Transcriptomic profiling and regulatory pathways of cardiac resident macrophages in aging.

Cardiovascular diseases are an array of age-related disorders, and accumulating evidence suggests a link between cardiac resident macrophages (CRMs) and the age-related disorders. However, how does CRMs alter with aging remains elusive. In the present study, aged mice (20 months old) have been employed to check for their cardiac structural and functional alterations, and the changes in the proportion of CRM subsets as well, followed by sorting of CRMs, including C-C Motif Chemokine Receptor 2 (CCR2)+ and CCR2- CRMs, which were subjected to Smart-Seq. Integrated analysis of the Smart-Seq data with three publicly available single-cell RNA-seq datasets revealed that inflammatory genes were drastic upregulated for both CCR2+ and CCR2- CRMs with aging, but genes germane to wound healing were downregulated for CCR2- CRMs, suggesting the differential functions of these two subsets. More importantly, inflammatory genes involved in damage sensing, complement cascades, and phagocytosis were largely upregulated in CCR2- CRMs, implying the imbalance of inflammatory response upon aging. Our work provides a comprehensive framework and transcriptional resource for assessing the impact of aging on CRMs with a potential for further understanding cardiac aging.

Atypical and delayed spinal cord MRI features of COVID-19-associated myelopathies: a report of four cases and literature review.

We reported four patients with coronavirus disease 2019 (COVID-19)-associated myelopathies, highlighting the delayed and atypical spinal cord magnetic resonance imaging (MRI) features and the literature review. All four patients were males, aged 37 to 72 years old. The latencies from COVID-19 to the onset of myelitis were 5, 15, 30, and 80 days. The initial symptoms were numbness and weakness of lower limbs in three cases, and back pain with weakness of lower limbs in one case. The peak symptoms included paraplegia, sphincter dysfunction, sensory disturbance level, and spastic gait. The EDSS scores were 7.5, 9.0, 9.0, and 7.5, respectively. Magnetic resonance imaging (MRI) showed delayed atypical spinal cord lesions at onset, i.e., two cases without lesions, one with linear spinal meningeal enhancement, and one with punctate lesions on T2-weighted imaging (T2WI). During the follow-up period, punctate, linear, and cloudy lesions in the lateral and posterior funiculus were seen on T2WI in the peak stage. The prominent features of spinal cord lesions were linear spinal meningeal enhancement, the mismatch of deteriorated clinical symptoms, and inapparent MRI findings. All four patients were left with an obvious disability, with two patients completely bedridden and two who could stand with support. This report highlights the recognition of COVID-19-associated myelopathy even months after initial infection, especially in patients with delayed and atypical spinal cord findings on MRI.

5' UTR CGG repeat expansion in GIPC1 is associated with oculopharyngodistal myopathy.

Oculopharyngodistal myopathy is a late-onset degenerative muscle disorder characterized by ptosis and weakness of the facial, pharyngeal, and distal limb muscles. A recent report suggested a non-coding trinucleotide repeat expansion in LRP12 to be associated with the disease. Here we report a genetic study in a Chinese cohort of 41 patients with the clinical diagnosis of oculopharyngodistal myopathy (21 cases from seven families and 20 sporadic cases). In a large family with 12 affected individuals, combined haplotype and linkage analysis revealed a maximum two-point logarithm of the odds (LOD) score of 3.3 in chromosomal region chr19p13.11-p13.2 and narrowed the candidate region to an interval of 4.5 Mb. Using a comprehensive strategy combining whole-exome sequencing, long-read sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal CGG repeat expansion in the 5' UTR of the GIPC1 gene that co-segregated with disease. Overall, the repeat expansion in GIPC1 was identified in 51.9% independent pedigrees (4/7 families and 10/20 sporadic cases), while the repeat expansion in LRP12 was only identified in one sporadic case (3.7%) in our cohort. The number of CGG repeats was <30 in controls but >60 in affected individuals. There was a slight correlation between repeat size and the age at onset. Both repeat expansion and retraction were observed during transmission but somatic instability was not evident. These results further support that non-coding CGG repeat expansion plays an essential role in the pathogenesis of oculopharyngodistal myopathy.

The non-syndromic clinical spectrums of mtDNA 3243A>G mutation.

The m.3243A >G mutation in the tRNA Leu (UUR) gene (MT-TL1) of the mitochondrial DNA is the most widely seen pathogenic mtDNA mutation which has major phenotypic variations. The clinical phenotype involves various organs such as the brain and nerves, skeletal muscles, heart, endocrine system, gastrointestinal tract, and skin. Some phenotypes conform to well established syndromes, while most of the symptoms appear individually or concomitant to other syndromes, making identification difficult. Furthermore, some progress has been made on cardiac manifestations as well as complications during pregnancy and perinatal period. This article provides a systematic review of the non-syndromic phenotypes and latest developments in m.3243A>G mutation.

Prevalence and Risk Factors of White Matter Lesions in Tibetan Patients Without Acute Stroke.

Background and Purpose- Studies on the prevalence and risk factors of white matter lesions (WMLs) in Tibetans living at high altitudes are scarce. We conducted this study to determine the prevalence and risks of WMLs in Tibetan patients without or with nonacute stroke. Methods- We undertook a retrospective analysis of medical records of patients treated at the People's Hospital of Tibetan Autonomous Region and identified a total of 301 Tibetan patients without acute stroke. WML severity was graded by the Fazekas Scale. We assessed the overall and age-specific prevalence of WMLs and analyzed associations between WMLs and related factors with univariate and multivariate methods. Results- Of the 301 patients, 87 (28.9%) had peripheral vertigo, 83 (27.3%) had primary headache, 52 (17.3%) had a history of stroke, 36 (12.0%) had an anxiety disorder, 29 (9.6%) had epilepsy, 12 (4.0%) had infections of the central nervous system, and 3 (1.0%) had undetermined diseases. WMLs were present in 245 (81.4%) patients, and 54 (17.9%) were younger than 40 years. Univariate analysis showed that age, history of cerebral infarction, hypertension, the thickness of the common carotid artery intima, and plaque within the intracarotid artery were related risks for WMLs. Ordered logistic analysis showed that age, history of cerebral ischemic stroke, hypertension, male sex, and atrial fibrillation were associated with WML severity. Conclusions- Risk factors for WMLs appear similar for Tibetans residing at high altitudes and individuals living in the plains. Further investigations are needed to determine whether Tibetans residing at high altitudes have a higher burden of WMLs than inhabitants of the plains.

Characteristics of acute ischemic stroke in hospitalized patients in Tibet: a retrospective comparative study.

BACKGROUND: Numerous studies on acute ischemic stroke (AIS) have been conducted at low-altitude regions, and the related findings have been used to guide clinical management. However, corresponding studies at high altitude are few. This study aimed to analyse the clinical characteristics of AIS patients at high-altitude regions through a hospital-based comparative study between Tibet and Beijing. METHODS: This study included the diagnoses of AIS patients from People's Hospital of Tibet Autonomous Region (PHOTAR) and Peking University First Hospital (PUFH) between 1 January 2014 and 31 December 2017, where data including patient demographics, treatment time, onset season, risk factors, infarction location, laboratory data, image examination results, treatments, and AIS subtype were collected and compared. Continuous and categorical variables were analysed with a two-sample t-test or Wilcoxon rank sum test and chi-square test, respectively. Significant risk factors were examined with binary logistic regression analysis. RESULTS: In total, 236 and 1021 inpatients from PHOTAR and PUFH were included, respectively. The PHOTAR patients were younger than the PUFH patients (P < 0.001). Young adult stroke, erythrocytosis, and hyperhomocysteinemia were more frequent in PHOTAR patients (all P < 0.001). Other vascular risk factors, including hypertension, diabetes mellitus, hyperlipidaemia, smoking and alcohol consumption history, were less prevalent in PHOTAR patients than in PUFH patients. The rate of intravenous thrombolysis and the rate of within intravenous thrombolysis window time were also lower in PHOTAR patients (both P < 0.001). The PHOTAR group also tended to have anterior circulation infarction. Erythrocytosis and hyperhomocysteinemia were independent risk factors in PHOTAR, and young adults accounted for a larger proportion of stroke cases. CONCLUSION: In Tibet, AIS patients were relatively younger, and anterior circulation infarctions were more common. Erythrocytosis and hyperhomocysteinemia may contribute to these differences. Here, young adult stroke also accounted for a higher proportion, and this may be associated with erythrocytosis. Our findings present the first hospital-based comparative study in Tibet and may contribute to policies for stroke prevention in this region.

Acute mitochondrial myopathy with respiratory insufficiency and motor axonal polyneuropathy.

BACKGROUND: Mitochondrial myopathies (MMs) are mainly presented with chronic muscle weakness and accompanied with other syndromes. MM with acute respiratory insufficiency is rare. AIMS: To reveal the clinical, pathological and molecular characteristics of a life-threatening MM. METHODS: Muscle biopsy and enzyme staining were performed in skeletal muscles. Mitochondrial DNA (mtDNA) sequencing was analyzed and heteroplasmy were quantified by pyrosequencing. RESULTS: All three patients had tachycardia, acute lactic acidosis, dyspnea and sudden severe muscle weakness. Two patients had calf edema and abdominal pain, and one had a heart attack. Electromyography in two patients showed dramatically decreased axonal amplitudes of motor nerves. Muscle biopsies showed ragged red fibers and dramatic mitochondrial abnormality. A mtDNA m.3243A>G mutation was identified in Patient 1 (mutation load: 29% in blood and 73% in muscle) and Patient 3 (79% in blood and 89% in muscle). A mtDNA m.8344A>G mutation was found in Patient 2 (mutation load 80.4% in blood). CONCLUSION: MM characterized by lactic acidosis, respiratory failure and acute motor axonal neuropathy is life threatening.

Adenylyl cyclase 6 activation negatively regulates TLR4 signaling through lipid raft-mediated endocytosis.

Proper intracellular localization of TLRs is essential for their signaling and biological function. Endocytosis constitutes a key step in protein turnover, as well as maintenance of TLR localization in plasma membrane and intracellular compartments, and thus provides important regulating points to their signaling. In this study, we demonstrate that adenylyl cyclase (AC) activation attenuates TLR4 signaling in a murine macrophage cell line (RAW 264.7) and bone marrow-derived macrophages when stimulated with LPS. We further show that the AC6 isoform plays a key role in negative regulation of TLR4 signaling by promoting protein degradation. TLR4 is normally endocytosed through the clathrin-mediated pathway, but concomitant AC6 activation shifts it to lipid raft-mediated endocytosis, which accelerates degradation of TLR4 and suppresses downstream signaling. Our studies unveil a new mechanism of negative regulation of TLR4 signaling through AC6-mediated endocytosis, which might provide a novel therapeutic approach for limiting inflammatory and autoimmune diseases.

Serum metabolomic profile of myasthenia gravis and potential values as biomarkers in disease monitoring.

OBJECTIVE: Serum metabolites from 19 myasthenia gravis (MG) patients and 15 normal controls were analyzed via untargeted metabolomics, including 6 pre/post-treatment paired MG patients, to assess the value of serum metabolites as biomarkers in monitoring MG. METHOD: Differential metabolites between MG patients and normal controls were identified through liquid and gas chromatography-mass spectrometry simultaneously. Principal component analysis and orthogonal partial least squares-discriminant analysis were conducted to identify the differential metabolites. Candidate metabolites and pathways associated with MG were selected through a random forest machine learning model. RESULT: A total of 310 differential metabolites were identified with a threshold of variable projected importance > 1 and P value < 0.05. Among these, 158 metabolites were upregulated and 152 were downregulated. The random forest machine learning model selected 5 metabolites as potential biomarkers associated with MG: lignoceric acid (AUC=0.944), uridine diphosphate-N-acetylglucosamine (AUC=0.951), arachidonic acid (AUC=0.951), beta-glycerophosphoric acid (AUC=0.933), and L-Asparagine (AUC=0.877). Further analysis using 6 paired MG patients pre- and post-immunosuppression treatment revealed 25 upregulated and 6 downregulated metabolites in post-treatment serum, which might be relevant to disease intervention. The significance remains elusive due to the limited number of patients. CONCLUSION: A subset of differential metabolites was identified in the serum of MG patients, some of which changed with immunosuppressive therapy. Small molecule metabolites may serve as valuable biomarkers for disease monitoring in MG.

Modulation of cardiac resident macrophages immunometabolism upon high-fat-diet feeding in mice.

Background: A high-fat diet (HFD) contributes to various metabolic disorders and obesity, which are major contributors to cardiovascular disease. As an essential regulator for heart homeostasis, cardiac resident macrophages may go awry and contribute to cardiac pathophysiology upon HFD. Thus, to better understand how HFD induced cardiac dysfunction, this study intends to explore the transcriptional and functional changes in cardiac resident macrophages of HFD mice. Methods: C57BL/6J female mice that were 6 weeks old were fed with HFD or normal chow diet (NCD) for 16 weeks. After an evaluation of cardiac functions by echocardiography, mouse hearts were harvested and cardiac resident CCR2- macrophages were sorted, followed by Smart sequencing. Bioinformatics analysis including GO, KEGG, and GSEA analyses were employed to elucidate transcriptional and functional changes. Results: Hyperlipidemia and obesity were observed easily upon HFD. The mouse hearts also displayed more severe fibrosis and diastolic dysfunction in HFD mice. Smart sequencing and functional analysis revealed metabolic dysfunctions, especially lipid-related genes and pathways. Besides this, antigen-presentation-related gene such as Ctsf and inflammation, particularly for NF-κB signaling and complement cascades, underwent drastic changes in cardiac resident macrophages. GO cellular compartment analysis was also performed and showed specific organelle enrichment trends of the involved genes. Conclusion: Dysregulated metabolism intertwines with inflammation in cardiac resident macrophages upon HFD feeding in mice, and further research on crosstalk among organelles could shed more light on potential mechanisms.

Association between high-resolution magnetic resonance vessel wall imaging characteristics and recurrent stroke in patients with intracranial atherosclerotic steno-occlusive disease: A prospective multicenter study.

BACKGROUND: High-resolution magnetic resonance vessel wall imaging (HRMR-VWI) is a promising technique for identifying intracranial vulnerable plaques beyond lumen narrowing. However, the association between HRMR-VWI characteristics and recurrent stroke remains uncertain. AIMS: This study aimed to investigate the association between HRMR-VWI characteristics and recurrent ipsilateral stroke in patients with symptomatic intracranial atherosclerotic steno-occlusive disease (ICAS). METHODS: This multicenter, observational study recruited first-ever acute ischemic stroke patients attributed to ICAS (>50% stenosis or occlusion) within 7 days after onset. Participants were assessed by multiparametric magnetic resonance imaging (MRI) including diffusion-weighted imaging, three-dimension time-of-flight magnetic resonance angiography, and three-dimensional T1-weighted HRMR-VWI. The patients were recommended to receive best medical therapy and were systematically followed up for 12 months. The association between HRMR-VWI characteristics and the time to recurrent ipsilateral stroke was investigated by univariable and multivariable analysis. RESULTS: Two hundred and fifty-five consecutive patients were enrolled from 15 centers. The cumulative 12 month ipsilateral recurrence incidence was 4.1% (95% confidence interval (CI): 1.6-6.6%). Patients with recurrent ipsilateral stroke exhibited higher rates of intraplaque hemorrhage (IPH) (30.0% vs 6.5%) and eccentric plaque (90.0% vs 48.2%), and lower occurrence of occlusive thrombus (10.0% vs 23.7%). Plaque length (5.69 ± 2.21 mm vs 6.67 ± 4.16 mm), plaque burden (78.40 ± 7.37% vs 78.22 ± 8.32%), degree of stenosis (60.25 ± 18.95% vs 67.50% ± 22.09%) and remodeling index (1.07 ± 0.27 vs 1.03 ± 0.35) on HRMR-VWI did not differ between patients with and without recurrent ipsilateral stroke. In the multivariable Cox regression analysis, IPH (hazard ratio: 6.64, 95% CI: 1.23-35.8, p = 0.028) was significantly associated with recurrent ipsilateral stroke after adjustment.Conclusions:Our results suggest intraplaque hemorrhage (IPH) is significantly associated with recurrent ipsilateral stroke and has potential value in the selection of patients for aggressive treatment strategies. DATA ACCESS STATEMENT: Data from this study are available and can be accessed upon request.

Two patients with congenital myasthenic syndrome caused by COLQ gene mutations and the consequent ColQ protein defect.

Objective: To report two cases of congenital myasthenic syndromes (CMS) in a Chinese family with mutations in the COLQ gene and to prove the consequence defect of the ColQ protein. Method: Clinical characteristics of the two children from the same family were described. Next-generation sequencing (NGS) and sanger sequencing was performed on the proband and family members. The consequence of the mutation was predicted by 3D protein structure prediction using I-TASSER. The wild type and mutant were transfected to 293T cells, and ColQ protein was detected by Western Blot. Results: The diagnosis of CMS was based on a symptom combination of fatigable muscle weakness, ptosis, scoliosis, and hypotonia, aggravation of muscle weakness after the neostigmine test, and a 46% decrement in repetitive nerve stimulation. A muscle biopsy was performed on the proband, revealing mild variation in the myofiber size. NGS data revealed two compound heterozygous mutations at c.173delC (p.Pro58Hisfs*22) and c.C706T (p.R236X) in the COLQ gene, where the former was a novel mutation. A 3D structure prediction showed two truncated ColQ proteins with 78aa and 235aa, respectively. The truncated ColQ protein was proved in 293T cells transfected with c.173delC or c.C706T mutants by Western Blot. Conclusions: The mutations of c.173delC and c.C706T in the COLQ gene led to truncated ColQ protein and contributed to the pathogenesis of CMS in this Chinese family.

Differences in treatment for Alzheimer's disease between urban and rural areas in China.

Introduction: In China, the increasing number of people with Alzheimer's disease (AD) poses a great challenge to families and the country. Economic and cultural differences cause a urban-rural gap in medical resources. This multicenter survey aimed to investigate the real-world practice of disease treatment among people with AD. Methods: People with AD and their caregivers from 30 provincial regions in mainland China were enrolled from October 2020 to December 2020 to be surveyed for their treatment experience. Logistic regression was used to explore the factors that influence medication adherence in all areas, urban areas, and rural areas. Results: In this survey, 1,427 participants came from urban areas, and 539 participants came from rural areas. Patients in urban areas were older (mean age 74 vs. 70, p = 0.001), less frequently had mild AD (36.0 vs. 52.1%, p < 0.001), and more often were cared for at professional institutions (8.8 vs. 3.2%, p < 0.001). In terms of pharmacotherapy, 77.8% of people accepted taking lifelong medication, whereas 61.3% of patients insisted on taking medications. Although 72.0% of rural people believed in taking lifelong medication, only 30.0% adhered to drug use. The major factors that influenced medication adherence for all patients with AD were regional distribution (p < 0.001, OR = 6.18, 95% CI: 4.93-7.74) and family earnings (p = 0.003, OR = 1.22, 95% CI: 1.07-1.38). In rural areas, family earnings (p = 0.008, OR = 1.44, 95% CI: 1.10-1.89) and severity of AD (p = 0.033, OR = 1.31, 95% CI: 1.02-1.68) were the main factors. Family earnings (p = 0.038, OR = 1.16, 95% CI: 1.01-1.34) was the only factor among urban areas. Among all non-pharmaceutical activities except for cognitive intervention, the participation rates of rural patients were significantly higher than those of urban patients (p < 0.05). Conclusion: Although national progress has been made in the public awareness of disease treatment, adequate diagnosis and medication adherence need to be prompted, especially in rural areas. Furthermore, lifelong treatment should be improved based on regional characteristics through the joint efforts of the government, health workers, and social volunteers.

Factors Associated With Alzheimer's Disease Patients' Caregiving Status and Family Caregiving Burden in China.

Background: The increasing prevalence of Alzheimer's disease (AD) has emerged as a major challenge worldwide. China as the most populous country in the globe is amid rapid aging of its population, highlighting the need for appropriate social and medical policies to meet the challenge. The current multicenter cross-sectional observational study aims to provide understanding of the current status of caring given to AD patients in China and investigate the factors that influence the family burden as well as the choice of care given to AD patients. Methods: A total of 1,675 patients with probable AD from 30 provincial regions of mainland China were enrolled in the current study from August 2019 to December 2019. We analyzed the caregiving status and its relationship with family burden and various socio-economical and medical factors. Results: In the current study, 90.87% of the AD patients enrolled adopted family care. The choice of caregiving method was influenced by factors including age (>80 years old, OR 0.648; 95% CI, 0.427-0.983), overall family burden (high, OR 0.574; 95% CI, 0.0.373-0.884), patients' income (OR 0.511; 95% CI, 0.330-0.789) and self-care ability (OR 0.329; 95% CI, 0.183-0.588). Conclusion: Family care is the primary method of care for AD patients in China and the institutional care system for AD patients is still underprepared in China.

Retinitis pigmentosa and molar tooth sign caused by novel AHI1 compound heterozygote pathogenic variants.

BACKGROUND: Joubert syndrome (JS) is a group of rare congenital disorders characterized by cerebellar vermis dysplasia, developmental delay, and retina dysfunctions. Herein, we reported a Chinese patient carrying a new variant in the AHI1 gene with mild JS, and the 3D structure of the affected Jouberin protein was also predicted. CASE PRESENTATION: The patient was a 31-year-old male, who presented difficulty at finding toys at the age of 2 years, night blindness from age of 5 years, intention tremor and walking imbalance from 29 years of age. Tubular visual field and retina pigmentation were observed on ophthalmology examinations, as well as molar tooth sign on brain magnetic resonance imaging (MRI). Whole exome sequence revealed two compound heterozygous variants at c.2105C>T (p.T702M) and c.1330A>T (p.I444F) in AHI1 gene. The latter one was a novel mutation. The 3D protein structure was predicted using I-TASSER and PyMOL, showing structural changes from functional ß-sheet and α-helix to non-functional D-loop, respectively. CONCLUSIONS: Mild JS due to novel variants at T702M and I444F in the AHI1 gene was reported. The 3D-structural changes in Jouberin protein might underlie the pathogenesis of JS.

Anti-inflammatory effects of α7-nicotinic ACh receptors are exerted through interactions with adenylyl cyclase-6.

BACKGROUND AND PURPOSE: Nicotinic ACh receptors containing the α7 sub-unit (α7-nAChRs) suppress inflammation through a wide range of pathways in immune cells. These receptors are thus potentially involved in a number of inflammatory diseases. However, the detailed mechanisms underlying the anti-inflammatory effects of α7-nAChRs remain to be described. EXPERIMENTAL APPROACH: Anti-inflammatory effects of α7-nAChR agonists were assessed in both murine macrophages (RAW 264.7) and bone marrow-derived macrophages (BMDM), stimulated with LPS, using immunoblotting, RT-PCR and luciferase reporter assays. The role of adenylyl cyclase-6 in the degradation of Toll-like receptor 4 (TLR4) following endocytosis, was explored via overexpression and knockdown. A mouse model of chronic obstructive pulmonary disease (COPD) induced by porcine pancreatic elastase was used to confirm key findings. RESULTS: Anti-inflammatory effects of α7-nAChRs were largely dependent on adenylyl cyclase-6 activation, as knockdown of adenylyl cyclase-6 considerably reduced the effects of α7-nAChR agonists while adenylyl cyclase-6 overexpression promoted them. We found that α7-nAChRs and adenylyl cyclase-6 are co-localized in lipid rafts of macrophages and directly interact. Activation of adenylyl cyclase-6 led to increased degradation of TLR4. Administration of the α7-nAChR agonist PNU-282987 attenuated pathological and inflammatory end points in a mouse model of COPD. CONCLUSION AND IMPLICATIONS: The α7-nAChRs inhibit inflammation through activating adenylyl cyclase-6 and promoting degradation of TLR4. The use of α7-nAChR agonists may represent a novel therapeutic approach for treating COPD and possibly other inflammatory diseases.

The Association between Neprilysin gene polymorphisms and Alzheimer's disease in Tibetan population.

OBJECTIVES: Alzheimer's disease (AD) is a well-known neurodegenerative disease, of which the hallmark is the disposition of ß-amyloid (Aß) in the form of plaque in the brain. Neprilysin (NEP) is the major enzyme to degrade Aß and prevent accumulation of Aß. The present study was undertaken to elucidate the correlation between the NEP gene polymorphisms and AD in Chinese Tibetan population. METHODS: Ninety-nine sporadic AD Tibetan patients and 113 healthy Tibetan controls were enrolled in this study. The genotype frequencies and allele frequencies of multiple NEP gene loci were analyzed using the case-control association analysis. RESULTS: No significant correlation was found between polymorphisms of NEP gene loci (rs9829757, rs1816558, rs6776185, rs3736187, rs701109, rs989692) and the occurrence of AD in Tibetan population. However, allele C of NEP gene locus (rs701109) and allele T of gene locus (rs3736187) were possible risk factors of male AD patients in Tibetan population. CONCLUSIONS: NEP gene loci (rs701109, rs989692, rs9829757, rs3736187, rs1816558, rs6776185) were polymorphic in Tibetan population. No difference was found between these loci but for that male gender combined with allele C of NEP gene locus (rs701109) and T of gene locus (rs3736187) might be risk factors for AD in Tibet.

Heteroplasmy and phenotype spectrum of the mitochondrial tRNALeu (UUR) gene m.3243A>G mutation in seven Han Chinese families.

The m.3243A > G mutation in the mitochondrial tRNALeu (UUR) gene is associated with a variety of phenotypic heterogeneity. The clinical spectrum and phenotypic-genotypic correlations in the Chinese patients are poorly understood. In the present study, we reported the clinical and genetic characterization, as well as haplogroups of seven Han Chinese families carrying the m.3243A > G mutation. Of the 39 matrilineal individuals, five suffered from mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), two had life-threatening mitochondrial myopathy (LTMM), and one patient had neuropathy, ataxia, and retinitis pigmentosa (NARP)-like syndrome. The LTMM and NARP like syndromes enriched the phenotypic profile of the m.3243A > G mutation. The heteroplasmy of the m.3243A > G mutation ranged from 16% to 59% in MELAS, 29% to 79% in LTMM, and 57% in a NARP-like syndrome patient. The levels ranged from 0% to 14% in patients that manifested with pure diabetes and pure hearing loss, and 0% to 5% in 13 normal family members. However, we particularly noticed heteroplasmy in four asymptomatic individuals in one LTMM family carried the heteroplasmy mutation ranged from 22% to 78%, implying that there were other modifying factors in this family. The modulation of the phenotype of mtDNA mutations requires further investigation.

Design of stroke imaging package study of intracranial atherosclerosis: a multicenter, prospective, cohort study.

BACKGROUND: Intracranial atherosclerosis (ICAS) is a major cause of stroke worldwide. However, much remains unknown regarding its underlying pathophysiology. High-resolution magnetic resonance imaging (HR-MRI) can clearly display intracranial vessel wall lesions in vivo. The aim of stroke imaging package study of ICAS (SIPS-ICAS) study is to explore the stroke mechanisms of symptomatic ICAS, the dynamic changes under aggressive medical treatment and their associations with clinical events using conventional MRI sequences plus HR-MRI. METHODS: This is a multicenter, prospective, cohort study recruiting first-ever acute ischemic stroke patients attributed to intracranial large artery stenosis (>50% or occlusion). Subjects undergo a pre-designed stroke imaging packages at baseline and are recommended to receive aggressive medical treatments. Participants will be followed up for functional outcome, stroke recurrence, and death events at 3, 6 and 12 months and retake HR-MRI imaging at 6 months. RESULTS: Enrollment began in November 2018 and 96 patients have been enrolled as of September 2019. CONCLUSIONS: The SIPS-ICAS study will provide insights into the pathophysiology of ICAS and identify specific imaging markers for risk stratification and prognosis prediction. At the same time, the feasibility and validity of the new stroke imaging package including HR-MRI will be assessed, which is promising for clinical routine use.

A novel Twinkle (PEO1) gene mutation in a Chinese family with adPEO.

PURPOSE: Autosomal dominant progressive external ophthalmoplegia (adPEO) is a genetically heterogeneous, adult-onset disease. Thus far, disease loci have been identified on four different nuclear genes. The purpose of this study is to identify the gene responsible for causing adPEO in a Chinese family. METHODS: Clinical data and genomic DNA of a Chinese adPEO family were collected following informed consent. Gene scan by two-point linkage analysis was performed for four genes, and mutation screening was conducted in the Twinkle (PEO1) gene by direct sequencing. RESULTS: A maximum two-point LOD score of 2.8 at theta=0.00 was obtained with marker D10S192 in close proximity to PEO1. A novel missense mutation (c.1423G>A, p.475A>T) was identified. CONCLUSIONS: This study widens the mutation spectrum of PEO1 and is the first to report the PEO1 mutation in the Chinese population.