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Spinocerebellar ataxia (SCA) type 1 (SCA1) is a rare autosomal dominant disorder that is characterized by worsening of disordered coordination, ataxia of the trunk, and other neurological symptoms. Physical activity improves both mobility and the daily living activities of patients with SCA. Intervention with daily regular treadmill exercise may slow the deterioration of cerebellar neurons in SCA1. Therefore, the signal changes and performance of cerebellar neurons after exercise in SCA1 was investigated in this study. We employed a transgenic mouse model of SCA1, generated by amplifying the cytosine‐adenine‐guanine trinucleotide repeat expansions, and the mice underwent 1 month of moderate daily treadmill exercise for 1 hour. The rotarod test revealed that the motor function of the SCA1 mice that underwent training was superior to that of the control SCA1 mice, which did not undergo training. Moreover, the cerebellar pathology revealed preserved Purkinje neurons stained by carbindin with an increase of the neuronal Per Arnt Sim domain protein 4, a key regulation in the structural and functional plasticity of neurons, in the excised SCA1 mice relative to the controls. The mechanism was related to an increase of phosphorylation of ribosomal protein S6, a downstream target of the mammalian target of rapamycin pathway, but not to autophagy activation. This study determined that regular treadmill exercise may play a crucial role in the viable support of cerebellar neurons in SCA1.

Background and aims Renal dysfunction is a potent risk factor for cardiovascular diseases, including stroke. This study aimed to evaluate the impact of admission estimated glomerular filtration rate (eGFR) levels on short-term (1-month) and long-term (1-year) mortality in patients with acute ischemic stroke. Methods From the Taiwan Stroke Registry data, we classified ischemic stroke patients, identified from April 2006 to December 2015, into 5 groups by eGFR at admission: ≥ 90, 60–89, 30–59, 15–29, and Results Among 52,732 ischemic stroke patients, 1480 died within one month. The 1-month mortality rate was over 5-fold greater in patients with eGFR Conclusions After acute ischemic stroke, patients with reduced eGFR are at elevated risks of short-term and long-term deaths in a graded relationship.

Background and Objective: Parkinson’s disease (PD) is a progressive neurological disorder characterized by an accumulation of Lewy bodies and degeneration of dopaminergic neurons in the substantia nigra. The treatment options currently available are only partly effective and fail to restore the lost dopaminergic neurons or slow the progression. β2-adrenoceptors (β2AR) are widely expressed in various human tissues and organs, regulate many important metabolic functions, and are targeted for treatment of various diseases. Studies have reported a link between chronic use of the β2AR antagonist propranolol and an increased risk of PD, and chronic use of β2AR agonists has been associated with a decreased risk of PD. We conducted a meta-analysis on the association between both β2AR agonist level and β2AR antagonist level and the risk of PD. Materials and Methods: A comprehensive electronic search was conducted on the databases of PubMed, ScienceDirect, ProQuest, Cochrane Library, and ClinicalKey from the start of each database until 30 June 2021. The objective was to identify prospective cohort and case–control studies that have reported on the association between β-adrenoceptor agonist level, antagonist level, and PD risk. Results: A meta-analysis of the data extracted from eight studies revealed that β2AR agonist use was associated with reduced PD risk (RR = 0.859, 95% confidence interval [CI] 0.741–0.995. p = 0.043). Compared with the control group, β2AR antagonist use was associated with an increased risk of PD (RR = 1.490, 95% CI, 1.195 to 1.857. p &lt, 0.005). Propranolol, a type of β2AR antagonist, was related to an increased risk of PD (RR = 2.820, 95% CI, 2.618 to 3.036. p &lt, 0.005). Conclusions: In this meta-analysis, β2AR agonists were associated with a decreased risk of PD, and β2AR antagonists were related with an increased risk of PD. However, further studies with larger sample sizes and an evaluation of the long-term effects of varying dosages of medications are needed.

Purpose Parkinson's disease (PD) is a progressive degenerative central nervous system disorder that particularly impairs motor function. As PD advances, gait disorders become more pronounced and are often difficult to treat with current pharmacological therapies. Physical activity improves both mobility in and the daily living activities of patients with PD. Mitochondrial alterations and oxidative stress contribute to PD progression. Therefore, the association between mitochondria and exercise in PD and the implicated regulation of mitochondrial proteins was explored in this study. Methods In this study, we developed a unilateral 6-hydroxydopamine rat model of PD and executed 4 weeks of treadmill training. Motor behavior was evaluated through gait change analysis (the CatWalk method) and rotational testing. The viability of dopaminergic neurons, mitochondrial function, and oxidative stress in the substantia nigra and striatum were investigated through Western blot and immunohistochemical staining. Key findings Treadmill training improved the performance of gait parameters in terms of maximal area, swing speed, stride length, and stance phase; treadmill training also reduced methamphetamine-induced rotation. This training not only improved dopaminergic neuron viability but also recovered mitochondrial function and attenuated oxidative stress in PD rats. The mechanism may be associated with the facilitation of mitochondrial turnover, including facilitation of mitochondrial fusion, fission, and clearance accompanying increased quantities of mitochondria. Significance Treadmill exercise improved gait speed and balance, reduced oxidative stress, improved mitochondrial fusion and fission, increased mitochondrial amounts, and potentially attenuated dopaminergic neuron degeneration. Consequently, mitochondrial quality was improved in PD rats.

Aims Parkinson disease (PD) is a common neurodegenerative disease. The aim of this study was to evaluate the risk of PD in patients with organophosphate (OP) or carbamate (CM) poisoning by using the Taiwan National Health Insurance Research Database. Methods We conducted a retrospective study involving a cohort of 45 594 patients (9128 patients with a history of OP or CM poisoning and 36 466 control patients) who were selected from the Taiwan National Health Insurance Research Database. The patients were observed for a maximum of 12 years to determine the rates of new-onset PD, and a Poisson regression model was used to identify the predictors of PD. The cumulative incidence of PD between the two cohorts was plotted through Kaplan-Meier analysis. Results During the study period, the incidence rate ratio (IRR) of PD in the OP or CM poisoning patients was 1.36-fold [95% confidence interval (CI)=1.26-1.47] higher than that in the control patients in the multivariable model. The absolute incidence of PD was the highest for the group aged ≥75 years in both cohorts (77.4 vs 43.7 per 10 000 person-years). However, the age-specific relative risk was higher for the group aged

Background: Clinical and epidemiological studies suggest that two of the most common geriatric diseases, type 2 diabetes and Parkinson’s disease (PD), are linked. These studies notably suggest that treatment of insulin resistance in type 2 diabetes may beneficially modify the pathophysiology of PD and help to maintain motor and nonmotor function. In this meta-analysis, we evaluate the efficacy of new antidiabetic agents in the treatment of PD. Methods: We systematically searched PubMed, Medline, ProQuest, ScienceDirect, ClinicalKey, and Cochrane Library from the date of their inception until 15 March 2020. Multiple efficacy parameters were compared between treatment groups. The results are expressed as mean differences with 95% confidence intervals (CIs) in a random-effects model. Results: A meta-analysis of the data extracted from three randomized control trials revealed that treatment with exenatide yielded significant improvements in scores on the Unified Parkinson’s Disease Rating Scale Part I (UPDRS-I) (−0.438, 95% CI, −0.828 to −0.048, p = 0.028), UPDRS Part IV (UPDRS-IV) (−0.421, 95% CI, −0.811 to −0.032, p = 0.034) and the Mattis Dementia Rating Scale (MDRS) (−0.595, 95% CI, −1.038 to −0.151, p = 0.009). At the 12-month follow-up, the UPDRS Part III (UPDRS-III) scores in the off-medication phase revealed significant improvements in patients using exenatide (−0.729; 95% CI, −1.233 to −0.225, p = 0.005). Treatment with pioglitazone did not yield significant improvements in UPDRS, MDRS, or Parkinson’s Disease Questionnaire scores. Conclusion: This meta-analysis suggests that exenatide use is associated with the alleviation of cognitive, motor and nonmotor symptoms. However, long-term studies with a large sample size of patients with PD of varying severity are required.

Rationale: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset progressive muscle disorder typically characterized by ptosis, difficulty in swallowing, and proximal limb weakness. Underdiagnosis of OPMD is common in Asian countries and results in delayed diagnoses and fatal events. Patient concerns: Here, we report the case of a 53-year-old female who suffered from progressive dysphagia and experienced several choking events involving solid material. An extensive family history of dysphagia was noted, and 2 family members had died as a result of aspiration. Diagnoses: PABPN1 genotyping and DNA sequence analysis revealed a heterozygous (GCG)10(GCA)3GCG mutation that led to the diagnosis of OPMD. Interventions: Rehabilitation exercises, namely, the Shaker exercise and the Masako maneuver, were suggested. Outcomes: Improved swallowing ability with safe food intake was noted after 2 months of training. Surgical intervention will be considered when progression of the disease is noted. Lessons: Underdiagnosis and a lack of awareness of OPMD may lead to choking, aspiration pneumonia, and death in multiple members of affected families. Currently, there is no definitive treatment for OPMD, but rehabilitation exercises and surgical intervention are helpful in relieving dysphagia.

Objective Depression is a highly prevalent disorder that is associated with disability. The aim of this study was to determine the relationship between depression and hyperlipidemia and whether the onset of depression is associated with administering statins to patients with hyperlipidemia. Material and Methods The data analyzed in this study were retrieved from the National Health Insurance Research Database in Taiwan. We identified newly diagnosed hyperlipidemia in 26,852 patients without a history of depression as the exposure group in the period of 2000–2002, and a comparison group comprised 107,408 patients. The differences between the exposure group and the comparison group were examined using a chi-square test to calculate categorical variables. The hazard ratio and the 95% confidence interval for depression were used in the logistic regression. Results The hyperlipidemia patients demonstrated a high risk for depression and comorbidities, such as hypertension, diabetes and sleep disorder, which indicated synergistic effects related to a high risk of depression in hyperlipidemia patients. Hyperlipidemia patients who had received statins exhibited a lower risk of depression than did those who had not received statins. Conclusion Our results suggested that hyperlipidemia increases the risk of depression and that using statins is associated with a decreased risk of depression in patients with hyperlipidemia.

Objective: Previous research has demonstrated that patients with a history of organophosphate poisoning tend to have a higher risk of neurological disorder. However, research on the rate of seizure development in patients after organophosphate poisoning is lacking. This study examined whether individuals with organophosphate poisoning have an increased risk of seizures through several years of follow-up. Patients and Methods: We conducted a retrospective study on a cohort of 45,060 individuals (9012 patients with a history of organophosphate poisoning and 36,048 controls) selected from the Taiwan National Health Insurance Research Database. The individuals were observed for a maximum of 12 years to determine the rate of new-onset seizure disorder. We selected a comparison cohort from the general population that was randomly frequency-matched by age, sex, and index year and further analyzed the risk of seizures using a Cox regression model adjusted for sex, age, and comorbidities. Results: During the study period, the risk of seizure development was 3.57 times greater in patients with organophosphate poisoning compared with individuals without, after adjustments for age, sex, and comorbidities. The absolute incidence of seizures was highest in individuals aged 20 to 34 years in both cohorts (adjusted hazard ratio = 13.0, 95% confidence interval = 5.40&minus, 31.4). A significantly higher seizure risk was also observed in patients with organophosphate poisoning and comorbidities other than cirrhosis. Conclusions: This nationwide retrospective cohort study demonstrates that seizure risk is significantly increased in patients with organophosphate poisoning compared with the general population.

Background aims The feasibility of delivering mitochondria using the cell-penetrating peptide Pep-1 for the treatment of MERRF (myoclonic epilepsy with ragged red fibers) syndrome, which is caused by point mutations in the transfer RNA genes of mitochondrial DNA, is examined further using cellular models derived from patients with MERRF syndrome. Methods Homogenesis of mitochondria (wild-type mitochondria) isolated from normal donor cells with about 83.5% preserved activity were delivered into MERRF fibroblasts by Pep-1 conjugation (Pep-1-Mito). Results Delivered doses of 52.5 μg and 105 μg Pep-1-Mito had better delivered efficiency and mitochondrial biogenesis after 15 days of treatment. The recovery of mitochondrial function in deficient cells receiving 3 days of treatment with peptide-mediated mitochondrial delivery was comprehensively demonstrated by restoration of oxidative phosphorylation subunits (complex I, III and IV), mitochondrial membrane potential, adenosine triphosphate synthesis and reduction of reactive oxygen species production. The benefits of enhanced mitochondrial regulation depended on the function of foreign mitochondria and not the existence of mitochondrial DNA and can be maintained for at least 21 days with dramatically elongated mitochondrial morphology. In contrast to delivery of wild-type mitochondria, the specific regulation of Pep-1-Mito during MERRF syndrome progression in cells treated with mutant mitochondria was reflected by the opposite performance, with increase in reactive oxygen species production and matrix metalloproteinase activity. Conclusions The present study further illustrates the feasibility of mitochondrial intervention therapy using the novel approach of peptide-mediated mitochondrial delivery and the benefit resulting from mitochondria-organelle manipulation.

Dyslipidemia is a major risk factor for cardiovascular complications in people with diabetes. Lowering low-density lipoprotein cholesterol (LDL-C) levels is effective in the primary and secondary prevention of diabetic vascular complications. However, LDL-C levels do not reflect all aspects of diabetic dyslipidemia, which is characterized by hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). Statins, nicotinic acid, and fibrates play a role in treating diabetic dyslipidemia. Atherosclerosis is a major disorder of the blood vessel wall in patients with diabetes. A number of antihyperlipidemic agents may be beneficial and exhibit effects at the actual site of vascular disease and not only on plasma lipoprotein concentrations. Several novel therapeutic compounds are currently being developed. These include additional therapeutics for LDL-C, triglycerides, HDL-C, and modulators of inflammation that can be used as possible synergic agents for the treatment of atherosclerosis and irregularities in plasma lipoprotein concentrations.

Objective: Migraines are one of the most common neurological disorders. Dementia is a neurodegenerative disease characterized by slow progressive memory loss and cognitive dysfunction. This retrospective cohort study investigates the association between migraines and dementia using a nationwide population-based database in Taiwan. Methods: We retrieved the data analyzed in this study from the National Health Insurance Research database (NHIRD) in Taiwan. We used multivariate Cox proportion-hazards regression models to assess the effects of migraines on the risk of dementia after adjusting for sociodemographic characteristics and comorbidities. Results: The migraine cohort had a higher prevalence of diabetes, hypertension, coronary artery disease, head injury and depression at baseline (p < 0.0001). After adjusting the covariates, migraine patients had a 1.33-fold higher risk of developing dementia [hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.22-1.46]. The sex-specific incidence rate of dementia was higher in men than in women in both cohorts, with an HR of 1.09 (95% CI 1.00-1.18) for men compared to women. Kaplan-Meier analysis shows that the cumulative incidence of dementia was 1.48% greater in the migraine cohort than in the nonmigraine cohort (log-rank test, p < 0.0001). Conclusions: This study shows that migraines are associated with a future higher risk of dementia after adjusting for comorbidities. Specifically, the association between migraine and dementia is greater in young adults than in older adults.

We explored the feasibility of mitochondrial therapy using the cell-penetrating peptide Pep-1 to transfer mitochondrial DNA (mtDNA) between cells and rescue a cybrid cell model of the mitochondrial disease myoclonic epilepsy with ragged-red fibres (MERRF) syndrome. Pep-1-conjugated wild-type mitochondria isolated from parent cybrid cells incorporating a mitochondria-specific tag were used as donors for mitochondrial delivery into MERRF cybrid cells (MitoB2) and mtDNA-depleted Rho-zero cells (Mitoρ°). Forty-eight hours later, translocation of Pep-1-labelled mitochondria into the mitochondrial regions of MitoB2 and Mitoρ° host cells was observed (delivery efficiencies of 77.48 and 82.96%, respectively). These internalized mitochondria were maintained for at least 15 days in both cell types and were accompanied by mitochondrial function recovery and cell survival by preventing mitochondria-dependent cell death. Mitochondrial homeostasis analyses showed that peptide-mediated mitochondrial delivery (PMD) also increased mitochondrial biogenesis in both cell types, but through distinct regulatory pathways involving mitochondrial dynamics. Dramatic decreases in mitofusin-2 (MFN2) and dynamin-related protein 1/fission 1 were observed in MitoB2 cells, while Mitoρ° cells showed a significant increase in optic atrophy 1 and MFN2. These findings suggest that PMD can be used as a potential therapeutic intervention for mitochondrial disorders.

Background and purpose Dementia is a neurodegenerative disorder that presents a progressive decline in cognitive function and loss of short-term memory with age. Several studies have shown that statin, an oral lipid-lowering drug, may reduce the risk of developing dementia. The objective of this study is to explore the association between statin and the development of dementia. Methods The data analyzed in this study were retrieved from the National Health Insurance Research Database in Taiwan. The sample consisted of 123 300 patients ≥ 20 years of age, including 61 650 dementia patients with statin use and 61 650 patients without statin use who were eligible for inclusion in this study. Univariate and multivariate Cox proportional hazard regression analyses were performed to measure the effects of statin use on the risk of dementia. Results The beneficial effect of statin on dementia was significant after adjusting for sociodemographic factors and comorbidities (adjusted hazard ratio of 0.92, 95% confidence interval 0.86–0.98). The sex- and age-specific analysis of adjusted hazard ratios showed a higher beneficial effect from statin treatment in women than in men, and the effect became more significant with age. Conclusion Statin therapy may help prevent the development of dementia, and both hydrophilic and lipophilic statins produce similar effects. However, the preventive characters and associated mechanisms must be further explored and identified.

Pneumoconiosis is a parenchymal lung disease that develops through the inhalation of inorganic dust at work. Cerebrovascular and cardiovascular events are leading causes of mortality and adult disability worldwide. This retrospective cohort study investigated the association between pneumoconiosis, and cerebrovascular and cardiovascular events by using a nationwide population-based database in Taiwan. The data analyzed in this study was retrieved from the Taiwan National Health Insurance Research Database. We selected 6940 patients with pneumoconiosis from the database as our study cohort. Another 27,760 patients without pneumoconiosis were selected and matched with those with pneumoconiosis according to age and sex as the comparison cohort. We used univariate and multivariate Cox proportional-hazard regression analyses to determine the association between pneumoconiosis and the risk of cerebrovascular and cardiovascular events after adjusting for medical comorbidities. After adjustment for age, sex, and comorbidities, the patients with pneumoconiosis exhibited a significantly higher incidence of ischemic stroke (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.05-1.24) than did those without pneumoconiosis. The incidence of hemorrhagic stroke was higher, but not significant, in the pneumoconiosis patients (HR 1.20, 95% CI 0.99-1.46). No statistically significant differences were observed between the pneumoconiosis and nonpneumoconiosis groups in acute coronary syndrome (HR 1.10, 95% CI 0.95-1.26). The findings of this study reveal an association between pneumoconiosis and a higher risk of cerebrovascular events after adjustment for comorbidities. Healthcare providers should control the related risk factors for primary prevention of stroke in pneumoconiosis patients.

Although gait change is considered a useful indicator of severity in animal models of Parkinson's disease, systematic and extensive gait analysis in animal models of neurological deficits is not well established. The CatWalk-assisted automated gait analysis system provides a comprehensive way to assess a number of dynamic and static gait parameters simultaneously. In this study, we used the Catwalk system to investigate changes in gait parameters in adult rats with unilateral 6-OHDA-induced lesions and the rescue effect of dopaminergic neuron transplantation on gait function. Four weeks after 6-OHDA injection, the intensity and maximal area of contact were significantly decreased in the affected paws and the swing speed significantly decreased in all four paws. The relative distance between the hind paws also increased, suggesting that animals with unilateral 6-OHDA-induced lesions required all four paws to compensate for loss of balance function. At 8 weeks post-transplantation, engrafted dopaminergic neurons expressed tyrosine hydroxylase. In addition, the intensity, contact area, and swing speed of the four limbs increased and the distance between the hind paws decreased. Partial recovery of methamphetamine-induced rotational response was also noted.

Diabetes is associated with an increased risk of various forms of cancer, such as cancer of the liver, colon, pancreas, breast, bladder, and kidney. Metformin, widely given to patients with type 2 diabetes, works by inhibiting hepatic glucose production through an LKB1 (serine-threonine liver kinase B1)/AMP-activated protein kinase (AMPK)–mediated mechanism. LKB1 is a well-recognized tumor suppressor. Activation of AMPK by LKB1 plays an important role in inhibiting cell growth. It has been suggested that metformin use in patients with diabetes may reduce their risk of cancer (1). Some studies have reported that diabetic patients taking metformin showed decreased cancer risk (2,3). However, several studies have shown that metformin does not reduce the risk of cancer in patients with diabetes (4,5). Little information is available on the subject considering non-Caucasian ethnicity. We used representative National Health Insurance datasets for Taiwan to form a cohort to …

Dementia is among various diseases affecting the elderly, who is also at a high risk for fractures. This study aimed to evaluate the association between fracture history and sequential risk of dementia in Taiwan. A retrospective cohort study was designed using the claims data of the entire insured residents covered by Taiwan's universal health insurance from 1998 to 2010. A total of 66,797 patients with fractures and 133,594 control subjects without fractures were matched in terms of age (±5 years), sex, and index year and then recruited. Fractures and dementia were defined in accordance with the International Classification of Diseases, 9th Revision, Clinical Modification. The influence of fractures on the risk of dementia was analyzed using a Cox proportional hazards model. After a 12-year follow-up period, 2775 and 3991 incident cases of dementia were reported in exposed and unexposed cohorts, respectively. The overall incidence rate of dementia in individuals with fractures was 41% higher than that in individuals without fractures (6.05 vs 4.30 per 1000 person-years) at an adjusted hazard ratio of 1.38 (95% confidence interval 1.32–1.45) after age, sex, urbanization, and individual disorders or comorbidities were adjusted. Considering fracture location, we found that patients with hip fractures were at a slightly high risk for dementia. The occurrence of multiple fractures at a single visit was also significantly associated with an increased risk of dementia. Fracture history is regarded as an independent risk factor of dementia in individuals aged ≥65 years, particularly those who suffered from multiple fractures and/or fractures located in the hip. Further studies are needed to support an independent role of fracture in dementia considering the clinical information and other comorbidities.

ntroduction: Pituitary apoplexy is a rare but life-threatening disorder. The clinical presentation includes severe headache, impaired consciousness, fever, visual disturbances, variable ocular paresis and hypoadrenalism. It usually results from sudden hemorrhage or infarction-induced swelling in a pituitary adenoma. Signs of meningeal irritation are very rare. The presentation of headache, fever, pleocytosis and meningism might lead to a misdiagnosis of septic meningitis. Case Report: We described a 71-year-old man who suffered from acute headache, fever, chills, dizziness and photophobia. Stiffness in the neck was notable and the cerebrospinal fluid study revealed neutrophilic pleocytosis. Empiric antibiotic therapy was administered for suspected septic meningitis but the symptoms persisted. Further brain imaging study showed pituitary adenoma with recent hemorrhage and the endocrine survey revealed a low cortisol level. Corticosteroid was added for pituitary apoplexy, and the patient recovered without surgical management. Conclusion: When a patient presents with fever, headache and meningeal irritation, it is important to include pituitary apoplexy in the differential diagnosis of infectious meningitis. Early treatment of pituitary apoplexy allows for aggressive endocrine management or neurosurgical decompression when required.

Abnormal magnetic resonance spectroscopic (MRS) signals in the basal ganglia may be one of the characteristics in mitochondrial disease. We report MRS study in a family with myoclonic epilepsy with ragged-red fibers (MERRF). Their MRS studies over the basal ganglia revealed decreased N-acetylaspartate/creatine ratio and increased choline/creatine ratio in the four symptomatic members, but normal in the two asymptomatic members. However, negative MRI study was found in all members of this family. Our report suggests that the increased choline/creatine ratio in basal ganglia MRS may be one of the early information to suspect MERRF disease.