Background: Increasing neuroimaging studies have revealed gray matter (GM) anomalies of several brain regions by voxel-based morphometry (VBM) studies in patients with amyotrophic lateral sclerosis (ALS). A voxel-wise meta-analysis was conducted to integrate the reported studies to determine the consistent GM alterations in ALS based on VBM methods.Methods: Ovid Medline, Pubmed, Emabase, and BrainMap database were searched for relevant studies.Data were extracted by two independent researchers. Voxel-wise meta-analysis was performed using the effect-size signed differential mapping (ES-SDM) software.Results: Twenty-nine VBM studies comprising 638 subjects with ALS and 622 healthy controls (HCs) met inclusion criteria.The global GM volumes of ALS patients were significantly decreased compared with those of HCs. GM reductions in patients were mainly located in the right precentral gyrus, the left Rolandic operculum, the left lenticular nucleus and the right anterior cingulate/paracingulate gyri. The right precentral gyrus and the left inferior frontal gyrus might be potential anatomical biomarkers to evaluate the severity of the disease, and longer disease duration was associated with more GM atrophy in the left frontal aslant tract and the right precentral gyrus in ALS patients.Conclusion: The results support that ALS is a complex degenerative disease involving multisystems besides the motor system.The mechanism of asymmetric atrophy of the motor cortex and the implication of Rolandic operculum involvement in ALS need to be further elucidated in future studies.

ObjectiveTo investigate the genetic contribution of ANXA11, a gene associated with amyotrophic lateral sclerosis (ALS), in Chinese ALS patients with and without cognitive dementia.MethodsSequencing all the coding exons of ANXA11 and intron-exon boundaries in 18 familial amyotrophic lateral sclerosis (FALS), 353 unrelated sporadic amyotrophic lateral sclerosis (SALS), and 12 Chinese patients with ALS-frontotemporal lobar dementia (ALS-FTD). The transcripts in peripheral blood generated from a splicing mutation were examined by reverse transcriptase PCR.ResultsWe identified 6 nonsynonymous heterozygous mutations (5 novel and 1 recurrent), 1 splice site mutation, and 1 deletion of 10 amino acids (not accounted in the mutant frequency) in 11 unrelated patients, accounting for a mutant frequency of 5.6% (1/18) in FALS, 2.3% (8/353) in SALS, and 8.3% (1/12) in ALS-FTD. The deletion of 10 amino acids was detected in 1 clinically undetermined male with an ALS family history who had atrophy in hand muscles and myotonic discharges revealed by EMG. The novel p. P36R mutation was identified in 1 FALS index, 1 patient with SALS, and 1 ALS-FTD. The splicing mutation (c.174-2A>G) caused in-frame skipping of the entire exon 6. The rest missense mutations including p.D40G, p.V128M, p.S229R, p.R302C and p.G491R were found in 6 unrelated patients with SALS.ConclusionsThe ANXA11 gene is one of the most frequently mutated genes in Chinese patients with SALS. A canonical splice site mutation leading to skipping of the entire exon 6 further supports the loss-of-function mechanism. In addition, the study findings further expand the ANXA11 phenotype, first highlighting its pathogenic role in ALS-FTD.

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Objective: Neurofilaments in CSF are promising biomarkers which might help in the diagnosis of motor neuron disease (MND). We aim to assess the diagnostic value of neurofilaments in CSF for MND.Methods: Pubmed, Emabase, and Web of Science were searched for relevant studies systematically. Articles in English that evaluated the utility of neurofilaments in CSF in the diagnosis of MND were included. Data were extracted by two independent investigators. Diagnostic indexes for neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) were calculated separately. Stata 12.0 software with a bivariate mixed-effects model was used to summarize the diagnostic indexes from eligible studies.Results: Five studies on NFL and eight studies on pNFH met inclusion criteria. For NFL, the pooled sensitivity and specificity were 81% (95% confidence interval [CI], 72–88%) and 85% (95% CI, 76–91%), respectively; the positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 5.5 (95% CI, 3.1–9.8) and 0.22 (95% CI, 0.14–0.35), respectively; the summary diagnostic odds ratio (DOR) was 25 (95% CI, 9–70), and the area under summary receiver operator characteristic curve (AUC) was 0.90 (95% CI, 0.87–0.92). For pNFH, the pooled sensitivity, specificity, PLR and NLR were 85% (95% CI, 80–88%), 85% (95% CI, 77–90%), 5.5 (95% CI, 3.6–8.4), and 0.18 (95% CI, 0.13–0.25), respectively; the DOR was 30 (95% CI, 16–58), and the AUC was 0.91 (95% CI, 0.88–0.93).Conclusion: Neurofilaments in CSF have a high value in the diagnosis of MND, though the optimal cutoff value remains to be further investigated.

We identified a high frequency of EDS symptoms in Chinese patients with ALS, and these patients might have more serious physical, cognitive and frontal behaviour impairment. Patients with ALS might improve quality of life from the timely recognition and optimised management of EDS symptoms. Our results further suggest that ALS is a heterogeneous disease that might exhibit abnormal sleep-wake patterns.

ObjectiveTo characterize the patterns of brain atrophy and perfusion as measured by arterial spin labeling (ASL)-MRI, in amyotrophic lateral sclerosis (ALS) patients with varying levels of cognitive deficit, including ALS with frontotemporal dementia (FTD).MethodsA total of 55 ALS patients and 20 healthy controls (HCs) were included, and all participants underwent neuropsychological assessments and MRI scans. According to their cognitive performance, ALS patients were further subclassified into ALS with normal cognition (ALS-Cn, n = 27), ALS with cognitive impairment (ALS-Ci, n = 17), and ALS-FTD (n = 11). Voxel-based comparisons of gray matter (GM) changes and cerebral blood flow (CBF) were conducted among the subgroups.ResultsThe whole-brain comparisons of GM changes and CBF among ALS-Ci, ALS-Cn, and HCs were not significantly different. However, the ALS-FTD patients demonstrated a similar pattern of GM loss and hypoperfusion with more significant alterations in the left frontal and temporal lobe compared with the HCs, ALS-Cn, and ALS-Ci patients. Decreased CBF was found in many of the same brain areas wherein structural alterations occurred, although isolated GM loss and hypoperfusion were also observed. In addition, for both GM and CBF abnormalities, a similar pattern of changes was found in the comparisons of ALS-FTD vs. ALS-Ci, ALS-FTD vs. ALS-Cn, and ALS-FTD vs. HCs, with the differences being most significant between ALS-FTD and HCs.ConclusionThe cognitive status of ALS patients is associated with different patterns of GM changes and cerebral perfusion. ASL-MRI might be a useful tool with which to investigate the pathological burden of ALS and to disclose the early signature of possible cognitive impairment.

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ObjectiveTo evaluate serum creatine kinase (CK) levels of amyotrophic lateral sclerosis (ALS) patients and to explore the relationship between CK levels and the clinical characteristics and survival prognosis of ALS patients.MethodsWe analyzed the CK levels of 185 ALS patients who underwent long-term follow-up. The relationship between CK levels and clinical features including sex, age, disease duration, site of onset, body mass index (BMI), serum creatinine (Cr), and spontaneous electromyographic activity was analyzed by univariate analysis and multiple linear regression. Kaplan–Meier and Cox proportional hazards models were used to explore whether CK levels were independently correlated with survival prognosis of ALS.ResultsBaseline serum CK was raised in 43% of participants. The median CK level was 160 U/L (range: 20–2,574 U/L), and 99% of patients had a baseline serum CK level less than 1,000 U/L. CK levels were significantly higher in male patients than in female patients [204 (169) versus 117 (111) U/L, p < 0.001] and in patients with limb onset ALS than with bulbar onset ALS (p < 0.001). CK levels were also correlated with serum Cr (p = 0.011) and the spontaneous potential score of electromyography (EMG) (p = 0.037) but not correlated with age (p = 0.883), disease duration (p = 0.116), or BMI (p = 0.481). Log CK was independently correlated with survival of ALS patients (HR = 0.457, 95% confidence interval 0.221–0.947, p = 0.035) after adjusting for age, sex, site of onset, serum Cr, and BMI.ConclusionSerum CK levels of ALS patients were correlated with sex, site of onsite, serum Cr, and spontaneous activity in EMG. Serum CK could be an independent prognostic factor for survival of ALS patients.