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.