Stages Of Amyotrophic Lateral Sclerosis Research Articles

Multiparametric Analysis of Sniff Nasal Inspiratory Pressure Test in Middle Stage Amyotrophic Lateral Sclerosis.

The relaxation rates and contractile properties of inspiratory muscles are altered with inspiratory muscle weakness and fatigue. This fact plays an important role in neuromuscular disorders patients and had never been extensively studied in amyotrophic lateral sclerosis (ALS). In this cross-sectional study, these parameters were investigated non-invasively through nasal inspiratory sniff pressure test (SNIP) in 39 middle stage spinal onset ALS subjects and compared with 39 healthy controls. ALS patients were also divided into three subgroups according to a decline in their percentage of predicted forced vital capacity (FVC%pred) as well as a decline in the ALS functional rating scale score and its respiratory subscore (R-subscore) in order to determine the best parameter linked to early respiratory muscle weakness. When compared with healthy subjects, middle stage ALS subjects exhibited a significantly lower (p < 0.0001) maximum relaxation rate and maximum rate of pressure development (MRPD), as well as a significantly higher (p < 0.0001) tau (τ), contraction time, and half-relaxation time. The results from receiver operating characteristic curves showed that MRPD (AUC 0.735, p < 0.001) and FVC%pred (AUC 0.749, p = 0.009) were the best discriminator parameters between ALS patients with ≤30 and >30 points in the ALS functional rating scale. In addition, 1/2RT (AUC 0.720, p = 0.01), FVC%pred (AUC 0.700, p = 0.03), τ (AUC 0.824, p < 0.0001), and MRPD (AUC 0.721, p = 0.01) were the parameters more sensitive in detecting a fall of three points in the R-subscore. On the other hand, MRPD (AUC 0.781, p < 0.001), τ (AUC 0.794, p = 0.0001), and percentage of predicted of SNIP (AUC 0.769, p = 0.002) were the parameters able to detect a fall in 30% of the FVC%pred in middle stage ALS patients. The contractile properties and relaxation rates of the diaphragm are altered in middle stage spinal onset ALS when compared with healthy subjects. These parameters are able to discriminate between those middle stage ALS subjects with early decline in inspiratory muscle function and those who not.

S57. The divergence phenomenon of CMAP/SNAP in early stage of amyotrophic lateral sclerosis

To evaluate the relationship of sensory fibers and functional status of motor fibers in patients with amyotrophic lateral sclerosis(ALS) through electrophysiological approach, and analyse the results. We retrospectively reviewed 64 case with early stage of upper limb-onset ALS admitted in our hospital from January 2010 to December 2015. Patients with ALS were graded as normal compound muscle action potential (CMAP) (23 cases) and abnormal CMAP group (41 cases) according to the CMAP of median nerve 39 healthy volunteers were included as control. Median and ulnar nerves electrophysiological study were performed using the Keypoint.net (Medoc Ltd) electromyogram device. The sensory nerve action potential (SNAP) amplitudes of Median and ulnar nerves were raised (28.80 ± 15.54) μV vs (21.06 ± 7.41) μV, t = 2.91, P < 0.01, (12.44 ± 4.64) μV vs (10.46 ± 2.77) μV, t = 2.41, P = 0.01 in ALS group, compared with control group. But the sensory conduction velocities (SCVs) had no difference. SNAP amplitudes of median nerve were raised (33.13 ± 13.33) μV vs (21.06 ± 7.41) μV, F = 6.39, P < 0.01 in the normal CMAP group, compared with the control group, but the SNAP amplitudes of ulnar nerve had no difference: Compared with the control group, the SNAP amplitudes of median nerve had no difference, but the SNAP amplitudes of ulnar nerve were raised (12.92 ± 5.01) μV vs (10.46 ± 2.78) μV, F = 3.71, P < 0.05 in abnormal CMAP group. ALS patients with onset of upper limb in the early stage may have increased SNAP in median and ulnar nerve,and show CMAP/SNAP separated phenomenon.

T130. Quantitative sudomotor axon reflex testing in anterior horn cell disorders

Autonomic disturbances in the form of hyperhidrosis, stiffness of fingers and aggravation of motor weakness on exposure to cold(Cold paresis) has been reported in anterior horn cell disorders like early stages of Amyotrophic lateral sclerosis (ALS), Brachial Monomelic Amyotrophy (BMMA) and Distal Bimelic Amyotrophy (DBMA). Quantitative sudomotor axon reflex test (QSART) was done to assess the functional integrity of postganglionic sympathetic sudomotor axons. 25 patients of BMMA, 10 patients with DBMA divided into two groups based on age (Group1: 20–30 years and Group2: 30–40 years) and 10 patients with ALS where recruited for the study and compared with equal cohort of age matched controls. General physical examination and anthropometric measurements were taken before recording. Sudomotor function of the study participants were evaluated by using Q-Sweat device manufactured by WR Medical Electronics. Resting sweat rate was recorded 5 min followed by iontophoretic stimulation. Baseline sweat volume, Total sweat volume and latency time from start of iontophoretic stimulation [acetylcholine-2 mA current strength for 5 min] to sweat response from 4 recording sites were measured. The variances in parameters like age, body weight, both height of both control and disease group were not significantly different and hence comparable. The mean age of BMMA patients: [Group1: 22.8 ± 3.8 and Group2: 33.8 ± 3.2 years] age matched controls - [Group1: 25.4 ± 2.7 and Group2: 35.1 ± 2.8 years]. There was no significant difference in baseline line sweat rate, latency and total sweat volume between controls and patients at four sites viz. Forearm, Proximal leg, Distal leg and Foot in both affected and unaffected limb. There was no significant difference between affected and unaffected limbs in above parameters in patients with BMMA. Similar results were obtained for patients in early stages of ALS (mean age 46.8 ± 3.2 years) and DBMA [Group1: 23.3 ± 4.8 and Group2: 38.0 ± 2.9 years]. Our findings suggests normal functioning of post ganglionic sudomotor fibers in BMMA and DBMA. The highly prevalent autonomic symptoms probably arise due to pre-ganglionic autonomic dysfunction and possibly in the cervical cord.

Cognitive phenotypes of sequential staging in amyotrophic lateral sclerosis

Sequential spread of TDP-43 load in the brain may be a pathological characteristic of amyotrophic lateral sclerosis (ALS). Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) based marker of this pathological feature. Cognitive deficits known to be present in a subset of ALS patients might act as an additional in vivo clinical marker of disease spread.N = 139 patients with ALS were tested with the Edinburgh Cognitive and Behavioural ALS screen (ECAS) in addition to DTI brain measures of pathological spread. Executive function, memory and disinhibited behaviour were selected for Cognitive-Staging criteria, as these cognitive functions are attributed to cerebral areas analogous to the pattern of MRI markers of TDP-43 pathology. ROC curve analyses were performed to define cut-off scores for cognitive stages 2 (executive function), stage 3 (disinhibited behaviour) and stage 4 (memory), and staging was performed according to the cognitive profile subsequently. Associations of Cognitive-Staging (stage 2–4) and MRI-Staging measures were determined.In total, 77 patients (55%) performed below ROC cut-off scores in either executive function or memory or both and/or were reported to have disinhibited behaviour which permitted Cognitive-Staging. The cognitive profile of patients with discrete MRI stages 2–4 correlated significantly with DTI parameters. For those patients with cognitive impairment, there was a high congruency between MRI and Cognitive-Staging with high specificity and sensitivity of executive functions for MRI stage 2, disinhibited behaviour for MRI stage 3 and moderate of memory for MRI stage 4.Cognitive impairment follows specific patterns in ALS and these patterns can be used for Cognitive-Staging with a high specificity compared to MRI-Staging. For the individual, cognitive screening is a fast and easy to apply measurement of cerebral function giving valuable information in a clinical context.

Aberrant Axon Branching Via Fos-B Dysregulation in FUS-ALS Motor Neurons

The characteristic structure of motor neurons (MNs), particularly of the long axons, becomes damaged in the early stages of amyotrophic lateral sclerosis (ALS). However, the molecular pathophysiology of axonal degeneration remains to be fully elucidated. In the present study, two sets of isogenic human-induced pluripotent stem cell (hiPSCs)-derived MNs were compared, and we found an abnormal increase in axon branching in the ALS-causative FUS-mutant lines. Moreover, we applied microfluidic devices that enable axon bundles to be produced for omics analysis and conducted RNA profiling of isolated axons. Thus, we identified increased level of Fos-B mRNA, the binding target of FUS, in FUS-mutant MNs. While Fos-B reduction using si-RNA or an inhibitor ameliorated the observed aberrant axon branching, Fos-B overexpression resulted in aberrant axon branching even in vivo. Analyzing the axonal fraction of hiPSC-derived MNs using microfluidic devices revealed that Fos-B is a key regulator of FUS-mutant axon branching. Funding Statement: This work was supported by Research and Study Project of Tokai University Educational System General Research Organization [to H.M]. Declaration of Interests: H.Ok. is a paid Scientific Advisor of SanBio Co.Ltd and K Pharma Inc. Y.O. is a scientific advisor for Kohjin Bio Co., Ltd. Other authors declare no competing financial interests. Ethics Approval Statement: All protocols were approved by the ethics committees of Tohoku University School of Medicine (No. 2010–306) and the Keio University School of Medicine (N0. 20080016).

Abnormal cortical brain integration of somatosensory afferents in ALS

ObjectivesInfraclinical sensory alterations have been reported at early stages of amyotrophic lateral sclerosis (ALS). While previous studies mainly focused on early somatosensory evoked potentials (SEPs), late SEPs, which reflect on cortical pathways involved in cognitive-motor functions, are relatively underinvestigated. Early and late SEPs were compared to assess their alterations in ALS. MethodsMedian and ulnar nerves were electrically stimulated at the wrist, at 9 times the perceptual threshold, in 21 ALS patients without clinical evidence of sensory deficits, and 21 age- and gender-matched controls. SEPs were recorded at the Erb point using surface electrodes and using a needle inserted in the scalp, in front of the primary somatosensory area (with reference electrode on the ear lobe). ResultsCompared to controls, ALS patients showed comparable peripheral (N9) and early cortical component (N20, P25, N30) reductions, while the late cortical components (N60, P100) were more depressed than the early ones. ConclusionsThe peripheral sensory alteration likely contributed to late SEP depression to a lesser extent than that of early SEPs. SignificanceLate SEPs may provide new insights on abnormal cortical excitability affecting brain areas involved in cognitive-motor functions.

Is there a glucose metabolic signature of spreading TDP-43 pathology in amyotrophic lateral sclerosis?

Recently, four neuropathological stages of amyotrophic lateral sclerosis (ALS) with spreading of transactive response DNA-binding protein-43 pathology were described. Although 18F-FDG PET has been useful in diagnosis and prognosis of ALS patients, in-vivo disease staging using glucose metabolic patterns across the different ALS stages has not been attempted so far. In this study, we investigated whether the discriminant brain regions of the neuropathological stage model can be translated to metabolic patterns for in-vivo staging of ALS. Furthermore, we examined the correlation of these metabolic patterns with disease duration, the Revised ALS Functional Rating Scale (ALSFRS-R) and the forced vital capacity (FVC). A total of 146 ALS patients (age 66.0±11.0 years; 86 male, 60 female) were divided into four metabolic stages depending on glucose metabolism in discriminant regions of neuropathological stages. 18F-FDG data were analysed voxel-based to compare local metabolic patterns between different stages. Additionally, correlation analyses were performed between pathologic stage and clinical parameters. Relative hypometabolism was present in regions known to be affected from the post-mortem pathological spread model, but relative hypermetabolism was also observed across the different ALS stages. In particular, stage 4 reflected a different frontotemporal pattern discordant with mere progression of stage 1-3, which may point to a potential different subgroup in ALS. Furthermore, metabolic stage correlated with disease duration (Spearman's ρ=-0.21, P=0.01) and FVC (Spearman's ρ=-0.24, P=0.04). The neuropathological ALS stages correspond to discriminative regional brain glucose metabolism patterns correlating with disease duration and forced vital capacity. Furthermore, metabolic stage 4 may represents a separate group of ALS progression towards frontotemporal dementia.

Peripheral nerve ultrasonography and nerve conduction study in progressive stage of amyotrophic lateral sclerosis

Background: High-resolution ultrasound has been used to evaluate several neuromuscular conditions.

Eye-gaze control technology for children, adolescents and adults with cerebral palsy with significant physical disability: Findings from a systematic review

ABSTRACTPurpose: The primary objective of this systematic review was to examine the effectiveness of eye-gaze control technology for facilitating communication across different social contexts for people with cerebral palsy and significant physical disability. Methods: Systematic review. Results: The search identified 756 potentially eligible articles, of which two, low level articles were eligible. One study reported positive results for achieving communication goals for children with cerebral palsy. The second concluded that eye-gaze control technology resulted in greater quality of life and less depression for adults with late stage amyotrophic lateral sclerosis when compared to non-users. Discussion: Research regarding the effectiveness of eye-gaze control technology used to access a laptop, tablet or computer on communication outcomes, participation, quality of life and self-esteem in children, adolescents and adults with cerebral palsy and significant physical disability is sparse. A scoping review to fully identify issues to inform clinical practice and future research is required.

P261 Cortical excitability changes in the earliest stages of amyotrophic lateral sclerosis (ALS)

Objectives To reveal CE changes in the earliest stages of ALS. Methods The prospective analysis of CE tested with TMS was done with 11 patients at the earliest stage of ALS when the diagnosis was considered as “possible ALS” according to the Awaji and El Escorial criteria. The “possible ALS” was established in 3 patients with signs of frontotemporal dementia and 4 patients had bulbar onset. In all patients, the resting motor threshold (RMT) was checked with the motor evoked potential (MEP) recorded bilateral from abductor pollicis brevis (ABP) and tibialis anterior (TA) muscles. There was no subjective weakness in target muscles but the normal or increased tendon reflexes. After 1.8–2.2 years of the follow up period, the diagnosis of ALS corresponded all the criteria of reliable disease with upper and lower motor neuron involvement. Results In the early stages of possible ALS the RMT registered from the upper and lower extremities was normal: APB 40 ± 5%, TA 65 ± 7%. The paradoxical “normality” did not correlate to clinical features provided evidence of upper motor neuron involvement.The MEP amplitude was normal. After 1.8–2.2 years, in all cases, the RMT increased or MEP was absent. Conclusions In the earliest stages of ALS the level of RMT doesn’t differ from measurements in normal individuals, and can’t be used as the parameter of suggesting CE changes. Significance The question of what one mean by early stages of ALS is the most vulnerable issue in investigations of CE in motor neuron disease.

High angular resolution diffusion imaging abnormalities in the early stages of amyotrophic lateral sclerosis

ObjectiveUsing magnetic resonance (MR) high angular resolution diffusion imaging (HARDI), we aimed at revealing possible microstructural alterations in the early stage of amyotrophic lateral sclerosis (ALS), still not completely elucidated. MethodsWe studied 22 patients with ALS, in stages 1 or 2 according to the King's staging system, compared to 18 healthy controls (HCs). Statistical mapping of HARDI-derived parameters and tractography measures were performed using the Q-ball imaging diffusion data model. ResultsWhen compared to HCs, the ALS group showed a highly significant decrease of generalized fractional anisotropy (GFA) and fiber length and density in the corticospinal tracts (CSTs) and in the corpus callosum (CC) (p<0.05, corrected level of significance). Moreover, stratifying the ALS population considering the disease phenotype, larger areas of decreased GFA were found in patients with bulbar phenotype compared to those with classic phenotype in several bilateral associative fiber tracts, such as superior and inferior longitudinal, inferior fronto-occipital and uncinate fasciculi. ConclusionsOur whole-brain HARDI results provided preliminary evidence of an early pattern of microstructural degeneration in ALS, mainly involving the CSTs and the CC, although divergent patterns of microstructural abnormalites could be related to different disease phenotypes.

Clinical diagnosis and management of cervical spondylotic amyotrophy

Objective: To investigate the clinical characteristics and surgical treatment of cervical spondylotic amyotrophy. Methods: Thirteen patients(13 man) with proximal (10) and distal(3) cervical spondylotic amyotrophy between November 2014 and September 2016 were included in this study. The average age of the patients was 55 (range, 47-66) years. The sex, age, clinical course, type of amyotrophy, lesion segment and postdecompression improvement in muscle power were reviewed. Results: Of 13 cervical spondylotic amyotrophy patients, 9 were performed on with cervical disectomy, 2 were performed on with cervical posterior operation, 2 remainding patients received nonoperative treatment. Cervical spondylotic amyotrophy patients were followed up 6-22 (average 10.6) months, muscle power of 4 patients (all proximal-type)were improved completely (the average recovery time were 4.4 months), muscle power of 6 patients were improved uncompletely, 1 patients failed to improve, the 2 remainding patients received nonoperative treatment had no change. Conclusion: Cervical spondylotic amyotrophy as a rare type of cervical spondylotic disorder, It should distinguish cervical spondylotic amyotrophy from amyotrophic lateral sclerosis, especially in the early stage of amyotrophic lateral sclerosis. A surgical treatment is recommended as the first line of proximal-type CSA, especially those with serious compression. It is important that clinicians should be aware that distal-type CSA had a poor results, resulting in a lower lower satisfaction, especially those with no, or insignificant, sensory disturbance.

Theory of Mind and Its Neuropsychological and Quality of Life Correlates in the Early Stages of Amyotrophic Lateral Sclerosis.

This study aims to explore the potential impairment of Theory of Mind (ToM; i.e., the ability to represent cognitive and affective mental states to both self and others) and the clinical, neuropsychological and Quality of Life (QoL) correlates of these cognitive abnormalities in the early stages of amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disease recently recognized as a part of the same clinical and pathological spectrum of frontotemporal lobar degeneration. Twenty-two consecutive, cognitively intact ALS patients, and 15 healthy controls, underwent assessment of executive, verbal comprehension, visuospatial, behavioral, and QoL measures, as well as of the ToM abilities by Emotion Attribution Task (EAT), Advanced Test of ToM (ATT), and Eyes Task (ET). ALS patients obtained significantly lower scores than controls on EAT and ET. No significant difference was found between the two groups on ATT. As regard to type of ALS onset, patients with bulbar onset performed worse than those with spinal onset on ET. Correlation analysis revealed that EAT and ET were positively correlated with education, memory prose, visuo-spatial performances, and “Mental Health” scores among QoL items. Our results suggest that not only “cognitive” but also “affective” subcomponents of ToM may be impaired in the early stages of ALS, with significant linkage to disease onset and dysfunctions of less executively demanding conditions, causing potential impact on patients’ “Mental Health.”

Increased Expressions of Plasma Galectin-3 in Patients with Amyotrophic Lateral Sclerosis.

Background:High expressions of galectin-3 were identified recently in the end stage of amyotrophic lateral sclerosis (ALS) patients, which suggested that immune reactivity and inflammatory mechanisms might play an important role in the pathogenesis of ALS. The purpose of this study was to investigate plasma galectin-3 levels in different groups and stages of ALS patients and the association with related clinical characteristics.Methods:A total of 51 patients with ALS and 60 normal controls (NCs) were recruited in this study. Plasma galectin-3 levels were determined using the enzyme-linked immunosorbent assay. Patients with ALS were divided into several groups according to their clinical characteristics: gender, type of disease onset, duration of disease, and clinical conditions of disease. Statistical analyses of the differences of galectin-3 levels between groups and the association with the clinical characteristics of disease were performed.Results:As compared with the NCs (201.64 [22.35–401.63] ng/ml), plasma galectin-3 levels were significantly elevated in the patients with duration >12 months (341.17 [69.12–859.22] ng/ml, P < 0.05), and the patients with limb onset of disease (254.14 [69.12–859.22] ng/ml, P < 0.05); however, no difference was found in the patients with duration ≤12 months (250.62 [109.77–334.92] ng/ml, P > 0.05), and the patients with bulbar onset of disease (251.79 [109.20–404.76] ng/ml, P > 0.05). In addition, galectin-3 levels were significantly increased in the female patients (263.27 [123.32–859.22] ng/ml, P < 0.05) while no difference was found in the male patients (220.39 [69.12–748.73] ng/ml, P > 0.05). The further statistical analyses showed that plasma galectin-3 levels were positively correlated with the duration of disease (r = 0.293, P = 0.037).Conclusions:Plasma galectin-3 levels were significantly increased in ALS patients with limb onset of disease, especially in ALS female patients, and positively correlated with the duration of disease, which suggested that plasma galectin-3 might be an interesting and useful factor associated with ALS.

Self-regulation of brain rhythms in the precuneus: a novel BCI paradigm for patients with ALS

Objective. Electroencephalographic (EEG) brain–computer interfaces (BCIs) hold promise in restoring communication for patients with completely locked-in stage amyotrophic lateral sclerosis (ALS). However, these patients cannot use existing EEG-based BCIs, arguably because such systems rely on brain processes that are impaired in the late stages of ALS. In this work, we introduce a novel BCI designed for patients in late stages of ALS based on high-level cognitive processes that are less likely to be affected by ALS. Approach. We trained two ALS patients via EEG-based neurofeedback to use self-regulation of theta or gamma oscillations in the precuneus for basic communication. Because there is a tight connection between the precuneus and consciousness, precuneus oscillations are arguably generated by high-level cognitive processes, which are less likely to be affected by ALS than processes linked to the peripheral nervous system. Main results. Both patients learned to self-regulate their precuneus oscillations and achieved stable online decoding accuracy over the course of disease progression. One patient achieved a mean online decoding accuracy in a binary decision task of 70.55% across 26 training sessions, and the other patient achieved 59.44% across 16 training sessions. We provide empirical evidence that these oscillations were cortical in nature and originated from the intersection of the precuneus, cuneus, and posterior cingulate. Significance. Our results establish that ALS patients can employ self-regulation of precuneus oscillations for communication. Such a BCI is likely to be available to ALS patients as long as their consciousness supports communication.

Association between estimated total daily energy expenditure and stage of amyotrophic lateral sclerosis

ObjectiveAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, and nutritional status is one of the major prognostic factors of ALS. The aim of this study was to investigate the relationship between total daily energy expenditure (TDEE) and progression of disease in ALS patients, as well as sex differences in TDEE. MethodsPatients with ALS (N = 370) were diagnosed according to El Escorial criteria and categorized into stage 2, 3, or 4 using a clinical staging system. TDEEs were calculated by summing resting energy expenditure (REE) and physical activity. REE was calculated using equations of Harris–Benedict or Mifflin St. Jeor, and physical activity was calculated using the ALS Functional Rating Scale-Revised, a physical activity coefficient, or adding 30% of REE. ResultsTDEE significantly decreased with progression of ALS stage and did not vary by sex. Actual energy intake was lower than TDEE in patients in all stages and lowest in patients with stage 3 ALS. Comparing TDEEs 1 to 5, TDEE 2 decreased with progression of ALS stage and was similar to the average TDEE. ConclusionsThe present study suggests that TDEE decreases with progression of ALS, and patients consume insufficient energy compared with required intake at all stages, particularly at stage 3, suggesting that nutrition support should be started at least before stage 3. Additionally, among the five equations for TDEE, TDEE 2 could be the best for evaluating the nutritional status of patients with ALS.

Neuropsychological assessment in different King's clinical stages of amyotrophic lateral sclerosis

Emerging evidence shows that cognitive deficits associated with frontal lobe dysfunction occur from early stages of amyotrophic lateral sclerosis (ALS). We aimed to assess neuropsychological functioning at different stages of ALS to further delineate the occurrence of cognitive impairment alongside the trajectory of ALS as defined by standard assessment procedures. We investigated several cognitive domains in 74 ALS patients classified into four different clinical stages of disease, according to a recently validated staging system for ALS (known as ‘King's’ system), and evaluated and compared the corresponding cognitive profiles. We found that data derived from global cognitive assessment and several executive (i.e. Frontal Assessment Battery and Trail Making Test B-A) and long-term memory (i.e. memory prose) tests were significantly different among the subsets of ALS patients, showing poorer performances with increasing clinical disability. In conclusion, our preliminary results support the notion that mainly frontotemporal abilities may be impaired during the ALS course and suggest that neuropsychological information could supplement the current clinical staging of patients. However, ALS-specific multi-domain screening instruments, which allow to correct neuropsychological scores for physical disability, should be validated in larger populations worldwide and routinely introduced in clinical practice.

IL-10 Controls Early Microglial Phenotypes and Disease Onset in ALS Caused by Misfolded Superoxide Dismutase 1.

While reactive microgliosis is a hallmark of advanced stages of amyotrophic lateral sclerosis (ALS), the role of microglial cells in events initiating and/or precipitating disease onset is largely unknown. Here we provide novel in vivo evidence of a distinct adaptive shift in functional microglial phenotypes in preclinical stages of superoxide dismutase 1 (SOD1)-mutant-mediated disease. Using a mouse model for live imaging of microglial activation crossed with SOD1(G93A) and SOD1(G37R) mouse models, we discovered that the preonset phase of SOD1-mediated disease is characterized by development of distinct anti-inflammatory profile and attenuated innate immune/TLR2 responses to lipopolysaccharide (LPS) challenge. This microglial phenotype was associated with a 16-fold overexpression of anti-inflammatory cytokine IL-10 in baseline conditions followed by a 4.5-fold increase following LPS challenge. While infusion of IL-10R blocking antibody, initiated at day 60, caused a significant increase in markers of microglial activation and precipitated clinical onset of disease, a targeted overexpression of IL-10 in microglial cells, delivered via viral vectors expressed under CD11b promoter, significantly delayed disease onset and increased survival of SOD1(G93A) mice. We propose that the high IL-10 levels in resident microglia in early ALS represent a homeostatic and compensatory "adaptive immune escape" mechanism acting as a nonneuronal determinant of clinical onset of disease. Significance statement: We report here for the first time that changing the immune profile of brain microglia may significantly affect clinical onset and duration of disease in ALS models. We discovered that in presymptomatic disease microglial cells overexpress anti-inflammatory cytokine IL-10. Given that IL-10 is major homeostatic cytokine and its production becomes deregulated with aging, this may suggest that the capacity of microglia to adequately produce IL-10 may be compromised in ALS. We show that blocking IL-10 increased inflammation and precipitated clinical disease onset, whereas overexpression of IL-10 in microglia using a gene therapy approach significantly delayed disease onset and increased survival of ALS mice. Based on our results, we propose that targeted overexpression of IL-10 in microglia may have therapeutic potential in ALS.

Importance of early recognition of amyotrophic lateral sclerosis-like disorders in the Egyptian population

Background Early stages of amyotrophic lateral sclerosis (ALS)-like syndrome when only one limb is affected can be missed by physicians suggesting other unrelated disorders especially with evidenced concomitant pathology of the same limb, leading to diagnostic pitfalls and unnecessary procedures. Objective The aim of this study was to support the diagnosis of early stages of ALS-like disorders in clinically suspected patients by electrophysiological studies (EDX) including segments that may be clinically unaffected, and searching for the possible etiology. Patients and methods This study was conducted on 120 adult patients with unilateral limb symptoms associated with irrelevant imaging abnormalities. Diagnostic workup included history taking, general and neurological examination, and EDX using the El Escorial diagnostic criteria. Further investigations included laboratory studies and paraneoplastic and hormonal assays. Results Motor nerve conduction studies revealed reduced amplitude of compound muscle action potential in 62.5% of patients, borderline conduction velocities, normal distal latencies, conduction block in one case, and normal sensory nerve conduction studies. Electromyography of the cranial, cervical, lumbosacral, and dorsal segments showed acute denervation in 80% of patients and chronic denervation in all segments in 35% and in three body segments in 65% of patients. Laboratory investigations revealed 50.83% of patients with chronic hepatitis C, with significant statistical association between EDX and laboratory results, 30.83% with hyperthyroidism, 8.33% with paraneoplastic syndrome, one case with multifocal motor neuropathy with conduction block, one case with myasthenia gravis, and 8.3% with negative results. Conclusion ALS-like disorder should be investigated whenever ALS is suspected, and further laboratory workup might unveil a coexisting ‘possibly causative’ pathological condition.

The study of sleep disordered breathing at an early stage of amyotrophic lateral sclerosis

The study of sleep disordered breathing at an early stage of amyotrophic lateral sclerosis