Optimizing breathlessness management in amyotrophic lateral sclerosis: insights from a comprehensive systematic review.

BACKGROUND: Breathlessness is a prevalent symptom affecting the quality of life (QOL) of Amyotrophic Lateral Sclerosis (ALS) patients. This systematic review explored the interventions for controlling breathlessness in ALS patients, emphasizing palliative care (PALC), non-invasive ventilation (NIV), opioids, and non-pharmacological strategies. METHODS: A comprehensive search of PubMed, Cochrane Library, and Web of Science databases was conducted. Eligibility criteria encompassed adults with ALS or motor neuron disease experiencing breathlessness. Outcomes included QOL and symptom control. Study designs comprised qualitative studies, cohort studies, and randomized controlled trials. RESULTS: Eight studies were included, most exhibiting low bias risk, comprising one randomized controlled trial, three cohort studies, two comparative retrospective studies, and two qualitative studies (interviews). Most studies originated from Europe, with one from the United States of America. The participants totaled 3423, with ALS patients constituting 95.6%. PALC consultations significantly improved symptom assessment, advance care planning, and discussions about goals of care. NIV demonstrated efficacy in managing breathlessness, with considerations for device limitations. Opioids were effective, though predominantly studied in non-ALS patients. Non-pharmacological strategies varied in efficacy among patients. CONCLUSION: The findings underscore the need for individualized approaches in managing breathlessness in ALS. PALC, NIV, opioids, and non-pharmacological strategies each play a role, with unique considerations. Further research, especially ALS-specific self-management studies, is warranted.

FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease.

This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations. These alterations cause various manifestations of mitochondrial dysfunction, particularly under stress conditions relevant to disease pathology. Importantly, rectifying FUS mutations in patient-derived induced pluripotent cells (iPSCs) preserves mtDNA integrity. Similarly, targeted introduction of human DNA Ligase 1 restores repair mechanisms and mitochondrial activity in FUS mutant cells, suggesting a potential therapeutic approach. Our findings unveil FUS's critical role in mitochondrial health and mtDNA repair, offering valuable insights into the mechanisms underlying mitochondrial dysfunction in FUS-associated motor neuron disease.

Fluctuating salience in those living with genetic risk of motor neuron disease: A qualitative interview study.

BACKGROUND: Motor neuron disease (MND) (also known as amyotrophic lateral sclerosis) is a life-limiting neurodegenerative condition. In up to 20% of people with MND, a pathogenic variant associated with autosomal dominant inheritance can be identified. Children of people carrying a pathogenic variant have a 50% chance of inheriting this and a higher, although harder to predict, chance of developing the disease compared to the general adult population. This paper explores the experience of living with the genetic risk of MND. METHODS: We undertook a UK-based interview study with 35 individuals, including: 7 people living with genetically-mediated forms of MND; 24 asymptomatic relatives, the majority of whom had an increased risk of developing the disease; and 4 unrelated partners. RESULTS: We explore how individuals make sense of genetic risk, unpacking the interplay between genetic knowledge, personal perception, experiences of the disease in the family, age and life stage and the implications that living with risk has for different aspects of their lives. We balance an emphasis on the emotional and psychological impact described by participants, with a recognition that the salience of risk fluctuates over time. Furthermore, we highlight the diverse strategies and approaches people employ to live well in the face of uncertainty and the complex ways they engage with the possibility of developing symptoms in the future. Finally, we outline the need for open-ended, tailored support and information provision. CONCLUSIONS: Drawing on wider literature on genetic risk, we foreground how knowledge of MND risk can disrupt individuals' taken-for-granted assumptions on life and perceptions of the future, but also its contextuality, whereby its relevance becomes more prominent at critical junctures. This research has been used in the development of a public-facing resource on the healthtalk.org website. PATIENT OR PUBLIC CONTRIBUTION: People with experience of living with genetic risk were involved throughout the design and conduct of the study and advised on aspects including the topic guide, sampling and recruitment and the developing analysis. Two patient and public involvement contributors joined a formal advisory panel.

Modeling Spinal Muscular Atrophy in Zebrafish: Current Advances and Future Perspectives.

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by degeneration of lower motor neurons (LMNs), causing muscle weakness, atrophy, and paralysis. SMA is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene and can be classified into four subgroups, depending on its severity. Even though the genetic component of SMA is well known, the precise mechanisms underlying its pathophysiology remain elusive. Thus far, there are three FDA-approved drugs for treating SMA. While these treatments have shown promising results, their costs are extremely high and unaffordable for most patients. Thus, more efforts are needed in order to identify novel therapeutic targets. In this context, zebrafish (Danio rerio) stands out as an ideal animal model for investigating neurodegenerative diseases like SMA. Its well-defined motor neuron circuits and straightforward neuromuscular structure offer distinct advantages. The zebrafish's suitability arises from its low-cost genetic manipulation and optical transparency exhibited during larval stages, which facilitates in vivo microscopy. This review explores advancements in SMA research over the past two decades, beginning with the creation of the first zebrafish model. Our review focuses on the findings using different SMA zebrafish models generated to date, including potential therapeutic targets such as U snRNPs, Etv5b, PLS3, CORO1C, Pgrn, Cpg15, Uba1, Necdin, and Pgk1, among others. Lastly, we conclude our review by emphasizing the future perspectives in the field, namely exploiting zebrafish capacity for high-throughput screening. Zebrafish, with its unique attributes, proves to be an ideal model for studying motor neuron diseases and unraveling the complexity of neuromuscular defects.

Supporting people with Motor Neuron Disease (MND) to make decisions about gastrostomy feeding tube placement: a survey of UK healthcare professionals' practice and beliefs.

OBJECTIVE: Understand the practice and beliefs of healthcare professionals (HCPs) supporting the decision-making of people with MND (pwMND) about gastrostomy placement, including identifying differences between professions. METHODS: An online cross-sectional survey disseminated to HCPs who support the decision-making of pwMND about gastrostomy placement. RESULTS: A total of 139 participants completed the survey including representation from a range of healthcare professions. A third (36/101, 36%) initiated discussions about gastrostomy later in practice than they believed was ideal. In relation to the outcome of declining compared to accepting gastrostomy, participants were more likely to discuss aspiration (80% vs. 68%), choking (76% vs. 58%) and prognosis (36% vs. 22%). Participants believed gastrostomies should be placed after a mean 8.1% weight loss since symptom-onset. More participants favored gastrostomy placement before pwMND presented with respiratory symptoms (45%) compared to onset of dysphagia (11%). Half believed pwMND placed gastrostomies too late. Participants were more likely to 'often'/'always' recommend pwMND to have a gastrostomy (23%) than continue without (7%) or decline (4%) gastrostomy, when believing these were the best option for pwMND. Nurses and dietitians discussed the broadest range of information, while doctors were more likely to discuss mortality risk and prognosis. CONCLUSION: There is variation in HCPs practice and beliefs about initiating discussions, the sharing of information and recommendations, and timing, about gastrostomy placement. The information shared varies by profession and there is evidence of sub-optimal communication between HCPs. Further research is required to understand how these findings may impact on the decision-making of pwMND about gastrostomy.

Electrochemical detection of the neurotransmitter glutamate and the effect of the psychotropic drug riluzole on its oxidation response.

Glutamate is the main excitatory neurotransmitter in the brain and plays a leading role in degenerative diseases, such as motor neuron diseases. Riluzole is a glutamate regulator and a therapeutic drug for motor neuron diseases. In this work, the interaction between glutamate and riluzole was studied using cyclic voltammetry and square-wave voltammetry at a glassy carbon electrode (GCE). It was shown that glutamate underwent a two-electron transfer reaction on the GCE surface, and the electrochemical detection limits of glutamate and riluzole were 483 µmol/L and 11.47 µmol/L, respectively. The results confirm that riluzole can promote the redox reaction of glutamate. This work highlights the significance of electrochemical technology in the sensing detection of the interaction between glutamate and related psychotropic drugs.

A prospective study for using cognitive decline as a predictor for survival and use of feeding/respiratory support for patients with motor neuron disease in Norway.

BACKGROUND: There is a need for knowledge regarding the medical management of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) with and without cognitive decline. It has scarcely been studied whether cognitive decline will influence the course of disease or interfere with the use of life-prolonging aids for respiration and nutrition. Cognitive decline may impact the length of illness. METHODS: Patients were prospectively recruited from an ALS outpatient clinic at Haukeland University Hospital. Participants underwent the standardized cognitive test Edinburgh Cognitive and Behavioral ALS Screen Norwegian version (ECAS-N), clinical examination, and were functionally assessed by the ALS Functioning Rating Scale-revised version (ALS-FRS-R). The time and indication for installation of a feeding tube [percutaneous endoscopic gastrostomy (PEG)] and/or respiratory aid [bilevel positive airway pressure device (BiPAP)] or invasive respirator were retrieved from the medical records. Kaplan-Meier tests were used to study the risk of death and the probability for implementing PEG and/or BiPAP in relation to time from diagnosis. The individual assessment was used for analyzing the establishment of aids in relation to point of death. RESULTS: A total of 40 patients were evaluated for the study, 31 of whom were finally included. None of the included patients did not use an invasive respirator. The patients were divided into two subgroups (normal cognition or cognitive decline, cut-off 92 points) according to their performance in the ECAS-N. The course of the disease, shown as a risk of death, was higher among the ALS/MND patients with cognitive decline compared to those with cognitive intact function throughout the study period. The cognitive status did not influence the fitting of aids. Use of aids did not influence the survival in subgroups significantly. CONCLUSIONS: The study demonstrated shorter survival for the patients with ALS/MND with cognitive decline compared to those without cognitive decline. The practice and implementation of both BiPAP and PEG did not differ among the ALS/MND patients with and without cognitive decline in Norway.

Clinical prognostic factors predicting survival of motor neuron disease patients with gastrostomy: A retrospective analysis.

INTRODUCTION/AIMS: Enteral feeding via gastrostomy is a key intervention to prevent significant weight loss in Motor Neuron Disease (MND). The aim of this study was to explore demographic, clinical, and nutritional factors associated with survival time in MND patients with gastrostomy. METHODS: The retrospective study analyzed 94 MND patients (n = 58 bulbar-onset and n = 36 limb-onset) who underwent gastrostomy between 2015 and 2021. The primary outcome was the survival time from gastrostomy insertion to death. Independent variables of interest explored were: age at gastrostomy insertion, disease onset type, known genetic cause, use of riluzole, non-invasive ventilation (NIV) use, forced vital capacity prior to gastrostomy, weight loss from diagnosis to gastrostomy insertion, and body mass index (BMI) at the time of gastrostomy insertion. RESULTS: The median survival time from gastrostomy to death was 357 days (± 29.3, 95%CI: 299.5, 414.5). Kaplan-Meier method and log-rank test revealed patients with lower body mass index <18.5 kg/m2 at the time of gastrostomy insertion (p = .023) had shorter survival. Cox proportional hazards model with multivariable adjustment revealed that older age (p = .008), and greater weight loss from diagnosis to gastrostomy (p = .003) were associated with shorter survival time post gastrostomy. Limb onset (p = .023), NIV use not being required (p = .008) and daily NIV use when required and tolerated (p = .033) were associated with longer survival. DISCUSSION: Preventing or minimizing weight loss from MND diagnosis and encouraging NIV use when clinically indicated are modifiable factors that may prolong the survival of MND patients with gastrostomy.

Can Some Anticancer Drugs Be Repurposed to Treat Amyotrophic Lateral Sclerosis? A Brief Narrative Review.

Amyotrophic lateral sclerosis (ALS) is a rare progressive motor neuron disease that, due to its high complexity, still lacks effective treatments. Development of a new drug is a highly costly and time-consuming process, and the repositioning of approved drugs can represent an efficient strategy to provide therapeutic opportunities. This is particularly true for rare diseases, which are characterised by small patient populations and therefore attract little commercial interest. Based on the overlap between the biological background of cancer and neurodegeneration, the repurposing of antineoplastic drugs for ALS has been suggested. The objective of this narrative review was to summarise the current experimental evidence on the use of approved anticancer drugs in ALS. Specifically, anticancer drugs belonging to different classes were found to act on mechanisms involved in the ALS pathogenesis, and some of them proved to exert beneficial effects in ALS models. However, additional studies are necessary to confirm the real therapeutic potential of anticancer drugs for repositioning in ALS treatment.

Assessment of diagnostic criteria for multifocal motor neuropathy in patients included in the Italian database.

BACKGROUND AND PURPOSE: This study aimed to assess the diagnostic criteria, ancillary investigations and treatment response using real-life data in multifocal motor neuropathy (MMN) patients. METHODS: Clinical and laboratory data were collected from 110 patients enrolled in the Italian MMN database through a structured questionnaire. Twenty-six patients were excluded due to the unavailability of nerve conduction studies or the presence of clinical signs and symptoms and electrodiagnostic abnormalities inconsistent with the MMN diagnosis. Analyses were conducted on 73 patients with a confirmed MMN diagnosis and 11 patients who did not meet the diagnostic criteria. RESULTS: The European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria were variably applied. AUTHOR: When applying the American Association of Electrodiagnostic Medicine criteria, an additional 17% of patients fulfilled the criteria for probable/definite diagnosis whilst a further 9.5% missed the diagnosis. In 17% of the patients only compound muscle action potential amplitude, but not area, was measured and subsequently recorded in the database by the treating physician. Additional investigations, including anti-GM1 immunoglobulin M antibodies, cerebrospinal fluid analysis, nerve ultrasound and magnetic resonance imaging, supported the diagnosis in 46%-83% of the patients. Anti-GM1 immunoglobulin M antibodies and nerve ultrasound demonstrated the highest sensitivity. Additional tests were frequently performed outside the EFNS/PNS guideline recommendations. CONCLUSIONS: This study provides insights into the real-world diagnostic and management strategies for MMN, highlighting the challenges in applying diagnostic criteria.

Euthanasia and assisted suicide in neurological diseases: a systematic review.

OBJECTIVE: To identify the neurological diseases for which euthanasia and assisted suicide are most frequently requested in the countries where these medical procedures are legal and the specific characteristics of euthanasia in some of these diseases, and to show the evolution of euthanasia figures. METHODS: We conducted a systematic literature review. RESULTS: Dementia, motor neuron disease, multiple sclerosis, and Parkinson's disease are the neurological diseases that most frequently motivate requests for euthanasia or assisted suicide. Requests related to dementia constitute the largest group, are growing, and raise additional ethical and legal issues due to these patients' diminished decision-making capacity. In some countries, the ratios of euthanasia requests to all cases of multiple sclerosis, motor neuron disease, or Huntington disease are higher than for any other disease. CONCLUSIONS: After cancer, neurological diseases are the most frequent reason for requesting euthanasia or assisted suicide.

A report of resources used by clinicians in the UK to support motor neuron disease genomic testing.

Genetic testing is a key decision-making point for people with motor neuron disease (MND); to establish eligibility for clinical trials, better understand the cause of their condition, and confirm the potential risk to relatives, who may be able to access predictive testing. Given the wide-reaching implications of MND genetic and predictive testing, it is essential that families are given adequate information, and that staff are provided with appropriate training. In this report we overview the information resources available to people with MND and family members around genetic testing, and the educational and training resources available to staff, based on information obtained through a freedom of information request to UK-based NHS Trusts. MND Association resources were most commonly used in information sharing, though we highlight distinctions between neurology and genetics centers. No respondents identified comprehensive training around MND genetic testing. We conclude with practice implications and priorities for the development of resources and training.

A comparison between bioelectrical impedance analysis and air-displacement plethysmography in assessing fat-free mass in patients with motor neurone diseases: a cross-sectional study.

AIM: To determine the validity of bioelectrical impedance analysis (BIA) in quantifying fat-free mass (FFM) compared to air-displacement plethysmography (ADP) in patients with a motor neurone disease (MND). METHODS: FFM of 140 patients diagnosed with MND was determined by ADP using the BodPod (i.e. the gold standard), and by BIA using the whole-body Bodystat. FFM values were translated to predicted resting energy expenditure (REE); the actual REE was measured using indirect calorimetry, resulting in a metabolic index. Validity of the BIA compared to the ADP was assessed using Bland-Altman analysis and Pearson's r. To assess the clinical relevance of differences, we evaluated changes in metabolic index and in individualized protein demand. RESULTS: Despite the high correlation between ADP and BIA (r = 0.93), averaged across patients, the assessed mean fat-free mass was 51.7 kg (± 0.9) using ADP and 54.2 kg (± 1.0) using BIA. Hence, BIA overestimated fat-free mass by 2.5 kg (95% CI 1.8-3.2, p < 0.001). Clinically, an increased metabolic index would be more often underdiagnosed in patients with MND using BIA (31.4% according to BIA versus 44.2% according to ADP, p = 0.048). A clinically relevant overestimation of ≥ 15 g in protein demand was observed for 4 (2.9%) patients using BIA. CONCLUSIONS: BIA systematically overestimates FFM in patients with MND. Although the differences are limited with ADP, underscoring the utility of BIA for research, overestimation of fat-free mass may have consequences for clinical decision-making, especially when interest lies in determining the metabolic index.

Using an expanded algorithm to estimate prevalence of amyotrophic lateral sclerosis in U.S. and UK.

BACKGROUND: There is an increasing need to better understand the burden of amyotrophic lateral sclerosis (ALS) using real-world data (RWD). However, identifying ALS cases using RWD presents several challenges due to the rarity of ALS and the differences in database coding systems. METHODS: MarketScan claims, and the UK Clinical Practice Research Datalink (CPRD) databases were searched for diagnosis codes of ALS or MND, the only drugs approved for treating ALS (riluzole and edaravone) and clinical visits with 12-month enrolment prior to 1 January 2011. The main algorithm required ≥ 1 ALS diagnosis code together with prescriptions or clinical visits. We expanded the existing algorithm to identify unspecific (possible) ALS group that had codes for motor neuron disease (MND) and the ALS drugs. The study period was from 1 January 2011 until 31 December 2020. RESULTS: We identified 16,246 patients with ≥ 1 ALS code in Marketscan (denominator n = 85,279,619), yet only 184 were found in the UK CPRD (denominator n = 21,318,589). Using the main algorithm 9,433 ALS patients were included in MarketScan, with a prevalence ranged between 4.5 per 100,000 in 2019 and 6.2 in 2015. In MarketScan, 3,658 (4.3 per 100,000) had ≥ 1 MND code and the ALS drug codes (possible cases). In CPRD, 47.9% of 2,785 patients with ≥ 1 MND code had a prescription for riluzole (6.3 per 100,000), regarded as possible ALS cases. CONCLUSIONS: The expanded algorithm enabled the identification of a large population with ALS, or possible ALS, and the estimation of ALS prevalence in MarketScan and CPRD.

Novel approaches to motoneuron disease/ALS treatment using non-invasive brain and spinal stimulation: IFCN handbook chapter.

Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives.

Neuromuscular ultrasound in combination with nerve conduction studies helps identify inflammatory motor neuropathies from lower motor neuron syndromes.

BACKGROUND AND PURPOSE: Identifying patients with inflammatory motor neuropathies (IMNs) is warranted since effective treatments are available and the prognosis of these patients differs from that of amyotrophic lateral sclerosis patients. METHODS: Between January 2019 and May 2022, 102 consecutive treatment-naïve lower motor neuron syndrome (LMNS) patients were recruited; these patients were suspected of having multifocal motor neuropathy, pure motor chronic inflammatory demyelinating polyneuropathy or amyotrophic lateral sclerosis with initial lower motor neuron presentation. Neuromuscular ultrasound (US) and nerve conduction studies (NCSs) were conducted at baseline. Relevant diagnostic investigations were performed if clinically warranted. The proposed US evidence of IMN was as follows: (i) nerve enlargement at ≥1 of the predetermined sites or (ii) absence of high intensity fasciculations in predefined muscle groups. Final diagnoses were made by experienced physicians after a prolonged follow-up period (≥12 months). IMN patients were defined as LMNS patients who experienced convincing improvements in response to immunotherapies. IMN patients without electrodiagnostic demyelinating features were diagnosed with treatment-responsive LMNS (TR-LMNS). RESULTS: In total, 16 patients were classified as IMN, including nine chronic inflammatory demyelinating polyneuropathy/multifocal motor neuropathy patients and seven TR-LMNS patients. Six TR-LMNS patients were identified by neuromuscular US. The sensitivity and specificity of NCSs, nerve US and muscle US were 56.3% and 100%, 43.8% and 90.7% and 68.8% and 97.7%, respectively. When these three modalities were combined, the sensitivity and specificity were 93.8% and 88.4%, respectively. CONCLUSION: Neuromuscular US studies are supplementary modalities to NCSs, and the combined use of these techniques might improve the identification of IMNs in LMNS patients.

Child Neurology: Allgrove Syndrome: An Intriguing Etiology of Motor Neuron Disease in Children

Motor neuron diseases are a rare group of neurodegenerative disorders with considerable phenotypic heterogeneity and a multitude of etiologies in the pediatric population. In this study, we report 2 unrelated adolescents (a boy and a girl) who presented with 4-6 years of progressive difficulty in walking, thinning of limbs, and gradually progressive darkening of the skin. Examination revealed generalized hyperpigmentation of skin and features suggestive of motor neuron involvement such as tongue atrophy, wasting of distal extremities, and brisk deep tendon reflexes. On detailed exploration for systemic involvement, history of dysphagia, inability to produce tears, and Addisonian crises were evident. An etiologic diagnosis of Allgrove syndrome, which is characterized by a triad of achalasia, alacrimia, and adrenal insufficiency was considered. Next-generation sequencing revealed pathogenic variants in the AAAS gene, confirming the diagnosis. Steroid replacement therapy was initiated along with relevant multidisciplinary referrals. The disease stabilized in the boy and a significant improvement was noted in the girl. These cases highlight the value of non-neurologic cues in navigating the etiologic complexities of motor neuron diseases in children and adolescents. It is imperative for neurologists to develop awareness of the diverse neurologic manifestations associated with Allgrove syndrome because they are often the first to be approached. A multidisciplinary team of experts including neurologists, endocrinologists, gastroenterologists, ophthalmologists, and dermatologists is essential for planning comprehensive care for these patients.

Wild-Type DCTN1 Suppresses the Aggregation of DCTN1 Mutants Associated with Perry Disease.

Perry disease, a rare autosomal dominant neurodegenerative disorder, is characterized by parkinsonism, depression or apathy, unexpected weight loss, and central hypoventilation. Genetic analyses have revealed a strong association between point mutations in the dynactin I gene (DCTN1) coding p150glued and Perry disease. Although previous reports have suggested a critical role of p150glued aggregation in Perry disease pathology, whether and how p150glued mutations affect protein aggregation is not fully understood. In this study, we comprehensively investigated the intracellular distribution of the p150glued mutants in HEK293T cells. We further assessed the effect of co-overexpression of the wild-type p150glued protein with mutants on the formation of mutant aggregates. Notably, overexpression of p150glued mutants identified in healthy controls, which is also associated with amyotrophic lateral sclerosis, showed a thread-like cytoplasmic distribution, similar to the wild-type p150glued. In contrast, p150glued mutants in Perry disease and motor neuron disease caused aggregation. In addition, the co-overexpression of the wild-type protein with p150glued mutants in Perry disease suppressed aggregate formation. In contrast, the p150glued aggregation of motor neuron disease mutants was less affected by the wild-type p150glued. Further investigation of the mechanism of aggregate formation, contents of the aggregates, and biological mechanisms of Perry disease could help develop novel therapeutics.

Nationwide survey of patients with multisystem proteinopathy in Japan.

OBJECTIVE: Multisystem proteinopathy (MSP) is an inherited disorder in which protein aggregates with TAR DNA-binding protein of 43 kDa form in multiple organs. Mutations in VCP, HNRNPA2B1, HNRNPA1, SQSTM1, MATR3, and ANXA11 are causative for MSP. This study aimed to conduct a nationwide epidemiological survey based on the diagnostic criteria established by the Japan MSP study group. METHODS: We conducted a nationwide epidemiological survey by administering primary and secondary questionnaires among 6235 specialists of the Japanese Society of Neurology. RESULTS: In the primary survey, 47 patients with MSP were identified. In the secondary survey of 27 patients, inclusion body myopathy was the most common initial symptom (74.1%), followed by motor neuron disease (11.1%), frontotemporal dementia (FTD, 7.4%), and Paget's disease of bone (PDB, 7.4%), with no cases of parkinsonism. Inclusion body myopathy occurred most frequently during the entire course of the disease (81.5%), followed by motor neuron disease (25.9%), PDB (18.5%), FTD (14.8%), and parkinsonism (3.7%). Laboratory findings showed a high frequency of elevated serum creatine kinase levels and abnormalities on needle electromyography, muscle histology, brain magnetic resonance imaging, and perfusion single-photon emission computed tomography. INTERPRETATION: The low frequency of FTD and PDB may suggest that FTD and PDB may be widely underdiagnosed and undertreated in clinical practice.

Factors associated with grief in informal carers of people living with Motor Neuron Disease: A mixed methods systematic review.

The purpose of this mixed methods systematic review was to identify factors associated with anticipatory grief, post-death grief, and prolonged grief in informal carers of people living with Motor Neuron Disease (MND) to inform future research and practice. Six electronic databases were searched and two quantitative and eight qualitative studies were identified. Five overarching themes were generated through thematic synthesis. The findings suggest that there are factors that may affect different grieving processes. It might be particularly important to target some factors prior and after the death of the person living with MND such as the knowledge about the progression of the disease, changes in relationships, anxiety and depressive symptoms of carers, and planning for death of the care recipient. Factors that may affect all three grieving processes were also identified such as negative experiences of caregiving, experiences of losses, end of life and psychological support, and emotional avoidance coping.