Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

Association of homocysteine, folate, and white matter hyperintensities in Parkinson's patients with different motor phenotypes.

OBJECTIVE: To investigate the association of homocysteine (Hcy), folate, and white matter hyperintensities in Parkinson's disease (PD) with different motor phenotypes. METHODS: Of the PD patients, 176 were included. Based on the Unified Parkinson's Disease Rating Scale, the PD patients were classified into postural instability gait disorder (PIGD) and non-PIGD phenotypes. According to the Fazekas score, patients were divided into the none/mild white matter hyperintensity (WMH) group and the moderate/severe WMH group. The relationship of Hcy, folate, and white matter hyperintensities (WMHs), and the motor phenotype of PD were analyzed. RESULTS: PD-PIGD patients had higher proportion of moderate/severe WMHs, Hcy levels, and lower folate levels than PD-non-PIGD patients (p all ≤ 0.001). In the subgroup analysis, patients with both PD-PIGD and moderate/severe WMHs had the highest Hcy and lowest folate levels compared with others. Binary logistic regression analysis showed that age, folate, and Hcy were independent risk factors for WMHs. In an a priori-determined stratified analysis, after adjustment for confounding factors, the odds ratio of WMHs was 8.01 (95% CI 2.700-23.767, p trend = 0.001) in the patients with Hcy levels in the highest quintile compared with the lowest quintile and 16.81 (95% CI 4.74-59.65, p trend < 0.001) in the patients with folate levels in the lowest quintile compared with the highest quintile. CONCLUSIONS: Our data showed a close association between WMHs and Hcy, folate especially in PD-PIGD patients. It can be speculated that higher Hcy and lower folate probably played important roles in the development of WMHs and motor heterogeneity in PD.

Altered cortical thickness and structural covariance networks in chronic low back pain.

BACKGROUND: Despite regional brain structural changes having been reported in patients with chronic low back pain (CLBP), the topological properties of structural covariance networks (SCNs), which refer to the organization of the SCNs, remain unclear. This study applied graph theoretical analysis to explore the alterations of the topological properties of SCNs, aiming to comprehend the integration and separation of SCNs in patients with CLBP. METHODS: A total of 38 patients with CLBP and 38 healthy controls (HCs), balanced for age and sex, were scanned using three-dimensional T1-weighted magnetic resonance imaging. The cortical thickness was extracted from 68 brain regions, according to the Desikan-Killiany atlas, and used to reconstruct the SCNs. Subsequently, graph theoretical analysis was employed to evaluate the alterations of the topological properties in the SCNs of patients with CLBP. RESULTS: In comparison to HCs, patients with CLBP had less cortical thickness in the left superior frontal cortex. Additionally, the cortical thickness of the left superior frontal cortex was negatively correlated with the Visual Analogue Scale scores of patients with CLBP. Furthermore, patients with CLBP, relative to HCs, exhibited lower global efficiency and small-worldness, as well as a longer characteristic path length. This indicates a decline in the brain's capacity to transmit and process information, potentially impacting the processing of pain signals in patients with CLBP and contributing to the development of CLBP. In contrast, there were no significant differences in the clustering coefficient, local efficiency, nodal efficiency, nodal betweenness centrality, or nodal degree between the two groups. CONCLUSIONS: From the regional cortical thickness to the complex brain network level, our study demonstrated changes in the cortical thickness and topological properties of the SCNs in patients with CLBP, thus aiding in a better understanding of the pathophysiological mechanisms of CLBP.

Altered volume of the amygdala subregions in patients with chronic low back pain.

Background: Neuroimaging studies have suggested a pivotal role for the amygdala involvement in chronic low back pain (CLBP). However, the relationship between the amygdala subregions and CLBP has not yet been delineated. This study aimed to analyze whether the amygdala subregions were linked to the development of CLBP. Methods: A total of 45 patients with CLBP and 45 healthy controls (HCs) were included in this study. All subjects were asked to complete a three-dimensional T1-weighted magnetic resonance imaging (3D-T1 MRI) scan. FreeSurfer 7.3.2 was applied to preprocess the structural MRI images and segment the amygdala into nine subregions. Afterwards, comparisons were made between the two groups in terms of the volumes of the amygdala subregions. Correlation analysis is utilized to examine the relationship between the amygdala subregion and the scale scores, as well as the pain duration in patients with CLBP. Additionally, logistic regression was used to explore the risk of the amygdala and its subregions for CLBP. Results: In comparison to HCs, patients with CLBP exhibited a significant enlargement of the left central nucleus (Ce) and left cortical nucleus (Co). Furthermore, the increased volume of the left Ce was associated with a higher risk of CLBP. Conclusion: Our study suggests that the left Ce and left Co may be involved in the pathophysiological processes of CLBP. Moreover, the volume of the left Ce may be a biomarker for detecting the risk of CLBP.

Gray matter atrophy in Parkinson's disease with dementia: evidence from meta-analysis of voxel-based morphometry studies.

Voxel-based morphometry (VBM) studies have provided cumulative evidence of gray matter (GM) atrophy in patients with Parkinson's disease with dementia (PDD) relative to healthy controls (HC). However, not all the studies reported entirely consistent findings. A systematic search for VBM studies of PDD patients and HC subjects published in PubMed and Embase databases from January 2000 to June 2012 was conducted. Meta-analysis was performed by using a newly improved voxel-based meta-analytic technique, effect size signed differential mapping, to quantitatively explore the GM abnormalities between PDD patients and HC subjects. A total of 6 cross-sectional VBM studies involving 105 PDD patients and 131 HC subjects met the inclusion criteria. Considerable regional GM decrease was detected in the medial temporal lobe (MTL) and basal ganglia. The findings of the present study remained largely unchanged in the entire brain jackknife sensitivity analyses. Meta-regression showed dementia severity correlated with the left MTL. The present meta-analysis provided evidence of PDD-related GM atrophy, which suggested MTL and basal ganglia were implicated in PDD. This finding could give us further insight about the pathophysiological basis revealed by structure abnormalities in PDD.

Gray matter atrophy in progressive supranuclear palsy: meta-analysis of voxel-based morphometry studies.

Voxel-based morphometry (VBM) studies have provided cumulative evidence of gray matter (GM) atrophy in patients with progressive supranuclear palsy (PSP) relative to healthy controls (HC). However, not all findings have been entirely concordant. Herein, we performed a quantitative meta-analysis study in order to consistently quantify GM anomalies in PSP. We conducted a systematic search for VBM studies of PSP patients and HC using PubMed and Embase databases from January 2000 to May 2012. Meta-analysis of these VBM studies was performed using a newly improved voxel-based meta-analytic technique, effect-size signed differential mapping. A total of 9 cross-sectional VBM studies that involved 143 PSP patients and 216 HC subjects met the inclusion criteria. Considerable regional GM volume decrease was detected in the thalamus, basal ganglia, midbrain, insular cortex, and frontal cortex. These findings remained largely unchanged following jackknife sensitivity analyses. The present meta-analysis provided evidence of PSP-specific GM atrophy. This finding might help contribute to our understanding of the neurobiological basis underlying PSP.

Gray matter atrophy in behavioral variant frontotemporal dementia: a meta-analysis of voxel-based morphometry studies.

BACKGROUND: Structural neuroimaging studies on behavioral variant frontotemporal dementia (bvFTD) using the voxel-based morphometry (VBM) method reported not entirely consistent findings. METHODS: A systematic review of VBM studies of bvFTD patients and healthy controls (HC) published in PubMed and Embase databases from 2000 to June 2011 was conducted. Meta-analysis was performed using a newly improved voxel-based meta-analytic tool, namely, effect size signed differential mapping, to quantitatively explore the gray matter (GM) changes between bvFTD patients and HC subjects. RESULTS: 11 VBM studies involving 237 bvFTD patients and 297 HC subjects met the inclusion criteria. Considerable regional GM volume decrease was detected in the anterior medial frontal cortex (BA 9), extending to other frontal areas (BA 8, 10, 46, 24, 32), and other brain areas, such as the insula cortex, as well as the subcortical striatal regions in patients with bvFTD compared with HC subjects. The findings of the present study remain largely unchanged in the entire brain jackknife sensitivity analyses. CONCLUSIONS: The present meta-analysis provides evidence of GM changes in the frontal-striatal-limbic brain areas in patients with bvFTD. Furthermore, GM atrophy in the fron-toinsular cortex and anterior cingulate cortex may be important anatomical changes for the diagnosis of patients with bvFTD.

GLIS1 rs797906: an increased risk factor for late-onset Parkinson's disease in the Han Chinese population.

BACKGROUND: Single nucleotide polymorphism (SNP) rs797906 of the GLIS family zinc finger 1 (GLIS1) gene has been linked to a risk of Parkinson's disease (PD) in genome-wide association studies of Caucasian populations. METHODS: A total of 380 unrelated Han patients with PD from the Department of Neurology, West China Hospital of Sichuan University, and 275 unrelated Han Chinese healthy controls (HC) from the same region were included. rs797906 SNP was genotyped using Sequenom iPLEX Assay technology. RESULTS: No significant differences were found in the genotype and allele frequencies for rs797906 between the PD and HC groups. There were no significant differences in genotype frequencies between early-onset PD and HC groups and between late-onset PD and HC groups. The frequency of allele 'A' for rs797906 in the late-onset PD group was significantly higher than that in the HC group (p = 0.046, OR 1.2726, 95% CI 1.0039-1.6132). Moreover, the frequency of allele 'A' in the late-onset PD group was significantly higher than that in the early-onset PD group (p = 0.001). CONCLUSION: We have found that allele 'A' of rs797906 SNP increases the risk for late-onset PD in the Han Chinese population. More associated studies with larger numbers of participants are needed to confirm the present findings.

Analysis of the genotype of diacylglycerol kinase delta single-nucleotide polymorphisms in Parkinson disease in the Han Chinese population.

Numerous Single-Nucleotide Polymorphisms (SNPs) of the Diacylglycerol Kinase Delta (DGKD) isoform 1 gene have been associated with Parkinson Disease (PD) in the genome-wide association studies of Caucasian population. This association has not been proven in the Han Chinese PD patients. This study included 376 unrelated Han Chinese PD patients from West China and 273 unrelated healthy controls from the same region. Five SNPs (rs2971859, rs1550532, rs2305539, rs2034762, and rs2242102) were genotyped using the Sequenom iPLEX Assay technology. No significant differences were observed in genotype frequencies and in the Minor Allele Frequency (MAF) in the five SNPs between PD patients and controls, early-onset PD and controls, late-onset PD and controls, and between early-onset and late-onset PD patients. The present study is the first to report on the lack of association of DGKD SNPs with PD in the Han Chinese population. More related studies involving larger numbers of participants are necessary to confirm the present finding.

Abnormal Spontaneous Neural Activity in Parkinson's Disease With "pure" Apathy.

BACKGROUND: Apathy is one of the most common non-motor symptoms of Parkinson's disease (PD). However, its pathophysiology remains unclear. METHODS: We analyzed resting-state functional magnetic resonance imaging (MRI) data acquired at a 3.0T MRI scanner using the amplitude of low-frequency fluctuation (ALFF) metric in 20 de novo, drug-naïve, non-demented PD patients with apathy (PD-A), 26 PD patients without apathy (PD-NA) without comorbidity of depressive or anxious symptoms, and 23 matched healthy control (HC) subjects. RESULTS: We found that the ALFF decreased significantly in the bilateral nucleus accumbens, dorsal anterior cingulate cortex (ACC), and left dorsolateral prefrontal cortex in patients with PD-A compared to patients with PD-NA and HC subjects. Furthermore, apathy severity was negatively correlated with the ALFF in the bilateral nucleus accumbens and dorsal ACC in the pooled patients with PD. CONCLUSION: The present study characterized the functional pattern of changes in spontaneous neural activity in patients with PD-A. With the aim to better elucidate the pathophysiological mechanisms responsible for these changes, this study controlled for the potentially confounding effects of dopaminergic medication, depression, anxiety, and global cognitive impairment. The findings of the current study add to the literature by highlighting potential abnormalities in mesocorticolimbic pathways involved in the development of apathy in PD.

Alterations of regional homogeneity in Parkinson's disease with "pure" apathy: A resting-state fMRI study.

BACKGROUND: Apathy is a prevalent and debilitating neuropsychiatric syndrome in Parkinson's disease (PD). However, its neural mechanisms are still unclear. METHODS: Forty-six de novo, drug-naïve, non-demented PD patients without depressive or anxious symptoms, of whom 26 were apathetic (PD-A) and 20 were not (PD-NA) according to the Apathy Scale (AS), and 23 matched healthy control (HC) subjects were enrolled in this study. The regional homogeneity (ReHo) approach based on resting-state functional MRI on a 3-T MR system was used to investigate apathy related local brain activity. RESULTS: Compared with both patients with PD-NA and HC subjects, patients with PD-A showed significantly lower ReHo values in the dorsal anterior cingulate cortex (ACC) and right caudate. Both the PD-A and PD-NA groups also demonstrated lower ReHo values in the right putamen compared to the HC group. Further correlation analyses revealed that AS scores were negatively correlated with the ReHo values in the dorsal ACC and right caudate in the pooled patients with PD. LIMITATIONS: The present results are preliminary due to the small sample size in the study. CONCLUSIONS: This study used ReHo for the first time to characterize "pure" apathy related regional spontaneous brain function within the frontostriatal circuits in PD. Our findings suggest that abnormal brain activity in the dorsal ACC and caudate may involve the pathological mechanisms of apathy in PD.

Obstructive sleep apnea in Parkinson's disease: a study in 239 Chinese patients.

OBJECTIVE: Our objective was to explore the clinical characteristics of Parkinson's disease (PD) comorbidity with obstructive sleep apnea (OSA), explore the correlation between OSA and PD features and identify factors that are independent predictors of OSA in PD patients. METHODS: In sum, 239 PD patients were divided into two groups according to the presence of OSA (apnea-hypopnea index (AHI) score ≥5) (PD-OSA vs PD-non-OSA). Blinded to sleep apnea status, participants underwent an extensive assessment to determine demographic features, concomitant disease, disease severity, polysomnography (PSG) characteristics and non-motor symptoms (NMSs). RESULTS: Of the 239 patients, 66 (27.62%) had an AHI score ≥5, including 14.2% (34/239) with mild, 6.7% (16/239) with moderate, and 6.7% (16/239) with severe sleep apnea. The binary logistic regression analyses indicated that age and male gender were risk factors for OSA, while rapid eye movement (REM) sleep disorder (RBD) and higher Levodopa equivalent dose (LED) were protective factors for OSA. PD-OSA patients had higher Epworth Sleepiness Scale (ESS) scores than those of PD-non-OSA patients. No differences were found for other NMSs between groups. CONCLUSION: Our data suggest that OSA in PD was lower in patients with RBD and higher LED. RBD and higher LDEs were significant protective factors for OSA in PD. OSA in PD was increased with age and male gender. Age and male gender were risk factors for OSA in PD. OSA can aggravate excessive daytime somnolence in PD patients but is not associated with other NMSs.

Alterations of brain local functional connectivity in amnestic mild cognitive impairment.

BACKGROUND: Resting-state functional magnetic resonance imaging studies using a regional homogeneity (ReHo) method have reported that amnestic mild cognitive impairment (aMCI) was associated with abnormalities in local functional connectivity. However, their results were not conclusive. METHODS: Seed-based d Mapping was used to conduct a coordinate-based meta-analysis to identify consistent ReHo alterations in aMCI. RESULTS: We identified 10 studies with 11 datasets suitable for inclusion, including 378 patients with aMCI and 435 healthy controls. This meta-analysis identified significant ReHo alterations in patients with aMCI relative to healthy controls, mainly within the default mode network (DMN) (bilateral posterior cingulate cortex [PCC], right angular gyrus, bilateral middle temporal gyri, and left parahippocampal gyrus/hippocampus), executive control network (right superior parietal lobule and dorsolateral prefrontal cortex), visual network (right lingual gyrus and left middle occipital gyrus), and sensorimotor network (right paracentral lobule/supplementary motor area, right postcentral gyrus and left posterior insula). Significant heterogeneity of ReHo alterations in the bilateral PCC, left parahippocampal gyrus/hippocampus, and right superior parietal lobule/angular gyrus was observed. Exploratory meta-regression analyses indicated that general cognitive function, gender distribution, age, and education level partially contributed to this heterogeneity. CONCLUSIONS: This study provides provisional evidence that aMCI is associated with abnormal ReHo within the DMN, executive control network, visual network, and sensorimotor network. These local functional connectivity alterations suggest coexistence of functional deficits and compensation in these networks. These findings contribute to the modeling of brain functional connectomes and to a better understanding of the neural substrates of aMCI. Confounding factors merit much attention and warrant future investigations.

Correction to: Alterations of brain local functional connectivity in amnestic mild cognitive impairment.

[This corrects the article DOI: 10.1186/s40035-018-0134-8.].

Cerebral glucose metabolic prediction from amnestic mild cognitive impairment to Alzheimer's dementia: a meta-analysis.

Brain 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been utilized to monitor disease conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's dementia (AD). However, the conversion patterns of FDG-PET metabolism across studies are not conclusive. We conducted a voxel-wise meta-analysis using Seed-based d Mapping that included 10 baseline voxel-wise FDG-PET comparisons between 93 aMCI converters and 129 aMCI non-converters from nine longitudinal studies. The most robust and reliable metabolic alterations that predicted conversion from aMCI to AD were localized in the left posterior cingulate cortex (PCC)/precuneus. Furthermore, meta-regression analyses indicated that baseline mean age and severity of cognitive impairment, and follow-up duration were significant moderators for metabolic alterations in aMCI converters. Our study revealed hypometabolism in the left PCC/precuneus as an early feature in the development of AD. This finding has important implications in understanding the neural substrates for AD conversion and could serve as a potential imaging biomarker for early detection of AD as well as for tracking disease progression at the predementia stage.

Aberrant pattern of regional cerebral blood flow in Alzheimer's disease: a voxel-wise meta-analysis of arterial spin labeling MR imaging studies.

Many studies have applied arterial spin labeling (ASL) to characterize cerebral perfusion patterns of Alzheimer's disease (AD). However, findings across studies are not conclusive. A quantitatively voxel-wise meta-analysis to pool the resting-state ASL studies that measure regional cerebral blood flow (rCBF) alterations in AD was conducted to identify the most consistent and replicable perfusion pattern using seed-based d mapping. The meta-analysis, including 17 ASL studies encompassing 327 AD patients and 357 healthy controls, demonstrated that decreased rCBF in AD patients relative to healthy controls were consistently identified in the bilateral posterior cingulate cortices (PCC)/precuneus, bilateral inferior parietal lobules (IPLs), and left dorsolateral prefrontal cortex. The meta-regression analysis showed that more severe cognitive impairment in the AD samples correlated with greater decreases of rCBF in the bilateral PCC and left IPL. This study characterizes an aberrant ASL-rCBF perfusion pattern of AD involving the posterior default mode network and executive network, which are implicated in its pathophysiology and hold promise for developing imaging biomarkers.