Early Amyotrophic Lateral Sclerosis Research Articles

Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. Orphazyme.

Multifocal motor neuropathy as a mimic of amyotrophic lateral sclerosis: Serum neurofilament light chain as a reliable diagnostic biomarker.

The clinical presentation of multifocal motor neuropathy (MMN) may mimic early amyotrophic lateral sclerosis (ALS) with predominant lower motor neuron (LMN) involvement, posing a diagnostic challenge. Both diseases have specific treatments and prognoses, highlighting the importance of early diagnosis. The aim of this study was to assess the diagnostic value of serum neurofilament light chain (NfL) in differentiating MMN from LMN dominant ALS. NfL was measured in serum in n = 37 patients with MMN and n = 37 age- and sex-matched patients with LMN dominant ALS, to determine the diagnostic accuracy. Clinical and demographic data were obtained at the time of NfL sampling. Serum NfL concentration was significantly lower in MMN patients compared to ALS patients (mean 20.7 pg/mL vs. 59.4 pg/mL, p < .01). NfL demonstrated good diagnostic value in discriminating the two groups (AUC 0.985 [95% CI 0.963-1.000], sensitivity 94.6%, specificity 100%, cut-off 44.00 pg/mL). NfL could be a helpful tool in differentiating MMN from LMN dominant ALS in those patients in whom electrophysiological and clinical examinations remain inconclusive early in the diagnostic process.

Amyotrophic lateral sclerosis mimicking radiculopathy: a case series.

ABSTRACTThe clinical findings of early stage amyotrophic lateral sclerosis (ALS) are similar to those of cervical or lumbar radiculopathy. In the current study, we describe 3 cases of ALS that were misdiagnosed as cervical or lumbar radiculopathy. Three patients (a 48-, a 52-, and an 80-year-old) visited our clinic due to motor weakness on either the upper or lower extremities. At other clinics or hospitals, they were diagnosed with radiculopathy due to herniated lumbar disc or cervical foraminal stenosis. The motor weakness in these patients was ipsilateral or bilateral but dominant on one side. Sensory deficits or bulbar symptoms were not observed. Of the 3 patients, 2 had neuropathic pain, but it was not dermatome related. We conducted an electrodiagnostic test and observed a low amplitude of compound motor action potential on the affected nerve and positive sharp waves on muscles of involved segments, including thoracic paraspinalis. All the patients were diagnosed with probable laboratory-supported ALS or possible ALS based on the established diagnostic criteria (El Escorial Criteria). In the present study, we showed three cases of ALS that were misdiagnosed as radiculopathy. Our study would be helpful for early and accurate diagnosis of patients with ALS.

Prognostic prediction by hypermetabolism varies depending on the nutritional status in early amyotrophic lateral sclerosis

To examine whether hypermetabolism could predict the prognosis of early amyotrophic lateral sclerosis (ALS) patients with differing nutritional profiles. This single-center, retrospective study examined the prognosis of ALS patients with hypermetabolism in relation to their nutritional status at hospitalization. The metabolic state was estimated by the ratio of measured resting energy expenditure (mREE) to lean soft tissue mass (LSTM) (mREE/LSTM), wherein patients with ratios ≥ 38 were defined as hypermetabolic. Malnutrition was defined as %ideal body weight < 0.9. Forty-eight patients were enrolled in this study. The hypermetabolic group had shorter survival in the normal-weight group but more prolonged survival in the malnutrition group. Multiplication of nutritional and metabolic factors, such as [(body mass index (BMI) − 19.8) × (mREE/LSTM − 38)], designated as BMI-muscle metabolism index (BMM index), successfully predicted the prognosis in the group with a high BMM index (≥ 1), which showed shorter survival and a faster rate of weight loss and functional decline. Multivariate analysis using the Cox model showed high BMM index was an independent poor prognostic factor (hazard ratio: 4.05; p = 0.025). Prognostic prediction by hypermetabolism varies depending on the nutritional status in ALS, and the BMM index is a consistent prognostic factor.

Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging of Phospholipid Changes in a Drosophila Model of Early Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a degenerative disease caused by motor neuron damage in the central nervous system, and it is difficult to diagnose early. Drosophila melanogaster is widely used to investigate disease mechanisms and discover biomarkers because it is easy to induce disease in Drosophila through genetic engineering. We performed matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) to investigate changes in phospholipid distribution in the brain tissue of an ALS-induced Drosophila model. Fly brain tissues of several hundred micrometers or less were sampled using a fly collar to obtain reproducible tissue sections of similar sizes. MSI of brain tissues of Drosophila cultured for 1 or 10 days showed that the distribution of phospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA), phosphatidylserine (PS), and phosphatidylinositol (PI), was significantly different between the control group and the ALS group. In addition, the lipid profile according to phospholipids differed as the culture time increased from 1 to 10 days. These results suggest that disease indicators based on lipid metabolites can be discovered by performing MALDI-MSI on very small brain tissue samples from the Drosophila disease model to ultimately assess the phospholipid changes that occur in early-stage ALS.

Ultra-early amplitude decrement after repetitive nerve stimulation supports early neuromuscular junction injury in amyotrophic lateral sclerosis: a prospective cross-sectional study.

The dying-back hypothesis holds that the damage to neuromuscular junctions and distal axons in amyotrophic lateral sclerosis occurs at the earliest stage of the disease. Previous basic studies have confirmed early damage to neuromuscular junctions, but it is difficult to obtain such evidence directly in clinical practice. In this prospective cross-sectional study, we recruited 22 patients with early amyotrophic lateral sclerosis with disease duration < 12 months and with clinical symptoms limited to the upper limbs. We also recruited 32 healthy controls. Repetitive nerve stimulation was performed, and patients were followed for 12 months. We found a significant change in the response to repetitive nerve stimulation in amyotrophic lateral sclerosis patients without spontaneous electromyographic activity. Patients that were prone to denervation had an increased decrement response of target muscles after repetitive nerve stimulation. These results suggest that changes in response to repetitive nerve stimulation may occur before denervation in amyotrophic lateral sclerosis patients. The damage to lower motor neurons is more obvious in patients with a higher percentage of repetitive never stimulation-related amplitude decrements. This study was approved by the Institutional Ethics Committee of Peking University Third Hospital (approval No. M2017198) on August 24, 2017.

Insomnia is frequent in amyotrophic lateral sclerosis at the time of diagnosis

Sleep-disordered breathing and sleep-related symptoms are frequent in patients with severe amyotrophic lateral sclerosis (ALS). We aimed to describe sleep quality, sleep structure, and the occurrence of sleep-disordered breathing in patients with early ALS, at the time of initial evaluation in a tertiary care center. Sleep-related symptoms were collected using questionnaires, the Pittsburgh Sleep quality Index (PSQI), and the Epworth Sleepiness Scale. Sleep was studied by inpatient overnight polysomnography. Fourteen men and 13 women (age 66 ± 12 years, ALSFRS-R 39 ± 6) were included, among which 12 patients had disease with bulbar onset. Eighteen (69%) patients complained of insomnia, fifteen of which (55%) reported poor sleep quality (PSQI > 5). No patient had an Epworth Sleepiness Scale > 10. Respiratory and polysomnography characteristics were similar between patients with poor or good sleep quality. Sleep efficiency and REM sleep duration were normal relative to normative values, while wake after sleep onset was increased. Fifteen patients had obstructive sleep apnea syndrome (8 mild, 3 moderate, and 4 severe). No patient had central apnea syndrome. Insomnia was highly prevalent in patients with early ALS, independent of respiratory impairment. Poor sleep quality was strongly associated with insomnia.

Patterns of Language Impairment in Early Amyotrophic Lateral Sclerosis.

To investigate the incidence and nature of language change and its relationship to executive dysfunction in a population-based incident amyotrophic lateral sclerosis (ALS) sample, with the hypothesis that patterns of frontotemporal involvement in early ALS extend beyond areas of executive control to regions associated with language processing. One hundred seventeen population-based incident ALS cases without dementia and 100 controls matched by age, sex, and education were included in the study. A detailed assessment of language processing including lexical processing, word spelling, word reading, word naming, semantic processing, and syntactic/grammatical processing was undertaken. Executive domains of phonemic verbal fluency, working memory, problem-solving, cognitive flexibility, and social cognition were also evaluated. Language processing was impaired in this incident cohort of individuals with ALS, with deficits in the domains of word naming, orthographic processing, and syntactic/grammatical processing. Conversely, phonological lexical processing and semantic processing were spared. Although executive dysfunction accounted in part for impairments in grammatical and orthographic lexical processing, word spelling, reading, and naming, primary language deficits were also present. Language impairment is characteristic of ALS at early stages of the disease and can develop independently of executive dysfunction, reflecting selective patterns of frontotemporal involvement at disease onset. Language change is therefore an important component of the frontotemporal syndrome associated with ALS.

Short echo-time Magnetic Resonance Spectroscopy in ALS, simultaneous quantification of glutamate and GABA at 3\u2009T

Cortical hyperexcitability has been found in early Amyotrophic Lateral Sclerosis (ALS) and is hypothesized to be a key factor in pathogenesis. The current pilot study aimed to investigate cortical inhibitory/excitatory balance in ALS using short-echo Magnetic Resonance Spectroscopy (MRS). Patients suffering from ALS were scanned on a 3 T Trio Siemens MR scanner using Spin Echo Full Intensity Acquired Localized (SPECIAL) Magnetic Resonance Spectroscopy in primary motor cortex and the occipital lobe. Data was compared to a group of healthy subjects. Nine patients completed the scan. MRS data was of an excellent quality allowing for quantification of a range of metabolites of interest in ALS. In motor cortex, patients had Glutamate/GABA and GABA/Cr- ratios comparable to healthy subjects. However, Glutamate/Cr (p = 0.002) and the neuronal marker N-acetyl-aspartate (NAA/Cr) (p = 0.034) were low, possibly due to grey-matter atrophy, whereas Glutathione/Cr (p = 0.04) was elevated. In patients, NAA levels correlated significantly with both hand strength (p = 0.027) and disease severity (p = 0.016). In summary SPECIAL MRS at 3 T allows of reliable quantification of a range of metabolites of interest in ALS, including both excitatory and inhibitory neurotransmitters. The method is a promising new technique as a biomarker for future studies on ALS pathophysiology and monitoring of disease progression.

Optimizing the Translational Value of Mouse Models of ALS for Dysphagia Therapeutic Discovery

The goal of this study was to compare dysphagia phenotypes in low and high copy number (LCN and HCN) transgenic superoxide dismutase 1 (SOD1) mouse models of ALS to accelerate the discovery of novel and effective treatments for dysphagia and early amyotrophic lateral sclerosis (ALS) diagnosis. Clinicopathological features of dysphagia were characterized in individual transgenic mice and age-matched controls utilizing videofluoroscopy in conjunction with postmortem assays of the tongue and hypoglossal nucleus. Quantitative PCR accurately differentiated HCN-SOD1 and LCN-SOD1 mice and nontransgenic controls. All HCN-SOD1 mice developed stereotypical paralysis in both hindlimbs. In contrast, LCN-SOD1 mice displayed wide variability in fore- and hindlimb involvement. Lick rate, swallow rate, inter-swallow interval, and pharyngeal transit time were significantly altered in both HCN-SOD1 and LCN-SOD1 mice compared to controls. Tongue weight, tongue dorsum surface area, total tongue length, and caudal tongue length were significantly reduced only in the LCN-SOD1 mice compared to age-matched controls. LCN-SOD1 mice with lower body weights had smaller/lighter weight tongues, and those with forelimb paralysis and slower lick rates died at a younger age. LCN-SOD1 mice had a 32% loss of hypoglossal neurons, which differed significantly when compared to age-matched control mice. These novel findings for LCN-SOD1 mice are congruent with reported dysphagia and associated tongue atrophy and hypoglossal nucleus pathology in human ALS patients, thus highlighting the translational potential of this mouse model in ALS research.

Diffusion tensor imaging in early amyotrophic lateral sclerosis using 3T magnetic resonance imaging

Diffusion tensor imaging in early amyotrophic lateral sclerosis using 3T magnetic resonance imaging

Temporal Expression of Mutant TDP-43 Correlates with Early Amyotrophic Lateral Sclerosis Phenotype and Motor Weakness.

Background: Mutant transactive response DNA-binding protein (TDP-43) is closely correlated to the inherited form of amyotrophic lateral sclerosis (ALS). TDP-43 transgenic rats can reproduce the core phenotype of ALS and constitutive expression of TDP-43 caused postnatal death.Objective: The study aimed to understand whether neurologic deficiency caused by mutant TDP-43 is dependent on its temporal expression.Method: Transgenic rats were established that express mutant human TDP-43 (M337V substitution) in neurons, then a Tet-off system was used to regulate its expression.Results: TDP-43 mutant transgenic rats developed significant weakness after the transgene was activated. Rats with expression of mutant TDP-43 at 30 days showed a more aggressive phenotype. More severe pathological changes in neurogenic atrophy were observed in these rats.Conclusion: Temporal expression of mutant TDP-43 in neurons promoted serious phenotype in rats. The dysfunction of TDP-43 had a profound impact on the development of motor neurons and skeletal muscles.

Diffusion tensor imaging in early amyotrophic lateral sclerosis at 3t MRI

Diffusion tensor imaging in early amyotrophic lateral sclerosis at 3t MRI

Correlation of frontal atrophy with behavioral changes in amyotrophic lateral sclerosis

AbstractBackgroundRecent studies have linked cognitive impairment in amyotrophic lateral sclerosis to frontotemporal pathology.AimWe examined possible associations between behavior changes and regional gray matter volume in early amyotrophic lateral sclerosis, and assessed whether the volume changes were independent of physical impairments.MethodsA total of 17 amyotrophic lateral sclerosis patients with Mini‐Mental State Examination score ≥ 24, no need for assistance in daily life and normal respiratory tests (respiratory function test and arterial blood gas analytes), and 11 age‐matched controls underwent structural magnetic resonance imaging. Behavioral changes were assessed with family‐rating Frontal Systems Behavior Scale. We applied voxel‐based morphometry to investigate the correlation between the Frontal Systems Behavior Scale and gray matter volume, and assessed the correlation of volume with amyotrophic lateral sclerosis Functional Rating Scale and respiratory tests.ResultsCurrent Frontal Systems Behavior Scale scores were significantly higher than retrospective scores assessing the status before onset, most notably in apathy. The volumes of right middle and left medial frontal gyri in amyotrophic lateral sclerosis were negatively correlated with the Frontal Systems Behavior Scale, whereas they were not correlated with amyotrophic lateral sclerosis Functional Rating Scale and respiratory tests. The volume of the right frontal cluster, but not the left medial frontal cluster, was significantly smaller than that of controls.ConclusionsRegional atrophy within the frontal lobe was associated with behavioral dysfunction in early amyotrophic lateral sclerosis, this association was independent of physical factors.

Advanced magnetic resonance neuroimaging in bulbar and limb onset early amyotrophic lateral sclerosis

Introduction:Amyotrophic lateral sclerosis (ALS) is a fatal and most common motor neuron disease, caused by progressive loss of motor neurons. Diffusion tensor imaging (DTI) and magnetic resonance spectroscopic (MRS) studies detect pathological changes in neuronal fibers in vivo. We evaluated the role of DTI and MRS in early course of the disease, which may prove beneficial in the early diagnosis and better management.Materials and Methods:Twenty-one patients with ALS and 13 age-matched controls received 1.5T DTI and three-dimensional multi-voxel MRS. Fractional anisotropy (FA), apparent diffusion coefficient, N-acetyl aspartate (NAA)/Creatine (Cr), and NAA/Choline (Ch) ratios were analyzed in various regions of the brain and compared with healthy controls. ALS patients were classified as definite, possible, and probable category, and patients were also studied in limb versus bulbar onset.Results:Decreased FA and increase mean diffusivity values in regions of corticospinal tract (CST) and corpus callosum (CC) was consistent finding in definite and probable disease category (P < 0.05). In possible disease, CC involvement was not significant. NAA/Cr and NAA/Ch ratios were lower in CC and regions of CST. However, in possible disease, CC involvement was not significant, while regions of CST were showing significant reduction in NAA/Cr and NAA/Ch ratios (P < 0.05).Conclusion:DTI and MRS detect changes associated with ALS even in the early phase of the disease. Bulbar onset and limb onset ALS patients show different pattern of involvement. Extramotor involvement suggested by CC involvement is a feature seen in bulbar onset patient and can suggest poor outcome in such patients. The present findings may be helpful for designing further studies in the direction of more early diagnosis of disease and its management.

Patterns of clinical and electrodiagnostic abnormalities in early amyotrophic lateral sclerosis

The distribution of clinical and neurophysiological abnormalities in patients with early amyotrophic lateral sclerosis (ALS) was investigated in an attempt to delineate patterns of disease spread. Clinical and electrodiagnostic data were collected from 150 ALS patients and analyzed based on the clinical region of onset. Asymmetry of clinical and neurophysiological abnormalities was more marked in upper limb-onset than lower limb-onset disease. Significant rostral-caudal gradients of clinical weakness were identified in bulbar- and lower limb-onset disease. Neurophysiological evidence of the ALS "split-hand" pattern was evident irrespective of the region of disease onset. Limbs with and without evidence of clinical weakness demonstrated similar rates of abnormality on electromyography. These findings suggest a pattern of disease spread in ALS. This study may serve to guide ongoing development of disease quantitation biomarkers and the targeting of future neuroprotective strategies.

Toxic neurofilamentous axonopathies– accumulation of neurofilaments and axonal degeneration

A number of neurotoxic chemicals induce accumulation of neurofilaments in axonal swellings that appear at varying distances from the cell body. This pathology is associated with axonal degeneration of different degrees. The clinical manifestation is most commonly that of a mixed motor-sensory peripheral axonopathy with a disto-proximal pattern of progression, as in cases of chronic exposure to n-hexane and carbon disulphide. It has been demonstrated that protein adduct formation is a primary molecular mechanism of toxicity in these axonopathies, but how this mechanism leads to neurofilament accumulation and axonal degeneration remains unclear. Furthermore, little is known regarding the mechanisms of neurofilamentous axonopathy caused by 3,3'-iminodipropionitrile, an experimental toxin that induces proximal axon swelling that is strikingly similar to that found in early amyotrophic lateral sclerosis. Here, we review the available data and main hypotheses regarding the toxic axonopathies and compare them with the current knowledge of the biological basis of neurofilament transport. We also review recent studies addressing the question of how these axonopathies may cause axonal degeneration. Understanding the mechanisms underlying the toxic axonopathies may provide insight into the relationship between neurofilament behaviour and axonal degeneration, hopefully enabling the identification of new targets for therapeutic intervention. Because neurofilament abnormalities are a common feature of many neurodegenerative diseases, advances in this area may have a wider impact beyond toxicological significance.

Microstructural Correlates of Emotional Attribution Impairment in Early Amyotrophic Lateral Sclerosis (S18.003)

Microstructural Correlates of Emotional Attribution Impairment in Early Amyotrophic Lateral Sclerosis (S18.003)

6. Electrodiagnostic abnormalities and patterns of spread in early amyotrophic lateral sclerosis

6. Electrodiagnostic abnormalities and patterns of spread in early amyotrophic lateral sclerosis

Cervical vestibular evoked myogenic potentials to air-conducted sound in early amyotrophic lateral sclerosis

Cervical vestibular evoked myogenic potentials (cVEMPs) provide assessment of lower-brainstem lesions affecting their neuronal pathways. We aimed to determine whether cVEMPs to air-conducted sound (ACS) are also abnormal in patients with early stages of amyotrophic lateral sclerosis (ALS), with or without bulbar involvement. cVEMPs were recorded in 22 ALS patients and 23 age- and sex-matched healthy volunteers. Their latencies and amplitudes were compared between the ALS patients and the control group. cVEMPs were obtained in all ALS patients and controls. P(13) and N(23) latencies and P(13)-N(23) amplitudes did not significantly differ between controls and ALS patients, either with or without bulbar involvement. We postulate that the ACS-cVEMP neural pathway is not affected in patients with early stages of ALS, even with clinical findings of bulbar involvement. Therefore, ACS-cVEMP is not a sensitive diagnostic tool for early detection of brainstem involvement in patients with ALS.