological description.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons in the brain, brainstem, and spinal cord. It has been proposed that bone marrow (BM)-derived cells might supply motor neurons and other cells with a cellular milieu more conducive to survival in ALS. Direct injection of stem cells in ALS is problematic because of the large expanse of the neuraxis that would need to be injected. We reasoned that transiently increasing the number of circulating hematopoietic stem cells might be a useful therapeutic approach. However, agents stimulating the activation and mobilization of hematopoietic stem cells may have adverse effects such as activation of microglial cells. We conducted a small pilot trial of the collection and reinfusion of granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) in ALS patients and found no adverse effects, paving the way for a properly powered therapeutic trial with an optimized regimen of G-CSF.

Epidemiological studies of the Guamanian variants of amyotrophic lateral sclerosis (ALS) and parkinsonism, amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC), have shown a positive correlation between consumption of washed cycad seed flour and disease occurrence. Previous in vivo studies by our group have shown that the same seed flour induces ALS and PDC phenotypes in out bred adult male mice. In vitro studies using isolated cycad compounds have also demonstrated that several of these are neurotoxic, specifically, a number of water insoluble phytosterol glucosides of which beta-sitosterol beta-D: -glucoside (BSSG) forms the largest fraction. BSSG is neurotoxic to motor neurons and other neuronal populations in culture. The present study shows that an in vitro hybrid motor neuron (NSC-34) culture treated with BSSG undergoes a dose-dependent cell loss. Surviving cells show increased expression of HSP70, decreased cytosolic heavy neurofilament expression, and have various morphological abnormalities. CD-1 mice fed mouse chow pellets containing BSSG for 15 weeks showed motor deficits and motor neuron loss in the lumbar and thoracic spinal cord, along with decreased glutamate transporter labelling, and increased glial fibrillary acid protein reactivity. Other pathological outcomes included increased caspase-3 labelling in the striatum and decreased tyrosine-hydroxylase labelling in the striatum and substantia nigra. C57BL/6 mice fed BSSG-treated pellets for 10 weeks exhibited progressive loss of motor neurons in the lumbar spinal cord that continued to worsen even after the BSSG exposure ended. These results provide further support implicating sterol glucosides as one potential causal factor in the motor neuron pathology previously associated with cycad consumption and ALS-PDC.

Objective: To determine the relationship of cerebral degeneration with survival in amyotrophic lateral sclerosis (ALS)., Methods: Patients with probable or definite ALS underwent magnetic resonance spectroscopic imaging (MRSI) of the brain between July 1996 and May 2002, and were followed prospectively until March 2004. Creatine (Cr), choline (Cho) and the neuronal marker N-acetylaspartate (NAA) were quantified as ratios in the motor cortex., Results: In 63 patients compared with 18 healthy people, NAA/Cho was reduced by 13% (p<0.001), NAA/Cr was reduced by 5% (p = 0.01) and Cho/Cr was increased by 8% (p = 0.01). NAA/Cho was used for survival analysis, given its larger effect size and superior test accuracy (a sensitivity of 67% and a specificity of 83%). Median survival after MRSI was 24 months. Multivariate analysis showed reduced survival for lower NAA/Cho (hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.08 to 0.72, p = 0.01), older age (HR 1.03, 95% CI 1.00 to 1.06, p = 0.04) and shorter symptom duration (HR 0.96, 95% CI 0.93 to 0.99, p = 0.01). Patients with NAA/Cho <2.11 had a reduced survival of 19.4 v 31.9 months (HR 2.05, 95% CI 1.12 to 4.03, p = 0.02)., Conclusions: Cerebral degeneration is predictive of reduced survival in ALS.

The care of patients with amyotrophic lateral sclerosis (ALS), which has classically focused on treatment of symptomatology, has now entered an encouraging new era of therapy targeted at the pathophysiology of the disease. However, an objective measure of disease progression and therapeutic response is sorely needed. Quantitative neuromuscular examinations, measurement of pulmonary function, disability scales, and even survival, are limited by variability due to a number of poorly controlled factors. Quantitative electromyography, positron emission tomography scanning, and magnetic cortical stimulation, provide potential objective indicators of disease progression, but require a large number of patients and a long observation period for adequate statistical power. We have examined the role of magnetic resonance spectroscopic imaging in detecting acute changes in motor cortical metabolism in response to riluzole therapy. N-acetylaspartate (NAA), the most prominent signal in proton spectra of normal brain, is a neuron-specific molecule. ALS patients were found to experience a significant increase in the NAA/creatine ratio within 3 weeks of initiation of riluzole therapy. As glutamate can trigger the generation of reactive oxygen species in neurons, we speculate that acute changes in NAA levels may reflect oxidative injury to mitochondria where NAA is synthesised. The advent of a useful test for upper motor neuron metabolic compromise may provide an objective, non-invasive, short duration measure with which to screen the efficacy of potential therapeutic agents for ALS.

Both a biologic imperative and an ethical imperative exist for providing the diagnosis of amyotrophic lateral sclerosis (ALS) as soon as possible and involving patients and their families in therapeutic decisions. The participation of excitotoxic mechanisms in ALS and the availability of riluzole, which may slow the rate of progression of ALS, provide the biologic rationale for early therapy in ALS. A neuroprotective agent, such as riluzole, is more effective at an early stage of disease, when more undamaged neurons remain. The development of effective therapy for ALS also provides the ethical basis for early announcement of diagnosis. When no primary treatment was available, an accepted approach was one of "protecting" the patient from the diagnosis, which was one of exclusion, requiring almost 100% certainty before announcement. The availability of a primary therapy, albeit not a cure, means that a diagnosis of ALS can now be offered as the most likely diagnosis with 90-95% certainty. The logical corollary of this new model is that patients must be involved immediately, to help decide when therapy is appropriate and to balance the relative personal significance of therapeutic gains versus adverse effects.

Riluzole, a glutamate antagonist, has been shown to be efficacious in the treatment of patients with amyotrophic lateral sclerosis (ALS), allowing prolonged survival and time to tracheostomy. The efficacy of riluzole in thought to result from reduced glutamate excitotoxicity on motor neurons of patients with ALS, but this has never been demonstrated directly in vivo. N-acetylaspartate (NAA), a compound that is readily measured in vivo using proton magnetic resonance spectroscopy, can be used as a surrogate marker for neuronal loss or sublethal injury. To determine whether riluzole reverses sublethal corticomotoneuron damage in patients with ALS we measured NAA/creatine (Cr) relative intensity ratios in the motor cortex before and after treatment with riluzole 50 mg bid. After 3 weeks of riluzole therapy in 11 patients NAA/Cr increased from 2.14 +/- 0.26 to 2.27 +/- 0.24 (p = 0.044), whereas, in 12 untreated patients NAA/Cr decreased from 2.17 +/- 0.20 to 2.08 +/- 0.20 (p = 0.099). Thus the change in NAA/Cr between the treated and untreated groups was 0.22 +/- 0.095 (p = 0.008). The magnitude of increase in NAA/Cr in those treated was not correlated with age, sex, duration of treatment or disease, the presence of probable or definite upper motor neuron (UMN) signs, bulbar features, or pre-treatment NAA/Cr. We conclude that magnetic resonance spectroscopy can provide a novel surrogate measure of neuronal integrity that demonstrates reversal of sublethal UMN injury in patients with ALS within weeks of initiating riluzole therapy.

Patients with motor neuron disease with thyroid disorders have been described, although the relationship between the two conditions is unclear. We treated a patient with amyotrophic lateral sclerosis who also had a follicular adenoma of the thyroid gland. Because thyroid gland plasma membranes contain high concentrations of complex gangliosides, such as GD1b, and some patients with motor neuron disease have IgM antibodies to GD1b, we decided to assay serum from this patient for the presence of antiganglioside antibodies. IgM antibodies to GD1b were detectable at serum dilutions of 1:500 and 1:1000 by enzyme-linked immunosorbent assay. While these titers are less than those usually described in patients with plasma cell dyscrasia, they are well in excess of normal values. Antibody to GM1 was also detectable at a lower (1:100) dilution. We do not know the importance of the anti-GD1b antibodies in this patient, but it is possible that antibodies to GD1b are involved in this and other cases of motor neuron disease associated with thyroid disease.

To investigate the pathogenesis of amyotrophic lateral sclerosis, we compared the effect of serum from patients with this disease on the regenerative sprouting of terminal axons in botulinum-treated mouse gluteus muscle with the effects of serum from controls and from patients with diabetic peripheral neuropathy. Serum from 9 of 19 patients with the sporadic form of amyotrophic lateral sclerosis and from 2 of 6 patients with the familial form caused a reduction in the proportion of sprouting terminal axons, as compared with that found in muscles treated with serum from controls or diabetic patients. Immunoglobulin from patients with amyotrophic lateral sclerosis, when tested on immunoblots, recognized a 56-kilodalton protein secreted by denervated rat diaphragm muscle; rabbit antiserum raised against this protein also suppressed terminal axonal sprouting. Thus, we have detected an antibody in the serum of patients with amyotrophic lateral sclerosis that inhibits sprouting of neurons and subsequent reinnervation of skeletal muscle. Whether this antibody is of primary pathogenic importance or represents a secondary response to neuromuscular destruction is not known. In either case, serum from patients with amyotrophic lateral sclerosis may provide reagents for studies of the trophic communications between muscle and motor neurons.

The article titled "Theme 07 - Pre-Clinical Therapeutic Strategies" was written by a large group of authors and published in the journal Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. The article discusses various pre-clinical therapeutic strategies for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The authors present a comprehensive review of the current research in this field, including potential therapeutic targets and approaches. This article would be useful for library patrons conducting research on ALS and FTD and provides a diverse range of perspectives on the topic. [Extracted from the article]