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Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Although idiopathic PD accounts for most of the cases, several genetic mutations have been found to cause PD. Mutations in the eukaryotic translation initiation factor 4-γ, 1 (EIF4G1) gene have been identified since 2011, which were reported to be associated with PD among Caucasians in subsequent research. However, this observation was not consistent. The contribution to other ethnic groups remains limited, with < 1% of sporadic cases. We conducted a case–control study to analyze if EIF4G1 is a risk factor for PD patients in Taiwan. Methods: There were 595 PD patients and 600 controls without neurological diseases enrolled in this study. Four reported mutations—A502V (c.1505C>T), G686C (c.2056 G>T), R1197W (c.3589C>T), and R1205H (c.3614G>A)—were analyzed. Results: There were no mutations found in either PD patients or controls. Conclusion: This study indicates that the EIF4G1 mutation is rare in Taiwan, which is consistent with other reports from Asia. Ethnicity could have a great influence on EIF4G1 in PD. Further large scale studies are warranted to evaluate the association of PD and EIF4G1 gene.

Abstract The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20–89 years; 33% female) and 885 controls (age: 19–84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen’s d effect sizes reached d = −1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Background: White matter (WM) tract alterations are early signs of cognitive impairment in Parkinson disease (PD) patients. Fixel-based analysis (FBA) has advantages over traditional diffusion tensor imaging in managing complex and crossing fibers. We used FBA to measure fiber-specific changes in patients with PD mild cognitive impairment (PD-MCI) and PD normal cognition (PD-NC). Methods: Seventy-one patients with PD without dementia were included: 39 PD-MCI and 32 PD-NC. All underwent diffusion-weighted imaging, clinical examinations, and tests to evaluate their cognitive function globally and in five cognitive domains. FBA was used to investigate fiber-tract alterations and compare PD-MCI with PD-NC subjects. Correlations with each cognitive test were analyzed. Results: Patients with PD-MCI were significantly older (p = 0.044), had a higher male-to-female ratio (p = 0.006) and total Unified Parkinson's Disease Rating Scale score (p = 0.001). All fixel-based metrics were significantly reduced within the body of the corpus callosum and superior corona radiata in PD-MCI patients (family-wise error-corrected P value

BackgroundIn Parkinson's disease (PD) brains, microglia are activated to release inflammatory factors to induce the production of reactive oxygen species (ROS) in neuron, and vice versa. Moreover, neuroinflammation and its synergistic interaction with oxidative stress contribute to the pathogenesis of PD.MethodsIn this study, we investigated whether in-house synthetic coumarin-chalcone derivatives protect human microglia HMC3 and neuroblastoma BE(2)-M17 cells against 1-methyl-4-phenyl pyridinium (MPP+)-induced neuroinflammation and associated neuronal damage.ResultsTreatment with MPP+ decreased cell viability as well as increased the release of inflammatory mediators including cytokines and nitric oxide in culture medium, and enhanced expression of microglial activation markers CD68 and MHCII in HMC3 cells. The protein levels of NLRP3, CASP1, iNOS, IL-1β, IL-6, and TNF-α were also increased in MPP+-stimulated HMC3 cells. Among the four tested compounds, LM-016, LM-021, and LM-036 at 10 μM counteracted the inflammatory action of MPP+ in HMC3 cells. In addition, LM-021 and LM-036 increased cell viability, reduced lactate dehydrogenase release, ameliorated cellular ROS production, decreased caspase-1, caspase-3 and caspase-6 activities, and promoted neurite outgrowth in MPP+-treated BE(2)-M17 cells. These protective effects were mediated by down-regulating inflammatory NLRP1, IL-1β, IL-6, and TNF-α, as well as up-regulating antioxidative NRF2, NQO1, GCLC, and PGC-1α, and neuroprotective CREB, BDNF, and BCL2.ConclusionThe study results strengthen the involvement of neuroinflammation and oxidative stress in PD pathogenic mechanisms, and indicate the potential use of LM-021 and LM-036 as dual inflammasome inhibitors in treating both NLRP1- and NLRP3-associated PD.

Abstract Diminished cognitive and physical functions negatively affect the daily functions of individuals. Although combined cognitive and physical training prevents instrumental activities of daily living (IADL) disability in older adults, no predictive model or mediation analysis of IADL after combined training exists. This study aims to employ prediction and mediation analysis to identify the predictors of IADL performance and to elucidate the mediators of the association between baseline global cognition and subsequent IADL performance following combined cognitive and physical training. This study involved 177 participants aged 60 years and older who underwent combined training. Cognitive function was measured with the Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Color Trails Test, Word List, and a dual task; physical function with the Timed Up and Go (TUG) test; daily function with the Lawton IADL Scale. We conducted regression analyses to identify the predictors of IADL performance, and mediation analysis to examine whether DSST and TUG mediate the relationship between MoCA and IADL. The pre-intervention DSST and TUG were significant independent predictors of post-intervention IADL. The association between the pre-intervention MoCA and post-intervention IADL was mediated by pre-intervention DSST and TUG. This study highlighted the importance of measuring and improving processing speed and functional mobility before and during interventions to enhance IADL outcomes. Trial registration: NCT03619577, 23/07/2018; NCT04689776, 29/12/2020.

It has been suggested that a common LRRK2 polymorphic variant (A419V (rs34594498 C >T)) may be a risk factor among Asians (especially in Taiwan). In this study, we examined this variant in a larger and independent Taiwan cohort. We found the frequency of the variant (A419V) to be very rare in our Taiwan PD and controls (?0.6%). Further studies were conducted in two other Chinese populations (Singapore and China), comprising of a total of 3004 subjects including 1517 PD patients and 1487 control subjects. However, our multi-center Chinese study revealed that the frequency of the variant was rare (?0.4%) and was not associated with risk of PD, suggesting that the variant is not a major risk factor for PD among Chinese, at least in our study population.

Huntington’s disease (HD) is characterized by progressive involuntary chorea movements and cognitive decline. Recent research indicates that metabolic disturbance may play a role in its pathogenesis. Bile acids, produced during cholesterol metabolism in the liver, have been linked to neurodegenerative conditions. This study investigated variations in plasma bile acid profiles among individuals with HD. Plasma levels of 16 primary and secondary bile acids and their conjugates were analyzed in 20 healthy controls and 33 HD patients, including 24 with symptoms (symHD) and 9 carriers in the presymptomatic stage (preHD). HD patients exhibited significantly higher levels of glycochenodeoxycholic acid (GCDCA) and glycoursodeoxycholic acid (GUDCA) compared to healthy controls. Conversely, isolithocholic acid levels were notably lower in the HD group. Neurotoxic bile acids (glycocholic acid (GCA) + glycodeoxycholic acid (GDCA) + GCDCA) were elevated in symHD patients, while levels of neuroprotective bile acids (ursodeoxycholic acid (UDCA) + GUDCA + tauroursodeoxycholic acid (TUDCA)) were higher in preHD carriers, indicating a compensatory response to early neuronal damage. These results underscore the importance of changes in plasma bile acid profiles in HD and their potential involvement in disease mechanisms. The identified bile acids (GCDCA, GUDCA, and isolithocholic acid) could potentially serve as markers to distinguish between HD stages and healthy individuals. Nonetheless, further research is warranted to fully understand the clinical implications of these findings and their potential as diagnostic or therapeutic tools for HD.

Abstract Background Approximately 10% to 20% of myasthenia gravis (MG) patients have experienced a myasthenic crisis (MC), which contributes to morbidity and mortality. MC triggered by infection is associated with poor outcomes. However, there is a lack of prognostic factors that clinicians can utilize to target interventions for preventing recurrent infection-triggered MC. This study aimed to characterize clinical manifestations, comorbidities, and biochemical profiles associated with recurrent infection-triggered MC in MG patients. Methods This retrospective study included 272 MG patients hospitalized with an infection requiring at least 3 days of antibiotics from January 2001 to December 2019. Patients were further stratified into non-recurrent or recurrent infection groups. Clinical features such as gender, age, concomitant diseases, acetylcholine receptor antibodies and biochemical data (including electrolytes and coagulants), muscle strength of pelvic and shoulder girdle, bulbar and respiratory function, management with an endotracheal tube, Foley catheter, or plasmapheresis, duration of hospitalization, and culture pathogens were recorded. Results The recurrent infection group was significantly older than the non-recurrent group (median age, 58.5 versus 52.0 years). Pneumonia was the most common infection and Klebsiella pneumoniae was the most common pathogen. The presence of concomitant diabetes mellitus, activated partial thromboplastin time prolongation, the duration of hospitalization, and hypomagnesaemia were independently associated with recurrent infection. The presence of deep vein thrombosis, thymic cancer, and electrolyte imbalances i.e., hypokalemia, and hypoalbuminemia were significantly associated with a risk for infection. The influence of endotracheal intubation, anemia, and plasmapheresis during hospitalization were inconsistent. Conclusions The independent risk factors for recurrent infections in MG patients identified in this study include the presence of concomitant diabetes mellitus, hypomagnesaemia, activated partial thromboplastin time prolongation, and longer duration of hospitalization, highlighting the need for targeted interventions to prevent recurrent infections in this population. Further research and prospective studies are warranted to validate these findings and refine interventions for optimizing patient care.

Abstract Background The effects of combined training can be affected by training characteristics such as frequency, session length, and duration. No empirical studies to date have directly compared how combined physical and cognitive training offered at different training frequencies affects cognitive function for older adults with cognitive decline. This study investigated the impact of training frequency on cognitive outcomes after combined physical and cognitive training for older adults with cognitive decline. Methods A quasi-experimental study was conducted in community facilities and day care centers. The study assigned 89 older adults with cognitive decline into high-frequency (HF) or low-frequency (LF) training groups. The participants received 90- to 105-min training sessions, one (LF) or three (HF) times a week, for 12 weeks. Outcome measures were the Montreal Cognitive Assessment, Word List subtest of the Wechsler Memory Scale, Digit Symbol Substitution Test (DSST), and Stroop Color Word Test. Results The HF group demonstrated greater improvement in immediate memory measured by the WL-IM (F = 8.7, P = 0.004) and in executive function measured by the SCWT (F = 5.89, P = 0.017) than the LF group. Compared with the HF group, the LF group showed a great improvement in delayed memory measured by the WL-DM (F = 9.62, P = 0.003). The HF and LF groups both increased in processing speed and global cognitive function. Conclusions Our study indicated that the different training frequency of combined physical and cognitive training may result in benefits on different cognitive functions in older adults with cognitive decline. These findings may assist clinical practitioners in choosing appropriate training frequencies based on various intervention purposes for the elderly with cognitive decline. Trial registration ClinicalTrials.gov Identifier NCT03619577 (08/08/2018).

Background: Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders, which characterized by increased pathological marker protein, α-synuclein (α-syn) and phosphorylated-Ser129-α-syn in the extracellular fluids. Current methods of measuring the p-Ser129-α-syn concentration in cerebrospinal fluid for PD are based on ELISA method, however, the amount of area under the curve (AUC) to predict PD is around 0.7-0.8. Higher confidence level of AUC in p-Ser129-α-syn quantification for the early diagnosis of PD would be essential. Methods: Detection of p-Ser129-α-syn in diluted human serum for diagnosis of PD was investigated by a modified paired surface plasma wave biosensor (PSPWB) using a quarter wave plate for better detection performance. The method combining an immunoassay and non-labeled technique measures the p-Ser129-α-syn level with high sensitivity and specificity. Ten patients with PD at early stage (Hohn & Yahr stage I and II) and 11 age-matched healthy control participants were recruited for measurement of serum p-Ser129-α-syn. Results: AUC of the p-Ser129-α-syn in diluted human serum was 0.92 and it shows that p-Ser129-α-syn in diluted human serum could be used as a sensitive biomarker for the diagnosis of PD in clinics. Results clearly show that the measured p-Ser129-α-syn concentration in diluted human serum displays a statistical significance between health control subjects and PD patients. Conclusions: P-Ser129-α-syn has low abundance in human serum, high detection sensitivity and specificity are critical to the success of the diagnosis of PD in clinics. In this study, a modified PSPWB was developed that the limit of detection at 1 ng/mL for p-Ser129-α-syn (standard) spiked into diluted human serum of a healthy control was performed. This result shows that the modified PSPWB can be used as a platform for detecting p-Ser129-α-syn in diluted human serum as a potential biomarker for PD.

Objective Combined physical (PHY) and cognitive (COG) training in sequential (SEQ) and simultaneous (SIMUL) sessions may delay the progression of cognitive impairment. To date, no study has directly compared in older adults with cognitive impairment the effects of COG training, PHY training, SEQ motor-cognitive training and SIMUL motor-cognitve training on specific indices of cognitive performance and activities of daily living (ADL). The purpose of this study was to determine whether SEQ and SIMUL motor-cognitive training can improve treatment outcomes compared with PHY or COG training alone. We also aimed to compare the effects of SEQ versus SIMUL motor-cognitive training on cognitive functions and instrumental ADL (IADL) in older adults with cognitive impairment. Methods A cluster randomized controlled trial was conducted. Eighty older adults with cognitive impairment were randomly assigned to COG, PHY, SEQ or SIMUL training groups. The intervention consisted of 90-min training sessions, totaling 36 sessions. Outcome measures were the Montreal Cognitive Assessment, three subtests of the Wechsler Memory Scale (WMS) and the Lawton IADL scale. Results Significant interaction effects between group and time were found in WMS-spatial span ( p = 0.04) and WMS-word lists ( p = 0.041). For WMS-spatial span, the SIMUL group showed outperformed the COG ( p = 0.039), PHY ( p = 0.010) and SEQ groups ( p = 0.017). For WMS-word lists, the SEQ group improve more than COG ( p = 0.013), PHY ( p = 0.030) and SIMUL ( p = 0.019) groups. No significant differences were found in IADL performance among four groups ( p = 0.645). Conclusions Our study showed SEQ and SIMUL motor-cognitive training led to more pronounced improvements in visuospatial working memory or verbal memory compared with isolated COG or PHY training for community-based older adults with cognitive impairment. For enhancing effects on IADL, we suggest the use of sensitive measurement tools and context-enriched cognitive training involving real-life task demands.

Movement disorders are common manifestations in autoimmune-mediated encephalitis. This group of diseases is suspected to be triggered by infection or neoplasm. Certain phenotypes correlate with specific autoantibody-related neurological disorders, such as orofacial-lingual dyskinesia with N-methyl-D-aspartate receptor encephalitis and faciobrachial dystonic seizures with leucine-rich glioma-inactivated protein 1 encephalitis. Early diagnosis and treatment, especially for autoantibodies targeting neuronal surface antigens, can improve prognosis. In contrast, the presence of autoantibodies against intracellular neuronal agents warrants screening for underlying malignancy. However, early clinical diagnosis is challenging because these diseases can be misdiagnosed. In this article, we review the distinctive clinical phenotypes, magnetic resonance imaging findings, and current treatment options for autoimmune-mediated encephalitis.

Background/Purpose: Genetic and environmental factors play significant roles in the pathogenesis of Parkinson's disease (PD). Recently, 17 novel risk loci of PD were identified in a meta-analysis of genome-wide association study (GWAS) in the European populations. In order to clarify if these risk loci are associated with PD in Taiwanese population, we conducted a case–control study including 14 of the novel risk loci and analyzed the genetic distribution and allele frequency. Methods: A total of 2798 subjects were recruited in this study. Genotyping was performed in 672 PD patients and 609 healthy controls by using Mass ARRAY, and data of another 1517 healthy controls from Taiwan Biobank were also examined. Results: Our results show that the dominant models of ITPKB rs4653767 (OR (95% CI) = 0.832 (0.699, 0.990), p = 0.038), IL1R2 rs34043159 (OR (95% CI) = 0.812 (0.665, 0.992), p = 0.041) and COQ7 rs11343 (OR (95% CI) = 0.304 (0.180, 0.512), p

Abstract Background Isaacs’ syndrome is a peripheral nerve hyperexcitability (PNH) syndrome due to peripheral motor nerve instability. Acquired Isaacs’ syndrome is recognized as a paraneoplastic autoimmune disease with possible pathogenic voltage-gated potassium channel (VGKC) complex antibodies. However, the longitudinal correlation between clinical symptoms, VGKC antibodies level, and drug response is still unclear. Case presentation A 45-year-old man had progressive four limbs soreness, muscle twitching, cramps, and pain 4 months before admission. Electromyography (EMG) studies showed myokymic discharges, neuromyotonia, and an incremental response in the high-rate (50 Hz) repetitive nerve stimulation (RNS) test. Isaacs’ syndrome was diagnosed based on clinical presentations and EMG reports. Serum studies showed positive VGKC complex antibodies, including leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. The acetylcholine receptor antibody was negative. Whole-body computed tomography (CT) and positron emission tomography revealed a mediastinal tumor with the great vessels encasement, right pleura, and diaphragm seeding. Biopsy confirmed a World Health Organization type B2 thymoma, with Masaoka stage IVa. His symptoms gradually improved and both LGI1 and CASPR2 antibodies titer became undetectable after concurrent chemoradiotherapy (CCRT) and high dose steroid treatment. However, his Isaacs’ syndrome recurred after the steroid was reduced 5 months later. Follow-up chest CT showed probable thymoma progression. LGI1 antibody turned positive again while CASPR2 antibody remained undetectable. Conclusions Our patient demonstrates that Isaacs’ syndrome could be the initial and only neuromuscular manifestation of malignant thymoma. His Isaacs’ syndrome is correlated well with the LGI1 antibody level. With an unresectable thymoma, long-term immunosuppressant therapy may be necessary for the management of Isaacs’ syndrome in addition to CCRT for thymoma.

Objective A meta-analysis of locus-based genome-wide association studies recently identified a relationship between AXIN1 and Parkinson’s disease (PD). Few studies of Asian populations, however, have reported such a genetic association. The influences of rs13337493, rs758033, and rs2361988, three PD-associated genetic variants of AXIN1, were investigated in the present study because AXIN1 is related to Wnt/β-catenin signaling. Methods A total of 2,418 individuals were enrolled in our Taiwanese cohort for analysis of the genotypic and allelic frequency. Polymerase chain reaction–restriction fragment length polymorphism analysis was employed for rs13337493 genotyping, and the Agena MassARRAY platform (Agena Bioscience, San Diego, CA, USA) was used for rs758033 and rs2361988 genotyping in 672 patients with PD and 392 controls. Taiwan Biobank data of another 1,354 healthy controls were subjected to whole-genome sequencing performed using Illumina platforms at approximately 30× average depth. Results Our results revealed that rs758033 {odds ratios [OR] (95% confidence interval [CI]) = 0.267 [0.064, 0.795], p = 0.014} was associated with the risk of PD, and there was a trend toward a protective effect of rs2361988 (OR [95% CI] = 0.296 [0.071, 0.884], p = 0.026) under the recessive model. The TT genotype of rs758033 (OR [95% CI] = 0.271 [0.065, 0.805], p = 0.015) and the CC genotype of rs2361988 (OR [95% CI] = 0.305 [0.073, 0.913], p = 0.031) were less common in the PD group than in the non-PD group. Conclusion Our findings indicate that the rs758033 and rs2361988 polymorphisms of AXIN1 may affect the risk of PD in the Taiwanese population.

BackgroundA recent Taiwanese study reported variants of the ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene linked to autosomal dominant parkinsonism with polyneuropathy. This study investigated the pathogenicity of UQCRC1 in a Taiwanese cohort of patients with Parkinson's disease (PD).MethodThis study involved 107 participants (98 with early-onset PD and nine with familial PD). All UQCRC1 coding exons and exon–intron boundaries were sequenced. The rarity and pathogenicity of the identified variants were analyzed. The carrier frequencies of our cohort and the Taiwan Biobank were compared through a Pearson's χ2 or Fisher's exact test along with Bonferroni corrections.ResultsThree missense variants (c.643G > C, p.D215H; c.800C > G, p.P267R, and c.923A > G, p.N308S) and seven rare variants were identified. No significant differences in the missense-variant carrier frequency were noted between our cohort and individuals in the Taiwan Biobank. Furthermore, no significant associations were noted between the variants and the risk of PD.ConclusionsOur study is not supporting a role of UQCRC1 variants in PD.

Abstract Background Patients with Parkinson’s disease (PD) can develop impulse control disorders (ICDs) while undergoing a pharmacological treatment for motor control dysfunctions with a dopamine agonist (DA). Conventional clinical interviews or questionnaires can be biased and may not accurately diagnose at the early stage. A wearable electroencephalogram (EEG)-sensing headset paired with an examination procedure can be a potential user-friendly method to explore ICD-related signatures that can detect its early signs and progression by reflecting brain activity. Methods A stereotypical Go/NoGo test that targets impulse inhibition was performed on 59 individuals, including healthy controls, patients with PD, and patients with PD diagnosed by ICDs. We conducted two Go/NoGo sessions before and after the DA-pharmacological treatment for the PD and ICD groups. A low-cost LEGO-like EEG headset was used to record concurrent EEG signals. Then, we used the event-related potential (ERP) analytical framework to explore ICD-related EEG abnormalities after DA treatment. Results After the DA treatment, only the ICD-diagnosed PD patients made more behavioral errors and tended to exhibit the deterioration for the NoGo N2 and P3 peak amplitudes at fronto-central electrodes in contrast to the HC and PD groups. Particularly, the extent of the diminished NoGo-N2 amplitude was prone to be modulated by the ICD scores at Fz with marginal statistical significance (r = − 0.34, p = 0.07). Conclusions The low-cost LEGO-like EEG headset successfully captured ERP waveforms and objectively assessed ICD in patients with PD undergoing DA treatment. This objective neuro-evidence could provide complementary information to conventional clinical scales used to diagnose ICD adverse effects.

Abstract Our study aimed to investigate the incidence, risk factors and time to occurrence of malignancy in patients with dermatomyositis (DM) and polymyositis (PM). The electronic medical records of 1100 patients with DM and 1164 patients with PM were studied between January 2001 and May 2019. Malignancies after myositis were diagnosed in 61 (5.55%) patients with DM and 38 (3.26%) patients with PM. The cumulative incidence of malignancies in patients with DM were significantly higher than patients with PM (hazard ratio = 1.78, log-rank p = 0.004). Patients with DM had a greater risk of developing malignancy than those with PM at 40–59 years old (p = 0.01). Most malignancies occurred within 1 year after the initial diagnosis of DM (n = 35; 57.38%). Nasopharyngeal cancer (NPC) was the most common type of malignancy in patients with DM (22.95%), followed by lung, and breast cancers. In patients with PM, colorectal, lung and hepatic malignancies were the top three types of malignancy. The risk factors for malignancy included old age (≥ 45 years old) and low serum levels of creatine phosphokinase (CPK) for patients with DM and male sex and low serum levels of CPK for patients with PM. Low serum levels of CPK in patients with myositis with malignancy represented a low degree of muscle destruction/inflammation, which might be attributed to activation of the PD-L1 pathway by tumor cells, thus inducing T-cell dysfunction mediating immune responses in myofibers. A treatment and follow-up algorithm should explore the occurrence of malignancy in different tissues and organs and suggested annual follow-ups for at least 5.5 years to cover the 80% cumulative incidence of malignancy in patients with DM and PM.

Abstract To evaluate the correlation between “hot cross bun” sign (HCBs) and disease severity in multiple system atrophy (MSA). We recruited patients with probable and possible MSA with parkinsonism (MSA-P) or the cerebellar ataxia (MSA-C) subtypes. Clinical and imaging characteristics were collected and comparison was performed between MSA-C and MSA-P cases. Spearman test was used to evaluate the correlation between HCBs and other variables. Curve estimate and general linear regression was performed to evaluate the relationship between HCBs and the Scale for Assessment and Rating of Ataxia (SARA). Unified Multiple System Atrophy Rating Scale (UMSARS) IV was used to assess the severity of disease. Multinomial ordered logistic regression was used to confirm the increased likelihood of disability for the disease. Eighty-one MSA with HCBs comprising of 50 MSA-C and 31 MSA-P were recruited. We demonstrated that the severity of HCBs showed a positive linear correlation with SARA scores in MSA-C. Multinomial ordered logistic regression test revealed that the increase in the HCBs grade may be associated with an increased likelihood of disability for the disease severity in MSA, especially in those with cerebellar ataxia subtype. We demonstrated that HCBs is a potential imaging marker for the severity of cerebellar ataxia. The increase in the HCBs grade may be associated with an increased likelihood of disability in MSA-C, but not MSA-P cases, suggesting that it may be a useful imaging indicator for disease progression in Chinese patients with MSA-C.

Background: Oxidative stress could participate in the pathogenesis of Parkinson's disease (PD). However, the role of genetic variation of superoxide dismutase 2 (SOD2), an important regulator against oxidative stress, in PD remains to be elucidated. Methods: We screened SOD2 gene variation by sequencing cDNA from 72 patients with early onset PD. A cohort of PD (n = 609) and ethnically matched controls (n = 681) were further examined for the identified sequence variant by PCR and NaeI restriction analysis. Results: Only a reported c.47T>C polymorphism (rs4880, SOD2 p.V16A) was found by cDNA sequencing. Case-control study of c.47T>C revealed that genotype and allele frequencies were in Hardy–Weinberg equilibrium in both patients and healthy controls. In a recessive model, those with CC genotype had a 2.61-fold increased risk of PD (95% CI: 1.08–6.30, P = 0.03) compared to subjects with TT and TC genotypes. Significant association between CC genotype and PD in non-smokers was also observed after stratification according to the history of smoking (3.54-fold increased risk of PD, 95% CI: 1.17–10.72, P = 0.02). Meta-analysis by combining studies of Chinese in China, Singapore, and Taiwan (total 2302 cases and 2029 controls) consistently showed CC genotype with increased risk of PD (OR = 1.77, 95% CI: 1.15–2.71, P = 0.01). Conclusion: Our findings demonstrate that SOD2 p.V16A may play a role in the susceptibility of PD in Han Chinese.

Abstract Objectives Blood–brain barrier (BBB) disruption is a critical pathological process involved in neuromyelitis optica spectrum disorder (NMOSD). Here, we characterized the profile of five cell adhesion molecules in patients with NMOSD. Methods We measured levels of cell adhesion molecules, including ICAM‐1, ICAM‐2, VCAM‐1, PECAM‐1, and NCAM‐1, in the serum of 28 patients with NMOSD, 24 patients with multiple sclerosis (MS), and 25 healthy controls (HCs). Results ICAM‐2 levels (median: 394.8 ng/mL) were increased in patients with NMOSD compared with MS (267.1 ng/mL, P = 0.005) and HCs (257.4 ng/mL, P = 0.007), and VCAM‐1 and ICAM‐1 levels were higher in patients with NMOSD (641.9 ng/mL and 212.7 ng/mL, respectively) compared with HCs (465 ng/mL [P = 0.013] and 141.8 ng/mL [P = 0.002], respectively). However, serum PECAM‐1 levels were lower in patients with NMOSD (89.62 ng/mL) compared with MS (106.9 ng/mL, P = 0.015) and HCs (107.2 ng/mL, P = 0.007). Receiver operating characteristic curve analysis revealed that PECAM‐1 (area under the curve (AUC): 0.729) and ICAM‐2 (AUC: 0.747) had adequate abilities to distinguish NMOSD from MS, and VCAM‐1 (AUC: 0.719), PECAM‐1 (area under the curve: 0.743), ICAM‐1 (AUC: 0.778), and ICAM‐2 (AUC: 0.749) exhibited potential to differentiate NMOSD and HCs. Serum levels of PECAM‐1 also demonstrated a negative correlation with Kurtzke Expanded Disability Status Scale scores in patients with NMOSD. Interpretation Our results reveal possible BBB breakdown signals specifically observed in NMOSD and highlight the potential role of cell adhesion molecules as biomarkers of this disease.

Alterations in lipid composition and disturbed lipoprotein metabolism are involved in the pathomechanism of Huntington’s disease (HD). Here, we measured 112 lipoprotein subfractions and components in the plasma of 20 normal controls, 24 symptomatic (sympHD) and 9 presymptomatic (preHD) HD patients. Significant changes were found in 30 lipoprotein subfractions and components in all HD patients. Plasma levels of total cholesterol (CH), apolipoprotein (Apo)B, ApoB-particle number (PN), and components of low-density lipoprotein (LDL) were lower in preHD and sympHD patients. Components of LDL4, LDL5, LDL6 and high-density lipoprotein (HDL)4 demonstrated lower levels in preHD and sympHD patients compared with controls. Components in LDL3 displayed lower levels in sympHD compared with the controls, whereas components in very low-density lipoprotein (VLDL)5 were higher in sympHD patients compared to the controls. The levels of components in HDL4 and VLDL5 demonstrated correlation with the scores of motor assessment, independence scale or functional capacity of Unified Huntington’s Disease Rating Scale. These findings indicate the potential of components of VLDL5, LDL3, LDL4, LDL5 and HDL4 to serve as the biomarkers for HD diagnosis and disease progression, and demonstrate substantial evidence of the involvement of lipids and apolipoproteins in HD pathogenesis.

Background: Neuromuscular ultrasound is a complementary technology that aids in the diagnosis of peripheral neuropathy. The interpretation of neuromuscular ultrasound results requires the use of accurate normative cross-sectional area (CSA) reference values. This study aims to provide CSA reference values specific to Taiwanese adults for Sonography of peripheral nerves in the upper and lower extremities.Methods: The study cohort included 66 healthy subjects (36 women; 30 men). A linear probe was used to measure the CSA of the median, ulnar, radial, tibial, sural, and peroneal nerves at multiple sites. These data were analyzed to determine standard ranges for the CSA at each site (reference range = mean ± 2 × SD) and identify correlations between the CSA and patient characteristics.Results: Normative CSA ranges were determined for all the assessed nerve sites, revealing that the nerve sizes in this Taiwanese population were smaller than Caucasian populations but comparable to those reported for other Asian cohorts. Men tended to have larger nerves than women, even after adjusting for height and weight. The size of ulnar nerve in the cubital tunnel and the peroneal nerve in the popliteal fossa correlated negatively with increasing age. The nerve size correlated positively with increasing weight and BMI at several sites, correlation of median nerve in the forearm with weight and BMI was significant after multiple testing. Significant correlation was also found between size of ulnar nerve in cubital tunnel and decreasing height.Conclusion: We provide reference ranges for neuromuscular ultrasound CSA values for the upper and lower extremities that are specific to the Taiwanese population. These reference values may be useful for evaluating peripheral neuropathy in Taiwanese subjects.

Background: Postpartum spinal cord infarction is a very rare disease. Only two cases have been reported in the English literature. Methods: We reported a 26 year old female who received second doses of the mRNA-1273 vaccine 52 days before delivery. She presented as sudden onset of paraplegia, sensory level, and sphincter incontinence at postpartum period. No history of heparin exposure was noted. Imaging findings confirmed the T10-11 level infarction and her anti–human heparin platelet factor 4 (anti-PF4) antibody was positive. After 7 days of dexamethasone therapy, her paraplegia and urinary incontinence gradually improved. Results: The CT angiography (CTA) of the artery of Adamkiewicz (Aka) showed tandem narrowing, most conspicuous at the T10-11 level, which was presumably due to partial occlusion of the arteriolar lumen. The thoracolumbar spine magnetic resonance imaging with contrast medium showed owl’s eyes sign at the T10 and T11 levels. We compared our case with two other case reports from the literature. Conclusions: Post-partum spinal cord infarction with positive anti-PF4 antibody and relatively thrombocytopenia are the characteristics of our case.

Microstructure damage in white matter might be linked to regional and global atrophy in Huntington’s Disease (HD). We hypothesize that degeneration of subcortical regions, including the basal ganglia, is associated with damage of white matter tracts linking these affected regions. We aim to use fixel-based analysis to identify microstructural changes in the white matter tracts. To further assess the associated gray matter damage, diffusion tensor-derived indices were measured from regions of interest located in the basal ganglia. Diffusion weighted images were acquired from 12 patients with HD and 12 healthy unrelated controls using a 3 Tesla scanner. Reductions in fixel-derived metrics occurs in major white matter tracts, noticeably in corpus callosum, internal capsule, and the corticospinal tract, which were closely co-localized with the regions of increased diffusivity in basal ganglia. These changes in diffusion can be attributed to potential axonal degeneration. Fixel-based analysis is effective in studying white matter tractography and fiber changes in HD.

The authors show that Galectin-3 is up–regulated in brain tissues from patients and a mouse model of Huntington’s disease (HD) and correlates with disease severity. Galectin-3 accumulates at damaged lysosomes in HD microglia, prevents the clearance of damaged lysosomes, and promotes inflammation.

Parkinson’s disease (PD) is a neurodegenerative disorder related to nigrostriatal dopaminergic neuron degeneration and iron accumulation. As a cellular oxygen sensor, prolyl hydroxylase domain containing protein 2 (PHD2, encoded by egl-9 family hypoxia inducible factor 1, EGLN1) modifies hypoxia-inducible factor alpha (HIF-α) protein for proteasomal destruction under normoxic condition. In addition, 2-oxoglutarate- (OG-) dependent dioxygenase activity of PHD2 is involved in the oxygen and iron regulation of iron-responsive element binding protein 2 (IRP2) stability. Previously increased expression of EGLN1 was found in the substantia nigra of the parkinsonian brain. We investigated the possible role of c.380 G > C (p.C127S) of EGLN1 gene in Taiwanese patients with PD. 479 patients and 435 healthy controls were recruited. Polymerase chain reaction and BsmAI restriction enzyme analysis were applied for analysis. An association between CC genotype and reduced PD risk in the recessive model (CC vs. GG + GC) was found. Our study provides a link between EGLN1 c.380 G > C SNP and the development of PD.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease, and α-synuclein plays a critical role in the pathogenesis of PD. Studies have revealed controversial results regarding the correlation between motor severity and α-synuclein levels in peripheral blood from patients with PD.Objective: We examined α-synuclein levels in plasma or serum in patients with PD and investigated the relationship between plasma or serum α-synuclein level and motor symptom severity.Methods: We recruited 88 participants (48 patients with PD and 40 healthy controls). Clinical information was collected, and venous blood was drawn from each participant to be processed to obtain plasma or serum. The plasma or serum α-synuclein level was detected using monoclonal antibodies with magnetic nanoparticles, and was measured through immunomagnetic reduction. Plasma or serum α-synuclein levels were quantitatively detected.Results: In patients with PD, the means of plasma and serum α-synuclein level were 3.60 ± 2.53 and 0.03 ± 0.04 pg/mL, respectively. The areas under the receiver operating characteristic curve of plasma and serum α-synuclein for distinguishing patients with PD from healthy controls were 0.992 and 0.917, respectively. The serum α-synuclein level also showed a significant correlation with patients in H-Y stages 1–3 (r = 0.40, p = 0.025), implying that the serum α-synuclein level may be a potential marker of motor symptom severity in patients with early PD.Conclusions: Our data suggest that the α-synuclein level in serum or plasma can differentiate between healthy controls and patients with PD. Serum α-synuclein levels moderately correlate with motor severity in patients with early PD.

Abstract Pain is a distressing symptom of Parkinson disease (PD). We aim to determine whether the genetic variants of chronic pain-related genes contribute to pain in PD patients. We included 418 PD patients and evaluated pain severity on King’s PD pain scale. We genotyped rs6267, rs6269, rs4633, rs4818 and rs4680 of COMT, rs6746030 of SCN9A, and rs1799971 of OPRM1. In total, 193 participants (46.2%) experienced pain. Compared to pain-free PD patients, PD patients with pain had an earlier age of onset, longer disease duration, and higher depression and motor severity (P

Non-motor symptoms of Parkinson's disease (PD) have been receiving increasing attention. Approximately half of patients with PD have experience PD-related pain. We investigated the effect and mechanism of acupuncture in patients with PD who have pain. PD patients with pain were divided into acupuncture group and control group. Nine patients completed acupuncture treatment; seven patients who received only an analgesic agent underwent resting-state functional magnetic resonance imaging (rs-fMRI) twice. fMRI was performed to evaluate the functional connectivity of the brain regions. After treatment, a decrease in total scores on the King's Parkinson's Disease Pain Scale (KPPS) and Unified Parkinson's Disease Rating Scale was observed in the acupuncture group (−46.2 and −21.6%, respectively). In the acupuncture group, increased connectivity was observed in four connections, one in the left hemisphere between the middle temporal gyrus (MTG) and precentral gyrus, and three in the right hemisphere between the postcentral gyrus and precentral gyrus, supramarginal gyrus and precentral gyrus, and MTG and insular cortex. A significant correlation was noted between the changes in functional connectivity and KPPS. The involved connection was between the left middle frontal gyrus and the right precentral gyrus (R = −0.698, P = 0.037). Acupuncture could relieve pain in PD patients by modulating brain regions related to both sensory-discriminative and emotional aspects. The present study might increase the confidence of users that acupuncture is an effective and safe analgesic tool that can relieve PD-related pain.

Background: Studies have suggested that cytokines are crucial mediators in the pathogenesis of Parkinson’s disease (PD). The multifunctional cytokine interleukin (IL)-6 and its single nucleotide polymorphisms (SNPs) were found to have an impact on the development of PD. However, different studies in associations of IL-6 genetic variants with PD showed inconsistent results and it has never been explored in a Taiwanese population. Both IL-1α and IL-8 contribute to the same inflammation pathway. IL-1α genetic polymorphism has an effect on late-onset PD in Taiwan, whereas the associations of IL-8 genetic variants with PD in Taiwan remain to be investigated. Methods: This study examined the frequencies of polymorphisms within the critical promoter areas of the proinflammatory cytokine genes: IL-6 G-174C (rs1800795) and IL-8 A-251T (rs4073) in Taiwanese PD patients compared with age-and gender-matched healthy subjects. Comparisons were also made in genotype and allele frequencies of IL-6 G-174C (rs1800795) and IL-8 A-251T (rs4073) among different populations in previous studies. Results: In total, 1120 subjects, including 509 PD patients (female/male: 259/250) and 511 control subjects (female/male: 252/259), were recruited. We found no statistically significant differences in IL-6 G-174C (rs1800795) or IL-8 A-251T (rs4073) genotypic and allelic distribution between PD and controls, even after being stratified by age at onset and gender. Conclusions: The results did not demonstrate any association of IL-6 G-174C (rs1800795) or IL-8 A-251T (rs4073) with PD in a Taiwanese population. Despite the negative results, this is the first study in associations of IL-6 G-174C (rs1800795) and IL-8 A-251T (rs4073) with PD in Taiwan. The relevance of genetic variants of IL-6 G-174C (rs1800795) or IL-8 A-251T (rs4073) on PD susceptibility warrants further investigation.

Background: Virtual reality (VR) systems have been proven to increase motor performance in stroke and elderly patients. However, the effects have not been established in patients with Parkinson's disease (PD). The aim of this study was to examine the effects of VR-based training in improving muscle strength, sensory integration ability, and walking abilities in patients with PD through a randomized controlled trial. Methods: Thirty-six individuals who have been diagnosed with PD were randomly assigned to one of three groups (n = 12 for each group). Participants performed VR-based Wii Fit exercise (VRWii group) or traditional exercise (TE group) for 45 minutes, followed by treadmill training for another 15 minutes for 12 sessions in 6 weeks. Participants in the control group did not undergo the structured exercise program, but received fall-prevention education instead. The study outcomes included lower extremity muscle strength, sensory integration ability, walking velocity, stride length, and functional gait assessment. All outcomes were assessed at baseline, after training, and at 1 month follow-up. Results: Both the VRWii and TE groups showed more improvement in level walking velocity, stride length, functional gait assessment, muscle strength, and vestibular system integration compared with the control group after training and at 1 month follow-up. The VRWii training, but not the TE training, resulted in greater improvement in visual system integration than the control. Conclusion: VRWii training is as beneficial as TE in improving walking abilities, sensory integration ability, and muscle strength in patients with PD, and such improvements persisted for at least for 1 month. VRWii training is thus suggested to be implemented in patients with PD.

Background: Haplotype structure of the microtubule-associated protein tau (MAPT) gene is associated with various tauopathies in the Caucasian population. With the knowledge that the association between MAPT structure and disease may be distinct in different ethnics, we intend to investigate the haplotype structure of MAPT in Taiwanese and test it for association with Alzheimer's disease (AD). Methods: One hundred and eight AD patients and 108 sex- and-age matched healthy controls were recruited from the dementia outpatient clinic of Chang Gung Medical center. We genotyped the del-In9 marker that defines the extended H1 and H2 clades. We selected 21 single-nucleotide polymorphisms (SNPs) in the extended MAPT region from Japanese SNPs database and dbSNP database. Using the software TagIt, we analyzed the linkage disequilibrium structure of MAPT and compared the allele and genotype distribution between patient group and control group. Results: All the Taiwanese participants were H1 haplotypes. Linkage disequilibrium analysis showed the haplotype blocks in Taiwanese population had a smaller size in comparison to that of the Caucasian population. Single locus association showed significant p value in one of the tagging variants (rs242557) in our Taiwanese AD case-control cohorts. Conclusion: MAPT gene has four haplotype blocks in the Taiwanese population, each of around 40 kbp. In both European study and our study, the SNP rs242557 showed association with AD. Given the position of this SNP, the most possible explanation is that genetic variability in tau expression contributes to the risk of developing AD.