Person-specific differences in ubiquitin-proteasome mediated proteostasis in human neurons.

BACKGROUND: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in abnormal protein accumulation in Alzheimer's disease. It remains unclear if genetic variation affects the intrinsic properties of neurons that render some individuals more vulnerable to UPS impairment. METHODS: Induced pluripotent stem cell (iPSC)-derived neurons were generated from over 50 genetically variant and highly characterized participants of cohorts of aging. Proteomic profiling, proteasome activity assays, and Western blotting were employed to examine neurons at baseline and in response to UPS perturbation. RESULTS: Neurons with lower basal UPS activity were more vulnerable to tau accumulation following mild UPS inhibition. Chronic reduction in proteasome activity in human neurons induced compensatory elevation of regulatory proteins involved in proteostasis and several proteasome subunits. DISCUSSION: These findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation-prone proteins such as tau. HIGHLIGHTS: Polygenic risk score for AD is associated with the ubiquitin-proteasome system (UPS) in neurons. Basal proteasome activity correlates with aggregation-prone protein levels in neurons. Genetic variation affects the response to proteasome inhibition in neurons. Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis. Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge.

Comparing Low- or Standard-Dose Alteplase in Endovascular Thrombectomy: Insights From a Nationwide Registry.

BACKGROUND: Timely intravenous thrombolysis and endovascular thrombectomy are the standard reperfusion treatments for large vessel occlusion stroke. Currently, it is unknown whether a low-dose thrombolytic agent (0.6 mg/kg alteplase) can offer similar efficacy to the standard dose (0.9 mg/kg alteplase). METHODS: We enrolled consecutive patients in the multicenter Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke who had received combined thrombolysis (within 4.5 hours of onset) and thrombectomy treatment from January 2019 to April 2023. The choice of low- or standard-dose alteplase was based on the physician's discretion. The outcomes included successful reperfusion (modified Thrombolysis in Cerebral Infarction score, 2b-3), symptomatic intracerebral hemorrhage, 90-day modified Rankin Scale score, and 90-day mortality. The outcomes between the 2 groups were compared using multivariable logistic regression and inverse probability of treatment weighting-adjusted analysis. RESULTS: Among the 2242 patients in the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke, 734 (33%) received intravenous alteplase. Patients in the low-dose group (n=360) were older, had more women, more atrial fibrillation, and longer onset-to-needle time compared with the standard-dose group (n=374). In comparison to low-dose alteplase, standard-dose alteplase was associated with a lower rate of successful reperfusion (81% versus 87%; adjusted odds ratio, 0.63 [95% CI, 0.40-0.98]), a numerically higher incidence of symptomatic intracerebral hemorrhage (6.7% versus 3.9%; adjusted odds ratio, 1.81 [95% CI, 0.88-3.69]), but better 90-day modified Rankin Scale score (functional independence [modified Rankin Scale score, 0-2], 47% versus 31%; adjusted odds ratio, 1.91 [95% CI, 1.28-2.86]), and a numerically lower mortality rate (9% versus 15%; adjusted odds ratio, 0.73 [95% CI, 0.43-1.25]) after adjusting for covariates. Similar results were observed in the inverse probability of treatment weighting-adjusted models. The results were consistent across predefined subgroups and age strata. CONCLUSIONS: Despite the lower rate of successful reperfusion and higher risk of symptomatic intracerebral hemorrhage with standard-dose alteplase, standard-dose alteplase was associated with a better functional outcome in patients receiving combined thrombolysis and thrombectomy.

Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer's disease risk gene SORL1.

SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate the roles of SORL1 in human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in apolipoprotein E (APOE) and clusterin (CLU) and altered lipid profiles. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in postmortem brain. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1-null neurons but does not rescue APOE levels. Pathway analyses implicate transforming growth factor ß (TGF-ß)/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Taken together, these data provide a mechanistic link between strong genetic risk factors for AD.

Comparison of Humoral Antibody Responses and Seroconversion Rates between Two Homologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination in Patients Undergoing Maintenance Hemodialysis.

BACKGROUND: Hemodialysis patients are at an increased risk of SARS-CoV-2 infection and are excluded from preauthorization COVID-19 vaccine trials; therefore, their immunogenicity is uncertain. METHODS: To compare the antibody responses to homologous ChAdOx1 and mRNA-1273 SARS-CoV-2 vaccination in hemodialysis patients, 103 age- and sex-matched hemodialysis patients with two homologous prime-boost vaccinations were recruited to detect anti-receptor-binding domain (RBD) IgG levels and seroconversion rates (SCRs) 14 days after a prime dose (PD14), before and 28 days after a boost dose (pre-BD0 and BD28). RESULTS: Both mRNA-1273 and ChAdOx1 vaccinations elicited immunogenicity in study subjects, and the former induced higher anti-RBD IgG levels than the latter. The SCRs of both groups increased over time and varied widely from 1.82% to 97.92%, and were significantly different at PD14 and pre-BD0 regardless of different thresholds. At BD28, the SCRs of the ChAdOx1 group and the mRNA-1273 group were comparable using a threshold ≥ 7.1 BAU/mL (93.96% vs. 97.92%) and a threshold ≥ 17 BAU/mL (92.73% vs. 97.92%), respectively, but they were significantly different using a threshold ≥ 20.2% of convalescent serum anti-RBD levels (52.73% vs. 95.83%). The seroconversion (≥20.2% of convalescent level) at BD28 was associated with mRNA-1273 vaccination after being adjusted for age, sex, body mass index, and the presence of solicited reactogenicity after a prime vaccination. CONCLUSION: Our prospective, observational cohort indicates that a full prime-boost mRNA-1273 vaccination is likely to provide higher immune protection in hemodialysis patients compared to ChAdOx1, and this population with a prime-boost ChAdOx1 vaccination should be prioritized for a third dose.

Unveiling the Power of Anticancer Drug Screening: A Clinical Case Study Comparing the Effectiveness of Hollow Fiber Assay Microtube Array Membrane (MTAM-HFA) in Breast Cancer Patients.

Breast cancer is a severe public health problem, and early treatment with powerful anticancer drugs is critical for success. The researchers investigated the clinical results of a novel screening tool termed Microtube Array Membrane Hollow Fiber Assay (MTAM-HFA) in breast cancer patients in this clinical investigation. In all trial participants, the MTAM-HFA was utilized to identify active medicines for the treatment of breast cancer. The MTAM-HFA was shown to be extremely useful in predicting patient response to anticancer medication therapy in this study. Furthermore, the substantial association between the MTAM-HFA screening outcome and the clinical outcome of the respective patients emphasizes the promise of this unique screening technology in discovering effective anticancer medication combinations for the treatment of breast cancer. These findings indicate that the MTAM-HFA has clinical significance and might be a valuable tool in the development of tailored therapy for cancer care. This study provides helpful information for physicians and scientists working on breast cancer therapy research. The potential benefits of employing MTAM-HFA to find accurate therapies for breast cancer patients might lead to enhanced personalized medicine approaches to cancer care, resulting in better patient outcomes. Overall, the MTAM-HFA screening approach has the potential to revolutionize customized cancer therapy, providing hope to both patients and physicians.

Moving beyond amyloid and tau to capture the biological heterogeneity of Alzheimer's disease.

Alzheimer's disease (AD) manifests along a spectrum of cognitive deficits and levels of neuropathology. Genetic studies support a heterogeneous disease mechanism, with around 70 associated loci to date, implicating several biological processes that mediate risk for AD. Despite this heterogeneity, most experimental systems for testing new therapeutics are not designed to capture the genetically complex drivers of AD risk. In this review, we first provide an overview of those aspects of AD that are largely stereotyped and those that are heterogeneous, and we review the evidence supporting the concept that different subtypes of AD are important to consider in the design of agents for the prevention and treatment of the disease. We then dive into the multifaceted biological domains implicated to date in AD risk, highlighting studies of the diverse genetic drivers of disease. Finally, we explore recent efforts to identify biological subtypes of AD, with an emphasis on the experimental systems and data sets available to support progress in this area.

Cell-type-specific regulation of APOE levels in human neurons by the Alzheimer's disease risk gene SORL1.

SORL1 is strongly implicated in the pathogenesis of Alzheimer's disease (AD) through human genetic studies that point to an association of reduced SORL1 levels with higher risk for AD. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null iPSCs were generated, followed by differentiation to neuron, astrocyte, microglia, and endothelial cell fates. Loss of SORL1 led to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. Intriguingly, SORL1 loss led to a dramatic neuron-specific reduction in APOE levels. Further, analyses of iPSCs derived from a human aging cohort revealed a neuron-specific linear correlation between SORL1 and APOE RNA and protein levels, a finding validated in human post-mortem brain. Pathway analysis implicated intracellular transport pathways and TGF- ß/SMAD signaling in the function of SORL1 in neurons. In accord, enhancement of retromer-mediated trafficking and autophagy rescued elevated phospho-tau observed in SORL1 null neurons but did not rescue APOE levels, suggesting that these phenotypes are separable. Stimulation and inhibition of SMAD signaling modulated APOE RNA levels in a SORL1-dependent manner. These studies provide a mechanistic link between two of the strongest genetic risk factors for AD.

Can chronic kidney disease staging early predict outcome of large-artery ischemic stroke with impaired renal function?

Background: Ischemic stroke poses a major threat to human beings, and a prompt intravenous thrombolytic management remains the gold standard protocol for stroke sufferers. Although the role of thrombolytic therapy (r-tPA) for ischemic stroke patients and those with underlying impaired renal function has been advocated as effective treating strategy, there is still a lack of investigation as to finding out baseline important variables that are capable of early outcome prediction. Objectives: In this project, we hypothesize that the change of clinical chronic kidney disease (CKD) staging (delta stage = CKD stage after 3-month follow-up - CKD stage at admission) could serve as a crucial predictor of the prognosis of patients. Design: This is a cohort longitudinal retrospective study. Sources and Methods: A total of 765 cerebral artery ischemic stroke patients with impaired renal function were recruited and followed up for 1 year. Among them, 116 had received the thrombolytic treatment (r-tPA) after being evaluated at the triage in the emergency department and the rest had not (non-r-tPA). Propensity-matching was applied to compare the mortality between the r-tPA and non-r-tPA groups. Multiple logistic regression (LR) and decision tree (DT) algorithm were used to identify important prediction factors for mortality as well as the improvement in neurological function. Results: The 1-year mortality rates for r-tPA and non-r-tPA groups were 32.8% and 44.4%, respectively. The propensity-matched odds ratio of mortality for the r-tPA group compared with the non-r-tPA group is 0.469, with p = 0.003. Logistic regressions suggest that age, Hct, diabetes mellitus type 2, coronary artery disease, and delta stage are important factors for mortality for the non-r-tPA group, whereas age, diabetes mellitus type 2, chronic heart failure, hospital day, and delta stage are important factors for the r-tPA group. On the usage of antihypertensive drugs, ACEI/ARB was not associated with mortality (p = 0.198), whereas the diuretic was, with odds ratio at 1.619 (p = 0.025), indicating higher mortality after administration. Both LR and DT analyses indicate that delta stage is the most important predictor. For the r-tPA group, patients with delta stage ⩽0 had a 24% mortality, while that for delta stage >0 the mortality is 75%. For non-r-tPA patients, the corresponding mortalities were 30.9 and 66.3, respectively. Delta stage is also useful for predicting patients' improvement of neurological function, assessed by NIHSS, mRS, and Barthel Index. The areas under the curve for the three assessments are 0.83, 0.835, and 0.663, respectively. Conclusion: Large-artery ischemic stroke patients who received thrombolytic treatment had significantly lower mortality, even when presenting underlying impaired renal function. The change of CKD staging (delta stage) is capable of acting as a powerful clinical baseline surrogate for both r-tPA and non-r-tPA patients in terms of early outcome prediction. Long-term use of diuretics could be potentially harmful to this group of patients. Moreover, delta stage correlates well with clinical long-term neurological functionality assessment (NIHSS, mRS, and Barthel index), which is helpful in aiding urgent clinical decision-making.

Plasma extracellular vesicle tau, ß-amyloid, and α-synuclein and the progression of Parkinson's disease: a follow-up study.

Background: Plasma extracellular vesicle (EV) contents are promising biomarkers of Parkinson's disease (PD). The pathognomonic proteins of PD, including α-synuclein, tau, and ß-amyloid, are altered in people with PD (PwP) and are associated with clinical presentation in previous cross-sectional studies. However, the dynamic changes in these plasma EV proteins in PwP and their correlation with clinical progression remain unclear. Objective: We investigated the dynamic changes in plasma EV α-synuclein, tau, and ß-amyloid and their correlation with/prediction of clinical progression in PwP. Design: A cohort study. Methods: In total, 103 PwP and 37 healthy controls (HCs) completed baseline assessment and 1-year follow-up. Clinical assessments included Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III, Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA). Plasma EVs were isolated, and immunomagnetic reduction-based immunoassay was used to assess α-synuclein, tau, and ß-amyloid 1-42 (Aß1-42) levels within the EVs. Results: Compared with HCs, significant differences were noted in the annual changes in all three EV pathognomonic proteins in PwP. Although the absolute changes in plasma EV pathognomonic proteins did not significantly correlate with clinical changes, PwP with elevated baseline plasma EV tau (upper-half) levels demonstrated significantly greater decline in motor and cognition, and increased plasma EV α-synuclein levels were associated with postural instability and the gait disturbance motor subtype. For PwP with elevated levels of all three biomarkers, clinical deterioration was significant, as indicated by UPDRS-II scores, postural instability and gait disturbance subscores of UPDRS-III, and MMSE score. Conclusion: The combination of plasma EV α-synuclein, tau, and Aß1-42 may identify PwP with a high risk of deterioration. Our findings can elucidate the interaction between these pathognomonic proteins, and they may serve as treatment response markers and can be applied in treatment approaches for disease modification.

Endothelial Dysfunction in Neurodegenerative Diseases.

The cerebral vascular system stringently regulates cerebral blood flow (CBF). The components of the blood-brain barrier (BBB) protect the brain from pathogenic infections and harmful substances, efflux waste, and exchange substances; however, diseases develop in cases of blood vessel injuries and BBB dysregulation. Vascular pathology is concurrent with the mechanisms underlying aging, Alzheimer's disease (AD), and vascular dementia (VaD), which suggests its involvement in these mechanisms. Therefore, in the present study, we reviewed the role of vascular dysfunction in aging and neurodegenerative diseases, particularly AD and VaD. During the development of the aforementioned diseases, changes occur in the cerebral blood vessel morphology and local cells, which, in turn, alter CBF, fluid dynamics, and vascular integrity. Chronic vascular inflammation and blood vessel dysregulation further exacerbate vascular dysfunction. Multitudinous pathogenic processes affect the cerebrovascular system, whose dysfunction causes cognitive impairment. Knowledge regarding the pathophysiology of vascular dysfunction in neurodegenerative diseases and the underlying molecular mechanisms may lead to the discovery of clinically relevant vascular biomarkers, which may facilitate vascular imaging for disease prevention and treatment.

Mitochondrial Factor C20orf7 Facilitates the EMT-Mediated Cancer Cell Migration and the Proliferation of Colon Cancer In Vitro and In Vivo.

Colon cancer is a major malignant neoplasm with a low survival rate for late-stage patients. Therefore, the investigation of molecules regulating colon cancer progression and the discovery of novel therapeutic targets is critical. Mitochondria play a vital role in maintaining the homeostasis of cells. Abnormal mitochondrial metabolism alterations and the induction of glycolysis can facilitate tumor growth; therefore, targeting mitochondrial molecules is suggested to be a promising strategy for cancer treatment. In this study, we investigated the role of this largely unknown mitochondrial factor, chromosome 20 open reading frame 7 (C20orf7), in colon cancer progression. Clustered regularly interspaced short palindromic repeats (CRISPR) technology was utilized for C20orf7 depletion, and functional assays were performed to examine the regulation of C20orf7 in colon cancer cells. We demonstrated that C20orf7 facilitates epithelial-mesenchymal transition (EMT)-mediated cell migration and promotes the proliferation of colon cancer. The anti-cancer drug 5-fluorouracil (5FU) was also applied, and C20orf7 was targeted with a combination of 5FU treatment, which could further enhance the anti-cancer effect in the colon cancer cell line and the xenograft mice model. In summary, this study demonstrated, for the first time, that C20orf7 plays a promotional role in cancer tumorigenesis and could be a promising therapeutic target in colon cancer treatment.

Clinical Trials of New Drugs for Vascular Cognitive Impairment and Vascular Dementia.

Population aging has challenged the treatment of cognitive impairment or dementia. Vascular dementia is the second leading cause of dementia after Alzheimer's disease. Cognitive consequences after ischemic brain injury have been recognized as a preferred target for therapeutic strategies, prompting the search for potential agents. The keyword "vascular dementia" was used to search ClinicalTrials.gov to determine agents represented in phases I, II, III, and IV. The agents were classified on the basis of their mechanisms. Of the 17 randomized controlled trials meeting our inclusion criteria, 9 were completed in the past 10 years, and 8 are ongoing or in the planning stages. We also identified one trial in phase I, nine in phase II, six in phase III, and one in phase IV. Fewer trials of new drugs for improving cognition or ameliorating the behavioral and psychological symptoms of dementia target vascular dementia than Alzheimer's dementia. Drug trials on vascular dementia overlap with drug trials targeting functional outcomes in cerebrovascular disease. International pharmaceutical companies' investment in new drugs targeting VCI and vascular dementia remains insufficient.

Elevated ganglioside GM2 activator (GM2A) in human brain tissue reduces neurite integrity and spontaneous neuronal activity.

BACKGROUND: Alzheimer's Disease (AD) affects millions globally, but therapy development is lagging. New experimental systems that monitor neuronal functions in conditions approximating the AD brain may be beneficial for identifying new therapeutic strategies. METHODS: We expose cultured neurons to aqueous-soluble human brain extract from 43 individuals across a spectrum of AD pathology. Multi-electrode arrays (MEAs) and live-cell imaging were used to assess neuronal firing and neurite integrity (NI), respectively, following treatments of rat cortical neurons (MEA) and human iPSC-derived neurons (iN) with human brain extracts. RESULTS: We observe associations between spontaneous activity and Aß42:40 levels, between neurite integrity and oligomeric Aß, and between neurite integrity and tau levels present in the brain extracts. However, these associations with Aß and tau do not fully account for the effects observed. Proteomic profiling of the brain extracts revealed additional candidates correlated with neuronal structure and activity. Neurotoxicity in MEA and NI assays was associated with proteins implicated in lysosomal storage disorders, while neuroprotection was associated with proteins of the WAVE regulatory complex controlling actin cytoskeleton dynamics. Elevated ganglioside GM2 activator (GM2A) associates with reductions in both NI and MEA activity, and cell-derived GM2A alone is sufficient to induce a loss of neurite integrity and a reduction in neuronal firing. CONCLUSIONS: The techniques and data herein introduce a system for modeling neuronal vulnerability in response to factors in the human brain and provide insights into proteins potentially contributing to AD pathogenesis.

Association of AK4 Protein From Stem Cell-Derived Neurons With Cognitive Reserve: An Autopsy Study.

BACKGROUND AND OBJECTIVES: Identifying protein targets that provide cognitive reserve is a strategy to prevent and treat Alzheimer disease and Alzheimer disease related dementias (AD/ADRD). Previous studies using bulk human brain tissue reported 12 proteins associated with cognitive reserve. This study examined whether the same proteins from induced neurons (iNs) are associated with cognitive reserve of their human donors. METHODS: Induced pluripotent stem cell (iPSC) lines were generated from cryopreserved peripheral blood mononuclear cells of older adults who were autopsied as part of the Religious Orders Study or Rush Memory and Aging Project. Neurons were induced from iPSCs using a standard neurogenin2 protocol. Tandem mass tag proteomics analyses were conducted on iNs day 21. Cognitive reserve of their human donors was measured as person-specific slopes of cognitive change not accounted for by common neuropathologies. RESULTS: The 53 human donors died at a mean age of 91 years, all were non-Latino White, and 36 (67.9%) were female. Eighteen were diagnosed with Alzheimer dementia proximate to death, and 34 had pathologic AD diagnosis at autopsy. Approximately 60% of the donors had above-average cognitive reserve such that their cognition declined slower than an average person with comparable burdens of neuropathologies. Eight of the 12 candidate proteins were quantified in iNs proteomics analyses. Higher adenylate kinase 4 (AK4) expression in iNs was associated with lower cognitive reserve, consistent with the previous report for brain AK4 expression. DISCUSSION: By replicating cortical protein associations with cognitive reserve in human iNs, these data provide a valuable molecular readout for studying complex clinical phenotypes such as cognitive reserve in a dish.

Timing of symptomatic subsequent vertebral compression fracture associated with different demographic factors.

BACKGROUND: Symptomatic subsequent vertebral compression fracture (VCF; SVCF) is a common complication associated with poor outcomes. Accumulating evidence shows that demographic factors and incidences of symptomatic SVCFs differ during different periods after the primary vertebroplasty (VP). PURPOSE: To investigate the incidence and demographic factors of symptomatic SVCFs after the primary VP in different periods using registry data in the Taiwan National Health Insurance Research Database. METHODS: This retrospective cohort study included 28,343 patients aged ≥ 50 years with painful VCF treated with VP from 2002 to 2016. Symptomatic SVCF was defined as SVCF requiring another VP or re-admission. During the 2-year follow-up, 1955 patients received subsequent VP while 1,407 were readmitted. Cox proportional hazard models were used to compare the risks of subsequent VP or readmission. RESULTS: The cumulative incident rate of subsequent VP and re-hospitalization was 0.87 [95% confidence interval (CI), 0.82 ~ 0.92] and 0.62 (95% CI, 0.58 ~ 0.66) per 100 person-months, respectively, within the first 6 months after the primary VP, and it decreased over time. A multiple Cox regression model showed that age, osteopenia or osteoporosis, Charlson comorbidity index (CCI) were significant independent risk factors of subsequent VP or readmission within the first 6 months. CONCLUSIONS: This study demonstrated that the incidence of symptomatic SVCF peaked in the first 6 months after the primary VP. Age, osteoporosis or osteopenia, and CCI were determined to be risk factors in the first 6 months, but only osteoporosis or osteopenia and CCI were risk factors thereafter.

Exploring the Causal Effect of Constipation on Parkinson's Disease Through Mediation Analysis of Microbial Data.

Background and Aims: Parkinson's disease (PD) is a worldwide neurodegenerative disease with an increasing global burden, while constipation is an important risk factor for PD. The gastrointestinal tract had been proposed as the origin of PD in Braak's gut-brain axis hypothesis, and there is increasing evidence indicating that intestinal microbial alteration has a role in the pathogenesis of PD. In this study, we aim to investigate the role of intestinal microbial alteration in the mechanism of constipation-related PD. Methods: We adapted our data from Hill-Burns et al., in which 324 participants were enrolled in the study. The 16S rRNA gene sequence data were processed, aligned, and categorized using DADA2. Mediation analysis was used to test and quantify the extent by which the intestinal microbial alteration explains the causal effect of constipation on PD incidence. Results: We found 18 bacterial genera and 7 species significantly different between groups of constipated and non-constipated subjects. Among these bacteria, nine genera and four species had a significant mediation effect between constipation and PD. All of them were short-chain fatty acid (SCFA)-producing bacteria that were substantially related to PD. Results from the mediation analysis showed that up to 76.56% of the effect of constipation on PD was mediated through intestinal microbial alteration. Conclusion: Our findings support that gut dysbiosis plays a critical role in the pathogenesis of constipation-related PD, mostly through the decreasing of SCFA-producing bacteria, indicating that probiotics with SCFA-producing bacteria may be promising in the prevention and treatment of constipation-related PD. Limitations: 1) Several potential confounders that should be adjusted were not provided in the original dataset. 2) Our study was conducted based on the assumption of constipation being the etiology of PD; however, constipation and PD may mutually affect each other. 3) Further studies are necessary to explain the remaining 23.44% effect leading to PD by constipation.

Green Polymer Electrolytes Based on Polycaprolactones for Solid-State High-Voltage Lithium Metal Batteries.

Solid polymer electrolytes (SPEs) have attracted considerable attention for high energy solid-state lithium metal batteries (LMBs). In this work, potentially ecofriendly, solid-state poly(ε-caprolactone) (PCL)-based star polymer electrolytes with cross-linked structures (xBt-PCL) are introduced that robustly cycle against LiNi0.6 Mn0.2 Co0.2 O2 (NMC622) composite cathodes, affording long-term stability even at higher current densities. Their superior features allow for sufficient suppression of dendritic lithium deposits, as monitored by 7 Li solid-state NMR. Advantageous electrolyte|electrode interfacial properties derived from cathode impregnation with 1.5 wt% PCL enable decent cell performance until up to 500 cycles at rates of 1C (60 °C), illustrating the high potential of PCL-based SPEs for application in high-voltage LMBs.

Plasma Phosphorylated-tau181 Is a Predictor of Post-stroke Cognitive Impairment: A Longitudinal Study.

Introduction: Post-stroke cognitive impairment (PSCI) cannot be neglected because it drastically influences the daily life of patients and their families. However, there are no studies exploring the association between preclinical blood biomarkers of neurodegeneration including plasma amyloid-ß (Aß), tau, and brain-derived neurotrophic factor (BDNF) together with the risk of PSCI. This longitudinal study was to investigate whether these blood biomarkers with imaging markers of cerebral small vessel disease can improve the prediction for PSCI. In addition, we also explored the association between blood biomarkers with the trajectories of PSCI. Methods: Adult patients with first-ever acute ischemic stroke were recruited, and the cognitive and functional abilities of these patients were evaluated. Furthermore, blood biomarkers of neurodegeneration including plasma Aß-40, Aß-42, total tau, phosphorylated tau 181 (p-tau181), and BDNF levels and image markers of cerebral small vessel disease were measured. Each patient was followed up at 3 and 12 months at the outpatient department. Results: Of 136 patients, 40 and 50 patients developed PSCI at 3 and 12 months after stroke, respectively. In functional trajectories, 27 patients did not have PSCI at 3 months but did at 12 months. By contrast, the PSCI status of 17 patients at 3 months was reversed at 12 months. Patients with high-acute plasma p-tau181 had a significantly lower PSCI risk at 3 months (odds ratio [OR] = 0.62, 95% CI = 0.40-0.94, p = 0.0243) and 12 months (OR = 0.69, 95% CI = 0.47-0.99, p = 0.0443) after adjustment for covariates and image biomarkers. Discrimination and reclassification statistics indicated that the p-tau181 level can improve discrimination ability for PSCI at 3 and 12 months, respectively. In addition, the plasma p-tau181 level was the highest in subjects without PSCI followed by those with delayed-onset PSCI and early-onset PSCI with reversal, whereas the lowest plasma p-tau181 level was found among those with persistent PSCI, showing a significant trend test (p = 0.0081). Conclusion: Plasma p-tau181 is a potential biomarker for predicting early- and delayed-onset PSCI. Future studies should incorporate plasma p-tau181 as an indicator for timely cognitive intervention in the follow-up of patients with stroke.

A Pilot Study Exploring the Association of Entacapone, Gut Microbiota, and the Subsequent Side Effects in Patients With Parkinson's Disease.

Background and Aims: Entacapone, one of the most common drugs distributed among patients with Parkinson's disease, is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor that is used in addition to levodopa to control symptoms. However, there have been negative effects reported against entacapone, namely, gastrointestinal (GI) problems and drowsiness. In this pilot study, we aim to examine the hypothesis that the discomfort induced by entacapone might be originated from the shift of microbial composition by adjusting the effect of levodopa. Methods: The population in this pilot study consisted of 13 PD patients treated with levodopa only and 11 with both levodopa and entacapone. The 16S rRNA gene sequence data were processed, aligned, and categorized using the DADA2. Alpha diversity indices for Observed, Chao1, Shannon, and Simpson metrics were calculated with Phyloseq 1.32.0. Dissimilarities were calculated using unweighted unique fraction metrics (Unifrac), weighted Unifrac, and Canberra distance. Functional differences were calculated by PICRUSt2 based on the KEGG database. Results: Results of 16S rRNA sequencing analysis showed that while entacapone did not influence the species richness, the composition of the microbial community shifted considerably. Relative abundances of bacteria related to constipation and other GI disorders also altered significantly. Functional enrichment analysis revealed changes in the metabolic activity of alanine, aspartate, and glutamate. These amino acids are related to common side effects of entacapone such as auditory hallucinations, fatigue, and nightmare. Conclusion: Our findings provide testable hypothesis on the cause of unpleasant side effects of entacapone, which in the long run could possibly be reduced through gut microbiota manipulation.

APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer's pathology in trisomy 21 neurons.

Trisomy 21 (T21) causes Down syndrome and an early-onset form of Alzheimer's disease (AD). Here, we used human induced pluripotent stem cells (hiPSCs) along with CRISPR-Cas9 gene editing to investigate the contribution of chromosome 21 candidate genes to AD-relevant neuronal phenotypes. We utilized a direct neuronal differentiation protocol to bypass neurodevelopmental cell fate phenotypes caused by T21 followed by unbiased proteomics and western blotting to define the proteins dysregulated in T21 postmitotic neurons. We show that normalization of copy number of APP and DYRK1A each rescue elevated tau phosphorylation in T21 neurons, while reductions of RCAN1 and SYNJ1 do not. To determine the T21 alterations relevant to early-onset AD, we identified common pathways altered in familial Alzheimer's disease neurons and determined which of these were rescued by normalization of APP and DYRK1A copy number in T21 neurons. These studies identified disruptions in T21 neurons in both the axonal cytoskeletal network and presynaptic proteins that play critical roles in axonal transport and synaptic vesicle cycling. These alterations in the proteomic profiles have functional consequences: fAD and T21 neurons exhibit dysregulated axonal trafficking and T21 neurons display enhanced synaptic vesicle release. Taken together, our findings provide insights into the initial molecular alterations within neurons that ultimately lead to synaptic loss and axonal degeneration in Down syndrome and early-onset AD.