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• Transcranial magnetic stimulation is an objective biomarker of upper motor neuron dysfunction in motor neuron disease (MND). • Cortical hyperexcitability is mediated by cortical disinhibition and increased facilitation. • Neuroimaging biomarkers of upper motor neuron dysfunction in MND exhibit utility. Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility. [ABSTRACT FROM AUTHOR]

• Conventional nerve conduction studies, H-reflex studies, and needle electromyography are important tools for the diagnosis of Motor Neuron Disease (MND) • High-density surface EMG, nerve excitability testing, electrical impedance myography, MUNIX, and MScanFit are potential biomarkers for MND. • Neuromuscular ultrasonography can detect changes in nerve and muscle architecture including dynamic changes such as fasciculations. This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE), and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

• Autonomic function is impaired in fALS8 and involves parasympathetic and sympathetic divisions. • sALS and fALS8 present similar neurophysiological abnormalities but different autonomic complaints. • Sudomotor compromise in sALS and fALS8 is mediated by a small fiber, possibly length-dependent, autonomic neuropathy. To characterize and compare autonomic function in patients with sporadic (sALS) and familial ALS type 8 (fALS8). We selected 11 patients with sALS (7 men), 14 with fALS8 (8 men) and 26 controls (15 men). All groups were gender and age-matched. For each subject, Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT) was applied and data from heart rate variability, Quantitative Sudomotor Axon Reflex Test (QSART) and skin sympathetic response (SSR) were collected. These data were compared across groups using nonparametric tests. P-values < 0.05 were considered significant. SCOPA-AUT revealed predominant clinical complaints in thermoregulatory, pupillomotor and sexual domains in fALS8 relative to sALS as well as controls. Neurophysiological tests demonstrated significant differences in Valsalva ratio, Expiratory:Inspiratory index and RR minimum values in both ALS groups relative to controls. Sudomotor dysfunction was also observed in sALS and fALS8 groups, as shown by reduced medial forearm and foot QSART volumes and absence of SSR in lower limbs. Dysautonomia – cardiac and sudomotor - is part of the phenotype in sALS and fALS8. The profile of autonomic symptoms, however, is different in each group. Patients with fALS8 and sALS have autonomic dysfunction involving both sympathetic and parasympathetic divisions. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive disease for which no curative treatment is currently available. This study aimed to investigate whether cortico-spinal transcranial direct current stimulation (tDCS) could mitigate symptoms in ALS patients via a randomized, double-blind, sham-controlled trial, followed by an open-label phase. Thirty-one participants were randomized into two groups for the initial controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS), while Group 2 received cortico-spinal stimulation (real tDCS) for five days/week for two weeks (T1), with an 8-week (T2) follow-up (randomized, double-blind, sham-controlled phase). At the 24-week follow-up (T3), all participants (Groups 1 and 2) received a second treatment of anodal bilateral motor cortex and cathodal spinal stimulation (real tDCS) for five days/week for two weeks (T4). Follow-up evaluations were performed at 32-weeks (T5) and 48-weeks (T6) (open-label phase). At each time point, clinical assessment, blood sampling, and intracortical connectivity measures using transcranial magnetic stimulation (TMS) were evaluated. Additionally, we evaluated survival rates. Compared to sham stimulation, cortico-spinal tDCS significantly improved global strength, caregiver burden, and quality of life scores, which correlated with the restoration of intracortical connectivity measures. Serum neurofilament light levels decreased among patients who underwent real tDCS but not in those receiving sham tDCS. The number of completed 2-week tDCS treatments significantly influenced patient survival. Cortico-spinal tDCS may represent a promising therapeutic and rehabilitative approach for patients with ALS. Further larger-scale studies are necessary to evaluate whether tDCS could potentially impact patient survival. NCT04293484. • Cortico-spinal tDCS improves strength, caregiver burden, and quality of life in ALS. • Real tDCS restores intracortical connectivity and decreases serum neurofilament levels. • The number of tDCS treatments significantly influences ALS patient survival. • TDCS offers a new therapeutic and rehabilitative approach for ALS patients. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether the physical activity scale for the elderly (PASE) is a valid tool in measuring physical activity (PA) in people with motor neuron disease (MND) and to identify the demographic and clinical factors that predict PA participation in this population. A prospective, observational study involving 100 ambulant participants with MND. This study was conducted at a multidisciplinary specialist MND clinic. The clinic is fully funded by the local public health system and patients receiving care here are not expected to pay for their consultation. 190 patients with MND who had a physiotherapy appointment at the specialist clinic between July and October 2018 were screened. Of these, 100 participants (mean age 67 years [SD=12], 64% [n=64] men) who were ambulant (with or without assistance) were recruited (N=100). Not applicable. PASE questionnaire, amyotrophic lateral sclerosis functional rating scale—Revised (ALSFRS- r), forced vital capacity (FVC). The results showed that engagement in PA is generally low, with median PASE score of 57. The PASE had fair-moderate correlation with ALSFRS-R total scores (rho=0.607; P <.000) and FVC (rho=0.250; P =.030). Standard multiple regression analyses showed that disease severity (ALSFRS-R total score) was the strongest predictor of PA levels (β = 0.54; 95% confidence interval 0.02,0.06). The most frequently selected physical activities of choice for people with MND were activities around their homes and the biggest barrier to participation is fatigue. Present findings suggest that the PASE can be used to measure PA participation in people with MND. Details about activity of choice and barriers to participation present important considerations in designing exercise programs in this population to maximize compliance and therefore effectiveness. [ABSTRACT FROM AUTHOR]

[Display omitted] Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114–120 male and female SOD1G93A mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration–time curves (AUC plasma) of digoxin and sulfasalazine were not significantly different between SOD1G93A and WT mice for both sexes. However, the AUC plasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1G93A compared to WT mice, which was associated with lower AUC brain (female: 0.76-fold, male: 0.80-fold) and AUC spinal cord (female: 0.81-fold, male: 0.82-fold). The AUC stomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1G93A compared to WT mice, suggesting reduced gastric emptying in SOD1G93A mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1G93A compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1G93A mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range. [ABSTRACT FROM AUTHOR]

RNA-binding proteins (RBPs) are evolutionarily conserved across most forms of life, with an estimated 1500 RBPs in humans. Traditionally associated with post-transcriptional gene regulation, RBPs contribute to nearly every known aspect of RNA biology, including RNA splicing, transport, and decay. In recent years, an increasing subset of RBPs have been recognized for their DNA binding properties and involvement in DNA transactions. We refer to these RBPs with well-characterized DNA binding activity as RNA/DNA binding proteins (RDBPs), many of which are linked to neurological diseases. RDBPs are associated with both nuclear and mitochondrial DNA repair. Furthermore, the presence of intrinsically disordered domains in RDBPs appears to be critical for regulating their diverse interactions and plays a key role in controlling protein aggregation, which is implicated in neurodegeneration. In this review, we discuss the emerging roles of common RDBPs from the heterogeneous nuclear ribonucleoprotein (hnRNP) family, such as TAR DNA binding protein-43 (TDP43) and fused in sarcoma (FUS) in controlling DNA damage response (DDR). We also explore the implications of RDBP pathology in aging and neurodegenerative diseases and provide a prospective on the therapeutic potential of targeting RDBP pathology mediated DDR defects for motor neuron diseases and aging. • Dual Role of RDBPs : The review highlights the dual roles of RDBPs in RNA biology and DDR, emphasizing their crucial involvement in both nuclear and mitochondrial DNA repair processes. • Implications for Neurodegenerative Diseases : It explores how dysfunctions in RDBPs, such as TAR DNA binding protein-43 (TDP43) and fused in sarcoma (FUS), contribute to the pathology of age-associated neurodegenerative diseases like ALS and Alzheimer's disease through mechanisms like protein aggregation and genomic instability. • Potential Therapeutic Targets : The review discusses the therapeutic potential of targeting RDBP-mediated DDR defects, proposing various strategies including small molecule inhibitors, antisense oligonucleotides, and post-translational modifications to mitigate neurodegeneration and aging-related conditions. • Timely and Emerging Research : This review is timely, given the growing recognition of the importance of RDBPs in maintaining genomic stability and their impact on neurological health, providing valuable insights for future research and therapeutic development. [ABSTRACT FROM AUTHOR]

Seipin is encoded by the gene Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and FLD1 / SEI1 in yeast. The gain-of-function N88S mutation in the BSCL2 gene was identified in a cohort of autosomal dominant motor neuron diseases (MNDs) collectively known as seipinopathies. Previous work has shown that this mutation disrupts N-glycosylation, leading to the formation of inclusion bodies (IBs) and contributing to severe Endoplasmic Reticulum (ER) stress and cell death. In this work, we established a humanized yeast model of N88S seipinopathy that recapitulated the formation of IBs and activation of the unfolded protein response (UPR) observed in mammalian systems. Autophagy and the Hrd1-mediated endoplasmic reticulum-associated degradation (ERAD) were fully functional in cells expressing mutant homomers and WT-mutant heteromers of seipin, discarding the possibility that mutant seipin accumulate due to impaired protein quality control systems. Importantly, the N88S seipin form IBs that appear to induce changes in ER morphology, in association with Kar2 chaperone and the Hsp104 disaggregase. For the first time, we have determined that N88S homo-oligomers expressing cells present reduced viability, decreased antioxidant activity and increased oxidative damage associated with loss of mitochondrial membrane potential, higher reactive oxygen species (ROS) levels and lipid peroxidation. This was correlated with the activation of oxidative stress sensor Yap1. Moreover, activation of ERAD and UPR quality control mechanisms were essential for proper cell growth, and crucial to prevent excessive accumulation of ROS in cells expressing N88S homomers solely. Overall, this study provides new insights into the molecular underpinnings of these rare diseases and offers novel targets for potential pharmacological intervention. [Display omitted] • Lipid droplets (LDs) are ubiquitous organelles that play vital roles in lipid and energy homeostasis. • N88S seipin cause motor neuron diseases known as seipinopathies. • N88S seipin-associated protein aggregation cause ER stress and oxidative damage. • Mutant seipin homomers are the species that largely contribute to N88S-linked seipinopathy toxicity. • Co-expression of WT seipin in cells expressing mutant seipin attenuates some phenotypes associated with N88S toxicity. [ABSTRACT FROM AUTHOR]

Motor neurons are a remarkably powerful cell type in the central nervous system. They innervate and control the contraction of virtually every muscle in the body and their dysfunction underlies numerous neuromuscular diseases. Some motor neurons seem resistant to degeneration whereas others are vulnerable. The intrinsic heterogeneity of motor neurons in adult organisms has remained elusive. The development of high-throughput single-cell transcriptomics has changed the paradigm, empowering rapid isolation and profiling of motor neuron nuclei, revealing remarkable transcriptional diversity within the skeletal and autonomic nervous systems. Here, we discuss emerging technologies for defining motor neuron heterogeneity in the adult motor system as well as implications for disease and spinal cord injury. We establish a roadmap for future applications of emerging techniques – such as epigenetic profiling, spatial RNA sequencing, and single-cell somatic mutational profiling to adult motor neurons, which will revolutionize our understanding of the healthy and degenerating adult motor system. Single-cell and single-nucleus transcriptomics have enabled rapid scaling in our understanding of the adult mammalian motor system. Characterizing motor diversity establishes links between cell types and causative dysfunction in disease using human genetics data. Transcriptional profiles of mature motor neuron subtypes are a new benchmark for what constitutes an induced motor neuron in vitro. Emerging technologies hold the potential to assess somatic mutations and epigenetic profiles along with the transcriptome in rare and powerful motor neurons. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss. ALS is now associated with mutations in numerous genes, many of which cause disease in part through toxic gain-of-function mechanisms. Antisense oligonucleotides (ASOs) are small sequences of DNA that can reduce expression of a target gene at the post-transcriptional level, making them attractive for neutralizing mutant or toxic gene products. Advancements in the medicinal chemistries of ASOs have improved their pharmacodynamic profile to allow safe and effective delivery to the central nervous system. ASO therapies for ALS have rapidly developed over the last two decades, and ASOs that target SOD1, C9orf72, FUS, and ATXN2 are now in clinical trials for familial or sporadic forms of ALS. This review discusses the current state of ASO therapies for ALS, outlining their successes from preclinical development to early clinical trials. [ABSTRACT FROM AUTHOR]

The study of the role of retroviruses in amyotrophic lateral sclerosis (ALS) dates back to the 1960s shortly after transposable elements themselves were first discovered. It was quickly realized that in wild mice both horizontal and vertical transmissions of retroviral elements were key to the development of an ALS-like syndrome leading to the postulate that endogenous retroviruses (ERVs) contribute significantly to the pathogenicity of this disease. Subsequent studies identified retroviral reverse transcriptase activity in brains of individuals with ALS from Guam. However, except for a single study from the former Soviet Union, ALS could not be transmitted to rhesus macaques. The discovery of an ALS-like syndrome in human immunodeficiency virus (HIV) and human T cell leukemia virus infected individuals led to renewed interest in the field and reverse transcriptase activity was found in the blood and cerebrospinal fluid of individuals with sporadic ALS. However, exogenous retroviruses could not be found in individuals with ALS which further reinforced the possibility of involvement of a human ERV (HERV). The first demonstration of the involvement of a HERV was the discovery of the activation of human endogenous retrovirus-K subtype HML-2 in the brains of individuals with ALS. The envelope protein of HML-2 is neurotoxic and transgenic animals expressing the envelope protein develop an ALS-like syndrome. Activation of HML-2 occurs in the context of generalized transposable element activation and is not specific for ALS. Individuals with HIV-associated ALS show a remarkable response to antiretroviral therapy; however, antiretroviral trials in ALS down-regulate HML-2 without ameliorating the disease. This highlights the need for specific drugs to be developed against HML-2 as a novel therapeutic target for ALS. Other approaches might include antisense oligonucleotides, shRNA targeted against the envelope gene or antibodies that can target the extracellular envelope protein. Future clinical trials in ALS should consider combination therapies to control these ERVs. [ABSTRACT FROM AUTHOR]

• 37 adults with SMA 2–3 treated with nusinersen, followed for up to 30 months of treatment. • Median MRC score increased from baseline to visits at 6 and 14 months, not afterwards. • The median rate of MRC score increase was 1.85 points per year. • Revised hammersmith scale median score increased only from baseline to 6 months. • Revised hammersmith scale's calculated annual rate of change was 0 points. The effectiveness of nusinersen treatment in patients with spinal muscular atrophy (SMA) was established in clinical trials only for pediatric patients. Few cohort studies confirmed its benefit in adults up to 22 months of treatment. We report a longer-term observation of nusinersen treatment effects and safety in a large cohort of adult patients. Patients with SMA type 2 and 3 treated with nusinersen at Tel-Aviv Medical Center between March 2018 and September 2020 were prospectively recruited. Neurological impairment, motor, respiratory function, and side effects were recorded. We compared baseline measurements with those after 6, 14, and 26 months of treatment and calculated the annual rates of change. Overall, 37 patients were treated (21–64 years old). 16 completed 26 months, and 8 completed 30 months of treatment. The median score on the Medical Research Council strength scale increased from baseline to visits at 6 and 14 months (p ≤ 0.03), but not afterwards, with a median increase of 1.85 points per year. Revised Hammersmith Scale median score increased only from baseline to 6 months (p = 0.02), with a calculated annual rate of change of 0 points. No significant change was noticed in the respiratory function. The only side effect was post lumbar puncture headache. In conclusion, our study further supports the efficacy and safety of nusinersen treatment in adult patients with SMA2 and SMA3, with modest improvement in muscle strength, and stabilization of motor function over a relatively long period of observation. [ABSTRACT FROM AUTHOR]

The study aimed to explore the meaning for adolescents of living with a parent with amyotrophic lateral sclerosis (ALS). The design is qualitative. Interviews were conducted between December 2020 and April 2022 with 11 adolescents (8-25 y), living in households with a parent with ALS in Sweden. The analysis was phenomenologically hermeneutical. The adolescents were in a difficult and exposed situation, especially if the parent had a severe disability and assistant care providers were in the home. Witnessing the gradual loss of the parent in an indefinite battle against time, while still needing them, elicited grief-filled and hard-to-manage emotions. Everyday life was turned upside down, resulting in greater responsibility for the adolescents, not only in helping with household chores and assisting the ill parent, but also in emotionally protecting both parents. It forced the adolescents to mature faster and put their own life on hold, triggering experiences of being limited. This, together with changing family roles yet being more attached to home, reinforced the imbalance in the adolescents' lives. The interpreted whole of the adolescents' narratives revealed that living with a parent with ALS meant a challenging and grieving transition during an already transition-filled adolescence, which left the adolescents struggling to keep a foothold on a life torn apart. The unbalanced life situation may hinder the adolescents' identity formation and emancipation, which are developmentally important for managing a healthy and independent adulthood. The results emphasize the importance of early targeted support to reach this vulnerable group in order to secure their health. • Living with a parent with amyotrophic lateral sclerosis (ALS) was challenging. • The adolescents' lives were turned upside down, bringing increased responsibility. • They were forced to mature faster while becoming more attached to home. • This unbalanced life situation may disturb the identity formation and emancipation. • Early, targeted support is crucial to secure this vulnerable group's health. [ABSTRACT FROM AUTHOR]

Palliative care (PC) benefits patients with amyotrophic lateral sclerosis (ALS), however the needs of patients and caregivers and the optimal timing of PC discussions remains unclear. This study reports the analysis of PC consult notes from a larger feasibility trial. The specific aims of this analysis were to i) identify the PC needs of patients with ALS via qualitative analysis and ii) identify characteristics of patients and caregivers that could predict specific PC needs. This study was nested within a nonrandomized, prospective study of patients with ALS (and their caregivers) being treated at a multidisciplinary ALS clinic. Exclusion criteria of the main study were age <18 years, inability to complete questionnaires, and prior receipt of PC. All patients were offered a PC consultation (PCC); those who accepted were included in this nested study. Consultation notes were reviewed and thematic and content analyses were conducted. The occurrence of themes across patient and caregiver contextual variables were examined. Thirty-two PCCs were completed between October 2020 and April 2022. Six major themes were identified: PC roles (with subthemes encompassing the spectrum of specialist PC practice including symptom management and advance care planning), engagement with PC, patients' concerns for their caregivers, caregiver-specific concerns, finances, and COVID-19. An average of 12 topics were discussed per PCC (range = 3–22). Discussion of advance care planning, care coordination, and symptom management was common, and these topics were not discussed more frequently in PCCs with patients with lower functional status, more bulbar symptoms, or lower quality of life. Time from diagnosis did not impact topics of discussion. Patients reporting more symptoms of depression more frequently required psychological support, particularly regarding loss of independence, employment, and leisure activities. Patients with ALS and their caregivers have a wide range of PC needs. These needs vary irrespective of time from diagnosis, functional status, or quality of life, therefore PCC is recommended for all patients with ALS. PCC should be individualized based on patient and caregiver preferences. The study was registered with ClinicalTrials.gov (NCT04257760; https://clinicaltrials.gov/ct2/show/NCT04257760) on February 6, 2020. The first enrollment occurred on October 20, 2020. [ABSTRACT FROM AUTHOR]

• MRI can evaluate diaphragm and intercostal muscle function in neuromuscular disease. • Diaphragmatic motion is decreased both in myopathies and motor neuron disease. • Severe diaphragmatic impairment is often seen in patients with Pompe disease. The aim of this exploratory study was to evaluate diaphragmatic function across various neuromuscular diseases using spirometry-controlled MRI. We measured motion of the diaphragm relative to that of the thoracic wall (cranial-caudal ratio vs. anterior posterior ratio; CC-AP ratio), and changes in the diaphragmatic curvature (diaphragm height and area ratio) during inspiration in 12 adults with a neuromuscular disease having signs of respiratory muscle weakness, 18 healthy controls, and 35 adult Pompe patients – a group with prominent diaphragmatic weakness. CC-AP ratio was lower in patients with myopathies (n=7, 1.25±0.30) and motor neuron diseases (n=5, 1.30±0.10) than in healthy controls (1.37±0.14; p=0.001 and p=0.008), but not as abnormal as in Pompe patients (1.12±0.18; p=0.011 and p=0.024). The mean diaphragm height ratio was 1.17±0.33 in patients with myopathies, pointing at an insufficient diaphragmatic contraction. This was also seen in patients with Pompe disease (1.28±0.36), but not in healthy controls (0.82±0.33) or patients with motor neuron disease (0.82±0.24). We conclude that spirometry-controlled MRI enables us to investigate respiratory dysfunction across neuromuscular diseases, suggesting that the diaphragm is affected in a different way in myopathies and motor neuron diseases. Whether MRI can also be used to evaluate progression of diaphragmatic dysfunction requires additional studies. [ABSTRACT FROM AUTHOR]

To describe clinical and genetic studies on a patient with early-onset spinal muscular atrophyX3 (SMAX3) with novel variant of ATP7A. Clinical, neurophysiological, neuroimaging and pathological examinations were performed. Whole exome sequencing was applied to search genetic bases of this patient. The patient had gait abnormality from early infantile period. Muscle imaging at 42 years old showed predominant involvement of proximal muscles as compared to the distal muscles. The patient had a novel variant of ATP7A , which was the fourth genotype of ATP7A exhibited as SMAX3. Contrary to previous reports of distal motor neuropathy, the clinical and neuroimaging findings in this case revealed dominant involvement in the proximal portion of the extremities and trunk, which is similar to patients with type III SMA. The dominant involvement of proximal motor system in this patient may expand the phenotypic variability of SMAX3. We need to be aware of this disorder in differential diagnosis of patients with type III SMA-like phenotype. [ABSTRACT FROM AUTHOR]

Motor neuron diseases encompass a divergent group of conditions with considerable differences in clinical manifestations, survival, and genetic vulnerability. One of the key aspects of clinical heterogeneity is the preferential involvement of upper (UMN) and lower motor neurons (LMN). While longitudinal imaging patters are relatively well characterized in ALS, progressive cortical changes in UMN,- and LMN-predominant conditions are seldom evaluated. Accordingly, the objective of this study is the juxtaposition of longitudinal trajectories in 3 motor neuron phenotypes; a UMN-predominant syndrome (PLS), a mixed UMN-LMN condition (ALS), and a lower motor neuron condition (poliomyelitis survivors). A standardized imaging protocol was implemented in a prospective, multi-timepoint longitudinal study with a uniform follow-up interval of 4 months. Forty-five poliomyelitis survivors, 61 patients with amyotrophic lateral sclerosis (ALS), and 23 patients with primary lateral sclerosis (PLS) were included. Cortical thickness alterations were evaluated in a dual analysis pipeline, using standard cortical thickness analyses, and a z-score-based individualized approach. Our results indicate that PLS patients exhibit rapidly progressive cortical thinning primarily in motor regions; ALS patients show cortical atrophy in both motor and extra-motor regions, while poliomyelitis survivors exhibit cortical thickness gains in a number of cerebral regions. Our findings suggest that dynamic cortical changes in motor neuron diseases may depend on relative UMN and/or LMN involvement, and increased cortical thickness in LMN-predominant conditions may represent compensatory, adaptive processes. [ABSTRACT FROM AUTHOR]

The clinical severity of Sandhoff disease is known to vary widely. Furthermore, long-term follow-up report is very limited in the literature. We present a long-term follow-up report of a patient with juvenile-onset Sandhoff disease with a motor neuron disease phenotype. The patient had compound heterozygous variants of HEXB (p.Trp460Arg, p. Arg533His); the Trp460Arg was a novel variant. Long-term follow-up revealed no intellectual deterioration, swallowing dysfunction, or respiratory muscle dysfunction despite progressive weakness of the extremities and sensory disturbances. We need to be aware of Sandhoff disease in patients with juvenile-onset motor neuron disease. [ABSTRACT FROM AUTHOR]

Accurate and timely diagnosis of amyotrophic lateral sclerosis (ALS) is a diagnostic challenge given the lack of specific diagnostic and imaging biomarkers as well as the significant clinic overlap with mimic syndromes. We hypothesize that MR quantitative susceptibility mapping (QSM) can help differentiate ALS from mimic diagnoses. In a blinded retrospective study of MRIs with QSM from 2015 to 2018, we compared motor cortex susceptibility along the hand and face homunculi in ALS patients and patients with similar clinical presentations. Inclusion required a confirmed ALS or a mimic diagnosis. Comparative groups included age-matched patients with MRIs performed for non-motor neuron symptoms that were reported as normal or demonstrated leukoaraiosis. Quantitative susceptibility values were compared with ANOVA and Tukey-Kramer (post-hoc). ROC analysis and Youden's index were used to identify optimal cutoff values. Fifty ALS, 35 mimic, and 70 non-motor neuron symptom patients (35 normal, 35 leukoaraiosis) were included. Hand and face homunculus mean susceptibility values were significantly higher in the ALS group compared to the mimic (p =0.001, p =0.004), leukoaraiosis (p <0.001, p =0.003), and normal (p<0.001, p<0.001) groups. ROC curve analysis comparing ALS to mimics resulted in an area under the curve of 0.71 and 0.67 for the hand and face homunculus measurements, respectively. In differentiating ALS from mimics, Youden's index showed 100% specificity and 36% sensitivity for hand homunculus measurements. QSM has diagnostic potential in the assessment of suspected ALS patients, demonstrating very high specificity in differentiating ALS from mimic diagnoses. • Motor cortex quantitative susceptibility values were significantly higher in ALS patients compared to patients without motor neuron symptoms. • Significantly higher motor cortex quantitative susceptibility values were found in ALS patients compared to patients with diseases mimicking ALS. • Measurements along the hand homunculus showed 100% specificity in differentiating ALS from mimics. • Quantitative susceptibility mapping has a diagnostic role in differentiating ALS from disease mimics. [ABSTRACT FROM AUTHOR]

Transactive response DNA-binding protein 43 kDa (TDP-43), a multifunctional nucleic acid-binding protein, is a primary component of insoluble aggregates associated with several devastating nervous system disorders; mutations in TARDBP , its encoding gene, are a cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we review established and emerging roles of TDP-43 and consider how its dysfunction impinges on RNA homeostasis in the nervous system, thereby contributing to neural degeneration. Notably, improper splicing of the axonal growth-associated factor STMN2 has recently been connected to TDP-43 dysfunction, providing a mechanistic link between TDP-43 proteinopathies and neuropathy. This review highlights how a deep understanding of the function of TDP-43 in the brain might be leveraged to develop new targeted therapies for several neurological disorders. The list of diseases associated with TDP-43 aggregation has grown beyond ALS and FTD. Genetic findings implicate impaired proteostasis in disease pathogenesis, and molecular studies tie decreased protein turnover to TDP-43 aggregation. Mutations in the glycine-rich domain of TDP-43 incriminate altered phase separation in disease pathogenesis, and new mutations in the RNA recognition motifs potentially affect both RNA binding and solubility. Altered regulation of critical neuronal transcripts, including STMN2, is associated with the loss of TDP-43 function, providing a mechanistic link between TDP-43 and neuropathy. Aberrant changes in STMN2 expression in other neurodegenerative diseases spotlight the critical nature of this cytoskeletal regulator. Key TDP-43-regulated transcripts may serve as biomarkers for detecting, characterizing, and treating associated proteinopathies. [ABSTRACT FROM AUTHOR]

Although sex differences in amyotrophic lateral sclerosis (ALS) have not been studied systematically, numerous clinical and preclinical studies have shown sex to be influential in disease prognosis. Moreover, with the development of advanced imaging tools, the difference between male and female brain in structure and function and their response to neurodegeneration are more definitive. As discussed in this review, ALS patients exhibit a sex bias pertaining to the features of the disease, and their clinical, pathological, (and pathophysiological) phenotypes. Several epidemiological studies have indicated that this sex disparity stems from various aetiologies, including sex-specific brain structure and neural functioning, genetic predisposition, age, gonadal hormones, susceptibility to traumatic brain injury (TBI)/head trauma and lifestyle factors. • Sex along with factors such as genetics, site of onset and ethnicity contribute to ALS heterogeneity. • Sex differences is seen in major risk factors of ALS such as age, genetics, environment, physical activity. • ALS pathology such as neuroinflammation, neurodegeneration and muscle atrophy are also influenced by sex. • Due to the sex difference in response to treatment, it is important to include sex specific analysis in clinical trials. [ABSTRACT FROM AUTHOR]

• Onset latency of cutaneous silent period (CSP) is delayed in patients with motor neuron disease. • Patients with progressive muscular atrophy (PMA) have delayed onset latency of the CSP. • Delayed onset latency can be shortened by transcallosal ipsilateral corticospinal tract activation in PMA. To investigate the cutaneous silent period (CSP) by measuring its onset latency, duration and amount signal suppression in patients with motor neuron disease (MND) grouped according to the intensity of upper motor neuron involvement (UMN), and to test the effect of contralateral hand contraction. Painful stimulation was applied at the V finger, and contraction recorded from the abductor digiti minimi (ADM) muscle (baseline condition). Afterwards, CSP was studied during strong contralateral ADM contraction (test condition). 10–15 consecutive traces were recorded for each condition, signals were rectified, averaged, and analyzed offline. 46 patients were investigated, 15 with progressive muscular atrophy (PMA), 16 with typical amyotrophic lateral sclerosis (ALS), 15 with primary lateral sclerosis/predominant UMN-ALS (PLS+UMN-ALS), and 28 controls. In the baseline condition, all MND groups showed delayed onset latencies (p = 0.001). There was no significant difference in the CSP duration. Suppression was lower in the PLS + UMN-ALS group (p = 0.004). In the control group, contralateral contraction did not change CSP, but onset latency shortened significantly in the PMA group. CSP onset latency is delayed in all investigated groups of MND, including in PMA, indicating subclinical UMN involvement. Changes in CSP can indicate UMN lesion in MND. CSP should be explored to identify UMN involvement in MND. [ABSTRACT FROM AUTHOR]

• Studies indicate that individuals with ALS are at a greater risk of suicidal behavior than the general population in all analyzed countries. • Evidence shows that suicidal behavior occurs in the early stages of the disease, especially in the first months following diagnosis. • Major depressive disorder (MDD) is often undertreated, leading to this population's increased susceptibility to suicide. • More frequent and systematic mental health screenings could assist individuals with ALS and psychiatric suffering. Amyotrophic Lateral Sclerosis (ALS) leads to a drastic reduction in quality of life, generating intense psychological distress and predisposing those affected to mental illness and, in more severe cases, suicidal behavior. This is a systematic review aiming to estimate the frequency of wish to die, suicide ideation and suicide in individuals with ALS using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The following databases were used: Pubmed/MEDLINE, PsycINFO, Embase, SciELO, Biblioteca Virtual de Saúde (BVS), and Cochrane Library. The choice of appropriate descriptors, or their equivalents, to define the search terms was based on the technical and scientific vocabulary of each database. 13 articles were included in the present systematic review, of which three were cross-sectional studies, nine were cohort-type and there was one case-control study. The studies show that individuals with ALS have a higher risk of suicide in relation to the general population, and there is evidence that this risk is even higher in the early stages of the disease. Major Depressive Disorder was the most prevalent mental disorder in the studies included. This mental health concern is often undertreated, leading to the increased susceptibility of this population to suicide. In general, the study samples represent a highly heterogeneous population while many instruments used in the data collection were not uniform. The high degree of psychological vulnerability of this population, associated with a greater predisposition to suicidal behavior, should be minimized through public health measures. [ABSTRACT FROM AUTHOR]

• Nerve imaging abnormalities are common in amyotrophic lateral sclerosis (ALS). • On a group-level there is sonographic evidence of nerve atrophy in ALS. • Nerve cross-sectional areas in ALS and controls show a large amount of overlap. • Peripheral nerve ultrasound has the potential to differentiate between ALS and MMN. We systematically identified and reviewed 29 studies of peripheral nerve ultrasound or magnetic resonance imaging (MRN) in amyotrophic lateral sclerosis (ALS). The majority of the ultrasound studies reported smaller nerves and nerve roots in ALS compared to healthy controls, but there was a large overlap of the cross-sectional nerve area between ALS and controls. Most of the MRN studies confirmed nerve abnormalities demonstrating slight T2 hyperintensities and, sometimes, mild enlargement of more proximal nerve segments (plexus, roots) in ALS. The size of the proximal nerve segments, i.e. nerve roots, is thus somewhat incongruent between nerve ultrasound and MRN in ALS. Peripheral nerve ultrasound has the potential to differentiate between ALS and multifocal motor neuropathy (MMN) in that patients with MMN have significantly larger nerves. Conversely, there is an overlap of MRN abnormalities in ALS and MMN, restricting the techniques' utility in the clinical setting. A subgroup of patients with ALS seems to reveal a sonographic nerve pattern suggesting peripheral nerve inflammation. In the future, combined imaging with nerve ultrasound and MRN assessing parameters such as blood flow or textural markers may aid in the understanding of the deep nerve microstructure down to the fascicle level, and thus, in the classification of the nerve state as more degenerative or more inflammatory in ALS. This systematic review provides evidence that nerve imaging abnormalities are common in ALS. [ABSTRACT FROM AUTHOR]

• All affected individuals exhibit early-onset contractures. • They usually present with non-progressive muscle weakness of the lower limbs. • Sensory and motor nerve conduction studies reveal no abnormality. • EMG shows signs of chronic denervation. • MRI exhibits sparing of adductors and semitendinosus muscles in the thighs. The spinal muscular atrophies (SMA) affect lower motor neurons leading to important muscle atrophy and paralysis. Some cases of SMA affect mostly the lower limbs and are called autosomal dominant spinal muscular atrophy, lower extremity predominant (SMALED). So far, two genes have been identified to cause this phenotype, DYNC1H1 (SMALED1) and BICD2 (SMALED2). This pathology is rare, but patients exhibit classical features which should be recognised by physicians. We present two unrelated cases of SMALED2 with previously described c.320C> T BICD2 mutations. Our cases exhibit non-progressive weakness and atrophy of the lower limbs associated with contractures and unique muscle MRI findings suggestive of classical SMALED2. We also performed an extensive review of the literature to present the classical and atypical phenotypes of BICD2. Indeed, some features appear to be highly suggestive of the disease, including upper limb sparing, sparing of the adductors muscles on physical examination and MRI, congenital contractures and normal nerve conductions studies. [ABSTRACT FROM AUTHOR]

• EMG examination is important not just for diagnosis of ALS but also for its intrinsic prognostic value. • Denervation potentials can predict ventilatory dysfunction and survival in ALS. • The prognostic value of EMG is independent from the clinical phenotype of the patient. To verify whether the finding of denervation activity on EMG at the time of diagnosis has a prognostic value in amyotrophic lateral sclerosis (ALS). We retrospectively studied all the patients discharged with a diagnosis of ALS between January 2009 and January 2017. 92 patients met the inclusion criteria. We mainly verified three prognostic targets: (1) Time to non-invasive ventilation (NIV) or tracheostomy. (2) Time to percutaneous endoscopic gastrostomy or parental nutrition. (3) Survival. All EMG examinations were reviewed and a denervation score (DS) was calculated. The association of DS with clinical milestones was analysed, adjusting for disease duration, age , sex, and clinical phenotype. We found a significant association between bulbar DS and time to NIV/tracheostomy (HR: 3.34, 95% CI: 1.49 to 7.48, p = 0.002) and with survival (HR 3.633, 95% CI 1.681–7.848, p = 0.001), regardless of the clinical phenotype. Furthermore, we found a significant influence of a general DS on survival (HR: 2.62, 95% CI 1.335–5.160, p = 0.005). EMG assessment could be of value not just for ALS diagnosis but also for its intrinsic prognostic value. EMG could provide additional information about the rate of progression of ALS as early as the diagnosis is made. [ABSTRACT FROM AUTHOR]

• In vitro and in vivo models have helped elucidate ALS etiology and pathogenesis. • Mutations have been the main research targets in different ALS manifestations. • SOD1 animal models simulate some characteristics of the ALS. Amyotrophic Lateral Sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper motor neurons (UMN) and lower motor neurons (LMN). Disease affects people all over the world and is more prevalent in men. Patients with ALS develop extensive muscle wasting, paralysis and ultimately death, with a median survival of usually fewer than five years after disease onset. ALS may be sporadic (sALS, 90%) or familial (fALS, 10%). The large majority of fALS cases are associated with genetic alterations, which are mainly related to the genes SOD1, TDP-43, FUS, and C9ORF72. In vitro and in vivo models have helped elucidate ALS etiology and pathogenesis, as well as its molecular, cellular, and physiological mechanisms. Many studies in cell cultures and animal models, such as Caenorhabditis elegans , Drosophila melanogaster , zebrafish, rodents, and non-human primates have been performed to clarify the relationship of these genes to ALS disease. However, there are inherent limitations to consider when using experimental models. In this review, we provide an updated overview of the most used in vitro and in vivo studies that have contributed to a better understanding of the different ALS pathogenic mechanisms. [ABSTRACT FROM AUTHOR]

Movement disorders and neurodegenerative diseases are a variety of conditions that involve progressive neuronal degeneration, injury, or death. Establishing the correct diagnosis of a movement disorder or neurodegenerative process can be difficult due to the variable features of these conditions, unusual clinical presentations, and overlapping symptoms and characteristics. MRI has an important role in the initial assessment of these patients, although a combination of imaging and laboratory and genetic tests is often needed for complete evaluation and management. This document summarizes the imaging appropriateness data for rapidly progressive dementia, chorea, Parkinsonian syndromes, suspected neurodegeneration with brain iron accumulation, and suspected motor neuron disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease but currently has no effective treatment. Growing evidence suggests that proteome homeostasis underlies ALS pathogenesis. Protein production, trafficking, and degradation all shape the proteome. We present a hypothesis that proposes all genetic lesions associated with ALS (including in mRNA-binding proteins) cause widespread imbalance to an already metastable proteome. The impact of such dysfunction is felt across the entire proteome and is not restricted to a small subset of proteins. Proteome imbalance may cause functional defects, such as excitability alterations, and eventually cell death. While this idea is a unifying principle for all of ALS, we propose that stratification will appear that might dictate the efficacy of therapeutics based on the proteostasis network. The proteome of motor neurons is particularly vulnerable to proteome stress, even in comparison with other neurons. Proteome homeostasis is regulated by factors influencing protein production, trafficking, and degradation. Genetic evidence suggests that proteome dysfunction is a fundamental process underlying cellular dysfunction and death in ALS. Many proteins are found to be insoluble and a part of the inclusions found in motor neurons. [ABSTRACT FROM AUTHOR]

Movement disorders and neurodegenerative diseases are a variety of conditions that involve progressive neuronal degeneration, injury, or death. Establishing the correct diagnosis of a movement disorder or neurodegenerative process can be difficult due to the variable features of these conditions, unusual clinical presentations, and overlapping symptoms and characteristics. MRI has an important role in the initial assessment of these patients, although a combination of imaging and laboratory and genetic tests is often needed for complete evaluation and management. This document summarizes the imaging appropriateness data for rapidly progressive dementia, chorea, Parkinsonian syndromes, suspected neurodegeneration with brain iron accumulation, and suspected motor neuron disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. [ABSTRACT FROM AUTHOR]

• ALS rehabilitation treatment and impact on functional independence and/or quality of life. • Functional Independence and quality of life instruments most used to evaluate ALS. • Respiratory care, mental health, communication are the focus on ALS quality of life. • ALS Patient-Perceived outcomes about quality of life is limited by disease severity. Amyotrophic Lateral Sclerosis (ALS) leads to functional capacity decline, generating great impact in quality of life. Quality of life is directly related to physical integrity and functional independence. This systematic review aimed to analyze treatment protocols and their outcomes from clinical trials with focus on ALS rehabilitation that evaluated the effects on quality of life and functional independence from their intervention process. A literature search was conducted through MEDLINE-PubMed, Science Direct, Web of Science and Scopus databases. A total of 3630 articles were identified. Eleven studies met the inclusion criteria. They focused on different aspects of quality of life or functional independence, which are: respiratory care, mental health, communication skills and exercises. Use of bipap and inspiratory muscle training, anxiety and depression, communication devices implementation and exercises safety and tolerability were considered as key points. However, the drastic evolution of the disease is a limiting factor to the perception of quality of life improvement by patients. Further studies should be done to validate the benefits on patients' quality of life. [ABSTRACT FROM AUTHOR]

• Our study focused on the spectrum of prognostic factors of key outcomes in Motor neuron disease. • A total of 104 MND patients were recruited. • We found that bulbar onset was a significant risk predictor for survival, need of feeding support and ventilation aid. • Slower disease progression correlated with better outcomes. • Age of onset may differ among ethnic groups. • Male patients are more likely to develop ALS and have shorter survival duration. Knowledge of prognostic factors related to the survival of Motor Neuron Diseases (MND) remains scarce in Southeast Asia. To determine potential prognostic factors for survival, need for feeding and ventilation support in MND patients in a multi-racial Asian population. One hundred and four MND patients from the Singapore General Hospital (SGH) between January 2004 and December 2017 were reviewed. All relevant clinical data, demographic information were collected. Kaplan-Meier and Cox regression model were performed to identify potential prognostic factors for crucial outcomes (survival, need for feeding support and ventilation support). Mean age of onset was 59.54 ± 10.91 years, Mean age of onset in Malays was significantly younger than that of other ethnic groups (Malay: 54.18 ± 12.95 years; Non-Malay: 60.39 ± 10.38 years, p = 0.035). Fifty six of the male and 33of the female were diagnosed with ALS (90.3% vs. 78.6% p = 0.048). Mean overall survival duration from symptom onset was significantly longer in female than male patients (female: 39.2 ± 29.04 months; male: 29.4 ± 24.06 months, P = 0.03). In the multivariable Cox regression model, bulbar onset (aHR = 5.28, p = 0.035) correlated with poor survival outcome while longer duration from onset to second symptom (aHR = 0.96, P = 0.037) indicated better survival. Bulbar onset was a significant risk predictor for survival. Slower disease progression correlated with better outcomes. Age of onset may differ among ethnic groups. Male patients are more likely to develop Amyotrophic Lateral Sclerosis (ALS) and have shorter survival duration. [ABSTRACT FROM AUTHOR]

Multifocal motor neuropathy (MMN) is an acquired immune-mediated form of neuropathy characterized by upper and asymmetric limb weakness without sensory loss. The mean age of onset is 40 years (range, 20–70 years), and childhood-onset MMN is extremely rare. In the present report, we discuss a case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a immunoglobulin M (IgM) antibodies. A 12-year-old girl presented with progressive weakness of the upper extremities without sensory loss. Electrophysiological assessments revealed definite conduction blocks in the left median and bilateral radial nerves. She was diagnosed with MMN in accordance with the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria. Serological studies revealed that she tested positive for IgM antibodies to GM2 and GalNac-GD1a. Partial improvements in both muscle weakness and electrophysiological assessments were achieved after 8 months of high-dose intravenous immunoglobulin (IVIg) treatment. Although childhood-onset MMN is rare, most patients respond to IVIg treatment. This is the first case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a IgM antibodies. Although half of the adult patients with MMN test positive for anti-GM1 IgM antibodies, they were not detected in our patient. Comprehensive testing for serum anti-glycolipid antibodies in addition to GM1 may aid in the diagnosis of childhood-onset MMN. [ABSTRACT FROM AUTHOR]

Although hippocampal involvement in amyotrophic lateral sclerosis (ALS) has been consistently highlighted by postmortem studies, memory impairment remains under-recognized and the involvement of specific hippocampal subfields and their connectivity patterns are poorly characterized in vivo. A prospective multimodal neuroimaging study has been undertaken with 50 well-characterized ALS patients, 18 patients with Alzheimer's disease, and 40 healthy controls to evaluate their mesial temporal lobe profile. Patients with ALS and Alzheimer's disease have divergent hippocampal signatures. The cornu ammonis 2/3 subfield and the hippocampus-amygdala transition area are the most affected regions in ALS in contrast to Alzheimer's disease, where the presubiculum and subiculum are the most vulnerable regions. Tractography reveals considerable fornix and perforant pathway pathology in both patient groups. Mesial temporal lobe structures in ALS have a selective and disease-specific vulnerability profiles, and their white matter projections exhibit concomitant degeneration. Our combined gray and white matter analyses indicate a connectivity-based, network-defined involvement of interconnected temporal lobe structures as opposed to contiguous involvement of adjacent structures. Our findings underline the importance of screening for memory deficits and personalized management strategies in ALS. • Amyotrophic lateral sclerosis is associated with considerable hippocampal pathology. • Hippocampal subfields and their projections are selectively affected by ALS. • The imaging features of the hippocampus are consistent with postmortem findings in ALS. • The hippocampal profile of ALS is different from that of AD and healthy aging. • Memory deficits in ALS are notoriously under-recognized despite their clinical relevance. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the cerebellum's local and global functional characteristics in individuals with sporadic amyotrophic lateral sclerosis (sALS) and their correlation with clinical data. Resting-state functional magnetic resonance imaging was performed on 39 patients with sALS and on 23 healthy controls. Regional homogeneity (ReHo) in the cerebellum of all participants was analyzed, and the cerebellar regions with differences in ReHo were considered regions of interest (ROIs). In addition, the functional connectivity between the ROIs and other brain regions was analyzed. In patients with sALS, ReHo increased in parts of the posterior cerebellar lobe. Then, the two regions with increased ReHo of the cerebellum were used as seeds, and further analysis revealed that the connectivity of the right cerebellum to the right medial superior frontal gyrus, left lingual gyrus (calcarine sulcus), left precentral gyrus, left supplementary motor area, and right Crus II was significantly increased. The results demonstrate that resting-state functional connectivity changes in both motor and extra-motor regions of the cerebellum in patients with sALS, and that the cerebellum plays a pathophysiological role in sALS. [Display omitted] • Amyotrophic lateral sclerosis (ALS) affects upper and lower motor neurons. • Studies suggest that the cerebellum plays a role in the pathogenesis of ALS. • Enhanced FC between the cerebellum and motor cortex could be an ALS biomarker. [ABSTRACT FROM AUTHOR]

A common feature of adult-onset neurodegenerative diseases is the presence of characteristic pathological accumulations of specific proteins. These pathological protein depositions can vary in their protein composition, cell-type distribution, and intracellular (or extracellular) location. For example, abnormal cytoplasmic protein deposits which consist of the TDP-43 protein are found within motor neurons in patients with amyotrophic lateral sclerosis (ALS, a common form of motor neuron disease) and frontotemporal dementia (FTD). The presence of these insoluble intracellular TDP-43 inclusions suggests that restoring TDP-43 homeostasis represents a potential therapeutical strategy, which has been demonstrated in alleviating neurodegenerative symptoms in cell and animal models of ALS/FTD. We have reviewed the mechanisms that lead to disrupted TDP-43 homeostasis and discussed how small molecule-based therapies could be applied in modulating these mechanisms. This review covers recent advancements and challenges in small molecule-based therapies that could be used to clear pathological forms of TDP-43 through various protein homeostasis mechanisms and advance the way towards finding effective therapeutical drug discoveries for neurodegenerative diseases characterized by TDP-43 proteinopathies, especially ALS and FTD. We also consider the wider insight of these therapeutic strategies for other neurodegenerative diseases. [Display omitted] • Aging is a risk factor for ALS/FTD; adult-onset neurodegenerative diseases (NDD). • Presence of specific protein accumulations is a pathological factor in NDD. • TDP-43 proteinopathies are pathological hallmarks in ALS/FTD. • Maintaining TDP-43 homeostasis is a potential therapeutical strategy in ALS/FTD. • Small molecule-based approaches could enhance the clearance of pathological TDP-43. [ABSTRACT FROM AUTHOR]

• Motor neuron disease and malignancy (MND-M) forms continuum with motor neuron disease. • Lower motor neuron phenotype predominates with MND-M. • Cortical hyperexcitability is a pathogenic feature of MND-M. While some regard an association between motor neuron disease (MND) and malignancy as co-incidental, others have argued that it could represent a distinct clinical entity. The present study undertook in depth phenotyping along with assessment of cortical function to further explore disease pathophysiology in MND with malignancy (MND-M) patients. Clinical features along with assessment of peripheral and cortical function was undertaken in 13 MND-M and results were compared to sporadic and familial MND cohorts. From a cohort 13 patients (10 males; aged 65.2 ± 2.0 years), 38.5% were diagnosed with a haematological malignancy. The lower motor neuron phenotype predominated in the in the MND-M patients (χ2 = 10.8, P < 0.01), with the upper motor neuron (UMN) score being significantly reduced in MND-M patients compared to sporadic and familial MND cohorts (χ2 = 6.84, P < 0.01). The neurological deficits did not respond to treatment of the underlying malignancy in the majority of MND-M (92%) patients, and as such there were no significant differences in survival between the cohorts. Despite a paucity of UMN signs, cortical hyperexcitability was evident in MND-M patients, as indicated by reduction in short interval intracortical inhibition (P < 0.01) and increase in motor evoked potential amplitude (P < 0.01), that were similar to findings in sporadic and familial MND cohorts. The present study suggests that MND-M falls within the spectrum of MND. The concept of a co-incidental association between MND and malignancy is supported through the present study by the presence of cortical dysfunction, combined with clinical findings that can be explained within the spectrum of abnormality evident in classical MND phenotypes. [ABSTRACT FROM AUTHOR]

Our aim was to study motor unit number index (MUNIX) in myopathic disorders. We studied 11 patients with myopathy, and healthy controls. We obtained MUNIX, compound muscle action potential (CMAP), motor unit size index (MUSIX) and alpha (α, power exponent from MUNIX equation) measurements from three different muscles. MUNIX and CMAP were significantly lower in one muscle. This MUNIX decrease may not be related to motor neuron loss, but rather to muscle fiber atrophy. MUSIX and α did not change and may be useful in determining whether the MUNIX decrease is indeed due to motor unit loss. [ABSTRACT FROM AUTHOR]

• Kennedy patients exhibit severe balance deficits in conditions of absent vision. • Horizontal vestibulo-ocular reflex function is preserved. • The balance impairment stems from a diminished somatosensory input. • Some Kennedy patients face difficulties in producing fast eye movements. Spinal and bulbar muscular atrophy (Kennedy's disease) has been associated with balance dysfunction and falls. However, postural control has not been studied quantitatively. Here, we quantified upright stance and aimed to disentangle the role of vestibular, proprioceptive and oculomotor deficits. Static balance was assessed in Kennedy patients (n = 7) during quiet stance on a force platform under different visual and proprioceptive feedback conditions. Vestibular function was assessed with the video head impulse test. Sural nerve neurography was employed to evaluate the severity of peripheral neuropathy. Also, horizontal saccades were recorded and quantified by the main sequence relationship. Posturographic analyses revealed significantly increased body sway, more pronounced in conditions with closed eyes, which was also reflected in the calculated Romberg indices. Horizontal vestibulo-ocular reflex gains were normal, i.e. > 0.75. In contrast, compound sensory nerve action potentials were markedly decreased in all patients (mean = 2.4 μV). Two patients showed slow saccades with increased exponential main sequence constants. We conclude that Kennedy patients exhibit severe deficits in quiet stance. Postural instability is greatest in conditions of absent vision with reduced proprioception being the main determinant of unsteadiness. Some patients show slowed saccadic eye movements suggesting a nuclear abducens neuronopathy. [ABSTRACT FROM AUTHOR]

The hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic variant found in individuals with sporadic amyotrophic lateral sclerosis (ALS), occurring at a frequency of between 7 and 11% in cohorts of European ancestry. While limited data suggest that C9 -expansions (>30 repeats) are less frequent in African-Americans with ALS, there is no data on the frequency of C9 -expansions among ALS subjects residing in Africa. We therefore investigated the frequency of this expansion mutation (using repeat-primed PCR) in a cohort of 143 South Africans (SA) with ALS. The cohort included different genetic ancestry subgroups who self-identified as black African (n = 24), Cape mixed-African (M/A) (n = 65), white European ancestry (n = 51), and Indian ancestry (n = 3). Three M/A individuals had a family history of ALS (2%) and all had normal C9orf72 alleles. Of the 140 individuals with sporadic ALS who were successfully genotyped, 10 (7%) carried pathogenic C9 -expansions; four white and six M/A ancestry individuals, respectively. Our results highlight the importance of including Africans in genetic studies aimed at unravelling the genomic architecture in ALS and suggest pathogenetic mechanisms other than the C9orf72 expansion in black Africans with ALS. • 143 South Africans with ALS underwent C9orf72 repeat expansion genotyping. • Familial ALS was uncommon (2%) and these cases had normal C9orf72 alleles. • C9 -expansions (>30 repeats) were found in 7% of cases with sporadic ALS. • C9 -expansions were not found in 24 black Africans with ALS. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cells and their derivatives have become an important tool for researching disease mechanisms. It is hoped that they could be used to discover new therapies by providing the most reliable and relevant human in vitro disease models for drug discovery. This review will summarize recent efforts to use stem cell–derived neurons for drug screening. We also explain the current hurdles to using these cells for high-throughput pharmaceutical screening and developments that may help overcome these hurdles. Finally, we critically discuss whether induced pluripotent stem cell–derived neurons will come to fruition as a model that is regularly used to screen for drugs to treat neurological diseases. • Induced pluripotent stem cells are an attractive model for use in drug screening. • A small number of screens have been performed using stem cell–derived neurons. • Stumbling blocks remain which may restrict widespread use in drug screening. [ABSTRACT FROM AUTHOR]

Abstract Motor neuron disease (MND) includes both ALS and Progressive Muscular Atrophy (PMA) as variants. Abnormalities in brain excitability and upper motor neuron (UMN) function are characteristic of ALS, but by definition are absent in PMA. Transcranial magnetic stimulation (TMS) may be useful in demonstrating UMN pathology, but loss of muscle responsiveness with disease progression limits its usefulness in later stages of MND. We have developed a novel form of TMS comprised of 4 stimulating pulses that can enhance MEPs in target muscles already responding to traditional TMS inputs, in some cases even restoring MEPs in target muscles rendered unresponsive by the disease. An example of restored MEPs in response to this superconditioning TMS pattern (TMSsc) in a person with PMA is described, along with an unexpected finding. Despite a prolonged (> 5 year) history of movement paralysis in his right tibialis anterior (TA), immediately after cessation of TMSsc delivery the subject could now easily contract and relax this muscle; the presence of a latent pathway for voluntary innervation of his right TA was revealed. This modulation of central motor functional connectivity in response to TMSsc suggests a further, clinically-significant benefit of this form of noninvasive brain stimulation beyond its ability to enhance MEPs to traditional TMS inputs. Highlights • TMS is used to elicit motor evoked potentials (MEPs) in normal muscle. • MEPs from certain target muscles may fail in persons with MND. • We describe a novel 4-pulse TMS method that can restore MEPs in a subject with MND. • This TMS pattern unmasked voluntary movement in a muscle previously paralyzed. • This method may be useful for studies of brain plasticity, or neuromodulation. [ABSTRACT FROM AUTHOR]

Highlights • SMA fibroblasts have abnormal Golgi apparatus morphology which can be rescued by restoring SMN protein levels to normal. • Knockdown of the SMN binding partner α-COP produces a similar diffuse Golgi morphology. • α-COP over-expression restores normal Golgi morphology in SMA fibroblasts. • COPI-dependent intracellular trafficking is altered in cells after knockdown of SMN. Abstract We report here the finding of abnormal Golgi apparatus morphology in motor neuron like cells depleted of SMN as well as Golgi apparatus morphology in SMA patient fibroblasts. Rescue experiments demonstrate that this abnormality is dependent on SMN, but can also be rescued by expression of the COPI coatomer subunit alpha-COP. A motor neuron-like cell line containing an inducible alpha-COP shRNA was created to generate a parallel system to study knockdown of SMN or alpha-COP. Multiple assays of COPI-dependent intracellular trafficking in cells depleted of SMN demonstrate that alpha-COP function is suboptimal, including failed sequestration of plasma membrane proteins, altered binding of mRNA, and defective targeting and transport of Golgi-resident proteins. [ABSTRACT FROM AUTHOR]

Abstract Background This study is a descriptive review of the clinical and treatment outcome differences in HIV-infected patients with motor neuron syndrome (MNS) and HIV-uninfected patients with motor neuron disease (MND). Methods A retrospective analysis of patients with MND/S was performed at Inkosi Albert Luthuli Central Hospital (IALCH), Durban, South Africa between 2003 and 2017. Results One hundred and thirty six patients were included in the study, 101 (76%) were HIV-uninfected and 35 (26%) were HIV-infected. Ninety four percent of the HIV-infected cohort were <50 years, median 41, IQR (33–45), p < 0.001, had median ALS functional rating scale revised (ALSFRS-R) score of 28, IQR [ 24–30 ] and 40% of these patients on anti-retroviral therapy (ART) survived longer than 10 years. Ninety one percent of the HIV-uninfected cohort were >50 years, median 66, IQR(57–74), P < 0.001, had median ALSFRS-R score of 44 (IQR 42–45) and 93% died within 5 years of their illness. Conclusion HIV-infected MNS patients were younger, had more severe disease at presentation and survived longer if treated with ART with possible reversal of the disease process, compared to patients with MND. Highlights • MNS is an uncommon neurological syndrome of HIV • HIV and HERV-K may have an important aetiological association in MNS. • MNS reverses with ART • ART in early MND maybe useful. [ABSTRACT FROM AUTHOR]

Highlights • Konzo is an irreversible upper motor neurone disease in sub-Saharan Africa. • The pathogeny remains unclear. • The disease is linked to the chronic consumption of insufficiently processed cassava. • The clinical spastic paraparesis is symmetrical, permanent and irreversible. • The disease leads to neurocognitive impairments and neurodevelopmental delays. Abstract Epidemics of neurodegenerative diseases putatively caused by food toxins have been reported in the tropics with no clear understanding of their pathogenetic mechanisms. These diseases include the disease named Konzo that has been well documented in sub-Sahara Africa, mostly among children and women of childbearing age. Outbreaks of Konzo have occurred in the Democratic Republic of Congo, Mozambique, Tanzania, Central African Republic, Angola, Cameroun, and most recently in Zambia. The main clinical picture consists of a symmetrical, permanent and irreversible spastic paraparesis (motor neuron disease) with no signs of sensory or genitourinary impairments. Recently, cognitive impairments and neurodevelopmental delays have been reported among school-aged and very young children. The exact pathogenetic mechanisms of the disease remain unknown. Epidemiological studies consistently show an association between outbreaks of the disease and chronic dietary reliance on insufficiently processed cyanogenic cassava (manioc or tapioca). Biochemical and toxicological studies suggest that the metabolites of linamarin (α-Hydroxyisobutyronitrile β-D-glucopyranoside, the main cassava cyanogen), notably cyanide (mitochondrial toxin), thiocyanate (AMPA chaotropic agent), and cyanate (protein carbamoylating agent) may play an important role in the pathogenesis of Konzo. Experimental data suggest that thiol-redox and protein- folding mechanisms may also be perturbed. Factors of susceptibility including genetics, poor nutrition, poverty and dietary cyanogen exposure, or their interactions have been suggested. Serological studies have ruled out the role of retroviruses such as the human lymphotropic viruses HIV-I/II or HTLV-I/II. Because there is no cure for Konzo, prevention of the disease remains of paramount importance. Prospects for cognitive rehabilitation still need to be explored and tested. [ABSTRACT FROM AUTHOR]

Highlights • New Zealand now has a motor neurone disease patient registry. • In one year the registry has captured almost half the patient population. • The registry has already facilitated patient participation in research studies. Abstract There are only limited treatments currently available for Motor Neurone Disease, each with modest benefits. However, there is a large amount of research and drug discovery currently underway worldwide. The New Zealand Motor Neurone Disease Registry was established in 2017 to facilitate participation in research and clinical trials, and to aid researchers in planning and recruitment. The NZ MND Registry is an opt in patient registry which collects demographic, contact and clinical data for those who choose to enrol. We report anonymised aggregated data from the first year's enrolment. 12th July 2018, there were 142 participants enrolled in the NZ MND Registry. Participant sex distribution reflects the demographics reported worldwide, but ethnicity is divergent from what is seen in New Zealand overall, with an over-representation of people who identify as New Zealand European. 85.5% of participants are diagnosed with sporadic MND and 6.1% with familial MND. The remainder were participants who have not been diagnosed but have a family history, or positive genetic test for a MND-causing mutation. Levels of disability are reported using ALSFRS-R scores, and show that the majority of participants are within the higher range of the scale. The registry has facilitated entry of patients into three studies to date. The establishment of the NZ MND Registry illustrates a swift launch of a rare disease patient registry. The role of patient registries is an ever changing one, but with clear utility at every point of along the pathway to drug discovery. [ABSTRACT FROM AUTHOR]

Abstract Purpose Diffusion tensor imaging (DTI) and quantitative susceptibility mapping (QSM) have been proposed as methods to aid in the diagnosis of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), both diseases affecting upper motor neurons. We test the performance of DTI and QSM alone and in combination to distinguish patients with diseases affecting upper motor neurons (ALS/PLS) from patients with other motor symptom-predominant neurologic disorders. Methods 3.0 Tesla MRI with DTI and QSM in patients referred to a subspecialty neurology clinic for evaluation of motor symptom-predominant neurologic disorders were retrospectively reviewed. Corticospinal tract fractional anisotropy and maximum motor cortex susceptibility were measured. Subjects were categorized by diagnosis and imaging metrics were compared between groups using Student's t -tests. Receiver operating characteristic curves were generated for imaging metrics alone and in combination. Results MRI scans for 43 patients with ALS or PLS and 15 patients with motor symptom predominant, non-upper motor neuron disease (mimics) were reviewed. Fractional anisotropy was lower (0.57 vs. 0.60, p < 0.01) and maximum motor cortex magnetic susceptibility higher (64.4 vs. 52.7, p = 0.01) in patients with ALS/PLS compared to mimics. There was no significant difference in area under the curve for these metrics alone (0.73, 0.63; p > 0.05) or in combination (0.75; p > 0.05). Conclusion We found significant differences in DTI and QSM metrics in patients with diseases affecting upper motor neurons (ALS/PLS) compared to mimics, but no significant difference in the performance of these metrics in diagnosing ALS/PLS compared to mimics. Highlights • QSM maximum motor cortex susceptibility is higher in ALS/PLS compared to mimics. • DTI fractional anisotropy is lower in patients with ALS/PLS compared to mimics. • No significant difference in the performance of DTI vs QSM in diagnosing ALS/PLS [ABSTRACT FROM AUTHOR]

Highlights • Experts routinely use ultrasound to evaluate both common and rare disorders of nerve and muscle. • Accumulated evidence now puts diagnostic neuromuscular ultrasound on par with EMG and NCS. • Medical centers must acquire ultrasound equipment to keep electrodiagnostic laboratories current. Abstract Over the last two decades, dozens of applications have emerged for ultrasonography in neuromuscular disorders. We wanted to measure its impact on practice in laboratories where the technique is in frequent use. After identifying experts in neuromuscular ultrasound and electrodiagnosis, we assessed their use of ultrasonography for different indications and their expectations for its future evolution. We then identified the earliest papers to provide convincing evidence of the utility of ultrasound for particular indications and analyzed the relationship of their date of publication with expert usage. We found that experts use ultrasonography often for inflammatory, hereditary, traumatic, compressive and neoplastic neuropathies, and somewhat less often for neuronopathies and myopathies. Usage significantly correlated with the timing of key publications in the field. We review these findings and the extensive evidence supporting the value of neuromuscular ultrasound. Advancement of the field of clinical neurophysiology depends on widespread translation of these findings. [ABSTRACT FROM AUTHOR]