A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS

Correlation of frontal atrophy with behavioral changes in amyotrophic lateral sclerosis

Background: Recent studies have linked cognitive impairment in amyotrophic lateral sclerosis (ALS) to frontotemporal pathology. Aim: We examined possible associations between behavior changes and regional gray matter volume in early ALS and assessed whether the volume changes were independent of physical impairments. Methods: Seventeen ALS patients with Mini-Mental State Examination ≥24, no need for assistance in daily life, normal respiratory tests (respiratory function test and arterial blood gas analytes), and eleven age-matched controls, underwent structural MRI. Behavioral changes were assessed with family-rating Frontal Systems Behavior Scale (FrSBe). We applied voxel-based morphometry to investigate the correlation between FrSBe and gray matter volume and assessed the correlation of volume with ALS Functional Rating Scale (ALSFRS) and respiratory tests. Results: Current FrSBe 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 ALS were negatively correlated with FrSBe, whereas they were not correlated with ALSFRS and respiratory tests. The volume of right frontal cluster, but not left medial frontal cluster, was significantly smaller than that of controls. Conclusions: Regional atrophy within frontal lobe was associated with behavioral dysfunction in early ALS, this association was independent of physical factors

Frontal assessment battery and frontal atrophy in amyotrophic lateral sclerosis

Objectives: To determine the potential utility of the frontal assessment battery (FAB)in assessing cognitive impairments in amyotrophic lateral sclerosis (ALS), we investigatedthe association between the FAB score and regional gray matter volume, andascertained whether the regional brain alterations related to cognitive impairmentsoccur in relatively mild stage of ALS.Materials and Methods: Twenty-fourALS patients with a Mini-MentalStateExamination score of >23, a normal score on the Self-RatingDepression Scale, little orno disturbance in speech and handling utensils on the ALS Functional Rating Scale(ALSFRS), and normal measures on respiratory tests (respiratory function test and arterialblood gas analysis), and two age-matchednormal control groups (one for FABassessment and the other for brain morphometry) underwent FAB testing and structuralmagnetic resonance imaging. We applied voxel-basedmorphometry to investigatethe relationship between the FAB score and regional brain alteration, andassessed the relationship between the altered regional brain volume and ALSFRS orrespiratory tests.Results: Frontal assessment battery scores were significantly lower in ALS patientsthan in normal controls. Volume reduction in the right orbitofrontal gyrus in ALS wascorrelated with a lower FAB score. There was no correlation between the right orbitofrontalgyrus volume and ALSFRS or respiratory tests.Conclusions: The results suggest that the FAB is an adequate tool for detecting cognitiveimpairments related to frontal lobe pathology in the relatively mild stage of ALS,independent of physical dysfunctions