Cases Of Motor Neuron Disease Research Articles

Spinal cord neurone loss and foot placement changes in a rat knock-in model of amyotrophic lateral sclerosis type 8

Abstract Amyotrophic Lateral Sclerosis is an age-dependent cell type-selective degenerative disease. Genetic studies indicate that Amyotrophic Lateral Sclerosis is part of a spectrum of disorders ranging from spinal muscular atrophy to frontotemporal dementia that share common pathological mechanisms. Amyotrophic Lateral Sclerosis type 8 is a familial disease caused by mis-sense mutations in VAPB. VAPB is localised to the cytoplasmic surface of the endoplasmic reticulum where it serves as a docking point for cytoplasmic proteins and mediates inter-organelle interactions with the endoplasmic reticulum membrane. A gene knock-in model of Amyotrophic Lateral Sclerosis type 8 based on the VapBP56S mutation and VapB gene deletion have been generated in the rat. These animals display a range of age-dependent phenotypes distinct from those previously reported in mouse models of Amyotrophic Lateral Sclerosis type 8. A loss of motor neurones in VapBP56S/+ and VapBP56S/P56Sanimals is indicated by a reduction in the number of large choline acetyl transferase-staining cells in the spinal cord. VapB-/-animals exhibit a relative increase in cytoplasmic TDP-43 levels compared to the nucleus, but no large protein aggregates. Concomitant with these spinal cord pathologies VapBP56S/+, VapBP56S/P56S and VapB-/-animals exhibit age-dependent changes in paw placement and exerted pressures when traversing a CatWalk apparatus, consistent with a somatosensory dysfunction. Extra motor dysfunction is reported in half the cases of motor neurone disease, and this is the first indication of an associated sensory dysfunction in a rodent model of Amyotrophic Lateral Sclerosis. Different rodent models may offer complementary experimental platforms with which to understand the human disease.

Clinicopathological correlates in the frontotemporal lobar degeneration-motor neuron disease spectrum.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.

Pathogenic motor neuron disease‐linked mutations distinctly alter TDP‐43 nanoscale dynamics

AbstractBackgroundThe hallmark of motor neuron disease (MND) pathology is the abnormal accumulation of insoluble proteins that form inclusions in motor neurons within the spinal cord and primary motor cortex. How, why, and when these proteins begin to aggregate has not been fully elucidated. In up to 97% of all MND cases, TAR DNA‐binding protein‐43 (TDP‐43) is a key protein that is mislocalised from its native nuclear presence into cytoplasmic inclusions. Furthermore, genetic mutations in TDP‐43 are implicated in familial MND, further linking the function of this protein to this neurodegenerative disease. The precise mechanism that drives the aggregation of TDP‐43 in MND is unknown, however identifying the changes in the dynamics of the protein within the nucleus could shed light on how the different mutations contribute to its altered function in MND.MethodWe applied nanoscale single‐molecule imaging to identify the changes in the dynamics and localisation of TDP‐43 caused by well characterised pathogenic‐causing mutation. This was done by tagging the proteins with the photoconvertible fluorescent protien ‐ mEOS3.2. Single molecule imaging was subsequently carried out in cells and neurons expressing the proteins.ResultWe observe that the different pathogenic mutations uniquely influence the mobility of TDP‐43. Most of the MND‐linked mutations inhibit the movement of TDP‐43 similar to how oxidative stressors such as arsenite induce inclusions of TDP‐43 thereby immobilising the molecules. Furthermore, our data indicates that post‐translational modifications in TDP‐43 such as acetylation similarly restricts its dynamics within the nucleus.ConclusionTogether, our data suggests that the confinement of mobility of TDP‐43 is a key step in the formation of toxic aggregates in disease.

Ayurved Management of Amyotrophic Lateral Sclerosis (Motor Neuron Disease)

Motor neurons are nerve cells that send electrical output signals to the muscles, affecting the muscles’ ability to function. Motor neuron disease (MND) can appear at any age, but the symptoms usually appear after the age of 50 years. It affects more males than females. The most common type of MND is amyotrophic lateral sclerosis (ALS). A 56-year-old male patient had heaviness and weakness in left lower limb for 4 months. The condition rapidly progressed in the 4 months prior and found difficulty in climbing stairs and swelling in the left foot. Gradually he developed slowness of speech hence consulted allopathic hospital and treated with glutamate blockers, muscle relaxant and physiotherapy. His response to allopathic medications found to be slow. The present case report deals with the case of MND and its Ayurvedic diagnosis and management. Difficulty in differential diagnosis exists between the conditions like Sarvanga Vata, Avrita Vata and Saama Vata. Upashaya- Anupashaya Pariksha is beneficial to solve the problem in differential diagnosis. Swedana and Matra Vasti procedures are found to be beneficial in the management of MND.

Clinical Profile of Various Mnd Cases that Presented to a Tertiary Centre over the Past 3 Years

INTRODUCTION: Motor neurone disease (MND) is a disabling and ultimately fatal disease of the motor system, with few effective treatments. Considerable heterogeneity is observed in the clinical motor features of MND, with extra-motor manifestations now also recognized as part of the condition. Progressive motor weakness and bulbar dysfunction lead to premature death, usually from respiratory failure. Diagnosis remains clinical. There are no specific laboratory markers which make the diagnosis independent of the clinical pattern but there are a few appropriate investigations to exclude mimics. The clinical syndrome once observed is recognized easily because of a distinctive appearance and course. OBJECTIVES: To demonstrate and compare the etiology, demography &amp; clinical profile of various forms of Motor Neuron Diseases DESIGN: Cross sectional (Observational) study SETTING: Sapthagiri Institute of Medical Sciences &amp; Research Centre METHODS: 30 MND cases diagnosed clinically (as per Awaji Shima modification of the El Escorial Criteria) with few supportive investigations that presented to our centre over the past 3 years were compiled and compared CONCLUSIONS: Mortality rates in MND depends on type of MND and subtypes like Madras Motor Neuron disease, SMA, PLS has the slowest progression and best prognosis of all the subtypes. Secondary MND due to exposure to heavy metals has faster progression and worst prognosis

VRK1 mutation associated with adult-onset spinal muscular atrophy and persistently elevated creatine kinase (P3-8.011)

<h3>Objective:</h3> NA <h3>Background:</h3> NA <h3>Design/Methods:</h3> We present a patient with persistently elevated creatinine kinase and a clinical syndrome consistent with adult-onset spinal muscular atrophy (dSMA) without pontocerebellar atrophy secondary to a vaccinia-related kinase 1 (VRK1) mutation. <h3>Results:</h3> A 46-year-old male presented for evaluation of persistently elevated creatinine kinase, leg weakness, and decreased balance for more than 5 years. He reported mild weakness mainly in the lower extremities and reduced calf size. The patient has had persistently elevated creatine kinase (CK) for the past 5 years, ranging from 580–7,000 units/L. On examination, he had bilateral high arches, calf fasciculations, and atrophy. Motor showed decreased strength in feet dorsiflexion and minimal bilateral hand interosseous weakness. Reflexes were normal except for the absent left ankle reflex. The rest of the neurologic examination was unremarkable. EMG/NCS showed reduced motor responses with diffuse neurogenic changes in the right arm and leg concerning for motor neuropathy. CK level remained elevated along with aldolase; otherwise negative myopathy labs. The neuropathy panel showed two pathogenic mutations of the VRK1 gene, variant c1072C&gt;T (p.Arg358) and c.356 A&gt;G (p.His119Arg), consistent with compound heterozygosity. <h3>Conclusions:</h3> VRK1 mutation is a rare cause of distal predominant spinal muscular atrophy. This disease is characterized by slowly progressive distal symmetric limb muscle weakness and atrophy, frequently leading to foot deformities such as pes cavus, with minimal or no sensory involvement. Mild elevations in CK can be seen in up to 50% of motor neuron disease cases. Our patient’s presentation was consistent with adult-onset spinal muscular atrophy. There was no pontocerebellar hypoplasia, which has also been described with this mutation. Creatine kinase level remained very elevated in our patient, beyond what has previously been described in the literature. Future investigation should be done to determine the significance of this, including whether there may be a myopathic component to this illness. <b>Disclosure:</b> Dr. Rodriguez-Hernandez has nothing to disclose. Dr. Carranza-Renteria has nothing to disclose. Dr. Faktorovich has a non-compensated relationship as a Board of Directors with Brother’s Brother Foundation that is relevant to AAN interests or activities.

Protective Effects of Lovastatin in a Population-Based ALS Study and Mouse Model.

The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications. We constructed a large, population-based case-control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1 year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1G93A mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies. We observed previously established medical associations for MND and an inverse dose-response association between lovastatin and MND, with 28% reduced risk at 40 mg/day. In SOD1G93A mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn. Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881-892.

The diversity of hereditary neuromuscular diseases: Experiences from molecular diagnosis

Hereditary neuromuscular diseases (NMDs) are a group of rare disorders, and the diagnosis of these diseases is a substantial burden for referral centers. Although next-generation sequencing (NGS) has identified a large number of genes associated with hereditary NMDs, the diagnostic rates still vary across centers. Patients with a suspected hereditary NMD were referred to neuromuscular specialists at the National Taiwan University Hospital. Molecular diagnoses were performed by employing a capture panel containing 194 genes associated with NMDs. Among the 50 patients referred, 43 had a suspicion of myopathy, and seven had polyneuropathy. The overall diagnostic rate was 58%. Pathogenic variants in 19 genes were observed; the most frequent pathogenic variant found in this cohort (DYSF) was observed in only four patients, and 10 pathogenic variants were observed in one patient each. One case of motor neuron disease was clinically mistaken for myopathy. A positive family history increased the diagnostic rate (positive: 72.7% vs. negative: 56.3%). Fourteen patients with elevated plasma creatine kinase levels remained without a diagnosis. The application of NGS in this single-center study proves the great diversity of hereditary NMDs. A capture panel is essential, but high-quality clinical and laboratory evaluations of patients are also indispensable.

Identifying key signs of motor neurone disease in primary care: a nested case–control study using the QResearch database

ObjectiveTo confirm the symptoms and signs for motor neuron disease (MND) in the Red Flag tool; to quantify the extent to which the key symptoms and signs are associated with...

Sports and trauma as risk factors for Motor Neurone Disease: New Zealand case-control study.

ObjectivesTo assess whether sports, physical trauma and emotional trauma are associated with motor neurone disease (MND) in a New Zealand case–control study (2013–2016).MethodsIn total, 321 MND cases and 605 population controls were interviewed collecting information on lifetime histories of playing sports, physical trauma (head injury with concussion, spine injury) and emotional trauma (14 categories). ORs were estimated using logistic regression adjusting for age, sex, ethnicity, socioeconomic status, education, smoking status, alcohol consumption and mutually adjusting for all other exposures.ResultsHead injury with concussion ≥3 years before diagnosis was associated with MND (OR 1.51, 95% CI: 1.09–2.09), with strongest associations for two (OR 4.01, 95% CI: 1.82–8.86), and three or more (OR 2.34, 95% CI: 1.00–5.45) head injuries. Spine injury was not associated with MND (OR 0.81, 95% CI: 0.48–1.36). Compared to never playing sports, engaging in sports throughout childhood and adulthood increased MND risk (OR 1.81, 95% CI: 1.01–3.25), as was more than 12 years playing football/soccer (OR 2.35, 95% CI: 1.19–4.65). Reporting emotionally traumatic events in more than three categories was associated with MND (OR 1.88, 95% CI: 1.17–3.03), with physical childhood abuse the only specific emotional trauma associated with MND (OR 1.82, 95% CI: 1.14–2.90), particularly for those reporting longer abuse duration (OR(5–8 years) 2.26, 95% CI: 1.14–4.49; OR(>8 years) 3.01, 95% CI: 1.18–7.70). For females, having witnessed another person being killed, seriously injured or assaulted also increased MND risk (OR 2.68, 95% CI: 1.06–6.76).ConclusionsThis study adds to the evidence that repeated head injury with concussion, playing sports in general, and playing football (soccer) in particular, are associated with an increased risk of MND. Emotional trauma, that is physical abuse in childhood, may also play a role.

Occupational exposures to pesticides and other chemicals: a New Zealand motor neuron disease case–control study

ObjectivesTo assess associations between occupational exposures to pesticides and other chemicals and motor neuron disease (MND).MethodsA population-based case–control study that included 319 MND cases (64% male/36% female) recruited through the...

Analysis of incidence of motor neuron disease in England 1998–2019: use of three linked datasets

Objective: This study uses three linked datasets to provide an estimate of incidence of motor neuron disease (MND) in England from 1998 to 2019. Comparison is made to previous British studies. It examines age at diagnosis and ethnicity of those affected. Methods: The literature was searched for studies of MND incidence in Great Britain from 1995 to date. The QResearch and linked Hospital Episode Statistics and Death register databases were searched from 1998 to 2019 for cases of MND, and incidence calculated from 16.8 million adults and 112 million adult years of data. Results: We found 6437 adults with a diagnosis of MND giving an incidence of MND of 5.69/100,000 person years (95% CI 5.51–5.88); 6.57 (6.41–6.99) in men and 4.72 (4.49–4.97) in women when age-standardized to the 2011 UK population. The median age of diagnosis was 72 years. Peak incidence occurred in the 80–84 year age group in men and 75–79 in women. Age-standardized incidence was as high in Bangladeshi, Black Caribbean, Indian, other Asian and Pakistani people as in White people. Black African and Chinese people had a lower incidence. Conclusion: The use of three linked national datasets captured 33% more people than a primary care dataset alone. Patients were older than in previous studies and rates were high in all ethnic groups studied except Black African and Chinese people. We present the highest incidence of MND reported globally in the past 50 years. Methodological differences may in part explain differences with previous reports. The use of national datasets may have captured additional MND patients with serious comorbidities who have not seen a neurologist before death. A limitation of this approach is that unlike population registers, which minimize false positive diagnosis by neurologist review of each patient, we cannot review diagnosis for individuals as data are anonymized.

Brain MRI signatures of atrophy in genetic frontotemporal lobar degeneration

AbstractBackgroundGenetic heterogeneity underlying different clinical presentations of the frontotemporal lobar degeneration (FTLD) spectrum hampers the identification of useful biomarkers that may be able to monitor disease progression and/or facilitate the enrolment in clinical trials. The aim of this study was to assess cortical, subcortical and cerebellar grey matter (GM) atrophy using magnetic resonance imaging (MRI) in patients affected by disorders of the FTLD spectrum with known genetic mutations.MethodSixty‐six patients carrying FTLD‐related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty‐one patients with sporadic FTLD (sFTLD) matched for age, sex and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls (HC). A whole‐brain voxel‐based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were also obtained.ResultCompared with HC, GM volume loss on VBM was generally greater and more diffuse in genetic FTD (gFTD) cases, followed by sporadic FTD (sFTD) cases and genetic MND (gMND) cases, whereas sporadic MND (sMND) showed very focal atrophy of the motor cortex. Patients carrying GRN and C9ORF72 mutations showed the most widespread cortical volume loss, whereas SOD1 and TARDBP patients were the least atrophic. Greater atrophy of the parietal cortices and thalami was found, globally, in genetic FTLD patients compared with sporadic FTLD and, particularly, in C9‐MND patients compared with sMND. When assessing deep GM volumes, genetic FTLD patients showed significant volume loss compared with sporadic FTLD in the caudate nuclei and thalami. In particular, greater atrophy of the left caudate and right thalamus was found in C9MND compared with sMND. At the cerebellar level, greater atrophy of the right lobule VIIb could discriminate genetic FTLD from sporadic FTLD patients.ConclusionOur data suggest that measures of deep GM and cerebellar involvement might be useful markers of genetic FTLD, particularly C9ORF72‐related disorders, regardless of the clinical presentation within the FTLD spectrum.Supported by: Italian Ministry of Health (RF‐2011‐02351193; GR‐2011‐02351217) and European Research Council (StG‐2016_714388_NeuroTRACK).

Epidemiology and survival trends of motor neurone disease in Northern Ireland from 2015 to 2019.

This study evaluates the incidence, prevalence and survival trends of motor neurone disease (MND) in Northern Ireland from 2015 to 2019. 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. 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 67years; median time to diagnosis was 12months (95% confidence interval 11.2, 12.8); survival from diagnosis was 12months (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). The incidence and prevalence of MND in Northern Ireland has increased over the last 10years, 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.

Potential of immunoglobuline treatment in motor neuron diseases associated to blood-brain barrier damage

Motor neuron diseases (MND) are inherently complex and may result in several different diagnoses with challenging treatment. Here, we report two cases of MND showing clinical improvement after immunoglobuline infusion.

Structural MRI Signatures in Genetic Presentations of the Frontotemporal Dementia/Motor Neuron Disease Spectrum.

Background and ObjectivesTo assess cortical, subcortical, and cerebellar gray matter (GM) atrophy using MRI in patients with disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations.MethodsSixty-six patients carrying FTLD-related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty-one patients with sporadic FTLD (sFTLD) matched for age, sex, and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls. A whole-brain voxel-based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were obtained.ResultsCompared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas patients with sporadic MND (sMND) showed focal motor cortical atrophy. Patients carrying C9orf72 and GRN mutations showed the most widespread cortical volume loss, in contrast with GM sparing in SOD1 and TARDBP. Globally, patients with gFTLD showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, patients with gFTLD showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, patients with gFTLD showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of patients with gFTLD with a C9orf72 mutation showed an inverse correlation with Frontal Behavioral Inventory scores.DiscussionMeasures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly C9orf72-related disorders, regardless of the clinical presentation within the FTLD spectrum.

CLINICAL CHARACTERISTICS OF MOTOR NEURON DISEASE : A SINGLE CENTRE DATA FROM GUJARAT STATE.

Motor Neuron Disease (MND) is a heterogenous group of disorders with degeneration of upper and/or lower motor neurons. Limited data is available for clinical characteristics of MND from western India. Methods: We retrospectively observed all cases of MND, evaluated at our centre. Those with conrmed diagnosis, exclusion of secondary causes and with one year of minimal follow up were included, for the anaysis. RESULTS: Out of 51 patients of MND, 36 were diagnosed as Amyotropic Lateral Sclerosis (ALS) and 15 patients were having pure Lower Motor Neuron(LMN) type of MND. Male: female ration was 2.8:1 in ALS group , with mean age of 50 years. Out of 10 bulbar onset MND patients, 5 died in the follow-up period. In the LMN subgroup, younger onset monomelic amyotrophy, of upper limb onset (Hirayama) was commonest subtype. No patients with isolated Upper motor Neuron type of MND was found. SUMMARY: ALS subgroups of patients had younger age of onset in western Indian population, with signicant male rd preponderance. Hirayama disease was commonest LMN type of MND, with onset in 3 decade and more commonly seen in males

Sex-dependent effects of amyloid precursor-like protein 2 in the SOD1-G37R transgenic mouse model of MND

Motor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the End-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2−/− mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP family as a potential target for further investigation into the cause and regulation of MND.

Incidence, Prevalence, and Geographical Clustering of Motor Neuron Disease in the Netherlands.

ObjectiveTo assess time trends in motor neuron disease (MND) incidence, prevalence, and mortality and to investigate geographic clustering of MND cases in the Netherlands from 1998 to 2017, we analyzed data from the Netherlands Personal Records database, the Netherlands MND Center, and the Netherlands Patient Association of Neuromuscular Diseases.MethodsIn this prospective cohort study, Poisson regression was used to assess time trends in MND risk. We calculated age- and sex-standardized, observed, and expected cases for 1,694 areas. Bayesian smoothed risk mapping was used to investigate geographic MND risk.ResultsWe identified 7,992 MND cases, reflecting an incidence of 2.64 (95% confidence interval [CI] 2.62–2.67) per 100,000 person-years and a prevalence of 9.5 (95% CI 9.1–10.0) per 100,000 persons. Highest age-standardized prevalence and mortality rates occurred at a later age in men than in women (p < 0.001). Unadjusted mortality rates increased by 53.2% from 2.57 per 100,000 person-years in 1998 to 3.86 per 100,000 person-years in 2017. After adjustment for age and sex, an increase in MND mortality rate of 14.1% (95% CI 5.7%–23.2%, p < 0.001) remained. MND relative risk ranged from 0.78 to 1.43 between geographic areas; multiple urban and rural high-risk areas were identified.ConclusionsWe found a significant national increase in MND mortality from 1998 through 2017, explained only partly by an aging Dutch population, and a geographic variability in MND risk, suggesting a role for environmental or demographic risk factors.

Tissue microarray (TMA) use in post mortem neuropathology

BackgroundTissue microarrays (TMAs), where each block (and thus section) contains multiple tissue cores from multiple blocks potentially allow more efficient use of tissue, reagents and time in neuropathology. New methodThe relationship between data from TMA cores and whole sections was investigated using ‘virtual’ TMA cores. This involved quantitative assessments of microglial pathology in white matter lesions and motor neuron disease, alongside qualitative TDP-43 inclusion status in motor neuron disease cases. Following this, a protocol was developed for TMA construction. ResultsFor microglial pathology we found good concordance between virtual cores and whole sections for volume density using one 1.75 mm core (equivalent to a 2 mm core after accounting for peripheral tissue loss). More sophisticated microglial cell size and measures required two cores. Qualitative results of pTDP-43 pathology showed use of one 1.75 mm core gave a 100 % sensitivity and specificity within grey matter, and 88.3 % sensitivity and 100 % specificity within white matter. A method of producing the TMAs was suitable for immunohistochemistry both manually and by autostainer, with the minimal core loss from the microscope slide. Comparison with existing methodsTMAs have been used infrequently in post mortem neuropathology research. However, we believe TMAs give comparable tissue assessment results and can be constructed, sectioned and stained with relative ease. ConclusionsWe found TMAs could be used to assess both quantitative (microglial pathology) and qualitative pathology (TDP-43 proteinopathy) with greatly reduced quantities of tissue, time and reagents. These could be used for further work to improve data acquisition efficiency.