Long-term effects of a fat-directed FGF21 gene therapy in aged female mice.

Fibroblast growth factor 21 (FGF21) has been developed as a potential therapeutic agent for metabolic syndromes. Moreover, FGF21 is considered a pro-longevity hormone because transgenic mice overexpressing FGF21 display extended lifespan, raising the possibility of using FGF21 to promote healthy aging. We recently showed that visceral fat directed FGF21 gene therapy improves metabolic and immune health in insulin resistant BTBR mice. Here, we used a fat directed rAAV-FGF21 vector in 17-month-old female mice to investigate whether long-term FGF21 gene transfer could mitigate aging-related functional decline. Animals with FGF21 treatment displayed a steady, significant lower body weight over 7-month of the study compared to age-matched control mice. FGF21 treatment reduced adiposity and increased relative lean mass and energy expenditure associated with almost 100 folds higher serum level of FGF21. However, those changes were not translated into benefits on muscle function and did not affect metabolic function of liver. Overall, we have demonstrated that a single dose of fat-directed AAV-FGF21 treatment can provide a sustainable, high serum level of FGF21 over long period of time, and mostly influences adipose tissue homeostasis and energy expenditure. High levels of FGF21 alone in aged mice is not sufficient to improve liver or muscle functions.

Reductions in Motor Unit Firing are Associated with Clinically Meaningful Leg Extensor Weakness in Older Adults.

Weakness, one of the key characteristics of sarcopenia, is a significant risk factor for functional limitations and disability in older adults. It has long been suspected that reductions in motor unit firing rates (MUFRs) are one of the mechanistic causes of age-related weakness. However, prior work has not investigated the extent to which MUFR is associated with clinically meaningful weakness in older adults. Forty-three community-dwelling older adults (mean: 75.4 ± 7.4 years; 46.5% female) and 24 young adults (mean: 22.0 ± 1.8 years; 58.3% female) performed torque matching tasks at varying submaximal intensities with their non-dominant leg extensors. Decomposed surface electromyographic recordings were used to quantify MUFRs from the vastus lateralis muscle. Computational modeling was subsequently used to independently predict how slowed MUFRs would negatively impact strength in older adults. Bivariate correlations between MUFRs and indices of lean mass, voluntary activation, and physical function/mobility were also assessed in older adults. Weak older adults (n = 14) exhibited an approximate 1.5 and 3 Hz reduction in MUFR relative to non-weak older adults (n = 29) at 50% and 80% MVC, respectively. Older adults also exhibited an approximate 3 Hz reduction in MUFR relative to young adults at 80% MVC only. Our model predicted that a 3 Hz reduction in MUFR results in a strength decrement of 11-26%. Additionally, significant correlations were found between slower MUFRs and poorer neuromuscular quality, voluntary activation, chair rise time performance, and stair climb power (r's = 0.31 to 0.43). These findings provide evidence that slowed MUFRs are mechanistically linked with clinically meaningful leg extensor weakness in older adults.

Emerging Links between Nonalcoholic Fatty Liver Disease and Neurodegeneration.

The association between liver and brain health has gained attention as biomarkers of liver function have been revealed to predict neurodegeneration. The liver is a central regulator in metabolic homeostasis. However, in nonalcoholic fatty liver disease (NAFLD), homeostasis is disrupted which can result in extrahepatic organ pathologies. Emerging literature provides insight into the mechanisms behind the liver-brain health axis. These include the increased production of liver-derived factors that promote insulin resistance and loss of neuroprotective factors under conditions of NAFLD that increase insulin resistance in the central nervous system. In addition, elevated proinflammatory cytokines linked to NAFLD negatively impact the blood-brain barrier and increase neuroinflammation. Furthermore, exacerbated dyslipidemia associated with NAFLD and hepatic dysfunction can promote altered brain bioenergetics and oxidative stress. In this review, we summarize the current knowledge of the crosstalk between liver and brain as it relates to the pathophysiology between NAFLD and neurodegeneration, with an emphasis on Alzheimer's disease. We also highlight knowledge gaps and future areas for investigation to strengthen the potential link between NAFLD and neurodegeneration.

Chronic demyelination and myelin repair after spinal cord injury in mice: A potential link for glutamatergic axon activity.

Our prior work examining endogenous repair after spinal cord injury (SCI) in mice revealed that large numbers of new oligodendrocytes (OLs) are generated in the injured spinal cord, with peak oligodendrogenesis between 4 and 7 weeks post-injury (wpi). We also detected new myelin formation over 2 months post-injury (mpi). Our current work significantly extends these results, including quantification of new myelin through 6 mpi and concomitant examination of indices of demyelination. We also examined electrophysiological changes during peak oligogenesis and a potential mechanism driving OL progenitor cell (OPC) contact with axons. Results reveal peak in remyelination occurs during the 3rd mpi, and that myelin generation continues for at least 6 mpi. Further, motor evoked potentials significantly increased during peak remyelination, suggesting enhanced axon potential conduction. Interestingly, two indices of demyelination, nodal protein spreading and Nav1.2 upregulation, were also present chronically after SCI. Nav1.2 was expressed through 10 wpi and nodal protein disorganization was detectable throughout 6 mpi suggesting chronic demyelination, which was confirmed with EM. Thus, demyelination may continue chronically, which could trigger the long-term remyelination response. To examine a potential mechanism that may initiate post-injury myelination, we show that OPC processes contact glutamatergic axons in the injured spinal cord in an activity-dependent manner. Notably, these OPC/axon contacts were increased 2-fold when axons were activated chemogenetically, revealing a potential therapeutic target to enhance post-SCI myelin repair. Collectively, results show the surprisingly dynamic nature of the injured spinal cord over time and that the tissue may be amenable to treatments targeting chronic demyelination.

Impaired motor unit recovery and maintenance in a knock-in mouse model of ALS-associated Kif5a variant.

Kinesin family member 5A (KIF5A) is an essential, neuron-specific microtubule-associated motor protein responsible for the anterograde axonal transport of various cellular cargos. Loss of function variants in the N-terminal, microtubule-binding domain are associated with hereditary spastic paraplegia and hereditary motor neuropathy. These variants result in a loss of the ability of the mutant protein to process along microtubules. Contrastingly, gain of function splice-site variants in the C-terminal, cargo-binding domain of KIF5A are associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving death of upper and lower motor neurons, ultimately leading to degradation of the motor unit (MU; an alpha motor neuron and all the myofibers it innervates) and death. These ALS-associated variants result in loss of autoinhibition, increased procession of the mutant protein along microtubules, and altered cargo binding. To study the molecular and cellular consequences of ALS-associated variants in vivo, we introduced the murine homolog of an ALS-associated KIF5A variant into C57BL/6 mice using CRISPR-Cas9 gene editing which produced mutant Kif5a mRNA and protein in neuronal tissues of heterozygous (Kif5a+/c.3005+1G>A; HET) and homozygous (Kif5ac.3005+1G>A/c.3005+1G>A; HOM) mice. HET and HOM mice appeared normal in behavioral and electrophysiological (compound muscle action potential [CMAP] and MU number estimation [MUNE]) outcome measures at one year of age. When subjected to sciatic nerve injury, HET and HOM mice have delayed and incomplete recovery of the MUNE compared to wildtype (WT) mice suggesting an impairment in MU repair. Moreover, aged mutant Kif5a mice (aged two years) had reduced MUNE independent of injury, and exacerbation of the delayed and incomplete recovery after injury compared to aged WT mice. These data suggest that ALS-associated variants may result in an impairment of the MU to respond to biological challenges such as injury and aging, leading to a failure of MU repair and maintenance. In this report, we present the behavioral, electrophysiological and pathological characterization of mice harboring an ALS-associated Kif5a variant to understand the functional consequences of KIF5A C-terminal variants in vivo.

Psychometric evaluation of modified spinal muscular atrophy functional rating scale (SMAFRS) in adult patients using Rasch analysis.

INTRODUCTION/AIMS: The Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) was first developed as a secondary functional outcome measure to detect changes over time in patients with spinal muscular atrophy (SMA) in clinical trials. Its modified version evaluates 10 activities of daily living. The aim of the study was to analyze modified SMAFRS data using item response theory psychometric models. METHODS: A total of 253 responses from 41 adult patients with ambulatory and non-ambulatory SMA types 2, 3, and 4 were analyzed. Rasch analysis was used to explore item-person targeting, fit statistics, category response functioning, dimensionality, and differential item functioning. RESULTS: Most items had good fitting with the exception of "toileting" and "respiratory." There were no major floor or ceiling effects, and most items covered a good range of disability with only a negligible breech of uni-dimensionality from eating, dressing, and respiratory items. Differential item function highlighted differences in toileting, turning, transferring, walking, and respiratory items between ambulatory and non-ambulatory populations. DISCUSSION: Despite subtle misfitting of certain items, mainly related to respiratory and bulbar function, overall modified SMAFRS remained a psychometrically stable and unidimensional outcome measure. There were some differences in measuring properties of certain functional items between ambulatory and non-ambulatory items that need to be taken into consideration in clinical trial design. Overall, the modified SMAFRS is a psychometrically reliable tool in assessment of adult patients with SMA.

Harnessing cortical plasticity via gabapentinoid administration promotes recovery after stroke.

Stroke causes devastating sensory-motor deficits and long-term disability due to disruption of descending motor pathways. Restoration of these functions enables independent living and therefore represents a high priority for those afflicted by stroke. Here, we report that daily administration of gabapentin, a clinically approved drug already used to treat various neurological disorders, promotes structural and functional plasticity of the corticospinal pathway after photothrombotic cortical stroke in adult mice. We found that gabapentin administration had no effects on vascular occlusion, haemodynamic changes nor survival of corticospinal neurons within the ipsilateral sensory-motor cortex in the acute stages of stroke. Instead, using a combination of tract tracing, electrical stimulation and functional connectivity mapping, we demonstrated that corticospinal axons originating from the contralateral side of the brain in mice administered gabapentin extend numerous collaterals, form new synaptic contacts and better integrate within spinal circuits that control forelimb muscles. Not only does gabapentin daily administration promote neuroplasticity, but it also dampens maladaptive plasticity by reducing the excitability of spinal motor circuitry. In turn, mice administered gabapentin starting 1 h or 1 day after stroke recovered skilled upper extremity function. Functional recovery persists even after stopping the treatment at 6 weeks following a stroke. Finally, chemogenetic silencing of cortical projections originating from the contralateral side of the brain transiently abrogated recovery in mice administered gabapentin, further supporting the conclusion that gabapentin-dependent reorganization of spared cortical pathways drives functional recovery after stroke. These observations highlight the strong potential for repurposing gabapentinoids as a promising treatment strategy for stroke repair.

Intragenic complementation of amino and carboxy terminal SMN missense mutations can rescue Smn null mice.

Spinal muscular atrophy is caused by reduced levels of SMN resulting from the loss of SMN1 and reliance on SMN2 for the production of SMN. Loss of SMN entirely is embryonic lethal in mammals. There are several SMN missense mutations found in humans. These alleles do not show partial function in the absence of wild-type SMN and cannot rescue a null Smn allele in mice. However, these human SMN missense allele transgenes can rescue a null Smn allele when SMN2 is present. We find that the N- and C-terminal regions constitute two independent domains of SMN that can be separated genetically and undergo intragenic complementation. These SMN protein heteromers restore snRNP assembly of Sm proteins onto snRNA and completely rescue both survival of Smn null mice and motor neuron electrophysiology demonstrating that the essential functional unit of SMN is the oligomer.

Brief assessment of cognitive function in myotonic dystrophy: Multicenter longitudinal study using computer-assisted evaluation.

INTRODUCTION/AIMS: Myotonic dystrophy type 1 (DM1) is known to affect cognitive function, but the best methods to assess central nervous system involvement in multicenter studies have not been determined. In this study our primary aim was to evaluate the potential of computerized cognitive tests to assess cognition in DM1. METHODS: We conducted a prospective, longitudinal, observational study of 113 adults with DM1 at six sites. Psychomotor speed, attention, working memory, and executive functioning were assessed at baseline, 3 months, and 12 months using computerized cognitive tests. Results were compared with assessments of muscle function and patient reported outcomes (PROs), including the Myotonic Dystrophy Health Index (MDHI) and the 5-dimension EuroQol (EQ-5D-5L) questionnaire. RESULTS: Based on intraclass correlation coefficients, computerized cognitive tests had moderate to good reliability for psychomotor speed (0.76), attention (0.82), working memory speed (0.79), working memory accuracy (0.65), and executive functioning (0.87). Performance at baseline was lowest for working memory accuracy (P < .0001). Executive function performance improved from baseline to 3 months (P < .0001), without further changes over 1 year. There was a moderate correlation between poorer executive function and larger CTG repeat size (r = -0.433). There were some weak associations between PROs and cognitive performance. DISCUSSION: Computerized tests of cognition are feasible in multicenter studies of DM1. Poor performance was exhibited in working memory, which may be a useful variable in clinical trials. Learning effects may have contributed to the improvement in executive functioning. The relationship between PROs and cognitive impairment in DM1 requires further study.

Neuromuscular mechanisms of weakness in a mouse model of chronic alcoholic myopathy.

BACKGROUND: Weakness is a common clinical symptom reported in individuals with chronic alcohol use disorder. However, it remains unclear whether low strength in these individuals is directly related to excessive ethanol intake, other deleterious factors (lifestyle, environment, genetics, etc.), or a combination of both. Therefore, we examined whether (and how) ethanol reduces the muscle's force-producing capacity using a controlled in vivo preclinical mouse model of excessive ethanol intake. METHODS: To establish whether chronic ethanol consumption causes weakness, C57BL/6 female mice consumed 20% ethanol for 40 weeks (following a 2-week ethanol ramping period), and various measures of muscular force were quantified. Functional measures included all-limb grip strength and in vivo contractility of the left ankle dorsiflexors and plantarflexors. Once confirmed that mice consuming ethanol were weaker than age-matched controls, we sought to determine the potential neuromuscular mechanisms of muscle dysfunction by assessing neuromuscular excitation, muscle quantity, and muscle quality. RESULTS: Mice consuming chronic ethanol were 13 to 16% weaker (p ≤ 0.016) than controls (i.e., mice consuming 100% water) with the negative impact of ethanol on voluntary grip strength (ƞ2  = 0.603) being slightly larger than that of electrically stimulated muscle contractility (ƞ2  = 0.482). Relative to controls, lean mass and muscle wet masses were 9 to 16% lower in ethanol-consuming mice (p ≤ 0.048, ƞ2  ≥ 0.268). No significant changes were observed between groups for indices of neuromuscular excitation at the level of the motor unit, neuromuscular junction, or plasmalemma (p ≥ 0.259, ƞ2  ≤ 0.097), nor was muscle quality altered after 40 weeks of 20% ethanol consumption (p ≥ 0.695, ƞ2  ≤ 0.012). CONCLUSIONS: Together, these findings establish that chronic ethanol consumption in mice induces a substantial weakness in vivo that we interpret to be primarily due to muscle atrophy (i.e., reduced muscle quantity) and possibly, to a lesser degree, loss of central neural drive.

Dual SMN inducing therapies can rescue survival and motor unit function in symptomatic ∆7SMA mice.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by survival motor neuron (SMN) protein deficiency which results in motor neuron loss and muscle atrophy. SMA is caused by a mutation or deletion of the survival motor neuron 1 (SMN1) gene and retention of the nearly identical SMN2 gene. SMN2 contains a C to T change in exon 7 that results in exon 7 exclusion from 90% of transcripts. SMN protein lacking exon 7 is unstable and rapidly degraded. The remaining full-length transcripts from SMN2 are insufficient for normal motor neuron function leading to the development of SMA. Three different therapeutic approaches that increase full-length SMN (FL-SMN) protein production are approved for treatment of SMA patients. Studies in both animal models and humans have demonstrated increasing SMN levels prior to onset of symptoms provides the greatest therapeutic benefit. Treatment of SMA, after some motor neuron loss has occurred, is also effective but to a lesser degree. The SMN∆7 mouse model is a well characterized model of severe or type 1 SMA, dying at 14 days of age. Here we treated three groups of ∆7SMA mice starting before, roughly during, and after symptom onset to determine if combining two mechanistically distinct SMN inducing therapies could improve the therapeutic outcome both before and after motor neuron loss. We found, compared with individual therapies, that morpholino antisense oligonucleotide (ASO) directed against ISS-N1 combined with the small molecule compound RG7800 significantly increased FL-SMN transcript and protein production resulting in improved survival and weight of ∆7SMA mice. Moreover, when give late symptomatically, motor unit function was completely rescued with no loss in function at 100 days of age in the dual treatment group. We have therefore shown that this dual therapeutic approach successfully increases SMN protein and rescues motor function in symptomatic ∆7SMA mice.

A ketogenic diet combined with exercise alters mitochondrial function in human skeletal muscle while improving metabolic health.

Animal data indicate that ketogenic diets are associated with improved mitochondrial function, but human data are lacking. We aimed to characterize skeletal muscle mitochondrial changes in response to a ketogenic diet combined with exercise training in healthy individuals. Twenty-nine physically active adults completed a 12-wk supervised exercise program after self-selection into a ketogenic diet (KD, n = 15) group or maintenance of their habitual mixed diet (MD, n = 14). Measures of metabolic health and muscle biopsies (vastus lateralis) were obtained before and after the intervention. Mitochondria were isolated from muscle and studied after exposure to carbohydrate (pyruvate), fat (palmitoyl-l-carnitine), and ketone (ß-hydroxybutyrate+acetoacetate) substrates. Compared with MD, the KD resulted in increased whole body resting fat oxidation (P < 0.001) and decreased fasting insulin (P = 0.019), insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), P = 0.022], and visceral fat (P < 0.001). The KD altered mitochondrial function as evidenced by increases in mitochondrial respiratory control ratio (19%, P = 0.009), ATP production (36%, P = 0.028), and ATP/H2O2 (36%, P = 0.033) with the fat-based substrate. ATP production with the ketone-based substrate was four to eight times lower than with other substrates, indicating minimal oxidation. The KD resulted in a small decrease in muscle glycogen (14%, P = 0.035) and an increase in muscle triglyceride (81%, P = 0.006). These results expand our understanding of human adaptation to a ketogenic diet combined with exercise. In conjunction with weight loss, we observed altered skeletal muscle mitochondrial function and efficiency, an effect that may contribute to the therapeutic use of ketogenic diets in various clinical conditions, especially those associated with insulin resistance.

Mild SMN missense alleles are only functional in the presence of SMN2 in mammals.

Spinal muscular atrophy (SMA) is caused by reduced levels of full-length SMN (FL-SMN). In SMA patients with one or two copies of the Survival Motor Neuron 2 (SMN2) gene there are a number of SMN missense mutations that result in milder-than-predicted SMA phenotypes. These mild SMN missense mutation alleles are often assumed to have partial function. However, it is important to consider the contribution of FL-SMN as these missense alleles never occur in the absence of SMN2. We propose that these patients contain a partially functional oligomeric SMN complex consisting of FL-SMN from SMN2 and mutant SMN protein produced from the missense allele. Here we show that mild SMN missense mutations SMND44V, SMNT74I or SMNQ282A alone do not rescue mice lacking wild-type FL-SMN. Thus, missense mutations are not functional in the absence of FL-SMN. In contrast, when the same mild SMN missense mutations are expressed in a mouse containing two SMN2 copies, functional SMN complexes are formed with the small amount of wild-type FL-SMN produced by SMN2 and the SMA phenotype is completely rescued. This contrasts with SMN missense alleles when studied in C. elegans, Drosophila and zebrafish. Here we demonstrate that the heteromeric SMN complex formed with FL-SMN is functional and sufficient to rescue small nuclear ribonucleoprotein assembly, motor neuron function and rescue the SMA mice. We conclude that mild SMN missense alleles are not partially functional but rather they are completely non-functional in the absence of wild-type SMN in mammals.

Outcome measures in a cohort of ambulatory adults with spinal muscular atrophy.

INTRODUCTION: With the advent of disease-altering therapies for spinal muscular atrophy (SMA), there is a requirement to better characterize outcome measures, particularly in milder forms of disease. METHODS: Maximal voluntary isometric contraction testing and 6-minute walk test (6MWT) performed in ambulatory SMA adults as part of the SMA-VALIANT trial were analyzed. Test-retest reliability and correlation with other candidate biomarkers and outcomes were investigated. RESULTS: Maximal voluntary isometric contraction testing and 6MWT showed good test-retest reliability (intraclass correlation coefficient = 0.98 and 0.85, respectively). Maximal voluntary isometric contraction testing and 6MWT demonstrated very strong correlation (r = 0.83, P <. 0001), and each correlated with the SMA Functional Rating Scale (r = 0.7, P < .0001 and r = 0.65, P = .0001, respectively), lean muscle mass (r = 0.68, P < .0001 and r = 0.56, P = .001, respectively), and ulnar compound muscle action potential (r = 0.57, P = .0008 and r = 0.47, P = .008, respectively). DISCUSSION: Maximal voluntary isometric contraction testing and 6MWT are suitable outcomes for use in ambulatory adults with SMA. Maximal voluntary isometric contraction testing may be preferable because of superior test-retest reliability and closer associations with other outcomes and biomarkers of neuromuscular function.

Guidelines on clinical presentation and management of nondystrophic myotonias.

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.

Muscle contractility dysfunction precedes loss of motor unit connectivity in SOD1(G93A) mice.

INTRODUCTION: Electrophysiological measurements are used in longitudinal clinical studies to provide insight into the progression of amyotrophic lateral sclerosis (ALS) and the relationship between muscle weakness and motor unit (MU) degeneration. Here, we used a similar longitudinal approach in the Cu/Zn superoxide dismutase (SOD1[G93A]) mouse model of ALS. METHODS: In vivo muscle contractility and MU connectivity assays were assessed longitudinally in SOD1(G93A) and wild type mice from postnatal days 35 to 119. RESULTS: In SOD1(G93A) males, muscle contractility was reduced by day 35 and preceded MU loss. Muscle contractility and motor unit reduction were delayed in SOD1(G93A) females compared with males, but, just as with males, muscle contractility reduction preceded MU loss. DISCUSSION: The longitudinal contractility and connectivity paradigm employed here provides additional insight into the SOD1(G93A) mouse model and suggests that loss of muscle contractility is an early finding that may precede loss of MUs and motor neuron death. Muscle Nerve 59:254-262, 2019.

Defective membrane fusion and repair in Anoctamin5-deficient muscular dystrophy.

Limb-girdle muscular dystrophies are a genetically diverse group of diseases characterized by chronic muscle wasting and weakness. Recessive mutations in ANO5 (TMEM16E) have been directly linked to several clinical phenotypes including limb-girdle muscular dystrophy type 2L and Miyoshi myopathy type 3, although the pathogenic mechanism has remained elusive. ANO5 is a member of the Anoctamin/TMEM16 superfamily that encodes both ion channels and regulators of membrane phospholipid scrambling. The phenotypic overlap of ANO5 myopathies with dysferlin-associated muscular dystrophies has inspired the hypothesis that ANO5, like dysferlin, may be involved in the repair of muscle membranes following injury. Here we show that Ano5-deficient mice have reduced capacity to repair the sarcolemma following laser-induced damage, exhibit delayed regeneration after cardiotoxin injury and suffer from defective myoblast fusion necessary for the proper repair and regeneration of multinucleated myotubes. Together, these data suggest that ANO5 plays an important role in sarcolemmal membrane dynamics. Genbank Mouse Genome Informatics accession no. 3576659.

Natural history of infantile-onset spinal muscular atrophy.

OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed. RESULTS: Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17). INTERPRETATION: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891.

Infections and the relationship to treatment in neuromuscular autoimmunity.

INTRODUCTION: This study aimed to identify infections in patients with myasthenia gravis, dermatomyositis, and chronic inflammatory demyelinating polyradiculoneuropathy, and to investigate the relationship between infection and immunomodulation. METHODS: A retrospective chart review examined 631 patients with myasthenia gravis (n = 358), chronic inflammatory demyelinating polyradiculoneuropathy (n = 124), and dermatomyositis (n = 149) patients over a 10-year time period. RESULTS: Infection rates were similar at approximately 19% in all 3 diseases. Of the infections in which a causative organism was identified, pneumonia, sepsis, and opportunistic infections were the leading diagnoses. A multivariate model demonstrated a significant association between infection and an increased dose of plasma exchange, mycophenolate mofetil, and corticosteroid therapy. DISCUSSION: There are few large studies investigating rates of infections in patients with autoimmune neuromuscular disorders and the relationship to immunomodulation. This study not only demonstrates the remarkably similar infection rates across the 3 diseases studied, but also shows their relationship to commonly used immunotherapies. Muscle Nerve 57: 927-931, 2018.

SMN expression is required in motor neurons to rescue electrophysiological deficits in the SMNΔ7 mouse model of SMA.

Proximal spinal muscular atrophy (SMA) is the most frequent cause of hereditary infant mortality. SMA is an autosomal recessive neuromuscular disorder that results from the loss of the Survival Motor Neuron 1 (SMN1) gene and retention of the SMN2 gene. The SMN2 gene produces an insufficient amount of full-length SMN protein that results in loss of motor neurons in the spinal cord and subsequent muscle paralysis. Previously we have shown that overexpression of human SMN in neurons in the SMA mouse ameliorates the SMA phenotype while overexpression of human SMN in skeletal muscle had no effect. Using Cre recombinase, here we show that either deletion or replacement of Smn in motor neurons (ChAT-Cre) significantly alters the functional output of the motor unit as measured with compound muscle action potential and motor unit number estimation. However ChAT-Cre alone did not alter the survival of SMA mice by replacement and did not appreciably affect survival when used to deplete SMN. However replacement of Smn in both neurons and glia in addition to the motor neuron (Nestin-Cre and ChAT-Cre) resulted in the greatest improvement in survival of the mouse and in some instances complete rescue was achieved. These findings demonstrate that high expression of SMN in the motor neuron is both necessary and sufficient for proper function of the motor unit. Furthermore, in the mouse high expression of SMN in neurons and glia, in addition to motor neurons, has a major impact on survival.