Core and penumbra estimation using deep learning-based AIF in association with clinical measures in computed tomography perfusion (CTP).

OBJECTIVES: To investigate whether utilizing a convolutional neural network (CNN)-based arterial input function (AIF) improves the volumetric estimation of core and penumbra in association with clinical measures in stroke patients. METHODS: The study included 160 acute ischemic stroke patients (male = 87, female = 73, median age = 73 years) with approval from the institutional review board. The patients had undergone CTP imaging, NIHSS and ASPECTS grading. convolutional neural network (CNN) model was trained to fit a raw AIF curve to a gamma variate function. CNN AIF was utilized to estimate the core and penumbra volumes which were further validated with clinical scores. RESULTS: Penumbra estimated by CNN AIF correlated positively with the NIHSS score (r = 0.69; p < 0.001) and negatively with the ASPECTS (r = - 0.43; p < 0.001). The CNN AIF estimated penumbra and core volume matching the patient symptoms, typically in patients with higher NIHSS (> 20) and lower ASPECT score (< 5). In group analysis, the median CBF < 20%, CBF < 30%, rCBF < 38%, Tmax > 10 s, Tmax > 10 s volumes were statistically significantly higher (p < .05). CONCLUSIONS: With inclusion of the CNN AIF in perfusion imaging pipeline, penumbra and core estimations are more reliable as they correlate with scores representing neurological deficits in stroke. CRITICAL RELEVANCE STATEMENT: With CNN AIF perfusion imaging pipeline, penumbra and core estimations are more reliable as they correlate with scores representing neurological deficits in stroke.

The optimal pulse pressures for healthy adults with different ages and sexes correlate with cardiovascular health metrics.

Background: Pulse pressure (PP) may play a role in the development of cardiovascular disease, and the optimal PP for different ages and sexes is unknown. In a prospective cohort, we studied subjects with favorable cardiovascular health (CVH), proposed the mean PP as the optimal PP values, and demonstrated its relationship with healthy lifestyles. Methods and results: Between 1996 and 2016, a total of 162,636 participants (aged 20 years or above; mean age 34.9 years; 26.4% male subjects; meeting criteria for favorable health) were recruited for a medical examination program. PP in male subjects was 45.6 ± 9.4 mmHg and increased after the age of 50 years. PP in female subjects was 41.8 ± 9.5 mmHg and increased after the age of 40 years, exceeding that of male subjects after the age of 50 years. Except for female subjects with a PP of 40-70 mmHg, PP increase correlates with both systolic blood pressure (BP) increase and diastolic BP decrease. Individuals with mean PP values are more likely to meet health metrics, including body mass index (BMI) <25 kg/m2 (chi-squared = 9.35, p<0.01 in male subjects; chi-squared = 208.79, p < 0.001 in female subjects) and BP <120/80 mmHg (chi-squared =1,300, p < 0.001 in male subjects; chi-squared =11,000, p < 0.001 in female subjects). We propose a health score (Hscore) based on the sum of five metrics (BP, BMI, being physically active, non-smoking, and healthy diet), which significantly correlates with the optimal PP. Conclusion: The mean PP (within ±1 standard deviation) could be proposed as the optimal PP in the adult population with favorable CVH. The relationship between health metrics and the optimal PP based on age and sex was further demonstrated to validate the Hscore.

Increased risk of sleep-related movement disorder in patients with Helicobacter pylori infection: A nationwide population-based study.

Background and purpose: Evidence increasingly suggests that Helicobacter pylori infection (HPI) is associated with movement disorders such as Parkinson's disease (PD). However, the relationship between HPI and sleep-related movement disorders (SRMD) remains unknown. This nationwide population-based study tried to demonstrate whether patients with HPI have a higher risk of developing SRMD in a general adult population. Methods: The study cohort enrolled 9,393 patients who were initially diagnosed with HPI between 2000 and 2013. Notably, 37,572 age- and sex-matched controls without prior HPI were selected as the reference. A Cox proportional hazard regression analysis was performed for multivariate adjustment. Results: Patients with HPI had a higher risk of developing SRMD (adjusted hazard ratio [HR] = 2.18, 95% confidence interval [CI] = 1.26-3.82, p < 0.01). Patients with HPI aged ≥65 years exhibited the highest risk (HR = 3.01, 95% CI = 1.90-5.30, p < 0.001), followed by patients aged 45-64 years (HR = 1.69, 95% CI = 1.26-2.90, p <0.01) and <45 years (HR = 1.49, 95% CI = 1.12-2.49, p < 0.01). Patients were most likely to develop SRMD 5 years or more after diagnosis of HPI (HR = 3.33, 95% CI = 1.97-5.89, p < 0.001). The increased risk of SRMD in male patients with HPI (HR = 2.73, 95% CI = 1.53-4.79, p < 0.001) was greater than in female patients (HR = 1.14, 95% CI = 1.04-1.65, p < 0.05). Conclusion: Patients with HPI were associated with an increased risk for SRMD, with a higher risk in men, aged ≥65 years, and diagnosed for more than 5 years.

Urgent Demand of Network Access for Acute Ischemic Stroke Management in Taiwan.

Time is the major determinant in successful reperfusion therapy of acute ischemic stroke. The evolving diagnostic tools and treatment of acute stroke has made a great progress in the past 2 decades and is remolding current management practices. It demands a timely neurologic evaluation and a neuroimaging study to determine if stroke patients are appropriate candidates for reperfusion demands. Therefore, it is critical for the setting of stroke center accreditation levels and capabilities so that timely and appropriate treatment is initiated for the eligible stroke patients. Optimal acute ischemic stroke treatment requires all levels of stroke center network operating efficiently. In the future, Taiwan should revise the criteria of stroke center accreditation and set up the efficient acute stroke treatment network as soon as possible. Keywords: stroke, reperfusion, intra-arterial thrombectomy, intravenous recombinant tissue plasminogen activator.

Optimal Scaling Approaches for Perfusion MRI with Distorted Arterial Input Function (AIF) in Patients with Ischemic Stroke.

BACKGROUND: Diagnosis and timely treatment of ischemic stroke depends on the fast and accurate quantification of perfusion parameters. Arterial input function (AIF) describes contrast agent concentration over time as it enters the brain through the brain feeding artery. AIF is the central quantity required to estimate perfusion parameters. Inaccurate and distorted AIF, due to partial volume effects (PVE), would lead to inaccurate quantification of perfusion parameters. METHODS: Fifteen patients suffering from stroke underwent perfusion MRI imaging at the Tri-Service General Hospital, Taipei. Various degrees of the PVE were induced on the AIF and subsequently corrected using rescaling methods. RESULTS: Rescaled AIFs match the exact reference AIF curve either at peak height or at tail. Inaccurate estimation of CBF values estimated from non-rescaled AIFs increase with increasing PVE. Rescaling of the AIF using all three approaches resulted in reduced deviation of CBF values from the reference CBF values. In most cases, CBF map generated by rescaled AIF approaches show increased CBF and Tmax values on the slices in the left and right hemispheres. CONCLUSION: Rescaling AIF by VOF approach seems to be a robust and adaptable approach for correction of the PVE-affected multivoxel AIF. Utilizing an AIF scaling approach leads to more reasonable absolute perfusion parameter values, represented by the increased mean CBF/Tmax values and CBF/Tmax images.

Multidisciplinary approach to Fibromyalgia: What are we learning from updated evidence-based medicine?

Fibromyalgia (FM) is a disease characterized by amplified pain responses; here, hyperalgesia occurs in response to noxious stimuli, and allodynia occurs in response to non-noxious stimuli. The diagnosis of FM is often time consuming because it overlaps with psychosomatic symptoms. Indeed, most cases of FM are combined with other comorbidities, such as rheumatological diseases, mental disorders, or gastrointestinal disorders. The main symptoms of FM, which include pain, fatigue, and sleep disturbance, are poorly discriminatory and, thus, greatly increase the difficulty of diagnosis. The 2017 European League Against Rheumatism treatment guidelines of FM recommend that non-pharmacological therapies based on exercise should first be attempted after a diagnosis of FM. Although drug treatments appear to be effective, evidence supporting the use of this treatment modality is relatively weak. Obtaining a broad understanding of FM can help clinicians formulate individualized treatment to improve patient functions and quality of life. Key words: fibromyalgia, diagnostic criteria, non-pharmacological therapy.

Early Rehabilitation after Acute Stroke:The Golden Recovery Period.

Stroke is a leading cause of disability worldwide. Neuroplasticity, a condition wherein the brain's dynamic response to injury is heightened and rehabilitation might be effective, is observed shortly after acute stroke. However, although several trials have demonstrated that initiating treatment within 24 hours after stroke is potentially harmful, some have shown that early rehabilitation of patients is beneficial. Administration of constraint-induced movement therapy within two weeks after stroke appears to be beneficial for the upper extremities. In addition, intensive early post-stroke therapy may be beneficial for patients with severe aphasia. Novel approaches to early treatment of post-stroke dysphagia appear promising; however, the high rate of spontaneous improvement makes it difficult to gauge their benefits. Overall, although increasing evidence indicates that initiating rehabilitative strategies within two weeks after stroke is beneficial for some deficits, the optimal time for initiating post-stroke rehabilitation remains undetermined. Keywords: stroke, early rehabilitation, neuroplasticity, early mobilization.

Long-Term Use of Statins Lowering the Risk of Rehospitalization Caused by Ischemic Stroke Among Middle-Aged Hyperlipidemic Patients: A Population-Based Study.

Background: The long-term effects of statin use on rehospitalization due to ischemic stroke (reHospIS) in hyperlipidemic patients are still unknown. Therefore, we aimed to assess the long-term risks of reHospIS for hyperlipidemic patients who were taking statins and nonstatin lipid-lowering medicines on a regular basis. Methods and Materials: The National Health Insurance Research Database in Taiwan was used to conduct a 6-year cohort study of patients >45 years old (n = 9,098) who were newly diagnosed with hyperlipidemia and hospitalized for the first or second time due to ischemic stroke (IS). The risk of reHospIS was assessed using Cox proportional hazards regression model. Results: Nonstatin lipid-lowering medicines regular users were associated with a higher risk of reHospIS compared to stains users (hazard ratio, HR = 1.29-1.39, p < 0.05). Rosuvastatin was the most preferred lipid-lowering medicine with lower HRs of reHospIS in hyperlipidemic patients whether they developed diabetes or not. Bezafibrate regular users of hyperlipidemic patients developing diabetes (HR = 2.15, p < 0.01) had nearly 50% lower reHospIS risks than those without diabetes (HR = 4.27, p < 0.05). Age, gender, drug dosage, comorbidities of diabetes and heart failure (HF), and characteristics of the first hospitalization due to IS were all adjusted in models. Moreover, increasing trends of HRs of reHospIS were observed from Rosuvastatin, nonstatin lipid-lowering medicines, Lovastatin, and Gemfibrozil to Bezafibrate users. Conclusion: Statins were associated with long-term secondary prevention of reHospIS for hyperlipidemic patients. Rosuvastatin seemed to have the best protective effects. On the other hand, Bezafibrate appears to be beneficial for hyperlipidemic patients developing diabetes. Further research into the combination treatment of statin and nonstatin lipid-lowering medicines in hyperlipidemic patients developing diabetes is warranted.

Prevalence and association of lifestyle and medical-, psychiatric-, and pain-related comorbidities in patients with migraine: A cross-sectional study.

BACKGROUND AND OBJECTIVES: Migraine has been associated with many comorbidities. However, lifestyle factors and the presence of comorbid diseases have not previously been extensively studied in the same sample. This study aimed to compare the prevalence of unhealthy lifestyle factors and comorbid diseases between patients with migraine and migraine-free controls with subgroup analyses to determine the pathophysiology and possible consequences. METHODS: This cross-sectional study recruited 1257 patients with migraine between the ages of 20 and 65 years from a headache outpatient clinic in Taiwan and 496 non-migraine controls. All participants completed questionnaires regarding demographics, migraine diagnosis, sleep, headache burden, and medical, pain, and psychiatric conditions. Participants also underwent a structured interview. The associations between comorbidities and migraine were investigated and further stratified by sex and aura. RESULTS: Patients with migraine with aura had an unhealthier lifestyle compared with controls in the form of current smoking status (15.5% [67/431] vs. 11.5% [57/496], p = 0.013). Furthermore, medical- (e.g., thyroid disease; 7.2% [91/1257 vs. 2.8% [14/496]; p = 0.006), psychiatric- (e.g., depression; 6% [76/1257 vs. 2.6% [13/496]; p = 0.031), and pain-related (e.g., fibromyalgia; 8% [101/1257 vs. 3.2% [16/496]; p = 0.006) comorbidities were more prevalent in patients compared with controls. Subgroup analyses revealed that chronic migraine, migraine with aura, and female sex were associated with a greater number of significant comorbidities than episodic migraine, migraine without aura, and male patients with migraine, respectively. CONCLUSION: Individuals seeking treatment for migraine reported greater levels of smoking and medical, psychiatric, and pain conditions than non-treatment-seeking healthy controls who were recruited from the community. Understanding the relationship between migraine and comorbid diseases may improve medical care as well as the quality of life.

Increased risk of non-multiple sclerosis demyelinating syndromes in patients with preexisting septicaemia: a nationwide retrospective cohort study.

BACKGROUND: Growing evidence shows links between septicaemia and non-multiple sclerosis demyelinating syndromes (NMSDS); nevertheless, epidemiological data are still very limited. This study aimed to explore the relationship between septicaemia and NMSDS in a general population. METHODS: The study included 482 781 individuals diagnosed with septicaemia and 1 892 825 age/sex-matched non-septicaemia patients for the comparison. Data were drawn from a population-based nationwide National Health Insurance Research Database Taiwan, from 1 January 2002 to 31 December 2011. The two cohorts of patients with and without septicaemia were followed up for the occurrence of NMSDS. The Cox-proportional hazard regression model was performed to estimate adjusted HR after multivariate adjustment. RESULTS: Individuals with septicaemia had a 4.17-fold (95% CI 3.21 to 5.4, p < 0.001) higher risk to develop NMSDS compared with those without septicaemia. Patients aged <65 years had a greater NMSDS risk (<45 years: HR = 6.41, 95% CI 3.65 to 11.3, p < 0.001; 45-64 years: HR = 6.66, 95% CI 3.98 to 11.2, p < 0.001). Furthermore, females with septicaemia and individuals with higher severity of septicaemia were associated with increased risks of developing NMSDS. CONCLUSIONS: Our results indicated that patients with septicaemia were likely to develop NMSDS. A possible contributing role of septicaemia in increasing the hazard of NMSDS is proposed, based on the outcome that individuals with higher severity of septicaemia carried elevated threat of encountering NMSDS.

Increased risk of sleep apnoea among primary headache disorders: a nationwide population-based longitudinal study.

BACKGROUND: Primary headache disorders (PHDs) are associated with sleep problems. It is suggested that headache and sleep disorder share anatomical and physiological characteristics. We hypothesised that patients with PHDs were exposed to a great risk for developing sleep apnoea (SA). METHODS: In this retrospective longitudinal study, the data obtained from the Longitudinal Health Insurance Database in Taiwan were analysed. The study included 1346 patients with PHDs who were initially diagnosed and 5348 patients who were randomly selected and age/sex matched with the study group as controls. PHDs, SA, comorbidities and other confounding factors were defined based on International Classification of Diseases, Ninth Revision, Clinical Modification. Cox proportional hazards regressions were employed to examine adjusted HRs after adjusting with confounding factors. RESULTS: Our data revealed that patients with PHDs had a higher risk (HR 2.17, 95% CI 1.259 to 3.739, p<0.05) to develop SA compared with matched cohorts, whereas patients with migraine exhibited a high risk (HR 2.553, 95% CI 1.460 to 4.395, p<0.01). The results showed that patients with PHDs aged 18-44 exhibited highest risk of developing SA. In addition, males with PHDs exhibited an HR 3.159 (95% CI 1.479 to 6.749, p<0.01) for developing SA, respectively. The impact of PHDs on SA risk was progressively increased by various follow-up time intervals. CONCLUSION: Our results suggest that PHDs are linked to an increased risk for SA with sex-dependent and time-dependent characteristics.

Patterns of gray matter alterations in migraine and restless legs syndrome.

Objectives: Migraine and restless legs syndrome (RLS) are often comorbid and share elements of pathology; however, their neuroanatomical underpinnings are poorly understood. This study aimed to identify patterns of gray matter volume (GMV) alteration specific to and common among patients with RLS, migraine, and comorbid migraine and RLS. Methods: High-resolution T1-weighted images were acquired from 116 subjects: 27 RLS patients, 22 migraine patients, 22 patients with comorbid migraine and RLS, and 45 healthy controls. Direct group comparisons and conjunction analysis were first used to localize the distinct and shared neural signatures of migraine and RLS. We also investigated whether the shared neural signature could be replicated in an additional comorbid migraine/RLS group. Results: Compared with healthy controls, migraine patients showed GMV changes in the lateral occipital cortex, cerebellum, frontal pole, and middle frontal gyrus (MFG), and RLS patients showed GMV changes in the thalamus, middle temporal gyrus, anterior cingulate cortex, insular cortex, and MFG. In migraine, compared with RLS, GMV differences were found in the precuneus, lateral occipital and occipital fusiform cortex, superior frontal and precentral gyri, and cerebellum. Conjunction analyses for these disorders showed altered GMV in the MFG, also found in patients with comorbid migraine and RLS. The GMV of the MFG also correlated with sleep quality in patients with comorbid migraine and RLS. Interpretation: Migraine and RLS are characterized by shared and distinctive neuroanatomical characteristics, with a specific role of the MFG. These findings may be related to shared pathophysiology of these two distinct disorders.

Age-specific and gender-dependent impact of primary headache disorders on dementia risk: Population-based longitudinal study.

Dementia is a global burden of public health. Headache disorders are the third most common cause of disability worldwide and common problems in the elderly population. Few studies focused on the relationship between primary headache disorders (PHDs) and cognitive status, and the results remain controversial. The aim of this countrywide, population-based, retrospective study was to investigate potential association between PHDs and dementia risk.We enrolled 1346 cases with PHDs to match the 5384 individuals by age, gender and co-morbidities. The definition of PHDs, dementia, and risk factors of dementia was identified according to The International Classification of Diseases, Ninth Revision, Clinical Modification. Cox regression was administered for estimating hazard ratios (HR) for dementia.During more than 5 years of follow-up, PHDs individuals had 1.52 times (P <.05) greater risk to develop all dementia compared with individuals without PHDs. Elderly (aged ≥65 years) patients with PHDs displayed significantly higher risk to develop all dementia (P <.01) and non-Alzheimer non-vascular dementia (NAVD) P <.01). Female PHDs individuals were at higher risk of suffering from all dementia (P <.05) and NAVD (P <.05). The influence of PHDs on all dementia was highest in the first 2 years of observation.The results indicated PHDs are linked to a temporarily increased risk for dementia, mainly NAVD, with age-specific and gender-dependent characteristics.

The association between vertebrobasilar insufficiency and the risk of dementia: a nationwide register-based retrospective cohort study in Taiwan.

OBJECTIVES: Neurodegenerative disorders are reportedly characterised by decreased regional cerebral blood flow. However, the association between vertebrobasilar insufficiency (VBI) and dementia remains unclear. In this nationwide, population-based, retrospective cohort study, we explored the potential association between VBI and dementia. DESIGN: Nationwide population-based cohort study. SETTING: Patients with VBI were newly diagnosed between 2000 and 2005 from the Taiwan National Health Insurance Research Database. PARTICIPANTS: We included 3642 subjects as the VBI group. The control cohort included 14 568 randomly selected age-matched and sex-matched VBI-free individuals. OUTCOME MEASURES: All subjects were followed until the diagnosis of dementia, death or the end of 2010. Patients with VBI, dementia (viz, vascular and non-vascular, including Alzheimer's) subtypes and other confounding factors were identified according to the International Classification of Diseases Clinical Modification Codes. Cox proportional hazards regression analysis was employed to examine adjusted HRs after adjusting for confounding factors. RESULTS: Patients with VBI had a 1.807-fold (95% CI 1.643 to 1.988, p<0.001) higher risk to develop all-cause dementia than individuals without VBI. The risk was significantly higher in the VBI group than in the non-VBI group regardless of age (<65 years: HR: 2.997, 95% CI 1.451 to 6.454, p<0.001; ≥65 years: HR: 1.752, 95% CI 1.584 to 1.937, p<0.001). The VBI group had a higher risk of all-cause dementia than the non-VBI group regardless of sex and follow-up time intervals (<1 year, 1-2 years and≥2 years). CONCLUSION: Patients with VBI appear to have an increased risk of developing dementia. Further research is needed to investigate the underlying pathophysiology.

Low Pulse Pressure After Acute Ischemic Stroke is Associated With Unfavorable Outcomes: The Taiwan Stroke Registry.

BACKGROUND: Pulse pressure (PP) is related to cardiac function, arterial stiffness, fluid status, and vascular events. This study aimed to explore the prognostic role of PP upon admission in patients with acute ischemic stroke (AIS) based on a nation-wide stroke registry. METHODS AND RESULTS: We evaluated the association between PP upon admission and outcomes 3 months after a stroke in patients who had an AIS registered in the Taiwan Stroke Registry, including 56 academic and community hospitals between 2006 and 2013. Three months after the stroke, unfavorable outcomes were defined using a modified Rankin scale of 3 to 6. Of 33 530 patients (female, 40.6%; mean age, 68.8±13.3 years) who had an AIS, PP upon admission had a reverse J-curve association with an unfavorable outcome. After adjusting for clinical variables, including AIS subtypes, initial National Institutes of Health Stroke Scale, and systolic and diastolic blood pressure upon admission, a PP of <50 mm Hg was associated with unfavorable outcomes (P<0.0001). Compared with patients with a PP of 50 to 69 mm Hg, the odds ratios for unfavorable outcomes were 1.24 (95% CI, 1.14-1.36) with a PP of 30 to 49 mm Hg and 1.85 (95% CI, 1.50-2.28) with a PP of <30 mm Hg. Moreover, the prognostic impact of PP upon admission was similar across all AIS subtypes. CONCLUSIONS: Low PP upon admission was associated with unfavorable patient outcomes in AIS.

The potential impact of primary headache disorders on stroke risk.

BACKGROUND: Headache such as migraine is associated with stroke. Studies focused on primary headache disorders (PHDs) as a risk factor for stroke are limited. The purpose of this population-based cohort study was to explore whether patients with PHDs were at a high risk for developing stroke. METHODS: A total of 1346 patients with PHDs were enrolled and compared with 5384 age-, gender- and co-morbidity-matched control cohorts. International Classification of Diseases, Clinical Modification codes were administered for the definition of PHDs, stroke, and stroke risk factors. Cox proportional-hazards regressions were performed for investigating hazard ratios (HR). RESULTS: PHDs patients exhibited a 1.49 times (95% CI :1.15-1.98, p < 0.01) higher risk for developing ischaemic stroke compared with that of control cohorts. Both migraine (HR = 1.22, 95% CI :1.13-1.97, p < 0.05) and tension-type headache (HR = 2.29, 95% CI :1.22-2.80, p < 0.01) were associated with an increased risk of ischemic stroke. Females with PHDs were at greater risk of developing ischaemic stroke (HR = 1.49, 95% CI :1.13-1.90, p < 0.01) than those without PHDs. PHDs patient aged 45 to 64 years displayed significantly higher risk to develop ischaemic stroke (HR = 1.50, 95% CI: 1.11-2.10, p < 0.05) than the matched controls. The impact of PHDs on ischaemic stroke risk became gradually apparent by different following time intervals beyond 2 years after first diagnosis. CONCLUSION: PHDs is suggestive of an incremental risk for ischaemic stroke with gender-dependent, age-specific and time-dependent characteristics.

Nuclear Factor-kappaB-Dependent Sestrin2 Induction Mediates the Antioxidant Effects of BDNF Against Mitochondrial Inhibition in Rat Cortical Neurons.

Brain-derived neurotrophic factor (BDNF), in addition to its neurotrophic action, also possesses antioxidant activities. However, the underlying mechanisms remain to be fully defined. Sestrin2 is a stress-responsive gene implicated in the cellular defense against oxidative stress. Currently, the potential functions of sestrin2 in nervous system, in particular its correlation with neurotrophic factors, have not been well established. In this study, we hypothesized that BDNF may enhance sestrin2 expression to confer neuronal resistance against oxidative stress induced by 3-nitropropionic acid (3-NP), an irreversible mitochondrial complex II inhibitor, and characterized the molecular mechanisms underlying BDNF induction of sestrin2 in primary rat cortical cultures. We found that BDNF-mediated sestrin2 expression in cortical neurons required formation of nitric oxide (NO) with subsequent production of 3',5'-cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase (PKG). BDNF induced localization of nuclear factor-kappaB (NF-κB) subunits p65 and p50 into neuronal nuclei that required PKG activities. Interestingly, BDNF exposure led to formation of a protein complex containing at least PKG-1 and p65/p50, which bound to sestrin2 promoter with resultant upregulation of its protein products. Finally, BDNF preconditioning mitigated production of reactive oxygen species (ROS) as a result of 3-NP exposure; this antioxidative effect of BDNF was dependent upon PKG activity, NF-κB, and sestrin2. Taken together, our results indicated that BDNF enhances sestrin2 expression to confer neuronal resistance against oxidative stress induced by 3-NP through attenuation of ROS formation; furthermore, BDNF induction of sestrin2 requires activation of a pathway involving NO/PKG/NF-κB.

Inhibitor of Differentiation-1 and Hypoxia-Inducible Factor-1 Mediate Sonic Hedgehog Induction by Amyloid Beta-Peptide in Rat Cortical Neurons.

One major pathological hallmark of Alzheimer's disease (AD) is the accumulation of senile plaques mainly composed of neurotoxic amyloid beta-peptide (Aß) in the patients' brains. Sonic hedgehog (SHH) is a morphogen critically involved in the embryonic development of the central nervous system (CNS). In the present study, we tested whether Aß may induce SHH expression and explored its underlying mechanisms. We found that both Aß25-35 and Aß1-42 enhanced SHH expression in the primary cortical neurons derived from fetal rat brains. Immunohistochemistry revealed heightened expression of SHH in the cortex and hippocampus of aged (9 and 12 months old) AD transgenic mouse brains as compared to age-matched littermate controls. Chromatin immunoprecipitation (ChIP) assay demonstrated that Aß25-35 enhanced binding of hypoxia-inducible factor-1 (HIF-1) to the promoter of the Shh gene in primary cortical cultures; consistently, Aß25-35 induction of SHH was abolished by HIF-1α small interfering RNA (siRNA). Aß25-35 also time-dependently induced inhibitor of differentiation-1 (Id1) that has been shown to stabilize HIF-1α; further, Aß25-35-mediated induction of HIF-1α and SHH was both suppressed by Id1 siRNA. Pharmacological induction of HIF-1α by cobalt chloride and application of the cell-permeable recombinant Id1 proteins were both sufficient to induce SHH expression. Finally, both the SHH pathway inhibitor cyclopamine and its neutralizing antibody attenuated Aß cytotoxicity, albeit to a minor extent. These results thus established a signaling cascade of "Aß â†’ Id1 → HIF-1 → SHH" in primary rat cortical cultures; furthermore, SHH may in part contribute to Aß neurotoxicity.

Increased Risk of Dementia Among Sleep-Related Movement Disorders: A Population-Based Longitudinal Study in Taiwan.

Sleep-related movement disorders (SRMD) are sleep disorders. As poor sleep quality is associated with cognitive impairment, we hypothesized that SRMD patients were exposed to a great risk for developing dementia.The present study was aimed to retrospectively examine the association of SRMD and dementia risk.A retrospective longitudinal study was conducted using the data obtained from the Longitudinal Health Insurance Database (LHID) in Taiwan. The study cohort enrolled 604 patients with SRMD who were initially diagnosed and 2416 patients who were randomly selected and age/gender matched with the study group. SRMD, dementia, and other confounding factors were defined according to International Classification of Diseases Clinical Modification Codes. Cox proportional-hazards regressions were employed to examine adjusted hazard ratios (HR) after adjusting with confounding factors.Our data revealed that patients with SRMD had a 3.952 times (95% CI = 1.124-4.767) higher risk to develop all-cause dementia compared with individuals without SRMD. The results showed that SRMD patients aged 45 to 64 exhibited highest risk of developing all-cause dementia (HR: 5.320, 95% CI = 1.770-5.991), followed by patients age ≥65 (HR: 4.123, 95% CI = 2.066-6.972) and <45 (HR: 3.170, 95% CI = 1.050-4.128), respectively. Females with SRMD were at greater risk to develop all-cause dementia (HR: 4.372, 95% CI = 1.175-5.624). The impact of SRMD on dementia risk was progressively increased by various follow-up time intervals (<1 year, 1-2 years, and ≥2 years).The results suggest that SRMD is linked to an increased risk for dementia with gender-dependent and time-dependent characteristics.

Oncostatin M-dependent Mcl-1 induction mediated by JAK1/2-STAT1/3 and CREB contributes to bioenergetic improvements and protective effects against mitochondrial dysfunction in cortical neurons.

Oncostatin M (OSM), a cytokine in the interleukin-6 (IL-6) family, has been proposed to play a protective role in the central nervous system, such as attenuation of excitotoxicity induced by N-methyl-D-aspartate (NMDA) and glutamate. However, the potential neuroprotective effects of OSM against mitochondrial dysfunction have never been reported. In the present study, we tested the hypothesis that OSM may confer neuronal resistance against 3-nitropropionic acid (3-NP), a plant toxin that irreversibly inhibits the complex II of the mitochondrial electron transport chain, and characterized the underlying molecular mechanisms. We found that OSM preconditioning dose- and time-dependently protected cortical neurons against 3-NP toxicity. OSM stimulated expression of myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic Bcl-2 family member expressed in differentiating myeloid cells, that required prior phosphorylation of Janus kinase-1 (JAK1), JAK2, extracellular signal-regulated kinase-1/2 (ERK1/2), signal transducer and activator of transcription-3 (STAT3), STAT1, and cAMP-response element-binding protein (CREB). Pharmacological inhibitors of JAK1, JAK2, ERK1/2, STAT3, STAT1, and CREB as well as the siRNA targeting at STAT3 and Mcl-1 all abolished OSM-dependent 3-NP resistance. Finally, OSM-dependent Mcl-1 induction contributed to the enhancements of mitochondrial bioenergetics including increases in spare respiratory capacity and ATP production. In conclusion, our findings indicated that OSM induces Mcl-1 expression via activation of ERK1/2, JAK1/2, STAT1/3, and CREB; furthermore, OSM-mediated Mcl-1 induction contributes to bioenergetic improvements and neuroprotective effects against 3-NP toxicity in cortical neurons. OSM may thus serve as a novel neuroprotective agent against mitochondrial dysfunction commonly associated with pathogenic mechanisms underlying neurodegeneration.