Correlation analysis between excitability in the somatosensory cortex and structural changes in amyotrophic lateral sclerosis

The cortical silent period (C-SP) was elicited by transcranial magnetic stimulation in 25 normal subjects and 19 patients with amyotrophic lateral sclerosis (ALS). The inhibitory (S-X) period was highly stimulus intensity (SI)-dependent (mean r2 = 0.89 for both normals and patients with ALS). The range of the C-SP (difference between maximum and minimum S-X intervals) was age-dependent for normals (r2 = 0.701, P < 0.001) but not patients with ALS. Means, maximums and ranges for the C-SP were not significantly different between normal and ALS groups and thresholds to cortical stimulation were also comparable. There was a significant, linear, relation between the maximum C-SP and disease duration of ALS (P = 0.002). The maximum C-SP was shorter early in the disease. It is hypothesized that the reduced inhibition early in the course of ALS might reflect glutamate-induced corticomotoneuronal excitotoxicity.

Objective To study the effect of intestinal bacteria on motor ability of amyotrophic lateral sclerosis (ALS) mice models and its mechanism. Methods Twenty wild type C57BL/6J mice (WT group) and 20 SOD1-G93A transgenic ALS mice (ALS group) were selected as the research subjects. (1) Ten mice in both WT group and ALS group were selected, respectively; 5 mice in each group were fed in SPF environment, and the remaining 5 mice were fed in aseptic environment; they were defined as WT+SPF group, WT+aseptic group, ALS+SPF group and ALS+aseptic group. (2) Ten mice in WT group and ALS group were fed in sterile environment; 5 mice in each group were transplanted with fecal bacteria, and the remaining 5 mice were not interfered; they were defined as WT+transplantation group, WT+non-transplantation group, ALS+transplantation group and ALS+non transplantation group. The grip strength of mice was measured by grip force meter, the motor coordination ability of mice was tested by roller treadmill and rotating rod test, the number of motor neurons in the anterior horn of spinal cord was measured by Nissl staining, the expression of microglia activation marker ionic calcium junction protein (IBA-1) in spinal cord tissues was detected by immunohistochemical staining, and the expressions of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in spinal cord tissues were detected by Western blotting; the β-N-methylamino-L-alanine (BMAA) expression was detected by high performance liquid chromatography-tandem mass spectrometry. Results (1) The grip strength, drop latency and drop time of ALS+aseptic mice were significantly higher than those of ALS+SPF mice, the number of Nissl-stained positive cells was significantly larger than that of ALS+SPF mice, the number of IBA-1 positive cells was significantly smaller than that of ALS+SPF mice, the levels of TNF-α and IL-6 protein expressions and BMAA concentration were statistically lower than those of ALS+SPF mice (P<0.05). (2) The grip strength, drop latency and drop time of ALS+transplantion mice were significantly lower than those of ALS+non-transplantation mice, the number of Nissl-stained positive cells was significantly smaller than that of ALS+non-transplantation mice, the number of IBA-1 positive cells was significantly larger than that of ALS+non-transplantation mice, the TNF-α and IL-6 protein expressions and BMAA concentration were significantly higher than those of ALS+non-transplantation mice (P<0.05). Conclusion Imbalance of intestinal bacteria homeostasis can decrease the motor ability of ALS mice, which is related to the activation of microglia. Key words: Amyotrophic lateral sclerosis; Intestinal bacteria; Motor ability; Motor neuron; Microglia

Objective To investigate the difference of cerebral inter-hemispheric functional connectivity between the patients with amyotrophic lateral sclerosis ( ALS) and healthy controls ( HC) by a newly developed voxel-mirrored homotopic connectivity ( VMHC) method based on resting-state functional MRI ( rs-fMRI) , as well as its correlation to the structural imaging indices and clinical neurological scales .Methods Twenty patients with ALS ( ALS group ) and 20 age-, and sex-matched healthy controls ( HC group) were examined by rs-fMRI and diffusion tensor imaging ( DTI ) on 3.0 T MR imaging system ( Siemens Trio Tim ).The rs-fMRI data preprocessing were performed using data processing assistant for rs-fMRI ( DPARSF) based on Matlab 2009a, and the rs-fMRI data analysis toolkit ( REST) with an automated VMHC approach was utilized to calculate and compare the VMHC correlation coefficients between the ALS group and the HC group[P 0.05).Conclusions Abnormal VMHC coefficients were detected in ALS patients.The decreased VMHC in ACC and M1 are associated with the reduced micro-structure integrity of CC, meanwhile, and they may be related to disease severity. Key words: Amyotrophic lateral sclerosis ; Magnetic resonance imaging ; Brain ;

Since amyotrophic lateral sclerosis (ALS) can be accompanied by executive dysfunction, it is hypothesised that ALS patients will have impaired performance on tests of cognitive inhibition. We predicted that ALS patients would show patterns of abnormal activation in extramotor regions when performing tests requiring the inhibition of prepotent responses (the Stroop effect) and the inhibition of prior negatively primed responses (the negative priming effect) when compared to healthy controls. Functional magnetic resonance imaging was used to measure activation during a sparse sequence block design paradigm investigating the Stroop and negative priming effects in 14 ALS patients and 8 healthy age- and IQ-matched controls. Behavioural measures of performance were collected. Both groups’ reaction times (RTs) reflected the Stroop effect during scanning. The ALS and control groups did not differ significantly for any of the behavioural measures but did show significant differences in cerebral activation during both tasks. The ALS group showed increased activation predominantly in the left middle temporal gyrus (BA 20/21), left superior temporal gyrus (BA 22) and left anterior cingulate gyrus (BA 32). Neither group’s RT data showed clear evidence of a negative priming effect. However the ALS group showed decreased activation, relative to controls, particularly in the left cingulate gyrus (BA 23/24), left precentral gyrus (BA 4/6) and left medial frontal gyrus (BA 6). Greater cerebral activation in the ALS group accompanying the performance of the Stroop effect and areas of decreased activation during the negative priming comparison suggest altered inhibitory processing in ALS, consistent with other evidence of executive dysfunction in ALS. The current findings require further exploration in a larger study.

Studies of glucose, insulin, and lipid metabolism in amyotrophic lateral sclerosis and other neuromuscular disorders.

Early immune system changes in amyotrophic lateral sclerosis correlate with later disease progression.

Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and loss of various muscular functions. Dyslipidaemia is prevalent in amyotrophic lateral sclerosis with aberrant changes mainly in cholesterol ester and triglyceride. Despite this, little is known about global lipid changes in amyotrophic lateral sclerosis or in relation to disease progression. The present study incorporated a longitudinal lipidomic analysis of amyotrophic lateral sclerosis serum with a comparison with healthy controls using advanced liquid chromatography-mass spectrometry. The results established that diglyceride, the precursor of triglyceride, was enriched the most, while ceramide was depleted the most in amyotrophic lateral sclerosis compared with controls, with the diglyceride species (18:1/18:1) correlating significantly to neurofilament light levels. The prenol lipid CoQ8 was also decreased in amyotrophic lateral sclerosis and correlated to neurofilament light levels. Most interestingly, the phospholipid phosphatidylethanolamine and its three derivatives decreased with disease progression, in contrast to changes with normal ageing. Unsaturated lipids that are prone to lipid peroxidation were elevated with disease progression with increases in the formation of toxic lipid products. Furthermore, in vitro studies revealed that phosphatidylethanolamine synthesis modulated TARDBP expression in SH-SY5Y neuronal cells. Finally, diglyceride, cholesterol ester and ceramide were identified as potential lipid biomarkers for amyotrophic lateral sclerosis diagnosis and monitoring disease progression. In summary, this study represents a longitudinal lipidomics analysis of amyotrophic lateral sclerosis serum and has provided new insights into multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.

The aim of the present study was to determine whether significant differences in cortical excitability were evident across different body regions in healthy humans. Threshold tracking transcranial magnetic stimulation (TMS) was undertaken in 28 healthy controls. Short-interval intracortical inhibition [SICI between interstimulus intervals (ISI) 1-7 ms], intracortical facilitation (ICF, between ISI 10-30 ms), resting motor threshold (RMT), cortical silent period (CSP) duration (generated at stimulus intensity 150% RMT), and motor evoked potential amplitude were recorded from the abductor pollicis brevis (APB), tibialis anterior (TA), and trapezius muscles. These muscles were selected as they are frequently affected in neurodegenerative diseases, such as amyotrophic lateral sclerosis. SICI and ICF are measured as a percentage difference between conditioned and an unconditioned test response. SICI was significantly greater when recorded over the APB (9.9 ± 1.5%) and TA (8.6 ± 1.4%) muscles compared with the trapezius (4.5 ± 1.9%, P < 0.05). The CSP duration was significantly shorter (CSPtrapezius, 131.0 ± 6.3 ms; CSPTA, 175.7 ± 9.9 ms; CSPAPB, 188.3 ± 4.0 ms; P < 0.001) and ICF greater ( P < 0.01) in the trapezius muscle. There were no significant correlations between inhibitory and facilitatory processes recorded across the three muscles. The present study established significant differences in cortical excitability across three body regions, with evidence of more prominent inhibition and less facilitation in the limb muscles. NEW & NOTEWORTHY Cortical excitability of muscles with differing motor functions was assessed using threshold tracking transcranial magnetic stimulation. Significantly greater intracortical inhibition and less facilitation were evident over the limb muscles. These findings could relate to differences in the functional organization of the corticomotoneuronal system innervating different muscle regions.

New Forms of ALS/MND Defined by Mutations in New Genes

BackgroundSwallowing dysfunction is related to major cause of adverse events and an indicator of shorter survival among patients with neuromuscular disorders (NMD). It is critical to assess the swallowing function during disease progression, however, there are limited tools that can easily evaluate swallowing function without using videofluoroscopic or videoendoscopic examination. Here, we evaluated the longitudinal changes in tongue thickness (TT) and maximum tongue pressure (MTP) among patients with amyotrophic lateral sclerosis (ALS), myotonic dystrophy type 1 (DM1), and Duchenne muscular dystrophy (DMD).MethodsBetween 2010 and 2020, TT and MTP were measured from 21 ALS, 30 DM1, and 14 DMD patients (mean ages of 66.9, 44.5, and 21.4 years, respectively) at intervals of more than half a year. TT was measured, by ultrasonography, as the distance from the mylohyoid muscle raphe to the tongue dorsum, and MTP was determined by measuring the maximum compression on a small balloon when pressing the tongue against the palate. Then we examined the relationship between these evaluations and patient background and swallowing function.ResultsMean follow-up periods were 24.0 months in the ALS group, 47.2 months in the DM1group, and 61.1 months in the DMD group. The DMD group demonstrated larger first TT than the other groups, while the DM1 group had lower first MTP than the ALS group. The ALS group showed a greater average monthly reduction in mean TT than the DM1 group and greater monthly reductions in mean body weight (BW) and MTP than the other groups. Significant differences between the first and last BW, TT, and MTP measures were found only in the ALS group.ConclusionsThis study suggests that ALS is associated with more rapid degeneration of tongue function over several years compared to DMD and DM1.

Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons, resulting in muscle atrophy, spasticity, hyperreflexia, and paralysis. Inflammation plays an important role in the development of ALS, and associated with rapid disease progression. Current observational studies indicate the thinning of cortical thickness in patients with ALS is associated with rapid disease progression and cognitive changes. However, the effects of inflammatory cytokines on cortical thickness in patients with ALS are unclear. Here, we investigated the relationship between inflammatory cytokines and cortical thickness in patients with ALS. We evaluated 51 patients with ALS for inflammatory cytokines including interleukin (IL)-4, interferon (IFN)-α, IL-1β, IL-2, IL-5, IL-12, tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-8, IL-17, and IFN-γ and analyzed the correlation between these indicators and the ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score). Twenty-six patients with ALS and 26 controls were studied using whole-cortex analysis, and post-hoc analyses were performed to examine the correlation between brain cortical thickness and ALSFRS-R or ΔFS scores. IL-4, IFN-α, IL-1β, and IL-2 levels were significantly correlated with ALSFRS-R scores, and the IL-2 level was significantly correlated with ΔFS scores. After controlling for age and sex, the ALS group had thinner cortexes in multiple clusters across the brain than the control group. Further analyses revealed that cortical thickness in the right superior temporal and lingual gyrus regions was inversely correlated with ΔFS scores. There was a significant positive correlation between the clusters in the right lingual cortex and IL-2 level. These results suggest cortical thickness was reduced in patients with ALS in motor and non-motor cortical areas. Inflammatory factors (especially IL-2) were correlated with cortical thickness, and both were related to the disease progression rate, suggesting IL-2 plays an important role in ALS.

In-vivo evaluation of neuronal and glial changes in amyotrophic lateral sclerosis with diffusion tensor spectroscopy

Background: In recent years, the role of iron metabolism in amyotrophic lateral sclerosis (ALS) attracts more and more attention, and some studies have focused on the link between abnormal serum iron indicators and ALS. However, there are still big conflicts and inconsistency among different studies. To study the possible relationship between ALS and disturbed iron metabolism, we conducted this meta-analysis to conclude characteristics of abnormal serum iron-status indicator changes in ALS patients.Methods: We searched and screened main databases, including the PubMed, Embase, and Cochrane Library, to find studies related to the association between iron metabolism and ALS. The Revman 5.3 software was used to conduct meta-analysis.Results: Eleven studies were finally included in our analysis, composed of 1,599 ALS patients and 1,255 controls in total. The results showed that the ferritin level was much higher in ALS patients compared with controls (MD = 70.48, 95% CI [51.41, 89.55], p < 0.00001), and the transferrin level was decreased in ALS patients compared with controls (SMD = −0.28, 95% CI [−0.38, −0.18], p < 0.00001), while there was no statistical difference in iron levels (SMD = 0.48, 95% CI [−0.07, 1.03], p = 0.09) between ALS patients and controls.Conclusions: Our research finds unusual changes in several indicators representing iron status, which suggest possible iron metabolism abnormalities in ALS patients. That may provide evidence for the link between iron metabolism and the pathogenesis of ALS.

The identification of the chromosome 9 open reading frame 72 (c9orf72) gene hexanucleotide repeat expansion represents a major advance in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis. The pathophysiological mechanism by which the c9orf72 gene expansion leads to neurodegeneration is not yet elucidated. Cortical hyperexcitability is potentially an important pathophysiological process in sporadic ALS and familial ALS (FALS). To investigate whether cortical hyperexcitability forms the pathophysiological basis of c9orf72 FALS using the threshold-tracking transcranial magnetic stimulation technique. Prospective case-control single-center study that took place at hospitals and outpatient clinics from January 1, 2013, to January 1, 2015. Clinical and functional assessments along with transcranial magnetic stimulation studies were taken on 15 patients with c9orf72 FALS and 11 asymptomatic expansion carriers of c9orf72 who were longitudinally followed up for 3 years. Results were compared with 73 patients with sporadic ALS and 74 healthy control participants. Cortical excitability variables, including short-interval intracortical inhibition, were measured in patients with c9orf72 FALS and results were compared with asymptomatic c9orf72 carriers, patients with sporadic ALS, and healthy control participants. Mean (SD) short-interval intracortical inhibition was significantly reduced in patients with c9orf72 FALS (1.2% [1.8%]) and sporadic ALS (1.6% [1.2%]) compared with asymptomatic c9orf72 expansion carriers (10.2% [1.8%]; F = 16.1; P < .001) and healthy control participants (11.8% [1.0%]; F = 16.1; P < .001). The reduction of short-interval intracortical inhibition was accompanied by an increase in intracortical facilitation (P < .01) and motor-evoked potential amplitude (P < .05) as well as a reduction in the resting motor threshold (P < .05) and cortical silent period duration (P < .001). This study establishes cortical hyperexcitability as an intrinsic feature of symptomatic c9orf72 expansion-related ALS but not asymptomatic expansion carriers.

Cortico-efferent tract involvement in primary lateral sclerosis and amyotrophic lateral sclerosis: A two-centre tract of interest-based DTI analysis