Bei Cao

Reduced functional connectivity in early-stage drug-naive Parkinson's disease: a resting-state fMRI study

Although cardinal motor symptoms in Parkinsons disease (PD) are attributed to dysfunction of corticostriatal loops, early clinical nonmotor features are more likely to be associated with other pathologic mechanisms. We enrolled 52 early-stage drug-naive PD patients and 52 age- and sex-matched healthy controls and used resting-state functional connectivity magnetic resonance imaging to evaluate alteration of the functional brain network in PD, focusing in particular on the functional connectivity of the striatum subregions. Relative to healthy controls, the PD patient group showed reduced functional connectivity in mesolimbic-striatal and corticostriatal loops. Although the deceased functional connectivity within cortical sensorimotor areas was only evident in the most affected putamen subregion, reduced functional connectivity with mesolimbic regions was prevalent throughout the striatum. No increased functional connectivity was found in this cohort. By studying a cohort of early-stage drug-naive PD patients, we ruled out the potential confounding effect of prolonged antiparkinson medication use on the functional integration of neural networks. We demonstrate decreased functional integration across neural networks involving striatum, mesolimbic cortex, and sensorimotor regions in these patients and postulate that the prevalent disconnection in mesolimbic-striatal loops is associated with some early clinical nonmotor features in PD. This study offers additional insight into the early functional integration of neural networks in PD.

Functional connectome assessed using graph theory in drug-naive Parkinson’s disease

The purpose of this study is to investigate whether the topological organization of whole-brain functional network is disrupted in patients with Parkinson’s disease (PD). We employed resting-state functional MRI (R-fMRI) and graph theory to investigate the topological organization of the functional connectome in 47 early-stage drug-naïve PD patients and 47 healthy control subjects. Correlations between network properties and clinical variables were tested. Both the PD and control groups showed small-world architecture in brain functional networks. However, the PD patients had lower clustering coefficient and local efficiency relative to control subjects, indicating disrupted topologic organization and a shift toward randomization in their functional brain network. At node and connection level, reduced node centralities and connectivity strength were found mainly in temporal-occipital regions and also in sensorimotor regions of PD patients. In PD patients, altered global network properties correlated with cognitive function, while motor impairment was correlated with local connection changes. This study demonstrates a disruption of whole-brain topological organization of the functional brain networks in early-stage drug-naïve PD patients and this disruption might contribute to preclinical changes in cognitive process in these patients.

The impact of non-motor symptoms on the Health-Related Quality of Life of Parkinson's disease patients from Southwest China.

BACKGROUND The impact of non-motor symptoms (NMS) on the Health-Related Quality of Life (HRQoL) of patients with Parkinsons disease (PD) in the Chinese population are largely unknown. OBJECTIVES To study the impact of NMS on the HRQoL in Chinese PD patients. METHODS A total of 693 PD patients from Southwest China were included in the study. NMS of patients were evaluated by non-motor symptoms scale (NMSS) and Parkinsons disease questionnaire-39 item version (PDQ-39) was used to evaluate the HRQoL of PD. RESULTS The mean total score of NMSS was 37.2 ± 33.0 and the most prevalent NMS domain was sleep/fatigue (79.8%). There was a significant strong positive correlation between total NMSS score (rs = 0.71, P < 0.01), sleep/fatigue domain (rs = 0.60, P < 0.01) and PDQ-39 SI. Mood/apathy (rs = 0.55, P < 0.01), attention/memory (rs = 0.42, P < 0.01), gastrointestinal (rs = 0.44, P < 0.01) and Miscellany domains (rs = 0.46, P < 0.01) moderately correlated with PDQ-39 SI. A strong correlation was found between PDQ-39 SI (rs = 0.71, P < 0.01), emotional well-being (rs = 0.62, P < 0.01), cognitions (rs = 0.62, P < 0.01), and the total score of NMSS. Moderate correlation was found between mobility (rs = 0.45, P < 0.01), activities of daily living (rs = 0.43, P < 0.01), stigma (rs = 0.42, P < 0.01), communication (rs = 0.47, P < 0.01), bodily discomfort (rs = 0.46, P < 0.01) and the total score of NMSS. Female, H-Y stage, UPDRS-III and NMSS total score were the potential determinants of worse HRQoL of PD patients. CONCLUSIONS NMS have close association with various aspects of the HRQoL. Severe NMS may be related to dramatic decline of the HRQoL of PD patients.

Mutation scanning of the COQ2 gene in ethnic Chinese patients with multiple-system atrophy

Multiple-system atrophy (MSA) is a fatal neurodegenerative disorder with unknown etiology. It is widely considered to be a nongenetic disorder, but accumulating evidence suggests that several genes are linked to MSA. Recently, functionally impaired variants in the coenzyme Q2 4-hydroxybenzoate polyprenyltransferase (COQ2) gene have been reported to increase the risk of MSA in familial and sporadic Japanese patients. In this study, we investigated the mutation spectrum of COQ2 and analyzed the association between the common variant Val393Ala in exon 7 of COQ2 and MSA in a Chinese population. This study included 312 sporadic MSA patients from the Department of Neurology, West China Hospital of Sichuan University. All 7 exons of COQ2 in all the patients and exon 7 in 598 healthy controls (HCs) were directly sequenced. Novel candidate mutations and variations were confirmed by direct sequencing in 300 HCs. Two novel nonsynonymous variants, including p.R173H and p.N386I, and a reported missense variant, p.L162F, were found in 4 patients (p.R173H in 2 patients). However, the Val393Ala variant was not detected in the above 4 patients. Thirteen MSA patients (4.17%) and 18 controls (3.01%) had the heterozygous variant (Val393Ala/NM) of COQ2. No significant differences existed in the genotype frequency and minor allele frequency of Val393Ala between patients and controls or between MSA characterized predominantly by cerebellar ataxia and by pakinsonism groups. The mutation frequency of COQ2 is 1.28% in a Chinese MSA population. The common variant Val393Ala in COQ2 does not appear to be associated with MSA in ethnic Chinese.

Large C9orf72 repeat expansions are seen in Chinese patients with sporadic amyotrophic lateral sclerosis

An intronic GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene was considered as the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Caucasian populations. Using repeat-primed polymerase chain reaction analysis and Southern blotting methods, we assessed the frequency and size of hexanucleotide repeat expansion in a cohort of 918 sporadic ALS (SALS) patients and 632 control individuals of Han Chinese origin. We identified 8 (0.87%) of the SALS patients and none of control individuals as carriers of C9orf72 expansions with 700-3500 repeats. A comprehensive neuropsychological battery was conducted on 4 expansion-positive ALS patients, where 3 patients were found to have cognitive impairment. All expansion-positive patients were genotyped for the previously reported 20 single-nucleotide polymorphism (SNP) risk haplotypes on chromosome 9p21. Among them, 13 SNP risk haplotypes were shared in all expansion carriers, suggesting a common founder from European ancestry. Further meta-analysis demonstrated that the intermediate expansion size with 24-30 repeats, rare in both patients and controls, were significantly associated with the risk for ALS. To our knowledge, this is the first study to identify a proportion of Chinese SALS patients carrying this pathologic expansion of up to ∼3500 repeats and to completely elaborate the 20-SNP risk haplotypes in Chinese expansion-positive patients, providing indispensable evidence for the origin, geographical range, and population prevalence of the C9orf72-associated ALS.

Screening for cognitive impairment in a Chinese ALS population

Abstract Despite growing interest in cognitive impairment of ALS patients, there are only limited studies available that characterize cognitive deficits in the Chinese ALS population through highly sensitive and specific screening tools. The Chinese version of the Addenbrooke’s Cognitive Examination-revised (ACE-R) and mini-mental state examination (MMSE) were applied to evaluate cognitive function in 145 sporadic ALS patients and 50 healthy controls. The mean onset age was 50.72 ± 12.38 years. Results showed that the prevalence of cognitive deficits was 14.48% and 30.34% based on the MMSE and ACE-R, respectively. Patients had a broad range of cognitive impairment domains, including language (26.21%), orientation/attention (24.13%), visuospatial ability (24.13%), memory (23.45%) and verbal fluency (22.76%). Logistic regression indicated that older age of onset, female gender and lower educational levels were potential determinants of cognitive deficits in ALS. Multiple regression analyses showed that the cognitive deficit during the baseline visit was not associated with the progression rate of ALS. In conclusion, cognitive impairment is common in Chinese ALS patients, but does not necessarily worsen the progression of ALS. ACE-R is superior to MMSE in detecting deficits in patients. Cognitive impairment in ALS patients may relate to age of onset, female gender and lower education level.

Non-motor symptoms and quality of life in tremor dominant vs postural instability gait disorder Parkinson's disease patients.

To explore the differences in the features and impact on quality of life (QOL) of non‐motor symptoms (NMS) of tremor dominant (TD) and postural instability gait disorder (PIGD) phenotypes early Parkinsons disease (PD), as well as the determinants of poor QOL for TD and PIGD phenotypes.

Depression and anxiety in amyotrophic lateral sclerosis: Correlations between the distress of patients and caregivers

Introduction: Depression and anxiety are common in amyotrophic lateral sclerosis (ALS) patients and caregivers. Methods: In this study we investigated 93 ALS patients and their 93 caregivers. Depression and anxiety were quantified by the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale, respectively. Results: Very strong correlations between depression and anxiety were found among patients and their caregivers. The severity of depression and anxiety of patients correlated moderately with that of their caregivers. No correlations were found between the severity of depression and anxiety and ALS Functional Rating Scale–Revised (ALSFRS‐R) score or for disease duration among patients and caregivers. However, severity of depression and anxiety in caregivers correlated with their age. Conclusions: Depression and anxiety in ALS patients and their caregivers were associated closely with each other but not with physical disability or disease duration in our Chinese population. Muscle Nerve 51: 353–357, 2015

Genetic Variants of SNCA Are Associated with Susceptibility to Parkinson's Disease but Not Amyotrophic Lateral Sclerosis or Multiple System Atrophy in a Chinese Population.

Background The polymorphisms of α-synuclein (SNCA), rs3775444, rs3822086 and rs11931074 that are strongly associated with Parkinson’s disease (PD) in Caucasian populations, were examined in this study to elucidate the role of polymorphisms in different ethnic backgrounds. The possible associations of these three polymorphisms were also investigated in PD, amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA) in a Chinese population based on the overlapping of clinical manifestations and pathological characteristics of these three neurodegenerative diseases. Methods A total of 1276 PD, 885 sporadic ALS (SALS), 364 MSA patients, and 846 healthy controls (HCs) were included. All subjects were genotyped for the three polymorphisms using Sequenom iPLEX Assay technology. Results Significant differences in the genotype distributions (p = 5.99E-06 and p = 4.98E-06, respectively) and the minor allele frequency (MAF) (p = 2.16E-06 and p = 2.15E-06, respectively) of SNCA rs3822086 (C) and rs11931074 (G) were observed between PD and HCs. However, no differences were found in the genotype distributions and MAF of SNCA rs3775444 (T) between PD and HCs. Haplotype that incorporated the three SNPs further strengthened the association with PD (best haplotype, p = 9.62E-005). No significant differences in the genotype distributions and MAF of the SNPs were found between SALS and HCs, MSA and HCs, and subgroups of PD and SALS. However, the MAF of SNCA rs3775444 (T) was significantly higher in MSA patients with frontal lobe dysfunction than MSA patients without dysfunction (p = 0.0002, OR 2.53, 95%CI: 1.55-4.15). Conclusion Our results suggest that the rs3822086 (C) allele and rs11931074 (G) allele in SNCA decrease the risk for PD, and SNCA rs11931074 may affect frontal lobe dysfunction of MSA in the Chinese population. However, these SNCA polymorphisms are not likely a common cause of SALS or MSA.

Decreased Resting-State Interhemispheric Functional Connectivity in Parkinson's Disease.

Background. Abnormalities in white matter integrity and specific functional network alterations have been increasingly reported in patients with Parkinsons disease (PD). However, little is known about the inter-hemispheric interaction in PD. Methods. Fifty-one drug naive patients with PD and 51 age- and gender-matched healthy subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. We compared the inter-hemispheric resting-state functional connectivity between patients with PD and healthy controls, using the voxel-mirrored homotopic connectivity (VMHC) approach. Then, we correlated the results from VMHC and clinical features in PD patients. Results. Relative to healthy subject, patients exhibited significantly lower VMHC in putamen and cortical regions associated with sensory processing and motor control (involving sensorimotor and supramarginal cortex), which have been verified to play a critical role in PD. In addition, there were inverse relationships between the UPDRS motor scores and VMHC in the sensorimotor, and between the illness duration and VMHC in the supramarginal gyrus in PD patients. Conclusions. Our results suggest that the functional coordination between homotopic brain regions is impaired in PD patients, extending previous notions about the disconnection of corticostriatal circuit by providing new evidence supporting a disturbance in inter-hemispheric connections in PD.