Publications by authors named "Beisha Tang"

309 Publications

Performance of Plasma Amyloid β, Total Tau, and Neurofilament Light Chain in the Identification of Probable Alzheimer's Disease in South China.

Front Aging Neurosci 2021 27;13:749649. Epub 2021 Oct 27.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Alzheimer's disease (AD) is the most common type of dementia and has no effective treatment to date. It is essential to develop a minimally invasive blood-based biomarker as a tool for screening the general population, but the efficacy remains controversial. This cross-sectional study aimed to evaluate the ability of plasma biomarkers, including amyloid β (Aβ), total tau (t-tau), and neurofilament light chain (NfL), to detect probable AD in the South Chinese population. A total of 277 patients with a clinical diagnosis of probable AD and 153 healthy controls with normal cognitive function (CN) were enrolled in this study. The levels of plasma Aβ42, Aβ40, t-tau, and NfL were detected using ultra-sensitive immune-based assays (SIMOA). Lumbar puncture was conducted in 89 patients with AD to detect Aβ42, Aβ40, t-tau, and phosphorylated (p)-tau levels in the cerebrospinal fluid (CSF) and to evaluate the consistency between plasma and CSF biomarkers through correlation analysis. Finally, the diagnostic value of plasma biomarkers was further assessed by constructing a receiver operating characteristic (ROC) curve. After adjusting for age, sex, and the apolipoprotein E () alleles, compared to the CN group, the plasma t-tau, and NfL were significantly increased in the AD group ( < 0.01, Bonferroni correction). Correlation analysis showed that only the plasma t-tau level was positively correlated with the CSF t-tau levels ( = 0.319, = 0.003). The diagnostic model combining plasma t-tau and NfL levels, and age, sex, and alleles, showed the best performance for the identification of probable AD [area under the curve (AUC) = 0.89, sensitivity = 82.31%, specificity = 83.66%]. Blood biomarkers can effectively distinguish patients with probable AD from controls and may be a non-invasive and efficient method for AD pre-screening.
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http://dx.doi.org/10.3389/fnagi.2021.749649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579066PMC
October 2021

Molecular chaperones and Parkinson's disease.

Neurobiol Dis 2021 Dec 7;160:105527. Epub 2021 Oct 7.

Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha 410011, China; Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha 410011, China. Electronic address:

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs). Mutations in PD-related genes lead to neuronal pathogenesis through various mechanisms, with known examples including SNCA/α-synuclein (PAKR1), Parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7), and LRRK2 (PARK8). Molecular chaperones/co-chaperones are proteins that aid the folding of other proteins into a functionally active conformation. It has been demonstrated that chaperones/co-chaperones interact with PD-related proteins and regulate their function in PD. HSP70, HSP90 and small heat shock proteins can prevent neurodegeneration by regulating α-syn misfolding, oligomerization and aggregation. The function of chaperones is regulated by co-chaperones such as HSP110, HSP40, HOP, CHIP, and BAG family proteins. Parkin, PINK1 and DJ-1 are PD-related proteins which are associated with mitochondrial function. Molecular chaperones regulate mitochondrial function and protein homeostasis by interacting with these PD-related proteins. This review discusses critical molecular chaperones/co-chaperones and PD-related proteins which contribute to the pathogenesis of PD, hoping to provide new molecular targets for therapeutic interventions to thwart the disease progression instead of only bringing symptomatic relief. Moreover, appreciating the critical role of chaperones in PD can also help us screen efficient biomarkers to identify PD at an early stage.
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http://dx.doi.org/10.1016/j.nbd.2021.105527DOI Listing
December 2021

METTL3-dependent RNA mA dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events.

Mol Neurodegener 2021 Sep 30;16(1):70. Epub 2021 Sep 30.

Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, 44106, USA.

Background: N6-methyladenosine (mA) modification of RNA influences fundamental aspects of RNA metabolism and mA dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA mA modification in the pathogenesis of Alzheimer disease (AD).

Methods: We investigated the mA modification and the expression of mA regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of mA levels on AD-related deficits both in vitro and in vivo.

Results: We found decreased neuronal mA levels along with significantly reduced expression of mA methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal mA modification in the hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied by extensive synaptic loss and neuronal death along with multiple AD-related cellular alterations including oxidative stress and aberrant cell cycle events in vivo. Inhibition of oxidative stress or cell cycle alleviated shMettl3-induced apoptotic activation and neuronal damage in primary neurons. Restored mA modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble Aβ oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued Aβ-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued Aβ-induced synaptic damage and cognitive impairment in vivo.

Conclusions: Collectively, these data suggested that METTL3 reduction-mediated mA dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.
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http://dx.doi.org/10.1186/s13024-021-00484-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482683PMC
September 2021

Effect of CAG repeats on the age at onset of patients with spinocerebellar ataxia type 2 in China.

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2021 Aug;46(8):793-799

Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008.

Objectives: Spinocerebellar ataxia type 2 (SCA2) is one of the most common autosomal dominant ataxias in the world. Several reports revealed that CAG repeats in some polyQ-containing genes may affect the age at onset (AAO) of patients with SCA2, however, little studies were conducted among Chinese patients with SCA2. Thus, the aim of this study is to evaluate the effect of CAG repeats on the AAO of patients with SCA2 in China.

Methods: A total of 119 patients with SCA2 were enrolled and were divided into 2 groups according to their major phenotype: 17 patients from 9 families with Parkinson's syndrome were grouped as the Parkinson's disease-SCA2 (PD-SAC2); 91 patients from 66 SCA2 families and 11 sporadic SCA2 patients were grouped as the ataxia-SCA2 (A-SCA2). Blood samples were obtained from the subjects, and the CAG repeat length in ATXN2 and other (CAG)-containing genes was screened using fluorescent PCR. The Spearman's rank correlation between the CAG repeat length in (CAG)-containing genes and AAO was analyzed. Regression analysis was performed to investigate whether the CAG repeat length could explain the variant of AAO. A -test was used to compare the difference of CAG repeat length in (CAG)-containing genes between the PD-SAC2 and A-SCA2 groups.

Results: The CAG repeat length in the longer allele of ATXN2 was negatively correlated with AAO of SCA2 (=-0.251, <0.05), and the CAG repeat length could explain 41.7% of the variation of AAO. AAO negatively correlated with the CAG repeat length in the shorter allele of ATXN7 (=-0.251, =0.006) or in the longer allele of TBP gene (=-0.197, =0.034). A tendency of delay in the AAO was also observed in patients with SCA2 carrying the CAG repeat within the ATXN3, CACNA1A, ATXN7, TBP, and RAI1. In addition, we found that the CAG repeat length in ATXN7 and ATXN2 between the A-SCA2 and the PD-SCA2 groups was significantly different (both <0.05).

Conclusions: The CAG repeat in ATXN2 is a major genetic factor for the AAO of patients with SCA2 in China. The CAG repeat length in ATXN3, CACNA1A, ATXN7, TBP, and RAI1 genes might be a potential factor associated with the AAO of SCA2. The CAG repeat in ATXN7 might be a potential factor affecting the Parkinson's syndrome in SCA2.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2021.210230DOI Listing
August 2021

CRISPR/Cas9 mediated gene correction ameliorates abnormal phenotypes in spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cells.

Transl Psychiatry 2021 09 17;11(1):479. Epub 2021 Sep 17.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive autosomal dominant neurodegenerative disease caused by abnormal CAG repeats in the exon 10 of ATXN3. The accumulation of the mutant ataxin-3 proteins carrying expanded polyglutamine (polyQ) leads to selective degeneration of neurons. Since the pathogenesis of SCA3 has not been fully elucidated, and no effective therapies have been identified, it is crucial to investigate the pathogenesis and seek new therapeutic strategies of SCA3. Induced pluripotent stem cells (iPSCs) can be used as the ideal cell model for the molecular pathogenesis of polyQ diseases. Abnormal CAG expansions mediated by CRISPR/Cas9 genome engineering technologies have shown promising potential for the treatment of polyQ diseases, including SCA3. In this study, SCA3-iPSCs can be corrected by the replacement of the abnormal CAG expansions (74 CAG) with normal repeats (17 CAG) using CRISPR/Cas9-mediated homologous recombination (HR) strategy. Besides, corrected SCA3-iPSCs retained pluripotent and normal karyotype, which can be differentiated into a neural stem cell (NSCs) and neuronal cells, and maintained electrophysiological characteristics. The expression of differentiation markers and electrophysiological characteristics were similar among the neuronal differentiation from normal control iPSCs (Ctrl-iPSCs), SCA3-iPSCs, and isogenic control SCA3-iPSCs. Furthermore, this study proved that the phenotypic abnormalities in SCA3 neurons, including aggregated IC2-polyQ protein, decreased mitochondrial membrane potential (MMP) and glutathione expressions, increased reactive oxygen species (ROS), intracellular Ca concentrations, and lipid peroxidase malondialdehyde (MDA) levels, all were rescued in the corrected SCA3-NCs. For the first time, this study demonstrated the feasibility of CRISPR/Cas9-mediated HR strategy to precisely repair SCA3-iPSCs, and reverse the corresponding abnormal disease phenotypes. In addition, the importance of genetic control using CRISPR/Cas9-mediated iPSCs for disease modeling. Our work may contribute to providing a potential ideal model for molecular mechanism research and autologous stem cell therapy of SCA3 or other polyQ diseases, and offer a good gene therapy strategy for future treatment.
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http://dx.doi.org/10.1038/s41398-021-01605-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448778PMC
September 2021

p38 MAPK-mediated loss of nuclear RNase III enzyme Drosha underlies amyloid beta-induced neuronal stress in Alzheimer's disease.

Aging Cell 2021 10 16;20(10):e13434. Epub 2021 Sep 16.

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia, USA.

MicroRNAs (miRNAs) are small noncoding RNAs ubiquitously expressed in the brain and regulate gene expression at the post-transcriptional level. The nuclear RNase III enzyme Drosha initiates the maturation process of miRNAs in the nucleus. Strong evidence suggests that dysregulation of miRNAs is involved in many neurological disorders including Alzheimer's disease (AD). Dysfunction of miRNA biogenesis components may be involved in the processes of those diseases. However, the role of Drosha in AD remains unknown. By using immunohistochemistry, biochemistry, and subcellular fractionation methods, we show here that the level of Drosha protein was significantly lower in the postmortem brain of human AD patients as well as in the transgenic rat model of AD. Interestingly, Drosha level was specifically reduced in neurons of the cortex and hippocampus but not in the cerebellum in the AD brain samples. In primary cortical neurons, amyloid-beta (Aβ) oligomers caused a p38 MAPK-dependent phosphorylation of Drosha, leading to its redistribution from the nucleus to the cytoplasm and a decrease in its level. This loss of Drosha function preceded Aβ-induced neuronal death. Importantly, inhibition of p38 MAPK activity or overexpression of Drosha protected neurons from Aβ oligomers-induced apoptosis. Taken together, these results establish a role for p38 MAPK-Drosha pathway in modulating neuronal viability under Aβ oligomers stress condition and implicate loss of Drosha as a key molecular change in the pathogenesis of AD.
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http://dx.doi.org/10.1111/acel.13434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521488PMC
October 2021

Blood Neurofilament Light Chain in Genetic Ataxia: A Meta-Analysis.

Mov Disord 2021 Sep 14. Epub 2021 Sep 14.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Background: No comprehensive meta-analysis has ever been performed to assess the value of neurofilament light chain (NfL) as a biomarker in genetic ataxia.

Objective: We conducted a meta-analysis to summarize NfL concentration and evaluate its utility as a biomarker in genetic ataxia.

Methods: Studies were included if they reported NfL concentration of genetic ataxia. We used log (mean ± SD) NfL to describe mean raw value of NfL. The effect size of NfL between genetic ataxia and healthy controls (HC) was expressed by mean difference. Correlation between NfL and disease severity was calculated.

Results: We identified 11 studies of 624 HC and 1006 patients, here referred to as spinocerebellar ataxia (SCA1, 2, 3, 6, and 7), Friedreich ataxia (FRDA), and ataxia telangiectasia (A-T). The concentration of blood NfL (bNfL) elevated with proximity to expected onset, and progressively increased from asymptomatic to preclinical to clinical stage in SCA3. Compared with HC, bNfL levels were significantly higher in SCA1, 2, 3, and 7, FRDA, as well as A-T, and the difference increased with the advancing disease in SCA3. bNfL levels correlated with disease severity in SCA3. There was a significant correlation between bNfL and longitudinal progression in SCA3. Additionally, bNfL increased with age in HC, yet this is probably masked by higher disease-related effects on bNfL in genetic ataxia.

Conclusions: bNfL can be used as a potential biomarker to predict disease onset, severity, and progression of genetic ataxia. Reference-value setting of bNfL should be divided according to age. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28783DOI Listing
September 2021

Absence of coding somatic single nucleotide variants within well-known candidate genes in late-onset sporadic Alzheimer's Disease based on the analysis of multi-omics data.

Neurobiol Aging 2021 Dec 21;108:207-209. Epub 2021 Jul 21.

Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences; Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA; School of Psychology, Shaanxi Normal University, Xi'an, Shaanxi, China. Electronic address:

Somatic mutations arise randomly or are induced by environmental factors, which may increase the risk of Alzheimer's disease (AD). Identifying somatic mutations in sporadic AD (SAD) may provide new insight of the disease. To evaluate the potential contribution of somatic single nucleotide variations (SNVs), particularly that of well-known AD-candidate genes, we investigated sequencing data sets from four platforms: whole-genome sequencing (WGS), deep whole-exome sequencing (WES) on paired brain and liver samples, RNA sequencing (RNA-seq), and single-cell whole-genome sequencing (scWGS) of brain samples from 16 AD patients and 16 non-AD individuals. We found that the average number, mean variant allele fractions (VAFs) and mutational signatures of somatic SNVs have similar distributions between AD brains and non-AD brains. We did not identify any somatic SNVs within coding regions of the APP, PSEN1, PSEN2, nor in APOE. This study shows that somatic SNVs within the coding region of AD-candidate genes are unlikely to be a common causal factor for SAD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.07.010DOI Listing
December 2021

The role of genetics in neurodegenerative dementia: a large cohort study in South China.

NPJ Genom Med 2021 Aug 13;6(1):69. Epub 2021 Aug 13.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and complicated etiology. There exist potential genetic component overlaps between different neurodegenerative dementias. Here, 1795 patients with neurodegenerative dementias from South China were enrolled, including 1592 with Alzheimer's disease (AD), 110 with frontotemporal dementia (FTD), and 93 with dementia with Lewy bodies (DLB). Genes targeted sequencing analysis were performed. According to the American College of Medical Genetics (ACMG) guidelines, 39 pathogenic/likely pathogenic (P/LP) variants were identified in 47 unrelated patients in 14 different genes, including PSEN1, PSEN2, APP, MAPT, GRN, CHCHD10, TBK1, VCP, HTRA1, OPTN, SQSTM1, SIGMAR1, and abnormal repeat expansions in C9orf72 and HTT. Overall, 33.3% (13/39) of the variants were novel, the identified P/LP variants were seen in 2.2% (35/1592) and 10.9% (12/110) of AD and FTD cases, respectively. The overall molecular diagnostic rate was 2.6%. Among them, PSEN1 was the most frequently mutated gene (46.8%, 22/47), followed by PSEN2 and APP. Additionally, the age at onset of patients with P/LP variants (51.4 years), ranging from 30 to 83 years, was ~10 years earlier than those without P/LP variants (p < 0.05). This study sheds insight into the genetic spectrum and clinical manifestations of neurodegenerative dementias in South China, further expands the existing repertoire of P/LP variants involved in known dementia-associated genes. It provides a new perspective for basic research on genetic pathogenesis and novel guiding for clinical practice of neurodegenerative dementia.
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http://dx.doi.org/10.1038/s41525-021-00235-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363644PMC
August 2021

Genetic etiology of a Chinese ataxia cohort: Expanding the mutational spectrum of hereditary ataxias.

Parkinsonism Relat Disord 2021 Aug 10;89:120-127. Epub 2021 Jul 10.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China; Laboratory of Medical Genetics, Central South University, Changsha, China; School of Basic Medical Science, Central South University, Changsha, China. Electronic address:

Introduction: Hereditary ataxias demonstrate a high degree of clinical and genetic heterogeneity. Understanding the genetic etiology of hereditary ataxias is crucial for genetic counseling and clinical management.

Methods: The clinical and genetic data of patients with familial or sporadic ataxias who referred to our tertiary medical center were retrospectively analyzed. Probands in this study underwent SCA repeat expansion panel firstly to screen for repeat expansion SCAs; those with negative results had NGS-targeted panels or WES testing to detect conventional mutations.

Results: A total of 223 patients were enrolled from 206 families. 5 kinds of coexisting SCA repeat expansions were observed (SCA3/SCA17, SCA3/SCA8, SCA2/SCA8, SCA3/SCA12 and SCA8/SCA12) in 12 patients from 8 families, among which SCA2/SCA8, SCA8/SCA12 and SCA3/SCA12 were reported for the first time. The coexistence of expanded SCA3 with SCA17 alleles was the most common in our study. NGS identified pathogenic/likely pathogenic variants in 12 ataxia causative genes in 13 probands. Spastic paraplegia ataxia was the most common diagnosis. Six novel mutations were detected in five ataxia-related genes.

Conclusion: Coexistence may not specific to a certain SCA subtype and the frequency might have been underestimated before. SCA repeat expansion panel should be considered in patients with overlapping SCA features. In addition, our study broadened the conventional mutation spectrum in ataxia-related genes. These results facilitate a better understanding of the genetic basis for hereditary ataxias.
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http://dx.doi.org/10.1016/j.parkreldis.2021.07.010DOI Listing
August 2021

Mutation spectrum of amyotrophic lateral sclerosis in Central South China.

Neurobiol Aging 2021 Nov 19;107:181-188. Epub 2021 Jun 19.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; Laboratory of Medical Genetics, Central South University, Changsha, Hunan, People's Republic of China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, People's Republic of China; National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. Electronic address:

To analyze the mutational spectrum of known ALS causative genes in China ALS patients. We comprehensively analyzed 51 ALS causative genes by combining different sequencing technologies in 753 unrelated ALS patients from Central South China. The mean age at onset (AAO) was 53.7±11.4 years. The AAO was earlier in the autosomal dominant (AD) ALS patients than in the sporadic ALS (sALS) patients. Bulbar onset was more frequent in females than in males. SOD1 was the most frequently mutated gene in the AD-ALS and the sALS patients, followed by the ATXN2 and FUS genes in the AD-ALS patients and the NEK1 and CACNA1H genes in the sALS patients. Patients with RDVs in the SOD1 or FUS genes had an earlier AAO than the mean AAO of all the patients, while the patients with RDVs in the NEK1 gene showed later onset. SOD1 gene was the most commonly mutated gene in ALS patients in China, followed by ATXN2 and NEK1. The phenotype might be determined synergistically by sex and genetic variants.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.06.008DOI Listing
November 2021

Genotype and phenotype distribution of 435 patients with Charcot-Marie-Tooth disease from central south China.

Eur J Neurol 2021 11 26;28(11):3774-3783. Epub 2021 Jul 26.

Department of Neurology, Third Xiangya Hospital, Central South University, Changsha, China.

Background And Purpose: The purpose was to provide an overview of genotype and phenotype distribution in a cohort of patients with Charcot-Marie-Tooth disease (CMT) and related disorders from central south China.

Methods: In all, 435 patients were enrolled and detailed clinical data were collected. Multiplex ligation-dependent probe amplification for PMP22 duplication/deletion and CMT multi-gene panel sequencing were performed. Whole exome sequencing was further applied in the remaining patients who failed to achieve molecular diagnosis.

Results: Among the 435 patients, 216 had CMT1, 14 had hereditary neuropathy with pressure palsies (HNPP), 178 had CMT2, 24 had distal hereditary motor neuropathy (dHMN) and three had hereditary sensory and autonomic neuropathy (HSAN). The overall molecular diagnosis rate was 70%: 75.7% in CMT1, 100% in HNPP, 64.6% in CMT2, 41.7% in dHMN and 33.3% in HSAN. The most common four genotypes accounted for 68.9% of molecular diagnosed patients. Relatively frequent causes were missense changes in PMP22 (4.6%) and SH3TC2 (2.3%) in CMT1; and GDAP1 (5.1%), IGHMBP2 (4.5%) and MORC2 (3.9%) in CMT2. Twenty of 160 detected pathogenic variants and the associated phenotypes have not been previously reported. Broad phenotype spectra were observed in six genes, amongst which the pathogenic variants in BAG3 and SPTLC1 were detected in two sporadic patients presenting with the CMT2 phenotype.

Conclusions: Our results provided a unique genotypic and phenotypic landscape of patients with CMT and related disorders from central south China, including a relatively high proportion of CMT2 and lower occurrence of PMP22 duplication. The broad phenotype spectra in certain genes have advanced our understanding of CMT.
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http://dx.doi.org/10.1111/ene.15024DOI Listing
November 2021

Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis.

Front Neurol 2021 24;12:628710. Epub 2021 Jun 24.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases. Therefore, we performed this study to address these gaps. In the present study, serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson's disease (PD), and 82 healthy controls (HCs). Multiple comparisons revealed that no significant differences existed between patients with ALS and other neurodegenerative diseases in immunoglobulin and complement levels. Meta-analysis based on data from our cohort and eight published articles was performed to evaluate the serum immunoglobulin and complement between patients with ALS and HCs. The pooled results showed that patients with ALS had higher C4 levels than HCs. In addition, we found that the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs, and the correlations between age at onset of ALS and IgG or IgA levels were significant positive. In conclusion, our data supplement existing literature on understanding the role of peripheral immunity in ALS.
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http://dx.doi.org/10.3389/fneur.2021.628710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264193PMC
June 2021

Mitochondrial genome variations are associated with amyotrophic lateral sclerosis in patients from mainland China.

J Neurol 2021 Jun 15. Epub 2021 Jun 15.

Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, Hunan, People's Republic of China.

Background: Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder. Mitochondrial dysfunction is involved in the complex pathophysiology of ALS; however, the role of mitochondrial DNA (mtDNA) variants in ALS is poorly understood. We aimed to elucidate the role of mtDNA variants in the pathogenesis of ALS.

Methods: The mitochondrial haplogroups of 585 ALS patients and 371 healthy controls were determined; 38 ALS patients and 42 controls underwent long-range polymerase chain reaction combined with next-generation sequencing technology to analyze whole mitochondrial genome variants.

Results: A higher percentage of variants accumulated in ALS patients than in controls. Analysis of coding region variations that were further stratified by mtDNA genes revealed that nonsynonymous variants were more vulnerable in ALS patients than in controls, particularly in the ND4L, ND5, and ATP8 genes. Moreover, pathogenic nonsynonymous variants tended to over-represent in ALS patients. Unsurprisingly, nonsynonymous variants were not related to the phenotype. Haplogroup analysis did not found evidence of association between haplogroups with the risk of ALS, however, patients belonging to haplogroup Y and M7c were prone to develop later onset of ALS.

Conclusions: This is the first study to profile mtDNA variants in ALS patients from mainland China. Our results suggest that an increase in the number of nonsynonymous variants is linked to the pathogenesis of ALS. Moreover, haplogroup Y and M7c may modulate the clinical expression of ALS. Our findings provide independent, albeit limited, evidence for the role of mtDNA in the pathogenesis of ALS.
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http://dx.doi.org/10.1007/s00415-021-10659-7DOI Listing
June 2021

Anxiety and depression in spinocerebellar ataxia patients during the COVID-19 pandemic in China: A cross-sectional study.

J Clin Neurosci 2021 Jun 30;88:39-46. Epub 2021 Mar 30.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China. Electronic address:

Coronavirus disease 2019 (COVID-19) is currently a global concern, and the psychological impact cannot be overlooked. Our purpose was to evaluate the anxiety and depression in spinocerebellar ataxia (SCA) patients during the pandemic and to analyse the influencing factors. We conducted an online questionnaire survey among 307 SCA patients from China and selected 319 healthy people matched by sex and age as the control group. The questionnaire included general information, the self-rating anxiety scale (SAS), and the self-rating depression scale (SDS). The relevant factors included COVID-19 risk factors, age, sex, body mass index (BMI), educational background, disease course, score on the scale for the assessment and rating of ataxia (SARA), Mini-mental State Examination (MMSE) and International Cooperative Ataxia Rating Scale (ICARS). The proportion of SCA patients with anxiety was 34.9%, and the proportion with depression was 56.7%. The SAS and SDS scores of the SCA patients were significantly higher than those of the control group (SAS: 45.8 ± 10.1 vs. 40.6 ± 8.9, P < 0.01; SDS: 55.1 ± 12.2 vs. 43.6 ± 11.9, P < 0.01). In SCA3, the risk of exposure to COVID-19, educational level, disease course and the severity of ataxia may be factors affecting patients' mental health. More attention should be paid to the mental health of SCA patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.jocn.2021.03.004DOI Listing
June 2021

Gene4PD: A Comprehensive Genetic Database of Parkinson's Disease.

Front Neurosci 2021 26;15:679568. Epub 2021 Apr 26.

National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China.

Parkinson's disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30-50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with ( = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.
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http://dx.doi.org/10.3389/fnins.2021.679568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107430PMC
April 2021

Cross-Disorder Analysis of De Novo Mutations in Neuropsychiatric Disorders.

J Autism Dev Disord 2021 May 10. Epub 2021 May 10.

National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Xiangya Road, Kaifu District, Changsha, 410013, Hunan, China.

The clinical similarity among different neuropsychiatric disorders (NPDs) suggested a shared genetic basis. We catalogued 23,109 coding de novo mutations (DNMs) from 6511 patients with autism spectrum disorder (ASD), 4,293 undiagnosed developmental disorder (UDD), 933 epileptic encephalopathy (EE), 1022 intellectual disability (ID), 1094 schizophrenia (SCZ), and 3391 controls. We evaluated that putative functional DNMs contribute to 38.11%, 34.40%, 33.31%, 10.98% and 6.91% of patients with ID, EE, UDD, ASD and SCZ, respectively. Consistent with phenotype similarity and heterogeneity in different NPDs, they show different degree of genetic association. Cross-disorder analysis of DNMs prioritized 321 candidate genes (FDR < 0.05) and showed that genes shared in more disorders were more likely to exhibited specific expression pattern, functional pathway, genetic convergence, and genetic intolerance.
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http://dx.doi.org/10.1007/s10803-021-05031-7DOI Listing
May 2021

The role of NOTCH3 variants in Alzheimer's disease and subcortical vascular dementia in the Chinese population.

CNS Neurosci Ther 2021 08 4;27(8):930-940. Epub 2021 May 4.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Aims: NOTCH3 gene mutations predominantly cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a common etiology of subcortical vascular dementia (SVaD). Besides, there may be a pathogenic link between NOTCH3 variants and Alzheimer's disease (AD). We aimed to study the role of NOTCH3 variants in AD and SVaD patients.

Methods: We recruited 763 patients with dementia (667 AD and 96 SVaD) and 365 healthy controls from the Southern Han Chinese population. Targeted capture sequencing was performed on NOTCH3 coding and adjacent intron regions to detect the pathogenic variants in AD and SVaD. The relationship between common or rare NOTCH3 variants and AD was further analyzed using Plink1.9.

Results: Five known pathogenic variants (p.R182C, p.C201S, p.R544C, p.R607C, and p.R1006C) and two novel likely pathogenic variants (p.C201F and p.C1061F) were detected in 16 SVaD patients. Additionally, no pathogenic or likely pathogenic variants were found in AD patients. NOTCH3 was not associated with AD in either single-variant association analysis or gene-based association analysis.

Conclusion: Our findings broaden the mutational spectrum of NOTCH3 and validate the pathogenic role of NOTCH3 mutations in SVaD, but do not support the notion that NOTCH3 variation influences the risk of AD.
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http://dx.doi.org/10.1111/cns.13647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265940PMC
August 2021

New Model for Estimation of the Age at Onset in Spinocerebellar Ataxia Type 3.

Neurology 2021 06 23;96(23):e2885-e2895. Epub 2021 Apr 23.

From the Department of Neurology (L.P., Z.C., M.L., L.L., H.P., Y.S., Y.P., Q.D., S.W., G.Z., L.W., H.Y., L.H., Y.X., Z.T., N.W., Y.G., X.H., L.S., J.L., B.T., H.J.), Department of Pathology (C.W.), National Clinical Research Center for Geriatric Disorders (Z.C., L.S., B.T., H.J.), Xiangya Hospital, Central South University; Department of Neurology (Z.L.), The Second Xiangya Hospital, Central South University; Key Laboratory of Hunan Province in Neurodegenerative Disorders (Z.C., L.S., J.L., B.T., H.J.), Center for Medical Genetics School of Life Sciences (K.X., J.L., C.C.), Hunan Key Laboratory of Medical Genetics (K.X., J.L., C.C.), School of Computer Science and Engineering (R.Q.), and School of Basic Medical Science (H.J.), Central South University, Changsha, Hunan, China; Department of Neurology (T.K.), University of Bonn; and German Center for Neurodegenerative Diseases (DZNE) (T.K.), Bonn, Germany.

Objectives: The aim of this study was to develop an appropriate parametric survival model to predict patient's age at onset (AAO) for spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) populations from mainland China.

Methods: We compared the efficiency and performance of 6 parametric survival analysis methods (exponential, weibull, log-gaussian, gaussian, log-logistic, and logistic) based on cytosine-adenine-guanine (CAG) repeat length at to predict the probability of AAO in the largest cohort of patients with SCA3/MJD. A set of evaluation criteria, including -2 log-likelihood statistic, Akaike information criterion (AIC), bayesian information criterion (BIC), Nagelkerke R-squared (Nagelkerke R^2), and Cox-Snell residual plot, were used to identify the best model.

Results: Among these 6 parametric survival models, the logistic model had the lowest -2 log-likelihood (6,560.12), AIC (6,566.12), and BIC (6,566.14) and the highest value of Nagelkerke R^2 (0.54), with the closest graph to the bisector Cox-Snell residual graph. Therefore, the logistic survival model was the best fit to the studied data. Using the optimal logistic survival model, we indicated the age-specific probability distribution of AAO according to the CAG repeat size and current age.

Conclusions: We first demonstrated that the logistic survival model provided the best fit for AAO prediction in patients with SCA3/MJD from mainland China. This optimal model can be valuable in clinical and research. However, the rigorous clinical testing and practice of other independent cohorts are needed for its clinical application. A unified model across multiethnic cohorts is worth further exploration by identifying regional differences and significant modifiers in AAO determination.
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http://dx.doi.org/10.1212/WNL.0000000000012068DOI Listing
June 2021

GPCards: An integrated database of genotype-phenotype correlations in human genetic diseases.

Comput Struct Biotechnol J 2021 22;19:1603-1611. Epub 2021 Mar 22.

National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

Genotype-phenotype correlations are the basis of precision medicine of human genetic diseases. However, it remains a challenge for clinicians and researchers to conveniently access detailed individual-level clinical phenotypic features of patients with various genetic variants. To address this urgent need, we manually searched for genetic studies in PubMed and catalogued 8,309 genetic variants in 1,288 genes from 17,738 patients with detailed clinical phenotypic features from 1,855 publications. Based on genotype-phenotype correlations in this dataset, we developed an user-friendly online database called GPCards (http://genemed.tech/gpcards/), which not only provided the association between genetic diseases and disease genes, but also the prevalence of various clinical phenotypes related to disease genes and the patient-level mapping between these clinical phenotypes and genetic variants. To accelerate the interpretation of genetic variants, we integrated 62 well-known variant-level and gene-level genomic data sources, including functional predictions, allele frequencies in different populations, and disease-related information. Furthermore, GPCards enables automatic analyses of users' own genetic data, comprehensive annotation, prioritization of candidate functional variants, and identification of genotype-phenotype correlations using custom parameters. In conclusion, GPCards is expected to accelerate the interpretation of genotype-phenotype correlations, subtype classification, and candidate gene prioritisation in human genetic diseases.
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http://dx.doi.org/10.1016/j.csbj.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042245PMC
March 2021

Characterizing the Expression Patterns of Parkinson's Disease Associated Genes.

Front Neurosci 2021 1;15:629156. Epub 2021 Apr 1.

Department of Geriatrics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.

Background: The expression pattern represents a quantitative phenotype that provides an in-depth view of the molecular mechanism in Parkinson's disease (PD); however, the expression patterns of PD-associated genes (PAGs) and their relation to age at onset (AAO) remain unclear.

Methods: The known PD-causing genes and PD-risk genes, which were collected from latest published authoritative meta-analysis, were integrated as PAGs. The expression data from Genotype-Tissue Expression database, Allen Brian Map database, and BrainSpan database, were extracted to characterize the tissue specificity, inhibitory-excitatory neuron expression profile, and spatio-temporal expression pattern of PAGs, respectively. The AAO information of PD-causing gene was download from Gene4PD and MDSgene database.

Results: We prioritized 107 PAGs and found that the PAGs were more likely to be expressed in brain-related tissues than non-brain tissues and that more PAGs had higher expression levels in excitatory neurons than inhibitory neurons. In addition, we identified two spatio-temporal expression modules of PAGs in human brain: the first module showed a higher expression level in the adult period than in the prenatal period, and the second module showed the opposite features. It showed that more PAGs belong to the first module that the second module. Furthermore, we found that the median AAO of patients with mutations in PD-causing genes of the first module was lower than that of the second module.

Conclusion: In conclusion, this study provided comprehensive landscape of expression patterns, AAO features and their relationship for the first time, improving the understanding of pathogenesis, and precision medicine in PD.
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http://dx.doi.org/10.3389/fnins.2021.629156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049291PMC
April 2021

Generation of spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cell line (CSUXHi005-A) from human urine epithelial cells.

Stem Cell Res 2021 05 17;53:102289. Epub 2021 Mar 17.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Diseases, Central South University, Changsha, Hunan, China; Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China; School of Basic Medical Science, Central South University, Changsha, Hunan, China. Electronic address:

Urine epithelial cells were harvested from a 32-year old female patient with spinocerebellar ataxia type 3 (SCA3) and reprogrammed into induced pluripotent stem cells (iPSCs) by non-integration system. The SCA3 derived iPSCs line, CSUXHi005-A, maintained 76 CAG expansions in the ATXN3 gene, was characterized by the expression of pluripotency markers and normal karyotype. The newly generated iPSCs retain the ability to differentiate into three germ layers by teratoma test, which provide an ideal tool for disease modeling, drug screening, and cellular therapy.
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http://dx.doi.org/10.1016/j.scr.2021.102289DOI Listing
May 2021

Downregulation of TOP2 modulates neurodegeneration caused by GGGGCC expanded repeats.

Hum Mol Genet 2021 May;30(10):893-901

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

GGGGCC repeats in a non-coding region of the C9orf72 gene have been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We previously showed that the GGGGCC expanded repeats alone were sufficient to cause neurodegeneration in Drosophila. Recent evidence indicates that GGGGCC expanded repeats can modify various gene transcriptomes. To determine the role of these genes in GGGGCC-mediated neurotoxicity, we screened an established Drosophila model expressing GGGGCC expanded repeats in this study. Our results showed that knockdown of the DNA topoisomerase II (Top2) gene can specifically modulate GGGGCC-associated neurodegeneration of the eye. Furthermore, chemical inhibition of Top2 or siRNA-induced Top2 downregulation could alleviate the GGGGCC-mediated neurotoxicity in Drosophila assessed by eye neurodegeneration and locomotion impairment. By contrast, upregulated Top2 levels were detected in Drosophila strains, and moreover, TOP2A level was also upregulated in Neuro-2a cells expressing GGGGCC expanded repeats, as well as in the brains of Sod1G93A model mice. This indicated that elevated levels of TOP2A may be involved in a pathway common to the pathophysiology of distinct ALS forms. Moreover, through RNA-sequencing, a total of 67 genes, involved in the pathways of intracellular signaling cascades, peripheral nervous system development, and others, were identified as potential targets of TOP2A to modulate GGGGCC-mediated neurodegeneration.
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http://dx.doi.org/10.1093/hmg/ddab079DOI Listing
May 2021

Preliminary Study of hsa-mir-626 Change in the Cerebrospinal Fluid in Parkinson's Disease.

Neurol India 2021 Jan-Feb;69(1):115-118

Department of Neurology, The Second Xiangya Hospital, Changsha, China.

Context: A host of microRNAs have been reported to suppress tumor growth, invasion, and metastasis and play roles in neurodegeneration disorders. Moreover, microRNA changes are found in the peripheral blood, cerebrospinal fluid (CSF), and brain tissues of central nervous system diseases, including glioma, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, and depression. Compared with other body fluids, CSF can reflect the brain pathological processes more accurately.

Aims: To understand whether microRNA expression may be misregulated in patients with PD, and further discover potential diagnostic biomarkers and promising therapeutic targets for PD.

Materials And Methods: Here, through real-time reverse-transcription polymerase chain reaction (RT-PCR), we compared CSF microRNA from 15 PD patients, 11 AD patients, and 16 controls with other neurologic disorders, such as encephalitis and Guillain-Barre syndrome.

Results: Finally, we identified hsa-miR-626 changes in the CSF of PD patients. The mean expression level of hsa-miR-626 was significantly reduced in the CSF of PD patients compared with AD patients and controls.

Conclusions: Our approach provides a preliminary research for identifying biomarkers in the CSF that could be used for the detection, diagnosis, and monitoring of PD.
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http://dx.doi.org/10.4103/0028-3886.310102DOI Listing
June 2021

Recommendations for the diagnosis and treatment of paroxysmal kinesigenic dyskinesia: an expert consensus in China.

Transl Neurodegener 2021 02 16;10(1). Epub 2021 Feb 16.

Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin Medical University; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China.

Paroxysmal dyskinesias are a group of neurological diseases characterized by intermittent episodes of involuntary movements with different causes. Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesia and can be divided into primary and secondary types based on the etiology. Clinically, PKD is characterized by recurrent and transient attacks of involuntary movements precipitated by a sudden voluntary action. The major cause of primary PKD is genetic abnormalities, and the inheritance pattern of PKD is mainly autosomal-dominant with incomplete penetrance. The proline-rich transmembrane protein 2 (PRRT2) was the first identified causative gene of PKD, accounting for the majority of PKD cases worldwide. An increasing number of studies has revealed the clinical and genetic characteristics, as well as the underlying mechanisms of PKD. By seeking the views of domestic experts, we propose an expert consensus regarding the diagnosis and treatment of PKD to help establish standardized clinical evaluation and therapies for PKD. In this consensus, we review the clinical manifestations, etiology, clinical diagnostic criteria and therapeutic recommendations for PKD, and results of genetic analyses in PKD patients performed in domestic hospitals.
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http://dx.doi.org/10.1186/s40035-021-00231-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885391PMC
February 2021

FDG-PET Profiles of Extratemporal Metabolism as a Predictor of Surgical Failure in Temporal Lobe Epilepsy.

Front Med (Lausanne) 2020 14;7:605002. Epub 2020 Dec 14.

Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, China.

Metabolic abnormality in the extratemporal area on fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is not an uncommon finding in drug-resistant temporal lobe epilepsy (TLE), however the correlation between extratemporal metabolic abnormalities and surgical long-term prognosis has not been fully elucidated. We aim to investigate FDG-PET extratemporal metabolic profiles predictive of failure in surgery for TLE patients. Eighty-two patients with unilateral TLE (48 female, 34 male; 25.6 ± 10.6 years old; 37 left TLE, 45 right TLE) and 30 healthy age-matched controls were enrolled. Patients were classified either as experiencing seizure-recurrence (SZR, Engel class II through IV) or seizure-free (SZF, Engel class I) at least 1 year after surgery. Regional cerebral metabolism was evaluated by FDG-PET with statistical parametric mapping (SPM12). Abnormal metabolic profiles and patterns on FDG-PET in SZR group were evaluated and compared with those of healthy control and SZF subjects on SPM12. Volume and intensity as well as special brain areas of abnormal metabolism in temporal and extratemporal regions were quantified and visualized. With a median follow-up of 1.5 years, 60% of patients achieved Engel class I (SZF). SZR was associated with left TLE and widespread hypometabolism in FDG-PET visual assessment ( < 0.05). All patients had hypometabolism in the ipsilateral temporal lobe but SZR was not correlated with volume or intensity of temporal hypometabolism (median, 1,456 vs. 1,040 mm; > 0.05). SZR was correlated with extratemporal metabolic abnormalities that differed according to lateralization: in right TLE, SZR exhibited larger volume in extratemporal areas compared to SZF (median, 11,060 vs. 2,112 mm; < 0.05). Surgical failure was characterized by Cingulum_Ant_R/L, Frontal_Inf_Orb_R abnormal metabolism in extratemporal regions. In left TLE, SZR presented a larger involvement of extratemporal areas similar to right TLE but with no significant (median, 5,873 vs. 3,464 mm; > 0.05), Cingulum_Ant_ R/L, Parietal_Inf_L, Postcentral_L, and Precuneus_R involved metabolic abnormalities were correlated with SZR. Extratemporal metabolic profiles detected by FDG-PET may indicate a prominent cause of TLE surgery failure and should be considered in predictive models for epilepsy surgery. Seizure control after surgery might be improved by investigating extratemporal areas as candidates for resection or neuromodulation.
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http://dx.doi.org/10.3389/fmed.2020.605002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793721PMC
December 2020

Polyglutamine-expanded ataxin3 alter specific gene expressions through changing DNA methylation status in SCA3/MJD.

Aging (Albany NY) 2020 12 19;13(3):3680-3698. Epub 2020 Dec 19.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.

DNA methylation has recently been linked to transcriptional dysregulation and neuronal dysfunction in polyglutamine (polyQ) disease. This study aims to determine whether (CAG) expansion in perturbs DNA methylation status and affects gene expression. We analyzed DNA methylation throughout the genome using reduced representation bisulfite sequencing (RRBS) and confirmed the results using MethylTarget sequencing. Dynamic changes in DNA methylation, transcriptional and translational levels of specific genes were detected using BSP, qRT-PCR and western blot. In total, 135 differentially methylated regions (DMRs) were identified between SCA3/MJD and WT mouse cerebellum. KEGG analysis revealed differentially methylated genes involved in amino acid metabolism, Hedgehog signaling pathway, thyroid cancer, tumorigenesis and other pathways. We focused on DMRs that were directly associated with gene expression. On this basis, we further assessed 7 genes, including 13 DMRs, for DNA methylation validation and gene expression. We found that the methylation status of the DMRs of and was negatively associated with their transcriptional and translational levels and that alteration of the DNA methylation status of DMRs and the corresponding transcription occurred before dyskinesia in SCA3/MJD mice. These results revealed novel DNA methylation-regulated genes, and , which may be useful for understanding the pathogenesis of SCA3/MJD.
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http://dx.doi.org/10.18632/aging.202331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906150PMC
December 2020

Genetic and Clinical Features in 24 Chinese Distal Hereditary Motor Neuropathy Families.

Front Neurol 2020 14;11:603003. Epub 2020 Dec 14.

Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.

Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of inherited neuropathies. The objectives of this study were to report the clinical and genetic features of dHMN patients in a Chinese cohort. We performed clinical assessments and whole-exome sequencing in 24 dHMN families from Mainland China. We conducted a retrospective analysis of the data and investigated the frequency and clinical features of patients with a confirmed mutation. Two novel heterozygous mutations in , c.373G>C (p.E125Q) and c.1015G>A (p.G339R), were identified and corresponded to the typical dHMN-V phenotype. Together with families with , and mutations, 29.2% of families (7/24) acquired a definite genetic diagnosis. One novel heterozygous variant of uncertain significance, c.1834G>A (p.G612S) in , was identified in a patient with mild dHMN phenotype. Our study expanded the mutation spectrum of mutations and added evidence that mutations are associated with both axonal Charcot-Marie-Tooth and dHMN phenotypes. Mutations in genes encoding aminoamide tRNA synthetase (ARS) might be a frequent cause of autosomal dominant-dHMN, and mutation might account for a majority of autosomal recessive-dHMN cases. The relatively low genetic diagnosis yield indicated more causative dHMN genes need to be discovered.
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http://dx.doi.org/10.3389/fneur.2020.603003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767876PMC
December 2020
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