Different risks of early-onset and late-onset Parkinson disease in individuals with mental illness.

We aimed to investigate the association of various mental illnesses, including depression, bipolar disorder, schizophrenia, insomnia, and anxiety, with the risk of early-onset Parkinson's disease (EOPD) (age <50 years) and compare it with that of late-onset PD (LOPD) (age ≥50 years). This nationwide cohort study enrolled 9,920,522 people who underwent a national health screening examination in 2009, and followed up until 31 December 2018. There was a significantly increased risk of EOPD and LOPD in individuals with mental illness, and EOPD showed a stronger association than LOPD (EOPD, hazard ratio (HR) = 3.11, 95% CI: 2.61‒3.72; LOPD, HR = 1.70, 95% CI: 1.66‒1.74; p for interaction <0.0001). Our results suggest that people with mental illnesses aged < 50 years are at a higher risk of PD than those aged ≥50 years. Future studies are warranted to elucidate the pathomechanism of EOPD in relation to mental illness.

Comparison of Particulate Steroid Injection vs Nonparticulate Steroid Injection for Lumbar Radicular Pain: A Systematic Review and Meta-analysis.

OBJECTIVE: The objective of this study was to identify the difference on pain intensity and disability between particulate and nonparticulate steroid injections in patients with lumbar radicular pain. Subgroup analysis by study design, type of particulate steroid, and follow-up duration were performed. DATA SOURCES: We performed the literature search in the PubMed, Embase, and Cochrane Library up March, 2023. STUDY SELECTION: Studies, including randomized controlled trials (RCTs) and nonrandomized studies, that compared particulate steroid injection and nonparticulate steroid injection in patients with lumbar radicular pain were independently reviewed by 2 reviewers for eligibility for inclusion. DATA EXTRACTION: Outcomes of interest were pain intensity and disability. Two reviewers independently assessed the quality of included studies using the revised Cochrane Risk of Bias (RoB2.0) tool for RCTs and the Risk of Bias in Nonrandomized Studies of Interventions Tool (ROBINS-I) for nonrandomized studies. Effect sizes were estimated using mean difference (MD) and standardized mean difference (SMD). DATA SYNTHESIS: A total of 10 studies were included in this meta-analysis. The results showed no significant difference in visual analog scale, disability score and the numbers of patients with 50% pain reduction between particulate and nonparticulate steroid injection groups (P>.05). Particulate steroid injections showed significant better effect in pain scale in RCTs (MD=0.62; 95% CI 0.08-1.16, P=.02). In subgroup analysis with steroid types, methylprednisolone showed better effect compared with dexamethasone, while dexamethasone showed better effect compared with betamethasone. CONCLUSIONS: This meta-analysis suggested no significant differences between the particulate and nonparticulate steroid groups in pain or disability score. Therefore, considering the safety profile of nonparticulate steroids, nonparticulate steroid injection may be helpful in patients with lumbar radicular pain.

Depressive Symptoms and the Subsequent Risk of Parkinson's Disease: A Nationwide Cohort Study.

OBJECTIVE: Only a few studies have focused on depressive symptoms and Parkinson's disease (PD) risk. As a time lag exists from the onset of depressive symptoms to the diagnosis of depression, elucidating the association between depressive symptoms and PD development might be helpful for the early prediction of PD. We investigate the association between depressive symptoms and subsequent PD risk using nationwide population-based cohort database. DESIGN AND SETTING: Cohort study using the Korean National Health Insurance Service data between 2007 and 2017, with longitudinal follow-up until 2019. PARTICIPANTS: A total of 98,296 elderly people responded to a self-reported questionnaire from the National Health Screening Program on depressive symptoms. MEASUREMENTS: The association between depressive symptoms such as 1) decreased activity or motivation, 2) worthlessness, and 3) hopelessness and PD risk was analyzed. RESULTS: During median 5.06-year follow-up, 839 PD cases occurred: 230 in individuals with depressive symptoms and 609 in those without symptoms. Results showed an increased risk of PD development in those with depressive symptoms (HR = 1.47, 95% CI, 1.26-1.71), with dose-response association between the number of depressive symptoms and PD risk. Even in those already diagnosed with depression, combined depressive symptoms were linked to a higher risk compared to those without symptoms (with symptoms, HR = 2.71, 95% CI, 2.00-3.68; without symptoms, HR = 1.84, 95% CI, 1.43-2.36). CONCLUSION: Individuals with depressive symptoms were at an increased risk of developing PD, and there was a dose-response association between the number of depressive symptoms and PD risk.

The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation.

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.

Association between lipid levels and the risk of Parkinson's disease in individuals with diabetes mellitus: A nationwide population-based cohort study.

INTRODUCTION: Many studies have examined the positive association between diabetes mellitus (DM) and the risk of Parkinson's disease (PD). Dyslipidemia has been reported to be prevalent in patients with diabetes; thus, lipid levels and the drugs for dyslipidemia could influence the development of PD in patients with DM. This study aimed to examine the association between lipid levels and the risk of PD in individuals with DM and evaluate whether the association changes with the use of statins. METHODS: This nationwide population-based retrospective cohort study included individuals with DM according to the International Classification of Diseases between 2009 and 2012. Among the 2,361,633 patients with DM followed up for up to 9 years, 17,046 were newly diagnosed with PD. Patients with DM were categorized into quartile groups of total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. RESULTS: There was an inverse association between lipid levels and PD development in the unadjusted model; however, this relationship became less significant after adjusting the use of statins in triglyceride and total cholesterol. In the analysis stratified by statin use, total cholesterol level was associated with decreased PD risk in non-statin users with DM; however, there was no significant association between total cholesterol level and PD risk in statin users. CONCLUSION: We found an inverse relationship between lipid levels and PD risk in patients with DM, which was influenced by statin use. Future studies about optimal target lipid levels relevant to PD risk considering statin dose in DM patients are needed.

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model.

Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aß and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.

GV16 acupoint stimulation with bee venom reduces peripheral hypersensitivity via activation of α2 adrenoceptors in a nitroglycerin-induced migraine mouse model.

Background: Peripheral hypersensitivities develop in the face and hindpaws of mice with nitroglycerin (NTG)-induced migraine. We evaluated whether diluted bee venom (DBV) injections at acupoints prevented these peripheral hypersensitivities and c-Fos expression in the trigeminal nucleus caudalis (TNC). Methods: NTG (10 mg/kg, intraperitoneal, i.p.) was administered every other day for nine days. DBV (0.1 mg/kg) was subcutaneously injected into the ST36 (Zusanli), LI4 (Hegu), or GV16 (Fengfu) acupoints 75 min after each NTG injection. Mice were pretreated with naloxone (5 mg/kg, i.p.) or yohimbine (5 mg/kg, i.p.) 30 min before the DBV injections. Results: NTG injection caused facial cold allodynia, hindpaw mechanical allodynia, and increased c-Fos-immunoreactive (ir) cells in the TNC. Repetitive DBV injections at GV16, but not the ST36, or LI4 acupoints, suppressed NTG-induced hindpaw mechanical allodynia and facial cold allodynia. The number of c-Fos-ir cells also decreased in response to DBV injections at the GV16 acupoint. Remarkably, pretreatment with yohimbine reversed the anti-allodynic effects of DBV injections and attenuated the decreased c-Fos expression in response to GV16 DBV treatment. Naloxone did not block the effects of GV16 DBV stimulation. Conclusion: These findings demonstrate that repetitive DBV treatment at the GV16 acupoint relieves NTG-induced facial and hindpaw hypersensitivities and decreases in c-Fos expression in the TNC via activation of the alpha-2 adrenoceptors, but not the opioid receptors.

APOE4-promoted gliosis and degeneration in tauopathy are ameliorated by pharmacological inhibition of HMGB1 release.

Apolipoprotein E4 (APOE4) is an important driver of Tau pathology, gliosis, and degeneration in Alzheimer's disease (AD). Still, the mechanisms underlying these APOE4-driven pathological effects remain elusive. Here, we report in a tauopathy mouse model that APOE4 promoted the nucleocytoplasmic translocation and release of high-mobility group box 1 (HMGB1) from hippocampal neurons, which correlated with the severity of hippocampal microgliosis and degeneration. Injection of HMGB1 into the hippocampus of young APOE4-tauopathy mice induced considerable and persistent gliosis. Selective removal of neuronal APOE4 reduced HMGB1 translocation and release. Treatment of APOE4-tauopathy mice with HMGB1 inhibitors effectively blocked the intraneuronal translocation and release of HMGB1 and ameliorated the development of APOE4-driven gliosis, Tau pathology, neurodegeneration, and myelin deficits. Single-nucleus RNA sequencing revealed that treatment with HMGB1 inhibitors diminished disease-associated and enriched disease-protective subpopulations of neurons, microglia, and astrocytes in APOE4-tauopathy mice. Thus, HMGB1 inhibitors represent a promising approach for treating APOE4-related AD.

Neuronal apoE4 induces early hyperexcitability in select populations of hippocampal neurons by altering Nell2 expression.

The impact of apolipoprotein E4 (apoE4), the strongest genetic risk factor for Alzheimer's disease (AD), on neuronal function remains unclear. We investigated this by examining excitatory neurons in the hippocampus of young and aged human apoE4 knock-in (apoE4-KI) and apoE3-KI mice using electrophysiology and single-nucleus RNA-sequencing (snRNA-seq). In young apoE4-KI mice, we identified region-specific subpopulations of excitatory neurons with hyperexcitability underlain by reduced cell size, which were eliminated by selective removal of neuronal apoE4. Aged apoE4-KI mice showed an increased fraction of hyperexcitable granule cells, a pronounced inhibitory deficit, and E/I imbalance in the dentate gyrus, contributing to network dysfunction. snRNA-seq analysis revealed neuron type-specific and age-dependent transcriptomic changes, identifying Nell2 overexpression in apoE4-KI mice. Reducing Nell2 expression in specific neuronal types of apoE4-KI mice with CRISPRi rescued their morphological and excitability phenotypes, supporting Nell2 overexpression as a cause for apoE4-induced neuronal dysfunction. Our findings highlight the early transcriptomic and morpho-electric alterations behind the apoE4-induced neuronal dysfunction in AD. HIGHLIGHTS: ApoE4 causes hyperexcitability of select hippocampal neurons in young apoE4 mice.ApoE4 causes dentate hyperexcitability and inhibitory deficit in aged apoE4 mice.snRNA-seq reveals apoE genotype-, cell type-, and age-dependent transcriptomic changes.Nell2 overexpression identified as a cause of apoE4-induced neuronal hyperexcitability.

High- versus Low-dose Steroid Injection for Adhesive Capsulitis (Frozen Shoulder): A Systematic Review and Meta-analysis.

BACKGROUND: Intraarticular steroid injections are a commonly used and proven treatment for frozen shoulder; however, there is no scientific basis for a certified dose. OBJECTIVES: This study aimed to identify the difference between high- and low-dose steroid injections treatments and suggest an appropriate dose. STUDY DESIGN: Systematic review and meta-analysis. METHODS: The MEDLINE, EMBASE, and Cochrane electronic databases were searched through February 15, 2023 for eligible randomized controlled trials. The effects of high- and low-dose steroid injections were calculated as standardized mean differences (SMD) in pain, shoulder range of motion (ROM), and functional improvement. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate evidence quality. RESULTS: Four studies with 274 patients were included in the final analysis. The meta-analysis showed that improvement in pain (SMD, 0.10; 95% CI, -0.12 to 0.32), ROM (SMD, 0.07; 95% CI, -0.05 to 0.19), and functional improvement (SMD, 0.08; 95% CI, -0.10 to 0.26) did not differ significantly between the high- and low-dose steroid injections. Subgroup follow-up analyses also showed no clinically significant differences in SMD for pain, ROM, and functional scale measurement in any subgroups (after 3 weeks, 6 weeks, and one year). One article described that, although there was no significant difference in adverse events frequency between the high- and low-dose groups, flushing tended to occur more frequently in the high-dose group. LIMITATIONS: Limitations are the small number of studies included in the meta-analysis, no disease stage considered, and a short follow-up period. CONCLUSIONS: This meta-analysis suggests there are no significant differences between the high- and low-dose steroid groups in pain, ROM, or functional improvement. Therefore, considering the side effects of high-dose steroids, starting with low-dose steroids is recommended. However, further studies are needed to establish exact protocols according to disease severity. KEY WORDS: Frozen shoulder, adhesive capsulitis, steroids, triamcinolone acetonide, injections, intraarticular, optimal dose, meta-analysis, randomized controlled trial.

Accessibility for Rehabilitation Therapy According to Socioeconomic Status in Patients With Stroke: A Population-Based Retrospective Cohort Study.

This study aimed to investigate accessibility for rehabilitation therapy according to socioeconomic status (SES) after stroke using nationwide population-based cohort data. We selected patients with a diagnosis with stroke (International Classification of Diseases, 10th Revision code: I60-64) and SES including residential area, income level, and insurance type were also assessed. Receiving continuous rehabilitation therapy was defined as accumulation of "Rehabilitative developmental therapy for disorder of central nervous system (claim code: MM105)" more than 41 times. Logistic regression analyses were performed to investigate the association between SES and rehabilitation therapy using odds ratios (ORs) and 95% confidence intervals (CIs). A total of 18,842 patients with stroke were enrolled. Rural area (OR, 0.745; 95% CI, 0.664-0.836) and medical aid (OR, 0.605; 95% CI, 0.494-0.741) were associated with lower rate of receiving rehabilitation therapy. As for income level, when lowest income group was used as a reference group, low-middle group showed an increased rate of receiving rehabilitation therapy (OR, 1.206; 95% CI, 1.020-1.426). Although rehabilitation therapy after stroke is covered with national health insurance program in Korea, there still existed disparities of accessibility for rehabilitation therapy according to SES. Our results would suggest helpful information for health policy in patients with stroke.

Clinical Practice Guideline for Stroke Rehabilitation in Korea-Part 1: Rehabilitation for Motor Function (2022).

This clinical practice guideline (CPG) is the fourth edition of the Korean guideline for stroke rehabilitation, which was last updated in 2016. The development approach has been changed from a consensus-based approach to an evidence-based approach using the Grading of Recommendations Assessment Development and Evaluation (GRADE) method. This change ensures that the guidelines are based on the latest and strongest evidence available. The aim is to provide the most accurate and effective guidance to stroke rehabilitation teams, and to improve the outcomes for stroke patients in Korea. Fifty-five specialists in stroke rehabilitation and one CPG development methodology expert participated in this development. The scope of the previous clinical guidelines was very extensive, making it difficult to revise at once. Therefore, it was decided that the scope of this revised CPG would be limited to Part 1: Rehabilitation for Motor Function. The key questions were selected by considering the preferences of the target population and referring to foreign guidelines for stroke rehabilitation, and the recommendations were completed through systematic literature review and the GRADE method. The draft recommendations, which were agreed upon through an official consensus process, were refined after evaluation by a public hearing and external expert evaluation.

Association between Low Blood Pressure and Subsequent Risk of Parkinson's Disease in Older Adults Aged ≥75 Years.

INTRODUCTION: The association between blood pressure (BP) and incidence of Parkinson's disease (PD) in older adults remains uncertain. Therefore, this study aimed to investigate the association between BP (high or low) and PD incidence in adults aged ≥75 years. METHODS: In this nationwide population-based cohort study, we enrolled participants aged ≥75 years without a prior PD diagnosis who had undergone health examination provided by the Korean National Health Insurance Service at least once from January 1, 2009, to December 31, 2012. The participants were followed up until December 31, 2019, or the date of their death. The Cox proportional hazards model was used to assess the risk of PD depending on systolic BP (SBP), diastolic BP (DBP), and pulse pressure. RESULTS: Overall, 963,525 participants were enrolled in the analysis and followed up until December 31, 2019, or the date of death (40.7% male, mean age 78.5 ± 3.6 years). The mean SBP and DBP were 131.4 ± 16.7 and 77.9 ± 10.3 mm Hg, respectively. During the 10-year follow-up period, 16,414 (1.7%) newly diagnosed cases of PD were reported. A significant inverse dose-response association was found between SBP and PD incidence. In the subgroup analysis, this association was maintained for most variables, including sex, use of antihypertensive medication, comorbidities, alcohol consumption, physical activity, and body mass index, except for smoking status. CONCLUSION: Lower SBP and DBP were associated with a higher PD incidence in older adults. These results may have substantial implications for determining the optimal BP control target in adults aged ≥75 years.

Korean vs. Western Exercise Capacity Nomograms for Korean Patients With Cardiovascular Disease.

BACKGROUND: Exercise capacity is known to be an independent predictor of cardiovascular events and mortality. However, most previous studies were based on Western populations. Further study is warranted for Asian patients according to ethnic or national standards. We aimed to compare prognostic values of Korean and Western nomograms for exercise capacity in Korean patients with cardiovascular disease (CVD). METHODS: In this retrospective cohort study, we enrolled 1,178 patients (62 ± 11 years; 78% male) between June 2015 and May 2020, who were referred for cardiopulmonary exercise testing in our cardiac rehabilitation program. The median follow-up period was 1.6 years. Exercise capacity was measured in metabolic equivalents by direct gas exchange method during the treadmill test. The nomogram for exercise capacity from healthy Korean individuals and a previous landmark Western study was used to determine the percentage of predicted exercise capacity. The primary endpoint was the composite of major adverse cardiovascular events (MACE; all-cause death, myocardial infarction, repeat revascularization, stroke and hospitalization for heart failure). RESULTS: A multivariate analysis showed that the risk of primary endpoint was more than double (hazard ratio [HR], 2.20; 95% confidence interval [CI], 1.10-4.40) in the patients with lower exercise capacity (< 85% of predicted) by Korean nomogram. The lower exercise capacity was one of the strong independent predictors along with left ventricular ejection fraction, age, and level of hemoglobin. However, the lower exercise capacity by Western nomogram could not predict the primary endpoint (HR, 1.33; 95% CI, 0.85-2.10). CONCLUSION: Korean patients with CVD with lower exercise capacity have higher risk of MACE. Considering inter-ethnic differences in cardiorespiratory fitness, the Korean nomogram provides more suitable reference values than the Western nomogram to determine lower exercise capacity and predict cardiovascular events in Korean patients with CVD.

Pre-aspirin use has no benefit on the neurological disability and mortality after cardiovascular events: A nation-wide population-based cohort study.

To evaluate the effects of aspirin in the primary prevention, we evaluated disability grades and mortality after ischemic/hemorrhagic stroke and myocardial infarction (MI). A retrospective nation-wide propensity score-matched cohort study was performed using the Korean National Health Information Database. From 3,060,639 subjects who were older than 55 and performed national health examinations in 2004 and 2005, we selected the aspirin group (N = 8770) was composed of patients who had received aspirin prior to cardiovascular events. Cox proportional hazards model was used to compare the acquisition times for neurologic disability grades and survival times between the aspirin and control groups. Only in hemorrhagic stroke, the severe neurologic disability risk was higher in the aspirin group (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.02-1.42). The aspirin group was associated with higher 90-day (HR, 1.33; 95% CI, 1.23-1.44) and long-term mortality risk (HR, 1.06; 95% CI, 1.03-1.10) after pooling 3 events. The old age was a strong risk factor for 90-day mortality in hemorrhagic stroke (50s: reference; 60s: HR 2.21, 95% CI 1.50-3.25; 70s: HR 3.63, 95% CI 2.48-5.30; 80s: HR 6.69, 95% CI 4.54-9.65; >90s: HR 11.28, 95% CI 6.46-19.70). Pre-aspirin use in cardiovascular events has detrimental effects on severe neurological disability in hemorrhagic stroke and short-/long-term mortality in 3 cardiovascular events. The use of aspirin for the primary prevention especially in the elderly should be very cautious because the old age is a strong risk factor for 90-day mortality after hemorrhagic stroke.

Comparing the effects of University of California Biomechanics Laboratory and custom-made semi-rigid insole on pedobarographic parameters in pediatric flexible flat foot.

BACKGROUND: Pediatric flexible flat foot (PFFF) is often associated with pain along the medial longitudinal arch and potential disability. There are several conservative treatment options for PFFF, ranging from intrinsic muscle exercises to orthosis, including University of California Biomechanics Laboratory (UCBL) and custom-made semi-rigid insoles. OBJECTIVES: To investigate and compare the effect of UCBL and custom-made semi-rigid insoles on pedobarographic and radiologic parameters in PFFF. STUDY DESIGN: This study prepared a retrospective chart review of 143 children diagnosed with PFFF between the age of 4 and 12 years. METHODS: Data of twenty-seven children with PFFF who were prescribed foot orthoses between the age of 4 and 12 years were retrospectively reviewed. Medical charts were retrospectively reviewed, and pedobarographic and radiological parameters assessed before and 1 year after application of orthoses were reviewed. RESULTS: The difference in the calcaneal pitch angle and the center of pressure excursion index (CPEI) were significantly improved in the custom-made semi-rigid insole group compared to that in the UCBL group. The contact area ratio of the midfoot and toe and CPEI at 1 year after wearing the insole was significantly improved in the custom-made semi-rigid insole group compared to that in the UCBL group. Moreover, the calcaneal pitch angle and CPEI were significantly improved 1 year after application of the insole in the custom-made semi-rigid insole group. CONCLUSIONS: This result showed that the custom-made semi-rigid insole is more effective in improving the deviation of the center pressure curve and calcaneal pitch angle than the UCBL. The custom-made semi-rigid insole may help relieve foot instability during gait and improve the medial longitudinal arch in children with PFFF.

Association between smoking and all-cause mortality in Parkinson's disease.

We aimed to investigate the association between smoking status and all-cause mortality of Parkinson's disease (PD). Among the whole nationwide population data from Korea National Health Insurance Service, newly diagnosed PD was selected, and all-cause mortality was evaluated. The systematic review was performed through a literature search on the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases. Among 26,080 individuals with PD, there was no significant association between smoking status and all-cause mortality in a nationwide cohort study (ex-smoker, HR 0.1.03, 95% CI 0.97-1.10; current smoker, HR 1.06, 95% CI 0.96-1.16). The systematic review, including six prospective cohort studies, also found a nonsignificant association. PD smokers tended to have fewer deaths from neurologic causes but were significantly more likely to die from smoking-related cancers such as lung cancer. We presented a nonsignificant association between smoking and mortality of PD, and cigarette smoking is not recommended in individuals with PD.

Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits.

Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.

Machine learning based risk prediction for Parkinson's disease with nationwide health screening data.

Although many studies have been conducted on machine learning (ML) models for Parkinson's disease (PD) prediction using neuroimaging and movement analyses, studies with large population-based datasets are limited. We aimed to propose PD prediction models using ML algorithms based on the National Health Insurance Service-Health Screening datasets. We selected individuals who participated in national health-screening programs > 5 times between 2002 and 2015. PD was defined based on the ICD-code (G20), and a matched cohort of individuals without PD was selected using a 1:1 random sampling method. Various ML algorithms were applied for PD prediction, and the performance of the prediction models was compared. Neural networks, gradient boosting machines, and random forest algorithms exhibited the best average prediction accuracy (average area under the receiver operating characteristic curve (AUC): 0.779, 0.766, and 0.731, respectively) among the algorithms validated in this study. The overall model performance metrics were higher in men than in women (AUC: 0.742 and 0.729, respectively). The most important factor for predicting PD occurrence was body mass index, followed by total cholesterol, glucose, hemoglobin, and blood pressure levels. Smoking and alcohol consumption (in men) and socioeconomic status, physical activity, and diabetes mellitus (in women) were highly correlated with the occurrence of PD. The proposed health-screening dataset-based PD prediction model using ML algorithms is readily applicable, produces validated results, and could be a useful option for PD prediction models.

Different Involvement of ASIC and TRPA1 in Facial and Hindpaw Allodynia in Nitroglycerin-Induced Peripheral Hypersensitivities in Mice.

The pathophysiological mechanism underlying migraine-associated peripheral hypersensitivity remains unclear. Acid-sensing ion channels (ASICs) and transient receptor potential ankyrin 1 (TRPA1) are known to be causative pathogenic factors of mechanical and cold allodynia, respectively. Here, we sought to investigate their involvement in cold and mechanical allodynia of the face and hindpaws, respectively, in a mouse model of repetitive nitroglycerin (NTG)-induced migraine. NTG (10 mg/kg) was administered to the mice every other day for 9 days, followed 90 min later by HC-030031 (a TRPA1 blocker) or amiloride (a non-selective ASIC blocker). Mechanical or cold sensitivity of the hindpaw and facial regions was quantified using von-Frey filaments or acetone solution, respectively. Immunohistochemistry revealed that c-Fos expression was significantly increased in the trigeminal nucleus caudalis region but not in the spinal cord. Amiloride treatment only reduced NTG-induced hindpaw mechanical allodynia, whereas HC-030031 treatment only improved facial cold allodynia. Interestingly, the number of c-Fos positive cells decreased to a similar level in each drug treatment group. These findings demonstrate that facial cold allodynia and hindpaw mechanical allodynia are differentially mediated by activation of TRPA1 and ASIC, respectively, in mice with repetitive NTG-induced hypersensitivity.