Colette Donaghy

Neurofilament levels are elevated in many neurodegenerative diseases and have shown promise as diagnostic and prognostic biomarkers in Amyotrophic Lateral Sclerosis (ALS), the most common form of Motor Neuron Disease (MND). This study assesses serum neurofilament light (NFL) and neurofilament heavy (NFH) chain concentrations in patients with ALS, other variants of motor neuron disease such as Progressive Muscular Atrophy (PMA) and Primary Lateral Sclerosis (PLS), and a range of other neurological diseases. It aims to evaluate the use of NFL and NFH to differentiate these conditions and for the prognosis of MND disease progression. NFL and NFH levels were quantified using electrochemiluminescence immunoassays (ECLIA). Both were elevated in 47 patients with MND compared to 34 patients with other neurological diseases and 33 healthy controls. NFL was able to differentiate patients with MND from the other groups with a Receiver Operating Characteristic (ROC) curve area under the curve (AUC) of 0.90 (p < 0.001). NFL correlated with the rate of disease progression in MND (rho 0.758, p < 0.001) and with the ALS Functional Rating Scale (rho −0.335, p = 0.021). NFL levels were higher in patients with ALS compared to both PMA (p = 0.032) and PLS (p = 0.012) and were able to distinguish ALS from both PMA and PLS with a ROC curve AUC of 0.767 (p = 0.005). These findings support the use of serum NFL to help diagnose and differentiate types of MND, in addition to providing prognostic information to patients and their families.

Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease and is the most common adult motor neuron disease. The disease pathogenesis is complex with the perturbation of multiple pathways proposed, including mitochondrial dysfunction, RNA processing, glutamate excitotoxicity, endoplasmic reticulum stress, protein homeostasis and endosomal transport/extracellular vesicle (EV) secretion. EVs are nanoscopic membrane-bound particles that are released from cells, involved in the intercellular communication of proteins, lipids and genetic material, and there is increasing evidence of their role in ALS. After discussing the biogenesis of EVs, we review their roles in the propagation of pathological proteins in ALS, such as TDP-43, SOD1 and FUS, and their contribution to disease pathology. We also discuss the ALS related genes which are involved in EV formation and vesicular trafficking, before considering the EV protein and RNA dysregulation found in ALS and how these have been investigated as potential biomarkers. Finally, we highlight the potential use of EVs as therapeutic agents in ALS, in particular EVs derived from mesenchymal stem cells and EVs as drug delivery vectors for potential treatment strategies.

Amyotrophic Lateral Sclerosis (ALS), Spinal Bulbar Muscular Atrophy (SBMA), and Spinal Muscular Atrophy (SMA) are motor neuron diseases (MNDs) characterised by progressive motor neuron degeneration, weakness and muscular atrophy. Lipid dysregulation is well recognised in each of these conditions and occurs prior to neurodegeneration. Several lipid markers have been shown to predict prognosis in ALS. Sphingolipids are complex lipids enriched in the central nervous system and are integral to key cellular functions including membrane stability and signalling pathways, as well as being mediators of neuroinflammation and neurodegeneration. This review highlights the metabolism of sphingomyelin (SM), the most abundant sphingolipid, and of its metabolite ceramide, and its role in the pathophysiology of neurodegeneration, focusing on MNDs. We also review published lipidomic studies in MNDs. In the 13 studies of patients with ALS, 12 demonstrated upregulation of multiple SM species and 6 demonstrated upregulation of ceramides. SM species also correlated with markers of clinical progression in five of six studies. These data highlight the potential use of SM and ceramide as biomarkers in ALS. Finally, we review potential therapeutic strategies for targeting sphingolipid metabolism in neurodegeneration.

Background and purpose: This study evaluates the incidence, prevalence and survival trends of motor neurone disease (MND) in Northern Ireland from 2015 to 2019.Methods: A capture–recapture analysis was performed using five independent data sources. Incidence and prevalence rates were standardized to the European Standard Population. Survival outcomes were analysed using Kaplan–Meier curves and Cox regression analysis.Results: Amongst 254 total cases of MND, capture–recapture analysis estimated three missing cases (case ascertainment 98.8%). Age standardized incidence of captured cases was 3.12 per 100,000 (2.73, 3.50) and standardized prevalence ranged from 9.45 to 6.49 per 100,000 from 2015 to 2019. Standardized incidence and prevalence rates in 2006 were 1.4 and 3.3 per 100,000 respectively. Of identified cases, 133 (52.4%) were male; 94.5% had amyotrophic lateral sclerosis; median age of onset was 67 years; median time to diagnosis was 12 months (95% confidence interval 11.2, 12.8); survival from diagnosis was 12 months (95% confidence interval 10.6, 15.4); 25 (9.8%) reported a family history of MND or frontotemporal dementia; and a known MND‐associated genetic mutation was identified in 7.9% of total cases, of which the most common was C9orf72 (5.7% of all patients). Factors associated with improved survival were younger age at onset, longer time to diagnosis, attendance at regional MND clinic, and initial neurology presentation as outpatient (all p < 0.001).Conclusion: The incidence and prevalence of MND in Northern Ireland has increased over the last 10 years, in line with increasing rates reported from other European countries. Improved survival was associated with younger age at onset, longer time to diagnosis, attendance at a regional MND clinic and outpatient presentation to a Neurology Department.

Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disease characterised by progressive deterioration of upper and lower motor neurons that eventually culminates in severe muscle atrophy, respiratory failure and death. There is a concerning lack of understanding regarding the mechanisms that lead to the onset of ALS and as a result there are no reliable biomarkers that aid in the early detection of the disease nor is there an effective treatment. This review first considers the clinical phenotypes associated with ALS, and discusses the broad categorisation of ALS and ALS-mimic diseases into upper and lower motor neuron diseases, before focusing on the genetic aetiology of ALS and considering the potential relationship of mutations of different genes to variations in phenotype. For this purpose, a systematic review is conducted collating data from 107 original published clinical studies on monogenic forms of the disease, surveying the age and site of onset, disease duration and motor neuron involvement. The collected data highlight the complexity of the disease’s genotype–phenotype relationship, and thus the need for a nuanced approach to the development of clinical assays and therapeutics.

Internationally, it is widely accepted that holistic care is as an integral part of the care for people with motor neurone disease (MND), and their informal carers. However the optimal role of generalist and specialist palliative care, and how it integrates with specialist neurology services, is not fully established. Using a qualitative approach we sought to examine end of life care for people with MND in Northern Ireland, and the role of specialist and generalist palliative care. Qualitative study involving a convenience sample of 13 bereaved carers recruited using the Northern Ireland MND Register. Data collection consisted of semi-structured interviews with the bereaved carers of patients who had died 3–24 months previously with a diagnosis of MND. Data were analysed using thematic analysis. Findings illuminated variations in relation to the levels of holistic care provided to this cohort of patients. Unmanaged respiratory and psychological symptoms caused perceived distress amongst patients. Participants’ experiences additionally highlighted reluctance amongst patients with MND to engage with services such as specialist palliative care. Conversely, for those who received input from specialist palliative care services carers portrayed these services to be of great benefit to the patient. Patients with MND in Northern Ireland may have many unmet holistic care needs. Key areas that require particular focus in terms of service development include neuromuscular respiratory physiotherapy and psychological services for patients. Future research must explore an optimal model of holistic care delivery for patients with MND and how this can be effectively integrated to best meet this patient cohorts palliative care needs.