Decoding genetic and pathophysiological mechanisms in amyotrophic lateral sclerosis and primary lateral sclerosis: A comparative study of differentially expressed genes and implicated pathways in motor neuron disorders.

Motor Neuron Disorders (MNDs), characterized by the degradation and loss of function of motor neurons, are recognized as fatal conditions with limited treatment options and no known cure. The present study aimed to identify the pathophysiological functions and affected genes in patients with MNDs, specifically Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). The GSE56808 dataset comprised three sample groups: six patients diagnosed with ALS (GSM1369650, GSM1369652, GSM1369654, GSM1369656, GSM1369657, GSM1369658), five patients diagnosed with PLS (GSM1369648, GSM1369649, GSM1369653, GSM1369655, GSM1369659), and six normal controls (GSM1369642, GSM1369643, GSM1369644, GSM1369645, GSM1369646, and GSM1369647). The application of computational analysis of microarray gene expression profiles enabled us to identify 346 significantly differentially expressed genes (DEGs), 169 genes for the ALS sample study, and 177 genes for the PLS sample study. Enrichment was carried out using MCODE, a Cytoscape plugin. Functional annotation of DEGs was carried out via ClueGO/CluePedia (v2.5.9) and further validated via the DAVID database. NRP2, SEMA3D, ROBO3 and, CACNB1, CACNG2 genes were identified as the gene of interest for ALS and PLS sample groups, respectively. Axonal guidance (GO:0007411) and calcium ion transmembrane transport (GO:0070588) were identified to be some of the significantly dysregulated gene ontology (GO) terms, with arrhythmogenic right ventricular cardiomyopathy (KEGG:05412) to be the top relevant KEGG pathway which is affected in MND patients. ROBO3 gene was observed to have distinctive roles in ALS and PLS-affected patients, hinting towards the differential progression of ALS from PLS. The insights derived from our comprehensive analysis accentuate the distinct variances in the underlying molecular pathogenesis of ALS and PLS. Further research should investigate the mechanistic roles of the identified DEGs and molecular pathways, leading to potential targeted therapies for ALS and PLS.

'A lightbulb moment': carers' experiences of behavioural symptoms in motor neurone disease before and after MiNDToolkit.

BACKGROUND: To explore carers' experiences of behavioural symptoms in Motor Neurone Disease (MND), before and after using the MiNDToolkit, a novel internet-based psychoeducational intervention to support management of behavioural symptoms (BehSymp) in MND. The study also investigated carers' views and acceptability of MiNDToolkit. METHODS: A qualitative process evaluation of carers engagement with, and acceptability of, the MiNDToolkit conducted using semi-structured interviews with carers (n = 11). All interviews were audio-recorded, professionally transcribed verbatim and analysed thematically. RESULTS: Five themes were identified: (1) In the dark: carers' experiences and reactions to BehSymp; (2) Others can see: the role of HCPs in identifying symptoms - and perceived opportunities for carers to receive support; (3) Shedding light: carers implementation and perceived impact of the MiNDToolkit content; (4) Acceptability and carers' engagement with MiNDToolkit; (5) Future implementation. Carers' experience of BehSymp was particularly distressing when symptoms were apparently out of context. MiNDToolkit appeared to support learning that BehSymp were part of MND. Content resonated with carers, who reported learning about the full picture of MND, which led to acceptance and use of newly learned strategies. Engagement with the platform was good, with varied input from HCPs. Greater and nuanced involvement from HCPs seem important to support management of BehSymp. Recommendations for a full-scale trial emerged, including adding a paper booklet to accompany the intervention and creation of new modules on emotional lability, changes in relationships, and transitioning to a care home. CONCLUSIONS: MiNDToolkit was acceptable to carers overall. Recommended improvements should be actioned in a full-scale trial.

Use of the combination of spirometry, arterial blood gas analysis and overnight oximetry to predict the outcomes of patients affected by motor neuron disease: The Milan-Torin respiratory score (Mi-To-RS).

BACKGROUND AND PURPOSE: The use of multiple tests, including spirometry, arterial blood gas (ABG) analysis and overnight oximetry (OvOx), is highly recommended to monitor the respiratory function of patients with motor neuron disease (MND). In this study, we propose a composite score to simplify the respiratory management of MND patients and better stratify their prognosis. MATERIALS AND METHODS: We screened the clinical charts of 471 non-ventilated MND patients referred to the Neuro-rehabilitation Unit of the San Raffaele Scientific Institute of Milan (January 2001-December 2019), collecting spirometric, ABG and OvOx parameters. To evaluate the prognostic role of each measurement, univariate Cox regression for death/tracheostomy was performed, and the variables associated with survival were selected to design a scoring system. Univariate and multivariate Cox regression analyses were then carried out to evaluate the prognostic role of the score. Finally, results were replicated in an independent cohort from the Turin ALS Center. RESULTS: The study population included 450 patients. Six measurements were found to be significantly associated with survival and were selected to design a scoring system (maximum score = 8 points). Kaplan-Meier analysis showed significant stratification of survival and time to non-invasive mechanical ventilation adaptation according to score values, and multivariate analysis confirmed the independent effect of the respiratory score on survival of each cohort. CONCLUSION: Forced vital capacity, ABG and OvOx parameters provide complementary information for the respiratory management and prognosis of MND patients and the combination of these parameters into a single score might help neurologists predict prognosis and guide decisions on the timing of the implementation of different diagnostic or therapeutic approaches.

The periprocedural respiratory safety of propofol sedation in patients with a motor neuron disease undergoing percutaneous endoscopic gastrostomy insertion.

Motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS), may cause swallowing and respiratory problems, due to muscle weakness. Chronic enteral feeding via percutaneous endoscopic gastrostomy (PEG) is often indicated in these patients. PEG insertion is normally performed with sedation. Some guidelines withhold sedation in MND patients, due to the risk of respiratory complications. These guidelines seem to be defensive however and evidence is lacking. Our aim was to examine periprocedural respiratory complications occurring in MND patients undergoing PEG insertion with propofol sedation. A retrospective monocentre study was conducted in a referral hospital with an experienced PEG team. Patients with MND who underwent PEG insertion with propofol sedation between January 1. 2016 to January 1. 2023 were analysed to identify periprocedural respiratory complications. 46 patients were included. In five patients (10.9%) respiratory adverse events (AE) occurred, of which two serious (4.3%) and four AE (8.7%). Serious AE (SAE) were fatal in both cases: aspiration pneumonia (2.2%) and hypercapnia (2.2%) a few days after insertion. Sedation may have influenced the first case. Respiratory AE consisted of desaturation in two (4.3%), mild aspiration pneumonia in one (2.2%), and apnea in one patient (2.2%). Compared to previous studies respiratory complications and mortality had comparable prevalences.

Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.

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.

The various forms of hereditary motor neuron disorders and their historical descriptions.

Motor neuron disorders comprise a clinically and pathologically heterogeneous group of neurologic diseases characterized by progressive degeneration of motor neurons (including both sporadic and hereditary diseases), affecting the upper motor neurons, lower motor neurons, or both. Hereditary motor neuron disorders themselves represent a vast and heterogeneous group, with numerous clinical and genetic overlaps that can be a source of error. This narrative review aims at providing an overview of the main types of inherited motor neuron disorders by recounting the stages in their historical descriptions. For practical purposes, this review of the literature sets out their various clinical characteristics and updates the list of all the genes involved in the various forms of inherited motor neuron disorders, including spinal muscular atrophy, familial amyotrophic lateral sclerosis, hereditary spastic paraplegia, distal hereditary motor neuropathies/neuronopathies, Kennedy's disease, riboflavin transporter deficiencies, VCPopathy and the neurogenic scapuloperoneal syndrome.

An online intervention for carers to manage behavioral symptoms in motor neuron disease (MiNDToolkit): a randomized parallel multi-center feasibility trial.

BACKGROUND: Evidence on management of behavioral symptoms in motor neuron disease (MND) is lacking. The MiNDToolkit, an online psychoeducational platform, supports carers dealing with behavioral symptoms (BehSymp). The study objectives were to ascertain recruitment and retention rates, carer and healthcare professional (HCP) use of the platform, and completion of online assessments, to inform a full-scale trial. Design: Randomized, parallel, multi-center, feasibility trial. SETTING: England and Wales, across diverse MND services; recruitment from July/21 to November/22; last participant follow-up in March/23. PARTICIPANTS: Carers of people with motor neuron disease (PwMND) with BehSymp, recruited through MND services. After confirming eligibility, participants completed screening and baseline assessments online via the MiNDToolkit platform and were randomized centrally in a 1:1 ratio to MiNDToolkit or control. INTERVENTION: MiNDToolkit offered tailored modules to carers for the 3-month study period. Carers in the intervention group could receive additional support from MiNDToolkit trained HCPs. The control group was offered access to the intervention at the end of the study. Data were collected on platform usage and psychosocial variables. MAIN OUTCOMES: One hundred and fifty-one carers from 11 sites were invited to join the study (letter, face-to-face); 30 were screened; 29 were randomized. Fifteen people were allocated to the control arm; 14 to intervention. Carers were mostly female; median age for was 62.5 (IQR: 58, 68; intervention) and 57 (IQR: 56, 70; controls). Study retention was high (24/29 = 82.76%); carers engaged with the platform on average 14 times (median (IQR):14.0 (10.0, 18.5)) during the study period. CONCLUSION: The MiNDToolkit study was feasible and well accepted by carers and trained HCPs. A definitive trial is warranted.

Implementation of the MiNDToolkit intervention for the management of behavioral symptoms in MND by healthcare professionals: a mixed-methods process evaluation.

OBJECTIVE: MiNDToolkit is a novel psychoeducational intervention for carers to support management of behavioral symptoms in people living with motor neuron disease (PlwMND). Implementation of MiNDToolkit involves delivery of an online intervention to carers, which is reinforced by trained healthcare professionals (HCPs). METHODS: A mixed-methods process evaluation of the MiNDToolkit feasibility trial was conducted, focusing on reinforcement of the intervention by HCPs. Quantitative data, descriptively analyzed, were included from platform analytics, questionnaire, and 10 semi-structured interviews with HCPs. Interviews were transcribed verbatim; data were inductively analyzed using Reflective Thematic Analysis. RESULTS: The MiNDToolkit training and platform is a beneficial and acceptable resource for HCPs with potential to increase knowledge and confidence in identifying and managing behavioral symptoms in MND. Implementation barriers included HCPs' perceptions that highlighting behavior changes would be burdensome to carers and assumptions that carers would take the initiative to ask for support from clinicians. Degree of intervention reinforcement varied, with most HCPs delegating intervention delivery solely to the online platform. CONCLUSIONS: Implementation of the MiNDToolkit was viewed to be feasible and the platform thought to increase accessibility of support to carers. The flexible approach to delivery (online platform and optional HCP reinforcement) is acceptable as an intervention for supporting carers of PlwMND with behavioral symptoms. However, MiNDToolkit should not negate HCP involvement in providing medical and practical information to PlwMND and families. Future research should explore ways to incorporate support for carers in the management of PlwMND alongside standard care, alongside tools such as the MiNDToolkit.

Advances in symptom management and in monitoring disease progression in motor neuron disease.

The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidisciplinary specialist care aims to address the multifaceted and interacting biopsychosocial problems associated with motor neuron disease that leads to proven benefits in both survival and quality of life. This chapter will explore principles, structure and details of treatment options, and make recommendations for practice and for future research.

Current neuroprotective therapies and future prospects for motor neuron disease.

Four medications with neuroprotective disease-modifying effects are now in use for motor neuron disease (MND). With FDA approvals for tofersen, relyvrio and edaravone in just the past year, 2022 ended a quarter of a century when riluzole was the sole such drug to offer to patients. The acceleration of approvals may mean we are witnessing the beginning of a step-change in how MND can be treated. Improvements in understanding underlying disease biology has led to more therapies being developed to target specific and multiple disease mechanisms. Consideration for how the pipeline of new therapeutic agents coming through in clinical and preclinical development can be more effectively evaluated with biomarkers, advances in patient stratification and clinical trial design pave the way for more successful translation for this archetypal complex neurodegenerative disease. While it must be cautioned that only slowed rates of progression have so far been demonstrated, pre-empting rapid neurodegeneration by using neurofilament biomarkers to signal when to treat, as is currently being trialled with tofersen, may be more effective for patients with known genetic predisposition to MND. Early intervention with personalized medicines could mean that for some patients at least, in future we may be able to substantially treat what is considered by many to be one of the most distressing diseases in medicine.

Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.

BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease. METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391). FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention. INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services. FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.

End of life decision making when home mechanical ventilation is used to sustain breathing in Motor Neurone Disease: patient and family perspectives.

BACKGROUND: Motor Neurone Disease (MND) leads to muscle weakening, affecting movement, speech, and breathing. Home mechanical ventilation, particularly non-invasive ventilation (NIV), is used to alleviate symptoms and support breathing in people living with MND. While home mechanical ventilation can alleviate symptoms and improve survival, it does not slow the progression of MND. This study addresses gaps in understanding end-of-life decision-making in those dependent on home mechanical ventilation, considering the perspectives of patients, family members, and bereaved families. METHODS: A UK-wide qualitative study using flexible interviews to explore the experiences of people living with MND (n = 16), their family members (n = 10), and bereaved family members (n = 36) about the use of home mechanical ventilation at the end of life. RESULTS: Some participants expressed a reluctance to discuss end-of-life decisions, often framed as a desire to "live for the day" due to the considerable uncertainty faced by those with MND. Participants who avoided end-of-life discussions often engaged in 'selective decision-making' related to personal planning, involving practical and emotional preparations. Many faced challenges in hypothesising about future decisions given the unpredictability of the disease, opting to make 'timely decisions' as and when needed. For those who became dependent on ventilation and did not want to discuss end of life, decisions were often 'defaulted' to others, especially once capacity was lost. 'Proactive decisions', including advance care planning and withdrawal of treatment, were found to empower some patients, providing a sense of control over the timing of their death. A significant proportion lacked a clear understanding of the dying process and available options. CONCLUSIONS: The study highlights the complexity and evolution of decision-making, often influenced by the dynamic and uncertain nature of MND. The study emphasises the need for a nuanced understanding of decision-making in the context of MND.

Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

Diagnostic value of neurofilaments in differentiating motor neuron disease from multifocal motor neuropathy.

OBJECTIVE: To evaluate the performance of serum neurofilament light chain (NfL) and cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain (pNfH) as diagnostic biomarkers for the differentiation between motor neuron disease (MND) and multifocal motor neuropathy (MMN). METHODS: This retrospective, monocentric study included 16 patients with MMN and 34 incident patients with MND. A subgroup of lower motor neuron (MN) dominant MND patients (n = 24) was analyzed separately. Serum NfL was measured using Ella automated immunoassay, and CSF pNfH was measured using enzyme-linked immunosorbent assay. Area under the curve (AUC), optimal cutoff values (Youden's index), and correlations with demographic characteristics were calculated. RESULTS: Neurofilament concentrations were significantly higher in MND compared to MMN (p < 0.001), and serum NfL and CSF pNfH correlated strongly with each other (Spearman's rho 0.68, p < 0.001). Serum NfL (AUC 0.946, sensitivity and specificity 94%) and CSF pNfH (AUC 0.937, sensitivity 90.0%, specificity 100%) performed excellent in differentiating MND from MMN. Optimal cutoff values were ≥ 44.15 pg/mL (serum NfL) and ≥ 715.5 pg/mL (CSF pNfH), respectively. Similar results were found when restricting the MND cohort to lower MN dominant patients. Only one MMN patient had serum NfL above the cutoff. Two MND patients presented with neurofilament concentrations below the cutoffs, both featuring a slowly progressive disease. CONCLUSION: Neurofilaments are valuable supportive biomarkers for the differentiation between MND and MMN. Serum NfL and CSF pNfH perform similarly well and elevated neurofilaments in case of diagnostic uncertainty underpin MND diagnosis.

The Palliative Care Needs of Patients with Multiple Sclerosis, Parkinson's Related Diseases, and Motor Neurone Disease: A Secondary Analysis of the OPTCARE Neuro Trial Data.

Background: Long-term neurological conditions include multiple sclerosis, Parkinson's-related diseases, and motor neurone disease. National and international guidelines recommend a palliative approach for advancing neurological disease, but there is little research describing and comparing the palliative care needs of these patients side by side. Objective: The aim of this study was to describe and compare the symptom burden and psychological distress of patients with multiple sclerosis, Parkinson's-related diseases, and motor neurone disease. Design: A cross-sectional secondary analysis of the OPTCARE Neuro trial data was performed. Setting/Subjects: Recruitment was from seven sites across the United Kingdom. Patients aged 18 years or older, severely affected by advanced stages of multiple sclerosis or Parkinson's-related diseases or any stage of motor neurone disease, with an unresolved symptom, and one other issue despite usual care were eligible. Measurements: Baseline demographics, Integrated Palliative care Outcome Scale (IPOS) Neuro, and Hospital Anxiety and Depression Scale (HADS) results were analyzed. Results: Data from 348 participants were analyzed. The mean IPOS Neuro-S24 score was 27, with no statistical difference found between groups (p = 0.341). The most common symptoms were poor mobility (68.5%), problems using legs (63%), and fatigue (34.8%). The HADS revealed that a quarter of participants met the criteria for a diagnosis of anxiety and depression. Conclusions: Multiple sclerosis, Parkinson's-related disease, and motor neurone disease patients who were eligible for the OPTCARE Neuro trial have unmet needs in the form of distressing physical and psychological symptoms. It is unclear how to address these needs. The answer likely lies in a collaborative approach between neurology, palliative care, psychology, and specialized allied health professionals. Future work should focus on investigating this.

Cost-effectiveness of acceptance and commitment therapy for people living with motor neuron disease, and their health-related quality of life.

BACKGROUND: Given the degenerative nature of the condition, people living with motor neuron disease (MND) experience high levels of psychological distress. The purpose of this research was to investigate the cost-effectiveness of acceptance and commitment therapy (ACT), adapted for the specific needs of this population, for improving quality of life. METHODS: A trial-based cost-utility analysis over a 9-month period was conducted comparing ACT plus usual care (n = 97) versus usual care alone (n = 94) from the perspective of the National Health Service. In the primary analysis, quality-adjusted life years (QALYs) were computed using health utilities generated from the EQ-5D-5L questionnaire. Sensitivity analyses and subgroup analyses were also carried out. RESULTS: Difference in costs was statistically significant between the two arms, driven mainly by the intervention costs. Effects measured by EQ-5D-5L were not statistically significantly different between the two arms. The incremental cost-effectiveness was above the £20,000 to £30,000 per QALY gained threshold used in the UK. However, the difference in effects was statistically significant when measured by the McGill Quality of Life-Revised (MQOL-R) questionnaire. The intervention was cost-effective in a subgroup experiencing medium deterioration in motor neuron symptoms. CONCLUSIONS: Despite the intervention being cost-ineffective in the primary analysis, the significant difference in the effects measured by MQOL-R, the low costs of the intervention, the results in the subgroup analysis, and the fact that ACT was shown to improve the quality of life for people living with MND, suggest that ACT could be incorporated into MND clinical services.

An introduction to neuropalliative care: A growing need.

Palliative care (PC) defined as 'an approach improving the quality of life of patients and their families facing problems associated with life-limiting illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual' aims to enhance the improve the remaining time that patients have, emphasising choice for patients and families.1 Patients with neurological disease such as Parkinson's (PD) and motor neurone disease (MND) benefit from PC earlier in disease with increasing emphasis over time. Understanding and communicating uncertain trajectories, honest prognostic communication when patients are ready and careful symptom control has been shown to enhance quality of life in patients and caregivers, giving greater autonomy to these patients when supported in decision-making by a palliative approach. Although obstacles to palliative care are frequent, there are strategies which can help overcome them.

Thalamic Alterations in Motor Neuron Diseases: A Systematic Review of MRI Findings.

BACKGROUND: Motor neuron diseases (MNDs) are progressive neurodegenerative disorders characterized by motor impairment and non-motor symptoms. The involvement of the thalamus in MNDs, especially in conditions such as amyotrophic lateral sclerosis (ALS), and its interaction with frontotemporal dementia (FTD), has garnered increasing research interest. This systematic review analyzed magnetic resonance imaging (MRI) studies that focused on thalamic alterations in MNDs to understand the significance of these changes and their correlation with clinical outcomes. METHODS: Following PRISMA 2020 guidelines, the PubMed and Scopus databases were searched from inception to June 2023 for studies related to MRI findings in the thalamus of patients with MNDs. Eligible studies included adult patients diagnosed with ALS or other forms of MND who underwent brain MRI, with outcomes related to thalamic alterations. Studies were evaluated for risk of bias using the Newcastle-Ottawa scale. RESULTS: A total of 52 studies (including 3009 MND patients and 2181 healthy controls) used various MRI techniques, including volumetric analysis, diffusion tensor imaging, and functional MRI, to measure thalamic volume, connectivity, and other alterations. This review confirmed significant thalamic changes in MNDs, such as atrophy and microstructural degradation, which are associated with disease severity, progression, and functional disability. Thalamic involvement varies across different MND subtypes and is influenced by the presence of cognitive impairment and mutations in genes including chromosome 9 open reading frame 72 (C9orf72). The synthesis of findings across studies indicates that thalamic pathology is a prevalent early biomarker of MNDs that contributes to motor and cognitive deficits. The thalamus is a promising target for monitoring as its dysfunction underpins a variety of clinical symptoms in MNDs. CONCLUSIONS: Thalamic alterations provide valuable insights into the pathophysiology and progression of MNDs. Multimodal MRI techniques are potent tools for detecting dynamic thalamic changes, indicating structural integrity, connectivity disruption, and metabolic activity.