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Abstract Objective TFG mutations have previously been implicated in autosomal recessive hereditary spastic paraplegia (HSP), also known as SPG57. This study aimed to investigate the clinical and molecular features of TFG mutations in a Taiwanese HSP cohort. Methods Genetic analysis of TFG was conducted in 242 unrelated Taiwanese HSP patients using a targeted resequencing panel covering the entire coding regions of TFG. Functional assays were performed using an in vitro cell model to assess the impact of TFG variants on protein function. Additionally, other representative TFG mutant proteins were examined to understand the broader implications of TFG mutations in HSP. Results The study identified a novel homozygous TFG c.177A>C (p.(Lys59Asn)) variant in a family with adolescent‐onset, pure form HSP. Functional analysis revealed that the Lys59Asn TFG variant, similar to other HSP‐associated TFG mutants, exhibited a low affinity between TFG monomers and abnormal assembly of TFG homo‐oligomers. These structural alterations led to aberrant intracellular distribution, compromising TFG's protein secretion function and resulting in decreased cellular viability. Interpretation These findings confirm that the homozygous TFG c.177A>C (p.(Lys59Asn)) variant is a novel cause of SPG57. The study expands our understanding of the clinical and mutational spectrum of TFG‐associated diseases, highlighting the functional defects associated with this specific TFG variant. Overall, this research contributes to the broader comprehension of the genetic and molecular mechanisms underlying HSP.

Hypermetabolism is a prominent characteristic of ALS patients. Aberrant activation of AMPK, an energy sensor regulated by adiponectin, is known to cause TDP-43 mislocalization, an early event in ALS pathogenesis. This study aims to evaluate the association between key energy mediators and clinical severity in ALS patients. We found that plasma adiponectin levels were significantly higher in ALS patients with ALSFRS-R scores below 38 compared to controls (p = 0.047). Additionally, adiponectin concentration was inversely correlated with ALSFRS-R scores (p = 0.021). Immunofluorescence staining of PBMCs revealed negative associations between AMPK activation, TDP-43 mislocalization, and ALSFRS-R scores. We then examined the hypothesis that adiponectin may activate the AMPK-TDP-43 axis in motor neurons. Our results demonstrated that adiponectin treatment of NSC34 cells and HiPSC-MNs induced AMPK activation and TDP-43 mislocalization in an adiponectin receptor-dependent manner. Collectively, these findings suggest that elevated plasma adiponectin may enhance AMPK activation, leading to TDP-43 mislocalization in both PBMCs and motor neurons of ALS patients. This highlights the potential involvement of the adiponectin-AMPK-TDP-43 axis in the dysregulated energy balance observed in ALS.

Abstract PAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot–Marie-Tooth disease (CMT2) and identified a missense mutation c.209 T > G (p.Met70Arg) in the INSC gene. Modeling the INSC M70R variant in Drosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of the INSC M70R mutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlight a potential therapeutic target for INSC-associated CMT2.

Abstract Gut microbiota rearrangement induced by cold temperature is crucial for browning in murine white adipose tissue. This study provides evidence that DUSP6, a host factor, plays a critical role in regulating cold-induced gut microbiota rearrangement. When exposed to cold, the downregulation of intestinal DUSP6 increased the capacity of gut microbiota to produce ursodeoxycholic acid (UDCA). The DUSP6-UDCA axis is essential for driving Lachnospiraceae expansion in the cold microbiota. In mice experiencing cold-room temperature (CR) transitions, prolonged DUSP6 inhibition via the DUSP6 inhibitor (E/Z)-BCI maintained increased cecal UDCA levels and cold-like microbiota networks. By analyzing DUSP6-regulated microbiota dynamics in cold-exposed mice, we identified Marvinbryantia as a genus whose abundance increased in response to cold exposure. When inoculated with human-origin Marvinbryantia formatexigens, germ-free recipient mice exhibited significantly enhanced browning phenotypes in white adipose tissue. Moreover, M. formatexigens secreted the methylated amino acid Nε-methyl-L-lysine, an enriched cecal metabolite in Dusp6 knockout mice that reduces adiposity and ameliorates nonalcoholic steatohepatitis in mice. Our work revealed that host-microbiota coadaptation to cold environments is essential for regulating the browning-promoting gut microbiome.

The emergence of next-generation probiotics (NGPs) has illuminated new possibilities for improving various diseases through food-grade supplements. In this study, a new gut bacterial species, designated as Akkermansia sp. BCRC 18949, was isolated from the feces of a healthy Taiwanese adult. The phylogenetic tree and whole genome sequencing analyses confirmed that this human commensal is a novel species belonging to the genus Akkermansia. Our results reveals that BCRC 18949 exhibits distinct mucin utilization abilities compared to ATCC BAA-835. Importantly, BCRC 18949 shows enhanced protection against DSS-induced colitis, while both species contribute differentially to restoring barrier integrity in DSS-treated mice. Furthermore, BCRC 18949 significantly restores the expression of colonic rhythmic genes, suggesting its potential role in maintaining circadian rhythm in the colon during colitis. Our findings provide valuable insights into the functional diversity of Akkermansia species and their potential therapeutic applications for colitis.

Background/purpose(s): Human breastmilk (BM) is important for microbiome maturation in infants across different body sites. Streptococcus and Staphylococcus are considered universally predominant genera in the BM microbiota. However, whether the differential abundance of Streptococcus and Staphylococcus in BM can differentially affect microbiome maturation in infants remains unclear. Methods: We recruited exclusively breastfeeding mothers from among the donors of the human milk bank established at National Cheng-Kung University Hospital. The donor mothers provided 35 BM samples at three months (3 M; before introducing children to complementary feeding) and 23 BM samples at six months (6 M; after introducing children to complementary feeding) postpartum. At both time points, samples from different body sites, including nasal swabs, oral swabs and stool, were collected from the mothers and their infants. Results: Maternal BMI was inversely associated with coagulase-negative Staphylococcus (CoNS) abundance in breastmilk. Staphylococcus caprae representation in BM CoNS showed a negative correlation with Streptococcus abundance. Network analysis revealed that infants fed Staphylococcus-dominated BM had better gut and nasal microbiota networks than infants fed Streptococcus-abundant BM during early infancy. Conclusion: Our work suggests that maternal metabolic status plays a crucial role in Staphylococcus/Streptococcus competition in BM, which in turn can impact the development of the infant microbiota. Our microbiota co-occurrence network analysis might serve as a helpful bioinformatic tool to monitor microbiota maturation during early infancy.

Abstract Objective Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders characterized by slowly progressive lower limb spasticity and weakness. HSP type 54 (SPG54) is autosomal recessively inherited and caused by mutations in the DDHD2 gene. This study investigated the clinical characteristics and molecular features of DDHD2 mutations in a cohort of Taiwanese patients with HSP. Methods Mutational analysis of DDHD2 was performed for 242 unrelated Taiwanese patients with HSP. The clinical, neuroimaging, and genetic features of the patients with biallelic DDHD2 mutations were characterized. A cell‐based study was performed to assess the effects of the DDHD2 mutations on protein expression. Results SPG54 was diagnosed in three patients. Among them, two patients carried compound heterozygous DDHD2 mutations, p.[R112Q];[Y606*] and p.[R112Q];[p.D660H], and the other one was homozygous for the DDHD2 p.R112Q mutation. DDHD2 p.Y606* is a novel mutation, whereas DDHD2 p.D660H and p.R112Q have been reported in the literature. All three patients manifested adult onset complex HSP with additional cerebellar ataxia, polyneuropathy, or cognitive impairment. Brain proton magnetic resonance spectroscopy revealed an abnormal lipid peak in thalamus of all three patients. In vitro studies demonstrated that all the three DDHD2 mutations were associated with a considerably lower DDHD2 protein level. Interpretation SPG54 was detected in approximately 1.2% (3 of 242) of the Taiwanese HSP cohort. This study expands the known mutational spectrum of DDHD2, provides molecular evidence of the pathogenicity of the DDHD2 mutations, and underlines the importance of considering SPG54 as a potential diagnosis of adult‐onset HSP.

For vegetarians or vegan athletes, improving the utilization of plant-based protein and the absorption of amino acids is crucial. This study explored the impact of combining pea protein with Lactiplantibacillus plantarum TWK10 and resistance training on amino acid absorption and exercise performance. Sixteen male and sixteen female participants were randomly assigned to either a control group (20 g of pea protein without TWK10) or a TWK10 group (20 g of pea protein combined with 1 × 1010 colony-forming units of TWK10). After 28 days of supplementation combined with resistance exercise training three times per week. All subjects underwent body composition and muscle strength performance, plasma and fecal samples were collected for microbiota analysis and blood amino acid concentrations. The TWK10 group showed a significant increase in muscle thickness and improvements were observed in 1 repetition maximum bench press, explosive, anaerobic power output compared to before the intervention, and were significantly higher than those in the control group (p

Abstract Clopidogrel is the most-widely used platelet P2Y12-inhibitor for secondary-prevention of ischemic stroke. Platelet P2Y12 reactivity before and after inhibitors can be measured with blood sampling by commercialized system. We aimed to evaluate (1) whether high-on-clopidogrel platelet P2Y12 reactivity (HCPR) is associated with short-term vascular events and (2) the predictors of HCPR in acute stroke. The inclusion criterion was patients with acute stroke who received clopidogrel within 12–48 h after the onset. Platelet reactivity was assayed at baseline and after clopidogrel treatment using the VerifyNow system. The primary endpoint was recurrent ischemic events within 21 days after stroke. Among 190 patients, 32(16.9%) had recurrent ischemic stroke. Multivariate analyses showed that HCPR was significantly associated with the short-term events with an odds-ratio of 2.5 (95% CI 1.1–5.7, p = 0.027). Patients with HCPR had significantly higher frequencies of high baseline platelet P2Y12 reactivity, impaired kidney function, and carrying one or two CYP2C19 loss-of-function alleles. A poor clopidogrel response score combining these factors was developed. Ten percent of patients with score 0, 20.3% of those with score 1, 38.3% of those with score 2, and 66.7% of those with score 3 had HCPR (χ2-test, p

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small‐vessel disease. Phenotype variability in CADASIL suggests the possible role of genetic modifiers. We aimed to investigate the contributions of the APOE genotype and Neurogenic locus notch homolog protein 3 (NOTCH3) variant position to cognitive impairment associated with CADASIL. Methods and Results Patients with the cysteine‐altering NOTCH3 variant were enrolled in a cross‐sectional study, including the Mini‐Mental State Examination (MMSE), brain magnetic resonance imaging, and APOE genotyping. Cognitive impairment was defined as an MMSE score

Abstract Objective NIPA1 mutations have been implicated in hereditary spastic paraplegia (HSP) as the cause of spastic paraplegia type 6 (SPG6). The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort. Methods We screened 242 unrelated Taiwanese patients with HSP for NIPA1 mutations. The clinical features of patients with a NIPA1 mutation were analyzed. Minigene‐based splicing assay, RT‐PCR analysis on the patients' RNA, and cell‐based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression. Results Two patients were identified to carry a different heterozygous NIPA1 mutation. The two mutations, c.316G>A and c.316G>C, are located in the 3′ end of NIPA1 exon 3 near the exon–intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring NIPA1 c.316G>A manifested spastic paraplegia, epilepsy and schizophrenia since age 17 years, whereas the individual carrying NIPA1 c.316G>C had pure HSP since age 12 years. We reviewed literature and found that epilepsy was present in multiple individuals with NIPA1 c.316G>A but none with NIPA1 c.316G>C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G>A mutation was associated with a significantly reduced NIPA1 protein expression. Interpretation SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The NIPA1 c.316G>A and c.316G>C mutations are associated with adolescent‐onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy.

Abstract Background Ovarian cancer has the highest mortality among gynecological cancers due to late diagnosis and lack of effective targeted therapy. Although the study of interplay between cancer cells with their microenvironment is emerging, how ovarian cancer triggers signaling that coordinates with immune cells to promote metastasis is still elusive. Methods Microarray and bioinformatics analysis of low and highly invasive ovarian cancer cell lines were used to reveal periostin (POSTN), a matrix protein with multifunctions in cancer, with elevated expression in the highly invasive cells. Anchorage independent assay, Western blot, RNA interference, confocal analysis and neutralizing antibody treatment were performed to analyze the effects of POSTN on tumor promotion and to explore the underlying mechanism. Chemotaxis, flow cytometry and cytokine array analyses were undertaken to analyze the involvement of POSTN in cancer-associated fibroblast (CAF) and macrophage modulation. Correlations between POSTN expression levels and clinical characteristics were analyzed using the Oncomine, commercial ovarian cancer cDNA and China Medical University Hospital patient cohort. In vivo effect of POSTN on metastasis was studied using a mouse xenograft model. Results Expression of POSTN was found to be elevated in highly invasive ovarian cancer cells. We observed that POSTN was co-localized with integrin β3 and integrin β5, which was important for POSTN-mediated activation of ERK and NF-κB. Ectopic expression of POSTN enhanced whereas knockdown of POSTN decreased cancer cell migration and invasion in vitro, as well as tumor growth and metastasis in vivo. POSTN enhanced integrin/ERK/NF-κB signaling through an autocrine effect on cancer cells to produce macrophage attracting and mobilizing cytokines including MIP-1β, MCP-1, TNFα and RANTES resulting in increased chemotaxis of THP-1 monocytes and their polarization to M2 macrophages in vitro. In agreement, tumors derived from POSTN-overexpressing SKOV3 harbored more tumor-associated macrophages than the control tumors. POSTN induced TGF-β2 expression from ovarian cancer cells to promote activation of adipose-derived stromal cells to become CAF-like cells expressing alpha smooth muscle actin and fibroblast activation protein alpha. Consistently, increased CAFs were observed in POSTN overexpressing SKOV3 cells-derived metastatic tumors. In clinical relevance, we found that expression of POSTN was positively correlated with advanced-stage diseases and poor overall survival of patients. Conclusions Our study revealed a POSTN-integrin-NF-κB-mediated signaling and its involvement in enhancing M2 macrophages and CAFs, which could potentially participate in promoting tumor growth. Our results suggest that POSTN could be a useful prognosis marker and potential therapeutic target.

Background/Purpose: The long-term disease course and efficacy of maintenance therapies have rarely been investigated in Asian patients with neuromyelitis optica spectrum disorder (NMOSD). Methods: Medical records of patients fulfilling the 2015 International Consensus Diagnostic Criteria for NMOSD at three medical centers in Taiwan were systematically analyzed. Linear regression analysis was performed to investigate factors related to annualized relapse rate (ARR); survival analysis was used to estimate the relapse-free intervals among therapies. Results: A total of 557 relapses affecting 648 regions (202 optic neuritis, 352 acute myelitis, and 94 brain syndromes) in 204 patients were analyzed during a follow-up period of 69.5 months (range, 1–420). Up to 36.1% of myelitis-onset patients and 24.0% of optic neuritis-onset patients exhibited a limited form disease, defined as having one or more relapses confined to the same region. The median ARR was significantly lower in patients with limited form disease than those with relapses involving multiple regions (0.30 vs. 0.47, respectively). An older age at disease onset was associated with a lower ARR (p = 0.023). Kaplan–Meier analysis showed that the estimated time (months) to next relapse was longest in rituximab-treatment group (58.0 ± 13.2), followed by immunosuppressant (48.5 ± 4.8) or prednisone (29.6 ± 4.6) groups, and shortest in those without maintenance therapy (27.6 ± 4.2) (p = 8.1 × 10−7). Conclusion: Limited form disease and older age at disease onset are associated with a lower relapse rate in NMOSD. Compared to no maintenance therapy, rituximab and immunosuppressant significantly reduce the relapse risks.

Background/purpose: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disorders characterized by slowly progressive lower limbs spasticity and weakness. HSP type 15 (SPG15) is an autosomal recessive subtype caused by ZFYVE26 mutations. The aim of this study was to investigate the frequency and clinical and genetic features of ZFYVE26 mutations in a Taiwanese HSP cohort. Methods: Mutational analysis of the coding regions of ZFYVE26 was performed by targeted resequencing in the 195 unrelated Taiwanese patients with HSP. All of the patients were of Han Chinese ethnicity. Clinical, neuropsychological, electrophysiological evaluations and imaging studies were collected. Results: Among the 195 patients, only one SPG15 patient was identified. The patient had a novel recessive ZFYVE26 frameshift truncating mutation, p.R1806Gfs∗36 (c.5415delC), and presented with insidious onset spastic weakness of lower-extremities and cognitive impairment. Neuropsychological assessment revealed deficits in executive function, visual naming, category verbal fluency, and manual dexterity. Brain MRI showed thin corpus callosum and the “ears of lynx” sign. Conclusion: SPG15 accounts for approximately 0.5% (1/195) of the Taiwanese HSP cohort. This study identified the first Taiwanese SPG15 case and delineated the clinical, genetic, neuropsychological, and neuroimaging features. These findings expand the mutational spectrum of ZFYVE26 and also broaden the knowledge of clinical and neuropsychological characteristics of SPG15.

Abstract Objective Mutations in the colony‐stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult‐onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult‐onset leukoencephalopathy. Methods Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1‐induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations. Results Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1‐induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin‐like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3–4 years. Diffusion‐restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients. Interpretation CSF1R mutations account for 3.5% (5/149) of the adult‐onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants.

Introduction: Two common variants of sortilin-related receptor 1 gene (SORL1), rs2298813 and rs1784933, have been associated with late-onset Alzheimer’s disease (AD) in the Han Chinese population in Taiwan. However, neuroimaging correlates of these two SORL1 variants remain unknown. We aimed to determine whether the two SORL1 polymorphisms were associated with any volumetric differences in brain regions in late-onset AD patients.Methods: We recruited 200 patients with late-onset AD from Taipei Veterans General Hospital. All patients received a structural magnetic resonance (MR) imaging brain scan and completed a battery of neurocognitive tests at enrollment. We followed up to assess changes in Mini-Mental State Examination (MMSE) scores in 155 patients (77.5%) at an interval of 2 years. Volumetric measures and cortical thickness of various brain regions were performed using FreeSurfer. Regression analysis controlled for apolipoprotein E status. Multiple comparisons were corrected for using the false discovery rate.Results: The homozygous major allele of rs2298813 was associated with larger volumes in the right putamen (p = 0.0442) and right pallidum (p = 0.0346). There was no link between the rs1784933 genotypes with any regional volume or thickness of the brain. In the rs2298813 homozygous major allele carriers, the right putaminal volume was associated with verbal fluency (p = 0.008), and both the right putaminal and pallidal volumes were predictive of clinical progression at follow-up (p = 0.020). In the minor allele carriers, neither of the nuclei was related to cognitive test performance or clinical progression.Conclusion: The major and minor alleles of rs2298813 had differential effects on the right lentiform nucleus volume and distinctively modulated the association between the regional volume and cognitive function in patients with AD.

Abstract Objective The NEK1 gene has been recently implicated in amyotrophic lateral sclerosis (ALS). This study aims to assess the influence of NEK1 variants on the occurrence of ALS and investigate the spectrum and clinical features of NEK1 loss‐of‐function (LOF) variants in a Taiwanese ALS cohort. Methods We screened 325 unrelated ALS patients for coding variants in NEK1 by targeted resequencing and queried the Taiwan Biobank database for NEK1 coding variants in 1000 Taiwanese healthy individuals. The clinical features of the patients with a NEK1 LOF variant were analyzed. Results Six patients and two healthy individuals carried NEK1 LOF variants. The rare missense variants with minor allele frequencies

Abstract Objectives To investigate the clinical, electrophysiological, neuroimaging characteristics and genetic features of SPG5 in Taiwan. Methods Mutational analysis of the coding regions of CYP7B1 was performed by utilizing targeted resequencing analysis of the 187 unrelated Taiwanese HSP patients. The diagnosis of SPG5 was ascertained by the presence of biallelic CYP7B1 mutations. The SPG5 patients received clinical, electrophysiological, and neuroimaging evaluations. Disease severity was assessed by using the Spastic Paraplegia Rating Scale (SPRS) and the disability score. Two microsatellite markers as well as 18 single‐nucleotide polymorphism (SNP) markers flanking CYP7B1 were genotyped to assess the founder effect of the CYP7B1 p.R112* mutation. Results Nineteen SPG5 patients from 17 families were identified. They typically presented an insidious onset progressive spastic paraparesis with proprioception involvement beginning at age 8 to 40 years. Their MRIs often showed white matter abnormalities in bilateral occipito‐parietal regions, spinal cord atrophy, and mild cerebellar atrophy. Six different mutations in CYP7B1 were recognized, including three novel ones (p.N131Ifs*4, p.A295V, and p.L439R). CYP7B1 p.R112* was the most common mutation and present in 88.2% of the 17 SPG5 pedigrees. The patients with homozygous CYP7B1 p.R112* mutations had a milder clinical severity. Detailed haplotype analyses demonstrated a shared haplotype in the 25 individuals carrying at least one single allele of CYP7B1 p.R112*, suggesting a founder effect. Interpretation This study delineates the distinct clinical and genetic features of SPG5 in Taiwan and provides useful information for the diagnosis and management of SPG5, especially in patients of Chinese descent.

In humans, aging is characterized by the progressive decline in biological, physiological, and psychological functions, and is a major risk factor in the development of chronic diseases. Therefore, the development of strategies aimed at attenuating aging-related disorders and promoting healthy aging is critical. In a previous study, we have demonstrated that Lactobacillus plantarum TWK10 (TWK10), a probiotic strain isolated from Taiwanese pickled cabbage, improved muscle strength, exercise endurance, and overall body composition in healthy humans. In this study, the effect of TWK10 on the progression of age-related impairments was investigated in mice. We found that TWK10 not only enhanced muscle strength in young mice, but also prevented the aging-related loss of muscle strength in aged mice, which was accompanied by elevated muscle glycogen levels. Furthermore, TWK10 attenuated the aging-associated decline in learning and memory abilities, as well as bone mass. Further analyses of gut microbiota using next-generation sequencing (NGS) of the 16S rRNA gene showed that the pattern of gut microbial composition was clearly altered following 8 weeks of TWK10 administration. TWK10-treated mice also experienced an increase in short-chain fatty acid (SCFA)-producing bacteria and higher overall levels of gut SCFA. Furthermore, TWK10 administration to some extent reversed the aging-associated accumulation of pathogenic bacterial taxa. In conclusion, TWK10 could be viewed as a potential therapeutic agent that attenuates aging-related disorders and provides health benefits by modulating the imbalance of gut microbiota.

Lactiplantibacillus plantarum TWK10, a probiotic strain, has been demonstrated to improve exercise performance, regulate body composition, and ameliorate age-related declines. Here, we performed a comparative analysis of viable and heat-killed TWK10 in the regulation of exercise performance, body composition, and gut microbiota in humans. Healthy adults (n = 53) were randomly divided into three groups: Control, TWK10 (viable TWK10, 3 × 1011 colony forming units/day), and TWK10-hk (heat-killed TWK10, 3 × 1011 cells/day) groups. After six-week administration, both the TWK10 and TWK10-hk groups had significantly improved exercise performance and fatigue-associated features and reduced exercise-induced inflammation, compared with controls. Viable TWK10 significantly promoted improved body composition, by increasing muscle mass proportion and reducing fat mass. Gut microbiota analysis demonstrated significantly increasing trends in the relative abundances of Akkermansiaceae and Prevotellaceae in subjects receiving viable TWK10. Predictive metagenomic profiling revealed that heat-killed TWK10 administration significantly enhanced the signaling pathways involved in amino acid metabolisms, while glutathione metabolism, and ubiquinone and other terpenoid-quinone biosynthesis pathways were enriched by viable TWK10. In conclusion, viable and heat-killed TWK10 had similar effects in improving exercise performance and attenuating exercise-induced inflammatory responses as probiotics and postbiotics, respectively. Viable TWK10 was also highly effective in regulating body composition. The differences in efficacy between viable and heat-killed TWK10 may be due to differential impacts in shaping gut microbiota.

Immune-mediated arthritis is an important chronic inflammatory disease of joints causing debilitating morbidity in affected patients. The mechanisms underlying immune-mediated arthritis have been intensively investigated, however the cellular and molecular factors contributing to the joint inflammation in different redox conditions have not been clearly elucidated. Previous research showed that phagocyte-produced reactive oxygen species (ROS) plays an anti-inflammatory role in K/BxN serum-transfer arthritis and NOX2-deficient mice tend to have more severe arthritis. Although many leukocytes play critical roles in the development of immune-mediated arthritis, the role of neutrophils, which are the main producers of ROS in inflammation, is still controversial. We hence assessed the immunomodulatory function of neutrophils from arthritic joints of NOX2-deficient and wild type mice in this study. We found more neutrophils accumulation in NOX2-deficient inflamed joints. RNA-sequencing and quantitative PCR revealed significantly increased expression of acute inflammation genes including IL1b, Cxcl2, Cxcl3, Cxcl10 and Mmp3 in activated neutrophils from the inflamed joints of NOX2-deficient mice. Moreover, gene set enrichment analysis (GSEA) showed enriched gene signatures in type I and II IFN responses, IL-6-JAK-STAT3 signaling pathway and TNF-α signaling pathway via NF-κB in NOX2-deficient neutrophils. In addition, we found that NOX2-deficient neutrophils expressed lower levels of PD-L1 and were less suppressive than WT neutrophils. Moreover, treatment of PD-L1-Fc decreased cytokine expression and ameliorated the severity of inflammatory arthritis. Our results suggest that NOX2-derived ROS is critical for regulating the function and gene expression in arthritic neutrophils. Both the strong pro-inflammatory and weakened anti-inflammatory functions of neutrophils due to abnormal redox regulation may be targets of treatment for immune-mediated arthritis.

Abstract Objective Charcot‐Marie‐Tooth disease (CMT) is a clinically and genetically heterogeneous group of inherited neuropathies. Mutations in more than 90 genes have been implicated in CMT; however, the mutational spectrum of CMT in Chinese population remains obscure. This study aims to provide a comprehensive overview of the frequency of mutations in Taiwanese patients with CMT and look for genotype‐phenotype correlations. Methods Mutational analyses were performed on 427 unrelated Taiwanese patients with CMT by polymorphic microsatellite markers analysis or real‐time fluorescent PCR for PMP22 duplication, Sanger sequencing for GJB1 mutations, and targeted sequencing covering 124 genes causing or relevant to inherited neuropathies. We also correlated the genotypes with the phenotypic features, such as age at disease onset and ulnar motor nerve conduction velocity. Results Pathogenic mutations were identified in 312 patients (73.1%; 312/427), including 208 patients with a PMP22 duplication, 40 patients with a GJB1 mutation, and 64 patients with a mutation in one of other 18 CMT genes. A confirmed molecular diagnosis was achieved in 84.4% (266/315) of the patients with demyelinating CMT and 41.1% (46/112) of the patients with axonal CMT. Mutations in MPZ, MFN2, or NEFL are the most frequent disease causes in patients with infantile‐onset CMT (≤2 years), while PMP22 duplications and mutations in GJB1, MFN2, or MPZ are the frequent causes among patients with childhood‐ or adolescence‐onset CMT (3–9 years). Interpretation This study provides a genotype‐phenotype landscape of CMT in Taiwan and highlights the unique spectrum of CMT genes frequencies among patients of Chinese origin.

Tissue plasminogen activator is the only U.S. FDA-approved therapy for ischemic stroke, while there is no specific medication for hemorrhagic stroke. Therefore, the treatment of acute stroke continues to be a major unmet clinical need. We explored the effects of miR-195 on neurovascular protection and its potential in treating acute stroke. Using both cellular and animal studies, we showed that miR-195’s beneficial effects are mediated by four mechanisms: (1) anti-apoptosis for injured neural cells by directly suppressing Sema3A/Cdc42/JNK signaling, (2) neural regeneration by promoting neural stem cell proliferation and migration, (3) anti-inflammation by directly blocking the NF-kB pathway, and (4) improvement of endothelial functions. We intravenously injected miR-195 carried by nanoparticles into rats with either ischemic or hemorrhagic stroke in the acute stage. The results showed that miR-195 reduced the size of brain damage and improved functional recovery in both types of stroke rats. The reduction of injured brain volume could be up to 45% in ischemic stroke and approximately 30% in hemorrhagic stroke. The therapeutic window between stroke onset and miR-195 treatment could be up to 6 h. Our data demonstrated that miR-195 possesses the potential to become a new drug to treat acute ischemic and hemorrhagic stroke. Keywords: microRNA, stroke, neuroprotection, neural stem cell, Sema3A

Abstract Objective The clinical and genetic profiles of hereditary transthyretin amyloidosis (ATTR) in Chinese populations remain elusive. We aim to characterize the features of ATTR in a Taiwanese cohort of Han Chinese descent. Methods Seventy‐nine patients with molecularly confirmed ATTR from 57 Taiwanese families were identified by sequencing the transthyretin gene (TTR). The clinical and electrophysiological data were scrutinized. Cardiac involvement of ATTR was evaluated by echocardiography and cardiac scintigraphy. Four microsatellite and seven single‐nucleotide polymorphism markers flanking TTR were genotyped to investigate the founder effect of the TTR Ala97Ser mutation. Results Most of the patients had a peripheral neuropathy with variable autonomic symptoms. The average age at disease onset (AO) was 58.2 ± 7.2 years, and the male patients had an earlier AO than female patients (56.6 ± 5.7 years vs. 61.8 ± 8.9 years, P = 0.013). Electrophysiological studies revealed a generalized axonal sensorimotor polyneuropathy and isolated median neuropathy in 84.5% and 15.5% of the patients, respectively. Up to 80% of the patients with ATTR had symptomatic or subclinical cardiac involvement. Six TTR mutations were identified in the participants including one novel mutation Glu89Asp. Among them, Ala97Ser was the most common mutation, accounting for 91.2% of the ATTR pedigrees. Detailed haplotype analyses demonstrated a shared haplotype in the 47 patients with the Ala97Ser mutation, suggesting a founder effect. Interpretation The present study delineates the distinct features of ATTR in Taiwan and provides useful information for the diagnosis and management of ATTR, especially in patients of Chinese descent.

Lactiplantibacillus plantarum TWK10 (TWK10), isolated from Taiwanese pickled cabbage, has been demonstrated to exert beneficial probiotic effects in both mice and humans. Here, we comprehensively assessed the safety of TWK10 using both in vivo and in vitro approaches, including whole-genome sequence analysis, an assessment of hemolytic activity, and performing an antimicrobial susceptibility test, the Ames bacterial reverse mutation assay, the chromosomal aberration test, a rodent peripheral blood micronucleus test, and the 28-day subacute oral toxicity assay. The results showed that there was no significant increase in the incidence of reverse mutations or chromosomal aberrations following exposure to TWK10. Moreover, no significant changes were detected either in the number of reticulocytes or the incidence of micronuclei in ICR mice, and no subacute toxicity was recorded in SD rats at the oral TWK10 dosage of 2000 mg/kg body weight/day repeated for 28 days. Additionally, TWK10 exhibited no hemolytic activity and was susceptible to all the antibiotics tested, except kanamycin. However, no antimicrobial resistance genes, virulence factors, or genes involved in biogenic amine synthesis were found in the genome of TWK10. Our findings demonstrated that TWK10 has high potential of being safe for human consumption as a probiotic.

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 mutations, is characterized by recurrent ischemic strokes and progressive cognitive decline. It remains unclear whether cerebral microbleeds (CMBs) can serve as a surrogate marker for disease progression in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. We aimed to investigate the CMB burdens in NOTCH3 mutation carriers at different disease stages and test their associations with cognitive performance. Methods and Results Forty‐nine individuals carrying NOTCH3 cysteine‐altering mutations received brain magnetic resonance imaging with T1‐weighted and susceptibility‐weighted images. Whole brain images were segmented into 14 regions using Statistical Parametric Mapping and FreeSurfer software, and semiautomatic methods were used to locate and quantify the number and volume of CMBs. In our study participants, the median of CMB counts was 13, with a wide individual variation (range, 0–286). CMBs were most frequently present in thalamus, followed by temporal lobe. In the whole brain, the CMB counts and CMB volume ratios (ie, CMB volume divided by the volume of corresponding brain region) gradually increased as the disease advanced. CMB counts in the thalamus and temporal and frontal lobes increased more rapidly than other brain regions as disease progressed. There were significant associations between Mini‐Mental State Examination scores and CMB counts in the frontal lobe, temporal lobe, and pons. Conclusions CMBs may have an influential role in the clinical manifestations of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CMB burdens and their distribution in different brain regions may be capable to serve as a disease marker for monitoring the disease severity of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Abstract Monocyte chemoattractant protein-1 (MCP-1, also known as chemokine CCL2) is a vital chemokine that mediates inflammation in Alzheimer’s disease (AD). We analyzed the associations between the baseline plasma MCP-1 level, longitudinal cognitive changes, and genetic effects of CCL2 rs1024611 and its receptor, CC-chemokine receptor 2 (CCR2) rs1799864, in AD. In total, 310 AD patients and 66 mild cognitive impairment (MCI) patients were followed for 2 years, and 120 controls were recruited at baseline for comparison. After adjusting for covariates using one-way analysis of covariance, AD patients had higher plasma MCP-1 levels compared with MCI patients and controls, and severe AD patients had the highest levels. After adjusting for covariates using generalized estimating equation analysis, the results showed that the baseline MCP-1 level was significantly correlated with changes in the two-year Mini-Mental Status Examination (p = 0.046). The A allele of CCR2 rs1799864 was associated with a higher MCP-1 level in AD and MCI patients. In conclusion, plasma MCP-1 might reflect the risk and disease course of AD. A higher plasma MCP-1 level is associated with greater severity and faster cognitive decline. Additionally, the CCR2 polymorphism may play a role in the regulation of MCP-1/CCR2 signaling in AD.

Abstract Background Clusterin and beta-amyloid (Aβ) are involved in the pathogenesis of Alzheimer’s disease (AD). The clinical significance of plasma clusterin and Aβ in AD progression remains controversial. Methods We recruited 322 patients with AD and 88 controls between August 2012 and June 2013. All participants were evaluated at baseline with a clinical assessment, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) scales. Patients with AD were evaluated annually with the MMSE and Neuropsychiatric Inventory (NPI) scale during the 2-year follow-up period. The levels of plasma clusterin, Aβ1–40, and Aβ1–42 at baseline were analyzed to study the longitudinal changes in the patient scores on the MMSE and NPI during the follow-up period. Results Patients in the highest tertile of plasma clusterin levels showed significantly lower MMSE scores than those in the lowest tertile (p = 0.04). After adjustment for multiple covariates using the generalized estimating equation analysis, there was a significant decrease in the MMSE scores over the 2-year follow-up period among AD patients in the highest tertile of plasma clusterin levels compared with those in the lowest tertile (−2.09, 95% confidence interval (CI) = −3.67 to −0.51, p = 0.01). In apolipoprotein E (ApoE)4-positive AD patients, baseline measurements of the ratio of plasma Aβ1–42/Aβ1–40 in the highest tertile predicted an increase in NPI agitation/aggression scores over the 2-year follow-up period (6.06, 95% CI = 1.20–10.62, p = 0.02). Conclusions Plasma clusterin could serve as a biomarker for the severity of cognitive decline. Plasma Aβ in ApoE4-positive AD could predict long-term agitation/aggression symptoms.

Abstract This study investigated the relationships among plasma biomarkers, regional brain atrophy, and clinical symptoms in patients with Alzheimer’s disease (AD; n = 177), mild cognitive impairment (MCI; N = 60) and controls (n = 108). The Mini-Mental Status Examination (MMSE), Clinical Dementia Rating (CDR), and Neuropsychiatric Inventory (NPI) subscales were administered to subjects. Magnetic resonance imaging was performed and medial temporal atrophy (MTA) and posterior atrophy (PA) were assessed visually. We examined associations among cognition, NPI score, plasma β-amyloid (Aβ) and clusterin levels, and regional brain atrophy in patients with AD by regression analysis. The mean MTA score was associated with the plasma Aβ1-42/Aβ1-40 ratio (r = 0.38, p = 0.01) and with MMSE scores (r = 0.43, p

[This corrects the article DOI: 10.1371/journal.pone.0187503.].

The inositol 1,4,5-triphosphate (IP3) receptor type 1 gene (ITPR1) encodes the IP3 receptor type 1 (IP3R1), which modulates intracellular calcium homeostasis and signaling. Mutations in ITPR1 have been implicated in inherited cerebellar ataxias. The aim of this study was to investigate the role of ITPR1 mutations, including both large segmental deletion and single nucleotide mutations, in a Han Chinese cohort with inherited cerebellar ataxias in Taiwan.Ninety-three unrelated individuals with molecularly unassigned spinocerebellar ataxia selected from 585 pedigrees with autosomal dominant cerebellar ataxias, were recruited into the study with elaborate clinical evaluations. The quantitative PCR technique was used to survey large segmental deletion of ITPR1 and a targeted sequencing approach was applied to sequence all of the 61 exons and the flanking regions of ITPR1. A novel ITPR1 mutation, c.7721T>C (p.V2574A), was identified in a family with dominantly inherited cerebellar ataxia. The proband has an adult-onset non-progressive pure cerebellar ataxia and her daughter is afflicted with a childhood onset cerebellar ataxia with intellectual sub-normalities.ITPR1 mutation is an uncommon cause of inherited cerebellar ataxia, accounting for 0.2% (1/585) of patients with dominantly inherited cerebellar ataxias in Taiwan. This study broadens the mutational spectrum of ITPR1 and also emphasizes the importance of considering ITPR1 mutations as a potential cause of inherited cerebellar ataxias.

Adrenoleukodystrophy (ALD) is a rare and progressive neurogenetic disease that may manifest disparate symptoms. The present study aims at investigating the role of ataxic variant of ALD (AVALD) in patients with adult-onset cerebellar ataxia, as well as characterizing their clinical features that distinguish AVALD from other cerebellar ataxias. Mutations in the ATP binding cassette subfamily D member 1 gene (ABCD1) were ascertained in 516 unrelated patients with ataxia. The patients were categorized into three groups: molecularly unassigned hereditary ataxia (n = 118), sporadic ataxia with autonomic dysfunctions (n = 296), and sporadic ataxia without autonomic dysfunctions (n = 102). Brain MRIs were scrutinized for white matter hyperintensity (WMH) in the parieto-occipital lobes, frontal lobes, corticospinal tracts, pons, middle cerebellar peduncles and cerebellar hemispheres. Two ABCD1 mutations (p.S108L and p.P623fs) previously linked to cerebral ALD and adrenomyeloneuropathy but not AVALD were identified. ALD accounts for 0.85% (1/118) of the patients with molecularly unassigned hereditary ataxia and 0.34% (1/296) of the patients with sporadic ataxia with autonomic dysfunctions. WMH in the corticospinal tracts and WMH in the cerebellar hemispheres were strongly associated with AVALD rather than other ataxias. To conclude, ALD accounts for approximately 0.39% (2/516) of adult-onset cerebellar ataxias. This study expands the mutational spectrum of AVALD and underscores the importance of considering ALD as a potential etiology of cerebellar ataxia.

Aim: The present study aimed to investigate the regulation and involvement of miR-221 in the differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs). The relationships between miR-221 and pro-inflammatory markers and adipokines were also explored. Methods: Eight adipose tissues were obtained from four obese (mean body mass index (BMI) =31.7 kg/m2) and four lean (mean BMI= 21.5 kg/m2) women. hASCs were induced to differentiate, and the related gene expression were measured in the hASC-differentiated adipocytes using real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR). Results: During adipogenesis, miR-221 was significantly down-regulated; furthermore, miR-221 levels were lower in hASC-differentiated adipocytes from obese subjects than in the corresponding adipocytes from lean subjects. Higher TNF-α mRNA levels were associated with lower levels of miR-221. In addition, the miR-221 levels in the adipocytes were inversely correlated with BMI. Conclusion: Our results support the link between miR-221 and obesity development as well as obesity related inflammatory status.

BACKGROUND:A small group of patients with inherited neuropathy that has been shown to be caused by mutations in the BSCL2 gene. However, little information is available about the role of BSCL2 mutations in inherited neuropathies in Taiwan. METHODOLOGY AND PRINCIPAL FINDINGS:Utilizing targeted sequencing, 76 patients with molecularly unassigned Charcot-Marie-Tooth disease type 2 (CMT2) and 8 with distal hereditary motor neuropathy (dHMN), who were selected from 348 unrelated patients with inherited neuropathies, were screened for mutations in the coding regions of BSCL2. Two heterozygous BSCL2 mutations, p.S90L and p.R96H, were identified, of which the p.R96H mutation is novel. The p.S90L was identified in a pedigree with CMT2 while the p.R96H was identified in a patient with apparently sporadic dHMN. In vitro studies demonstrated that the p.R96H mutation results in a remarkably low seipin expression and reduced cell viability. CONCLUSION:BSCL2 mutations account for a small number of patients with inherited neuropathies in Taiwan. The p.R96H mutation is associated with dHMN. This study expands the molecular spectrum of BSCL2 mutations and also emphasizes the pathogenic role of BSCL2 mutations in molecularly unassigned hereditary neuropathies.

Estrogen is involved in neuron plasticity and can promote neuronal survival in stroke. Its actions are mostly exerted via estrogen receptor alpha (ERα). Previous animal studies have shown that ERα is upregulated by DNA demethylation following ischemic injury. This study investigated the methylation levels in the ERα promoter in the peripheral blood of ischemic stroke patients.The study included 201 ischemic stroke patients, and 217 age- and sex-comparable healthy controls. The quantitative methylation level in the 14 CpG sites of the ERα promoter was measured by pyrosequencing in each participant. Multivariate regression model was used to adjust for stroke traditional risk factors. Stroke subtypes and sex-specific analysis were also conducted.The results demonstrated that the stroke cases had a lower ERα methylation level than controls in all 14 CpG sites, and site 13 and site 14 had significant adjusted p-values of 0.035 and 0.026, respectively. Stroke subtypes analysis showed that large-artery atherosclerosis and cardio-embolic subtypes had significantly lower methylation levels than the healthy controls at CpG site 5, site 9, site 12, site 13 and site 14 with adjusted p = 0.039, 0.009, 0.025, 0.046 and 0.027 respectively. However, the methylation level for the patients with small vessel subtype was not significant. We combined the methylation data from the above five sites for further sex-specific analysis. The results showed that the significant association only existed in women (adjusted p = 0.011), but not in men (adjusted p = 0.300).Female stroke cases have lower ERα methylation levels than those in the controls, especially in large-artery and cardio-embolic stroke subtypes. The study implies that women suffering from ischemic stroke of specific subtype may undergo different protective mechanisms to reduce the brain injury.

Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT) type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive.Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability.GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is originally featured with a strong clustering of mutations in NOTCH3 exons 3-6 and leukoencephalopathy with frequent anterior temporal pole involvement. The present study aims at characterizing the genotypic and phenotypic profiles of CADASIL in Taiwan. One hundred and twelve patients with CADASIL from 95 families of Chinese descents in Taiwan were identified by Sanger sequencing of exons 2 to 24 of NOTCH3. Twenty different mutations in NOTCH3 were uncovered, including 3 novel ones, and R544C in exon 11 was the most common mutation, accounting for 70.5% of the pedigrees. Haplotype analyses were conducted in 14 families harboring NOTCH3 R544C mutation and demonstrated a common haplotype linked to NOTCH3 R544C at loci D19S929 and D19S411. Comparing with CADASIL in most Caucasian populations, CADASIL in Taiwan has several distinct features, including less frequent anterior temporal involvement, older age at symptom onset, higher incidence of intracerebral hemorrhage, and rarer occurrence of migraine. Subgroup analyses revealed that the R544C mutation is associated with lower frequency of anterior temporal involvement, later age at onset and higher frequency of cognitive dysfunction. In conclusion, the present study broadens the spectrum of NOTCH3 mutations and provides additional insights for the clinical and molecular characteristics of CADASIL patients of Han-Chinese descents.

Whether the occurrence of posterior atrophy (PA) and medial temporal lobe atrophy (MTA) was correlated with cognitive and non-cognitive symptoms in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients are unclear.Patients with probable AD and MCI from a medical center outpatient clinic received attention, memory, language, executive function evaluation and Mini-Mental Status Examination (MMSE). The severity of dementia was rated by the Clinical Dementia Rating (CDR) Sum of Box (CDR-SB). The neuropsychiatric inventory (NPI) subscale of agitation/aggression and mood symptoms was also applied. Magnetic resonance imaging (MRI) was scored visually for the MTA, PA and white matter hyperintensity (WMH) scores.We recruited 129 AD and 31 MCI (mean age 78.8 years, 48% female) patients. MMSE scores, memory, language and executive function were all significantly decreased in individuals with AD than those with MCI (p < 0.01). MTA and PA scores reflected significant atrophy in AD compared to MCI; however, the WMH scores did not differ. The MTA scores were significantly correlated with the frontal, parieto-occipital and global WMH scores (p < 0.01) while the PA scores showed a correlation with the parieto-occipital and temporal WMH scores (p < 0.01). After adjusting for age, education, APOE4 gene and diagnostic group covariates, the MTA scores showed a significant association with MMSE and CDR-SB, while the right side PA scores were significantly associated with NPI-agitation/aggression subscales (p < 0.01).Regional atrophy is related to different symptoms in patients with AD or MCI. PA score is useful as a complementary measure for non-cognitive symptom.

To evaluate the risk of premotor symptoms, namely rapid eye movement behavior disorder (RBD), constipation, and depression among patients with newly diagnosed Parkinson disease (PD).A total of 705 PD patients and 2,820 control subjects were selected from the Taiwan National Health Insurance Research Database. Patients were traced back for a maximum of 14 years to determine the diagnoses of RBD, depression, and constipation. Logistic regression analysis was used to identify risk of premotor symptoms for PD. Moreover, subgroup analyses were performed by dividing the patients into a middle-age onset group (≤ 64 years) and an old-age onset group (≥ 65 years). The associations between these premotor symptoms and age of PD onset were further examined.An association was found between a history of premotor symptoms and newly diagnosed PD in which a high occurrence of premotor symptoms was identified in PD patients as compared to selected controls (4.3% vs. 1.2% for RBD, 40.4% vs. 24.0% for constipation, and 13.0% vs. 5.1% for depression). The strength of this association remained statistically significant after adjustment for potential confounders (3.69 fold risk for RBD, 2.36 for constipation, and 2.82 for depression, all p < 0.0001). The average interval between premotor symptoms and PD ranged from 4.5 to 6.2 years. RBD and depression carried higher risks for PD in the middle-age onset group than in the old-age onset group (7.20- vs. 2.24-fold risk for RBD, 6.06 vs. 1.40 for depression).The prevalence of premotor symptoms was higher among the PD patients than in the controls. Premotor symptoms appeared to be associated with a higher risk for PD in subjects with an earlier age of onset.

Several treatment guidelines for Parkinson's disease (PD) had been proposed in recent decades. The aim of current study was to investigate the initial medication utilized in newly diagnosed PD subjects in Taiwan during an eleven-year period.A total of 7,550 patients with newly diagnosed Parkinsonism were retrospectively enrolled from the National Health Insurance Research Database of Taiwan from 2000 to 2010. After excluding patients at risk of secondary or atypical Parkinsonism, those never receiving medication or having incomplete data, 1,645 subjects were included. The participants were then divided into four treating regimen groups, namely levodopa (LD) only group, dopamine agonist (DA) only group, LD+DA group, and No-LD, No-DA group. The demographic data and medication retention rate were compared across the four treatment groups.LD only and No-LD, No-DA regimens were the main initial choice of PD treatment in Taiwan. LD containing drugs were more often prescribed to the elderly population than the other two treatment regimens, while No-LD, No-DA medication was the major initial choice for younger patients. DA only regimen occupied only 3-4% of the initial PD prescriptions and was given predominantly by neurologists. Over the eleven-year period, there is a trend for the middle-aged population to receive medication containing LD as initial treatment. The one year retention rate of anti-Parkinsonism medication was around 30-50% in our population. Age, polypharmacy, change of one-year daily levodopa equivalent dosage and newly onset of dementia, stroke and psychiatric diseases all affect drug compliance in PD patients.This is the first long-term study to explore initial pharmacotherapies in an Asian PD population. We hope to provide evidence for adjusting government policies and public education of physicians and PD patients in the future.

BackgroundMutations in the PRRT2 gene have recently been identified in patients with familial paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and patients with sporadic PKD/IC from several ethnic groups. To extend these recent genetic reports, we investigated the frequency and identities of PRRT2 mutations in a cohort of Taiwanese patients with PKD/IC.Methodology and principal findingsWe screened all 3 coding exons of PRRT2 for mutations in 28 Taiwanese patients with PKD/IC. Among them, 13 had familial PKD/IC and 15 were apparently sporadic cases. In total, 7 disparate mutations were identified in 13 patients, including 8 familial cases and 5 apparently sporadic cases. The mutations were not present in 500 healthy controls. Four mutations were novel. One patient had a missense mutation and all other patients carried PRRT2 mutations putatively resulting in a protein truncation. Haplotype analysis revealed that 5 of the 7 patients with the PRRT2 p.R217Pfs*8 mutation shared the same haplotype linked to the mutation.Conclusions and significancePRRT2 mutations account for 61.5% (8 out of 13) of familial PKD/IC and 33.3% (5 out of 15) of apparently sporadic PKD/IC in the Taiwanese cohort. Most patients with the PRRT2 p.R217Pfs*8 mutation in Taiwan likely descend from a single common ancestor. This study expands the spectrum of PKD/IC-associated PRRT2 mutations, highlights the pathogenic role of PRRT2 mutations in PKD/IC, and suggests genetic heterogeneity within idiopathic PKD.