Motor Neuron Disease Phenotypes Research Articles

Analysis and occurrence of biallelic pathogenic repeat expansions in RFC1 in a German cohort of patients with a main clinical phenotype of motor neuron disease.

Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia. In the meantime, the phenotypic spectrum has expanded massively and now includes mimics of multiple system atrophy or parkinsonism. After identifying a patient with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) as a carrier of biallelic pathogenic repeat expansions in RFC1, we studied a cohort of 106 additional patients with a clinical main phenotype of motor neuron disease (MND) to analyze whether such repeat expansions are more common in MND patients. Indeed, two additional MND patients (one also with ALS and one with primary lateral sclerosis/PLS) have been identified as carrier of biallelic pathogenic repeat expansions in RFC1 in the absence of another genetic alteration explaining the phenotype, suggesting motor neuron disease as another extreme phenotype of RFC1 spectrum disorder. Therefore, MND might belong to the expanding phenotypic spectrum of pathogenic RFC1 repeat expansions, particularly in those MND patients with additional features such as sensory and/or autonomic neuropathy, vestibular deficits, or cerebellar signs. By systematically analyzing the RFC1 repeat array using Oxford nanopore technology long-read sequencing, our study highlights the high intra- and interallelic heterogeneity of this locus and allows the identification of the novel repeat motif 'ACAAG'.

TUBA4A downregulation as observed in ALS post-mortem motor cortex causes ALS-related abnormalities in zebrafish.

Disease-associated variants of TUBA4A (alpha-tubulin 4A) have recently been identified in familial ALS. Interestingly, a downregulation of TUBA4A protein expression was observed in familial as well as sporadic ALS brain tissue. To investigate whether a decreased TUBA4A expression could be a driving factor in ALS pathogenesis, we assessed whether TUBA4A knockdown in zebrafish could recapitulate an ALS-like phenotype. For this, we injected an antisense oligonucleotide morpholino in zebrafish embryos targeting the zebrafish TUBA4A orthologue. An antibody against synaptic vesicle 2 was used to visualize motor axons in the spinal cord, allowing the analysis of embryonic ventral root projections. Motor behavior was assessed using the touch-evoked escape response. In post-mortem ALS motor cortex, we observed reduced TUBA4A levels. The knockdown of the zebrafish TUBA4A orthologue induced a motor axonopathy and a significantly disturbed motor behavior. Both phenotypes were dose-dependent and could be rescued by the addition of human wild-type TUBA4A mRNA. Thus, TUBA4A downregulation as observed in ALS post-mortem motor cortex could be modeled in zebrafish and induced a motor axonopathy and motor behavior defects reflecting a motor neuron disease phenotype, as previously described in embryonic zebrafish models of ALS. The rescue with human wild-type TUBA4A mRNA suggests functional conservation and strengthens the causal relation between TUBA4A protein levels and phenotype severity. Furthermore, the loss of TUBA4A induces significant changes in post-translational modifications of tubulin, such as acetylation, detyrosination and polyglutamylation. Our data unveil an important role for TUBA4A in ALS pathogenesis, and extend the relevance of TUBA4A to the majority of ALS patients, in addition to cases bearing TUBA4A mutations.

P115: Biallelic variations in ATP13A2 manifesting with a complicated motor neuron disease phenotype

P115: Biallelic variations in ATP13A2 manifesting with a complicated motor neuron disease phenotype

Diagnostic utility of neurofilament markers for MND is limited in restricted disease phenotype and for differentiation from compressive myeloradiculopathies.

Misdiagnosis is frequent in early motor neuron disease (MND), typically compressive radiculopathy, or in patients with restricted MND phenotype. In this retrospective, single tertiary centre study, we measured levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (p-NfH) chain in cerebrospinal fluid (CSF) and of p-NfH in serum with commercially available ELISA kits and assessed their respective diagnostic performance as a marker of MND. The entire study population (n = 164) comprised 71 MND patients, 30 patients with compressive myelo- or radiculopathy, and 63 disease controls (DC). Among MND patients, we specified subgroups with only lower motoneuron involvement (MND-LMN, n = 15) and with confounding nerve roots or spinal cord compression (MND-C, n = 18), representing clinical diagnostic pitfalls. MND-LMN displayed significantly lower CSF NfL (p = 0.003) and p-NFH (p = 0.017), but not serum p-NfH (p = 0.347) levels compared to other MND patients (n = 56). The discriminative ability (area under the curve-AUC) of both CSF Nfs towards all MND patients was comparable to each other but significantly higher than that of p-NfH in serum (ps < 0.001). AUC of both CSF Nfs between MND-LMN and DC and also between MND-C and myelo-/radiculopathies were reduced, as compared to AUC between other MND and DC or myelo-/radiculopathies, respectively. Our results suggest that both Nfs in CSF represent a reliable diagnostic marker in a general MND population, fulfilling Awaji criteria. As for diagnostic pitfalls, and also for p-NfH in serum, their discriminative ability and, therefore, clinical utility appears to be limited.

Parkinsonian Syndromes in Motor Neuron Disease: A Clinical Study.

BackgroundParkinsonian syndromes may rarely occur in motor neuron disease (MND). However, previous studies are heterogeneous and mostly case reports or small case series. Therefore, we aimed to identify and characterize patients with concurrent parkinsonian syndromes extracted from a cohort of 1,042 consecutive cases diagnosed with MND at a tertiary Italian Center.MethodsDiagnosis of Parkinson's disease (PD), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) was made according to current criteria. Clinical characterization included: upper and lower motor neuron disease features, typical and atypical parkinsonian features, oculomotor disorders, cognitive testing, MRI features, and, when available molecular neuroimaging. Genetic testing was carried out for major MND and PD-associated genes.ResultsParkinsonian syndromes were diagnosed in 18/1042 (1.7%) of MND patients (7 PD, 6 PSP, 3 CBS, 2 other parkinsonisms). Based on phenotype, patients could be categorized into amyotrophic lateral sclerosis (ALS)-parkinsonism and primary lateral sclerosis (PLS)-parkinsonism clusters. Across the whole database, parkinsonism was significantly more common in PLS than in other MND phenotypes (12.1 vs. 1.1%, p = 5.0 × 10−10). MND patients with parkinsonian features had older age of onset, higher frequency of oculomotor disorders, cognitive impairment, and family history of parkinsonism or dementia. Two patients showed pathogenic mutations in TARDBP and C9orf72 genes.ConclusionSpecific patterns in MND-parkinsonism were observed, with PLS patients often showing atypical parkinsonian syndromes and ALS patients more frequently showing typical PD. Systematic clinical, genetic, and neuropathologic characterization may provide a better understanding of these phenotypes.

Shaky hands are a part of motor neuron disease phenotype: clinical and electrophysiological study of 77 patients.

In the sharp contrast with the existing literature, we frequently observe minipolymyoclonus, tremor and pseudodystonic thumb posturing in patients with motor neuron disease. We conducted a clinical and electrophysiological study to describe phenomenology, prevalence and pathophysiology of involuntary movements in motor neuron disease. We included 77 consecutive patients. Involuntary movements were assessed at rest and on action. Patients were videotaped. Arm muscle tone, power and deep tendon reflexes were evaluated. Accelerometry with electromyography was recorded in a subset of patients. Involuntary movements were observed in 68.9% of patients and could be separated into rest minipolymyoclonus, thumb tremor, pseudodystonic thumb posture, action minipolymyoclonus, and action tremor. One-third of patients reported negative impact of involuntary movements on hand use. Logistic regression showed that rest minipolymyoclonus and thumb tremor were more likely to occur in patients with more prominent distal muscle weakness and less spasticity. Similarly, action involuntary movements were more likely to appear in weaker patients. Patients with brisk tendon reflexes were more likely to display action tremor than action minipolymyoclonus. Action tremor was characterized by accelerometer and corresponding electromyography peak frequency, which decreased with mass loading, suggesting a mechanical-reflex tremor. Involuntary movements are common, but poorly recognized feature of motor neuron disease that may add to functional impairment. Results of our study suggest that involuntary movements are likely of peripheral origin, with a non-fused contraction of enlarged motor units being a common driving mechanism. Minipolymyoclonus appears if no synchronization of motor units occurs. When synchronization occurs via stretch reflex, mechanical-reflex tremor is generated.

A multiparametric activity profiling platform for neuron disease phenotyping and drug screening.

Patient stem cell–derived models enable imaging of complex disease phenotypes and the development of scalable drug discovery platforms. Current preclinical methods for assessing cellular activity do not, however, capture the full intricacies of disease-induced disturbances and instead typically focus on a single parameter, which impairs both the understanding of disease and the discovery of effective therapeutics. Here, we describe a cloud-based image processing and analysis platform that captures the intricate activity profile revealed by GCaMP fluorescence recordings of intracellular calcium changes and enables the discovery of molecules that correct 153 parameters that define the amyotrophic lateral sclerosis motor neuron disease phenotype. In a high-throughput screen, we identified compounds that revert the multiparametric disease profile to that found in healthy cells, a novel and robust measure of therapeutic potential quite distinct from unidimensional screening. This platform can guide the development of therapeutics that counteract the multifaceted pathological features of diseased cellular activity.

Frontotemporal Pathology in Motor Neuron Disease Phenotypes: Insights From Neuroimaging.

Frontotemporal involvement has been extensively investigated in amyotrophic lateral sclerosis (ALS) but remains relatively poorly characterized in other motor neuron disease (MND) phenotypes such as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA), post poliomyelitis syndrome (PPS), and hereditary spastic paraplegia (HSP). This review focuses on insights from structural, metabolic, and functional neuroimaging studies that have advanced our understanding of extra-motor disease burden in these phenotypes. The imaging literature is limited in the majority of these conditions and frontotemporal involvement has been primarily evaluated by neuropsychology and post mortem studies. Existing imaging studies reveal that frontotemporal degeneration can be readily detected in ALS and PLS, varying degree of frontotemporal pathology may be captured in PMA, SBMA, and HSP, SMA exhibits cerebral involvement without regional predilection, and there is limited evidence for cerebral changes in PPS. Our review confirms the heterogeneity extra-motor pathology across the spectrum of MNDs and highlights the role of neuroimaging in characterizing anatomical patterns of disease burden in vivo. Despite the contribution of neuroimaging to MND research, sample size limitations, inclusion bias, attrition rates in longitudinal studies, and methodological constraints need to be carefully considered. Frontotemporal involvement is a quintessential clinical facet of MND which has important implications for screening practices, individualized management strategies, participation in clinical trials, caregiver burden, and resource allocation. The academic relevance of imaging frontotemporal pathology in MND spans from the identification of genetic variants, through the ascertainment of presymptomatic changes to the design of future epidemiology studies.

Kennedy's disease: an under-recognized motor neuron disorder.

Kennedy's disease or spinal bulbar muscular atrophy is a rare, inherited and slowly progressive multisystem disease mostly manifesting with a motor neuron disease phenotype leading to disability. The slow progression, partial androgen insensitivity, electrophysiological evidence of sensory neuronopathy, and relatively spared central nervous system pathways help differentiate it from amyotrophic lateral sclerosis. To date, there is no treatment or cure with clinical care mainly focused on accurate diagnosis, symptom management, patient education, and genetic counselling.

Serum phosphorylated neurofilament heavy-chain levels reflect phenotypic heterogeneity and are an independent predictor of survival in motor neuron disease.

To investigate the prognostic role and the major determinants of serum phosphorylated neurofilament heavy -chain (pNfH) concentration across a large cohort of motor neuron disease (MND) phenotypes. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum pNfH concentration in 219 MND patients consecutively enrolled in our tertiary MND clinic. A multifactorial analysis was carried out to investigate the major clinical determinants of serum pNfH. Kaplan–Meier survival curves and Cox regression analysis were performed to explore the prognostic value of serum pNfH. Serum pNfH levels were not homogenous among MND phenotypes; higher concentrations in pyramidal, bulbar, and classic phenotypes were observed. C9orf72-MND exhibited higher pNfH concentrations compared to non-C9orf72 MND. Multiple linear regression analysis revealed mean MEP/cMAP and disease progression rate as the two major predictors of serum pNfH levels (R2 = 0.188; p ≤ 0.001). Kaplan–Meier curves showed a significant difference of survival among MND subgroups when divided into quartiles based on pNfH concentrations, log-rank X2 = 53.0, p ≤ 0.0001. Our study evidenced that higher serum pNfH concentration is a negative independent prognostic factor for survival. In Cox multivariate model, pNfH concentration showed the highest hazard ratio compared to the other factors influencing survival included in the analysis. pNfH differs among the MND phenotypes and is an independent prognostic factor for survival. This study provides supporting evidence of the role of pNfH as useful prognostic biomarker for MND patients. Neurofilament measurements should be considered in the future prognostic models and in clinical trials for biomarker-based stratification, and to evaluate treatment response.Electronic supplementary materialThe online version of this article (10.1007/s00415-020-09838-9) contains supplementary material, which is available to authorized users.

092 Motor neuron disease with malignancy: clinical and pathophysiological insights

IntroductionWhile some regard an association between motor neuron disease (MND) and malignancy as co-incidental, others have argued that it could represent a distinct clinical entity. The present study undertook in depth phenotyping along with assessment of cortical function to further explore disease pathophysiology in MND with malignancy (MND-M) patients.MethodsClinical features along with assessment of peripheral and cortical function was undertaken in 13 MND-M and results were compared to sporadic and familial MND cohorts.ResultsFrom a cohort 13 patients (10 males; aged 65.2±2.0 years), 30.8% were diagnosed with a haematological malignancy. The lower motor neuron phenotype predominated in the in the MND-M patients (χ2=10.8, P&lt;0.01), with the upper motor neuron (UMN) score being significantly reduced in MND-M patients compared to sporadic and familial MND cohorts (χ2=6.84, P&lt;0.01). The neurological deficits did not respond to treatment of the underlying malignancy in the majority of MND-M (92%) patients, and as such there were no significant differences in survival between the cohorts. Despite a paucity of UMN signs, cortical hyperexcitability was evident in MND-M patients, as indicated by reduction in short interval intracortical inhibition (P&lt;0.01) and increase in motor evoked potential amplitude (P&lt;0.01), that were similar to findings in sporadic and familial MND cohorts.ConclusionsThe present study suggests that MND-M falls within the spectrum of MND. A co-incidental association between MND and malignancy is underscored by cortical dysfunction and clinical findings which seems within the spectrum of abnormality evident in classical MND phenotypes.

Motor neuron disease with malignancy: Clinical and pathophysiological insights

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

Intrafamilial Variable Phenotype of Complicated Hereditary Spastic Paraplegia, Ataxia and Motor Neuron Disease Linked to a Novel KIF5A C-Terminal Domain Mutation

Objectives: To genetically investigate a hereditary neurodegenerative disease in a kindred with an intra-familial variable phenotype of complicated hereditary spastic paraplegia with and without cerebellar ataxia and motor neuron disease. Methods: With a detailed clinical evaluation, five members of a family with autosomal dominant inherited neurological illness were subjected for whole exome sequencing. The identified disease causing variation was validated functionally by demonstration of exon skipping on cDNA based amplification of KIF5A. Results: We have identified a kindred with multiple affected individuals who manifested complicated hereditary spastic paraplegia (proband), a maternal uncle manifested Amyotrophic lateral sclerosis/Ataxia phenotype and another symptomatic individuals with cerebellar ataxia phenotype. Genetic investigations by whole exome sequencing revealed a novel heterozygous c.3020+3 A>T variant in KIF5A gene segregating with only affected individuals. The variant resides near 3’splice site junction of exon 27 of KIF5A gene. KIF5A transcript was demonstrated to be have skipped exon 27 in RNA extracted from peripheral whole blood. Conclusions: It has also been documented that C-terminal variants of KIF5A are exclusively associated with the ALS phenotype. We reported a family carrying a C-term mutation with a very complex phenotype affecting spinal cord and cerebellar axis, which is contrary to the reported observation with other C-terminal KIF5A mutant allele. This findings allows an understanding of the role of this important family of gene to have a converging molecular alterations leading to Neurodegenration.

Variation in assistive technology use in Motor Neuron Disease according to clinical phenotypes and ALS Functional Rating Scale - Revised Score: A prospective observational study.

Assistive devices enhance independence and quality of life for people living with motor neuron disease (MND), but prescription can be challenging. Improved prescription of assistive devices, through improved understanding of the relationship between clinical phenotypes, Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) functional domain sub-scores and assistive technology required by people living with MND. Prospective, observational consecutive-sample study of 269 patients with MND diagnosis. MND phenotype, ALSFRS-R scores and assistive technology devices in use. A statistically significant difference in total concurrent assistive technology item use was found between phenotypes (p = 0.001), with those with ALS Bulbar onset using the least. There was also a statistically significant difference in assistive technology usage in five of seven assistive technology categories across the clinical phenotypes, namely orthoses (p < 0.000), mobility devices (p < 0.000), transfer devices (p < 0.000), communication devices (p < 0.000), and activities of daily living devices (p = 0.016). Correlations between ALSFRS-R sub-score items and assistive technology count confirmed the utility of this outcome measure for equipment prescription. Clinicians need to consider MND phenotype and/or ALSFRS-R domain sub-score in clinical decision-making regarding assistive technology, as this will determine the pattern of disease and its progression, and hence assistive technology required.

Brain MRI shows white matter sparing in Kennedy's disease and slow-progressing lower motor neuron disease.

The extent of central nervous system involvement in Kennedy's disease (KD) relative to other motor neuron disease (MND) phenotypes still needs to be clarified. In this study, we investigated cortical and white matter (WM) MRI alterations in 25 patients with KD, compared with 24 healthy subjects, 25 patients with sporadic amyotrophic lateral sclerosis (ALS), and 35 cases with lower motor neuron-predominant disease (LMND). LMND patients were clinically differentiated into 24 fast and 11 slow progressors. Whole-brain cortical thickness, WM tract-based spatial statistics and corticospinal tract (CST) tractography analyses were performed. No significant difference in terms of cortical thickness was found between groups. ALS patients showed widespread decreased fractional anisotropy and increased mean (MD) and radial diffusivity (radD) in the CST, corpus callosum and fronto-temporal extra-motor tracts, compared with healthy controls and other patient groups. CST tractography showed significant alterations of DT MRI metrics in ALS and LMND-fast patients whereas KD and LMND-slow patients were comparable with healthy controls. Our study demonstrated the absence of WM abnormalities in patients with KD and LMND-slow, in contrast with diffuse WM damage in ALS and focal CST degeneration in LMND-fast, supporting the use of DT MRI measures as powerful tools to differentiate fast- and slow-progressing MND syndromes, including KD.

Dysregulation of microRNA metabolism in motor neuron diseases: Novel biomarkers and potential therapeutics.

In the last 15 years, several classes of small regulatory RNAs have been identified, uncovering the widespread impact of non-coding elements in the human genome on cell homeostasis and human diseases. MicroRNAs (miRNAs) are a family of small, non-coding RNAs, which exert silencing of mRNA targets in a sequence-dependent fashion. Many miRNAs are specifically expressed in the central nervous system, where they display roles in differentiation, neuronal survival, neuronal plasticity and learning. On the other hand, deregulated miRNA/mRNA expression networks are deeply involved in neurodegeneration.Recent findings suggest a role for miRNAs in the pathogenesis of motor neuron diseases. In particular, cell-specific changes in miRNA profile are involved in the motor neuron disease phenotype and might be implicated in their selective vulnerability. Exploitation of noncoding RNAs, in particular miRNAs, for therapeutic strategies is being assessed for implementing current therapies. In this regard, the neuroprotective potential of certain miRNAs could represent a promising potential tool to improve therapies for motor-neuron diseases. This review focuses on emerging roles of miRNAs in motor neuron diseases and on their impact on neuron life-span and integrity.

The width of the third ventricle associates with cognition and behaviour in motor neuron disease.

An enlarged width of the third ventricle (WTV) has been described in amyotrophic lateral sclerosis (ALS) patients, although its clinical meaning is unknown. The aims of this study were to evaluate the contribution of demographical, clinical and genetic factors to the WTV in different motor neuron disease (MND) phenotypes and to assess its brain structural correlates. The WTV was measured by transcranial ultrasound in 107 MND patients (82 diagnosed with classical ALS, 16 with progressive muscular atrophy and 9 with primary lateral sclerosis) and 25 controls. Genetic analysis, and neurological and neuropsychological examinations were performed in patients. Brain volumetric analysis of MR images was obtained in 85 patients. The association of WTV with demographical, clinical, genetic and neuropsychological variables as well as with brain volumes was assessed by multivariable models. Eighteen patients were diagnosed with genetic MND and 42.3% of patients showed executive or behavioural impairment (EBI). MND patients showed larger WTV than controls. The WTV was significantly associated with age, spinal onset and the presence of EBI, but not with the genetic background, the phenotype or disability. Greater WTV was also associated with reduced subcortical grey matter volume, but not with the cortical or the white matter volume. The enlargement of the WTV found in the different MND phenotypes is attributable to the subcortical grey matter atrophy and is associated with cognitive and behavioural impairment. Larger longitudinal studies are needed to determine its role as biomarker in MND patients with frontotemporal dementia.

10. Phenotypic variability in motor neuron disease: Site of onset and patterns of disease spread

Background The clinical heterogeneity across motor neuron disease (MND) is well known, and largely attributed to differences in the relative mix of upper (UMN) and lower motor neuron (LMN) dysfunction, site of onset, and rate of disease progression. These differences hold prognostic significance and clues to patterns of disease spread. Objective understanding of motor dysfunction across these clinical phenotypes is thus pivotal for unravelling disease pathogenesis and mechanisms underpinning disease spread. Aims To investigate the sites of origin and patterns of disease spread across MND phenotypes using multimodal clinical and neurophysiological tools in all 4 limbs. Methods Patients were prospectively recruited from the Forefront Neurology Clinic (Brain and Mind Centre, Sydney) and diagnosed according to Awaji Criteria. Detailed clinical assessments were performed including classification by phenotype and site of onset. Neurophysiological studies were conducted in all 4-limbs. LMN dysfunction was investigated by recording CMAP and MUNIX responses, while UMN dysfunction was assessed using threshold tracking transcranial magnetic stimulation (TT-TMS). Results Lower limb TT-TMS techniques were first established in healthy subjects (n = 40). The clinical cohort consisted of 52 MND patients (31 males, 21 females, mean age 59.3 ± 6.8 yrs). Upper limb analysis showed evidence of cortical hyperexcitability with a significant reduction of averaged short interval intracortical inhibition (SICI) over both motor hemispheres, most prominently over the motor cortex contralateral to the affected upper-limb (controls 11.27 ± 1.12%; MND 3.6 ± 1.5%, p 0.01 ). Bulbar-onset patients had the greatest cortical hyperexcitability (SICI 2.6 ± 1.4%, p 0.01 ). For all phenotypes, there was a positive correlation between UMN and LMN dysfunction in the affected limbs and in faster disease progressors. This relationship was not observed in non-affected limbs (R2 = 0.03, p = 0.3) or slower progressors (R2 = 0.004, p = 0.7). Conclusion Cortical hyperexcitability was evident globally but there was heterogeneity amongst phenotypes, with bulbar-onset patients showing the greatest degree of hyperexcitability. In addition, a difference in the interplay of the two motor compartments was seen, lending pathophysiological insight into the prognostic differences between patients. Through deep phenotyping and novel testing across all compartments of the nervous system, differences in the prognosis and patterns of neuronal vulnerability in MND subtypes are thus evident. This multimodal analysis lends potential to develop robust biomarkers and offer new pathophysiological insights.

Adaptive equipment use by people with motor neuron disease in Australia: a prospective, observational consecutive cohort study

Purpose: People with motor neuron sisease require adaptive equipment to enhance life quality. This study aimed to examine total and concurrent equipment items prescribed with phenotype consideration.Methods: A prospective, observational consecutive cohort study was undertaken. Data regarding Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, phenotype, symptom onset and Functional Independence Measure (inpatients only) was recorded. Equipment utilized was coded by therapist as: speech devices; transfer devices; mobility devices (including power wheelchairs); orthoses; activities of daily living equipment; assisted technology and home modification equipment.Results: Two hundred and seventy-three people with motor neuron disease participated, mean age 67 years, mean amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score 32, a moderate level of disability. Equipment items per participant ranged from 0 to 20, median 5. The electric lift recliner chair was the most commonly used equipment item, used by 51.2% of the cohort. There was a statistically significant difference in equipment use between flail leg and bulbar (Md 11, 3 items, respectively; p = .005), and flail leg and cervical phenotypes (Md 11, 3.5 items respectively; p = .009).Conclusions: People with motor neuron disease have high equipment needs to optimize quality of life. Information regarding phenotype relative to equipment requirement, and most frequently prescribed equipment items can assist health-care providers anticipate equipment needs, burden and intensity for those with motor neuron disease.Implications for rehabilitationPeople with motor neuron disease have high concurrent equipment needs.Electric recliner lift chairs are the most frequently prescribed equipment item by those with motor neuron disease.There is variation in concurrent equipment needs relative to motor neuron disease phenotype.

Patterns of symptom development in patients with motor neuron disease

Objective: To investigate whether symptom development in motor neuron disease (MND) is a random or organized process. Methods: Six hundred patients with amyotrophic lateral sclerosis (ALS), upper motor neuron (UMN) or lower motor neuron (LMN) phenotypes were invited for a questionnaire concerning symptom development. A binomial test was used to examine distribution of symptoms from site of onset. Development of symptoms over time was evaluated by Kaplan-Meier analysis. Results: There were 470 respondents (ALS = 254; LMN = 100; UMN = 116). Subsequent symptoms were more often in the contralateral limb following unilateral limb onset (ALS: arms p = 1.05 × 10−8, legs p < 2.86 × 10−15; LMN phenotype: arms p = 6.74 × 10−9, legs p = 6.26 × 10−6; UMN phenotype: legs p = 4.07 × 10−14). In patients with limb onset, symptoms occurred significantly faster in the contralateral limb, followed by the other limbs and lastly by the bulbar region. Patterns of non-contiguous symptom development were also reported: leg symptoms followed bulbar onset in 30%, and bulbar symptoms followed leg onset in 11% of ALS patients. Conclusions: Preferred spread of symptoms from one limb to the contralateral limb, and to adjacent sites appears to be a characteristic of MND phenotypes, suggesting that symptom spread is organized, possibly involving axonal connectivity. Non-contiguous symptom development, however, is not uncommon, and may involve other factors.