Associations of liver dysfunction with incident dementia, cognition, and brain structure: A prospective cohort study of 431 699 adults.

The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross-sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow-up were included from the UK Biobank; 5542 all-cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; PFDR <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; PFDR = 0.010), AST to ALT ratio (HR, 1.195; PFDR <0.001), gamma-glutamyl transpeptidase (GGT; HR, 1.066; PFDR <0.001), alcoholic liver disease (ALD; HR, 2.872; PFDR <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; PFDR = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U-shaped association between Alb and AST and incident ACD (Pnonlinear <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver (PFDR <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (PFDR <0.05). In sensitivity analysis, metabolic dysfunction-associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence.

Associations between liver function and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in non-demented adults: The CABLE study.

Liver function has been suggested as a possible factor in the progression of Alzheimer's disease (AD) development. However, the association between liver function and cerebrospinal fluid (CSF) levels of AD biomarkers remains unclear. In this study, we analyzed the data from 1687 adults without dementia from the Chinese Alzheimer's Biomarker and LifestylE study to investigate differences in liver function between pathological and clinical AD groups, as defined by the 2018 National Institute on Aging-Alzheimer's Association Research Framework. We also examined the linear relationship between liver function, CSF AD biomarkers, and cognition using linear regression models. Furthermore, mediation analyses were applied to explore the potential mediation effects of AD pathological biomarkers on cognition. Our findings indicated that, with AD pathological and clinical progression, the concentrations of total protein (TP), globulin (GLO), and aspartate aminotransferase/alanine transaminase (ALT) increased, while albumin/globulin (A/G), adenosine deaminase, alpha-L-fucosidase, albumin, prealbumin, ALT, and glutamate dehydrogenase (GLDH) concentrations decreased. Furthermore, we also identified significant relationships between TP (ß = -0.115, pFDR < 0.001), GLO (ß = -0.184, pFDR < 0.001), and A/G (ß = 0.182, pFDR < 0.001) and CSF ß-amyloid1-42 (Aß1-42 ) (and its related CSF AD biomarkers). Moreover, after 10 000 bootstrapped iterations, we identified a potential mechanism by which TP and GLDH may affect cognition by mediating CSF AD biomarkers, with mediation effect sizes ranging from 3.91% to 16.44%. Overall, our results suggested that abnormal liver function might be involved in the clinical and pathological progression of AD. Amyloid and tau pathologies also might partially mediate the relationship between liver function and cognition. Future research is needed to fully understand the underlying mechanisms and causality to develop an approach to AD prevention and treatment approach.

Amyloid pathology mediates the associations between plasma fibrinogen and cognition in non-demented adults.

Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aß42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aß42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aß42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aß pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aß pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aß pathology. Fibrinogen was associated with both cognition and Aß pathology. Aß pathology may be a critical mediator for impacts of fibrinogen on cognition.

Anti-synthase syndrome associated with SARS-Cov-2 infection.

BACKGROUND: Anti-synthetase syndrome (AS) is a rare autoimmune idiopathic inflammatory myopathy (IIM) with diverse manifestations, including arthritis, interstitial lung disease (ILD), Raynaud's phenomenon, unexplained persistent fever, and mechanic's hands. CASE PRESENTATION: We present the case of a 72-year-old woman, previously healthy, who was admitted to our hospital for treatment of cough and rapid breathing. The patient had elevated white blood cells and C-reactive protein, and tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). She was initially diagnosed with community-acquired pneumonia and received tamoxifen for anti-infection treatment, but her dystonia worsened. She eventually required non-invasive ventilator support, tested positive for SARS-Cov-2 again, and started antiviral therapy, corticosteroids to reduce alveolar effusion, anticoagulation, and other treatments. However, her condition continued to deteriorate, with the lowest oxygenation index reaching only 80mmHg. Ultimately, she underwent tracheal intubation and mechanical ventilation. Chest CT revealed rapid progressive interstitial changes in her lungs, and her hands showed noticeable fraternization changes. At this point, we suspected that the novel coronavirus infection might be associated with autoimmune diseases. The patient's autoimmune antibody spectrum showed positive results for anti-recombinant RO-52 antibody and myositis-specific antibody anti-alanyl tRNA synthetase (anti-PL-12). The patient was treated with dexamethasone sodium phosphate for anti-inflammatory and anti-fibrotic effects. After successful extubation, the patient was discharged with only oral prednisone tablets at a dose of 30 mg. CONCLUSIONS: This case presents an early diagnosis and successful treatment of anti-synthetase syndrome combined with SARS-Cov-2 infection, emphasizing the importance of comprehensive physical examination. Additionally, it highlights the rapid progression of interstitial lung disease under SARS-Cov-2 infection, which is often difficult to distinguish on imaging. In cases where treatment for SARS-Cov-2 infection is ineffective, early screening for autoimmune diseases is recommended. As there is currently no standardized method for treating AS-ILD, the successful treatment of this case provides a reference for clinical research on anti-synthetase syndrome in the later stage.

Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy.

INTRODUCTION: To examine the extent to which positron emission tomography (PET)-, cerebrospinal fluid (CSF)-, and plasma-related amyloid-ß/tau/neurodegeneration (A/T/N) biomarkers are associated with Alzheimer's disease (AD) neuropathology at autopsy. METHODS: A total of 100 participants who respectively underwent antemortem biomarker measurements and postmortem neuropathology were included in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We examined the associations of PET-, CSF-, and plasma-related A/T/N biomarkers in combinations or alone with AD neuropathological changes (ADNC). RESULTS: PET- and CSF-related A/T/N biomarkers in combination showed high concordance with the ADNC stage and alone showed high accuracy in discriminating autopsy-confirmed AD. However, the plasma-related A/T/N biomarkers alone showed better discriminative performance only when combined with apolipoprotein E (APO)E ε4 genotype. DISCUSSION: This study supports that PET- and CSF-related A/T/N profiles can be used to predict accurately the stages of AD neuropathology. For diagnostic settings, PET-, CSF-, and plasma-related A/T/N biomarkers are all useful diagnostic tools to detect the presence of AD neuropathology. HIGHLIGHTS: PET- and CSF-related A/T/N biomarkers in combination can accurately predict the specific stages of AD neuropathology. PET- and CSF-related A/T/N biomarkers alone may serve as a precise diagnostic tool for detecting AD neuropathology at autopsy. Plasma-related A/T/N biomarkers may need combined risk factors when used as a diagnostic tool. Aß PET and CSF p-tau181/Aß42 were most consistent with Aß pathology, while tau PET and CSF p-tau181/Aß42 were most consistent with tau pathology.

Differences between ante mortem Alzheimer's disease biomarkers in predicting neuropathology at autopsy.

INTRODUCTION: This study aimed to assess whether biomarkers related to amyloid, tau, and neurodegeneration can accurately predict Alzheimer's disease (AD) neuropathology at autopsy in early and late clinical stages. METHODS: We included 100 participants who had ante mortem biomarker measurements and underwent post mortem neuropathological examination. Based on ante mortem clinical diagnosis, participants were divided into non-dementia and dementia, as early or late clinical stages. RESULTS: Amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) amyloid beta (Aß)42/phosphorylated tau (p-tau)181 showed excellent performance in differentiating autopsy-confirmed AD and predicting the risk of neuropathological changes in early and late clinical stages. However, CSF Aß42 performed better in the early clinical stage, while CSF p-tau181, CSF t-tau, and plasma p-tau181 performed better in the late clinical stage. DISCUSSION: Our findings provide important clinical information that, if using PET, CSF, and plasma biomarkers to detect AD pathology, researchers must consider their differential performances at different clinical stages of AD. HIGHLIGHTS: Amyloid PET and CSF Aß42/p-tau181 were the most promising candidate biomarkers for predicting AD pathology. CSF Aß42 can serve as a candidate predictive biomarker in the early clinical stage of AD. CSF p-tau181, CSF t-tau, and plasma p-tau181 can serve as candidate predictive biomarkers in the late clinical stage of AD. Combining APOE ε4 genotypes can significantly improve the predictive accuracy of AD-related biomarkers for AD pathology.

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial.

BACKGROUND: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. METHODS: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. RESULTS: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups. CONCLUSIONS: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. TRIAL REGISTRATION: ISRCTN, ISRCTN12233792 . Registered November 20th, 2017.

Macrophage Lxrα reduces atherosclerosis in Ldlr-/- mice independent of Arl7 transactivation.

BACKGROUND: Liver X receptor alpha (Lxrα) is a sterol-regulated transcription factor that limits atherogenesis by regulating cholesterol homeostasis and inflammation in macrophages. Transcriptional profiling identified the reverse cholesterol transport protein Arf-like 7 (Arl7, Arl4c) as a Lxrα target gene. We hypothesized that the LXR response element (LXRE) sequence on the murine macrophage Arl7 promoter may play a critical role in Lxrα's atherosuppressive effects. METHODS: Employing low density lipoprotein receptor-deficient mice with macrophage-specific Lxrα overexpression (Ldlr-/- MΦ-Lxrα), we constructed a novel in vivo Ldlr-/- MΦ-Lxrα Arl7MutLXRE model possessing macrophage-specific mutations within the Arl7 promoter LXRE sequences (Arl7MutLXRE) using the CRISPR/spCas9 genome editing technique. In vitro and in vivo transplantation studies were conducted using bone marrow-derived macrophages (BMDMs) and peritoneal macrophages (PMs). RESULTS: Ldlr-/-, Ldlr-/- MΦ-Lxrα, and Ldlr-/- MΦ-Lxrα Arl7MutLXRE mice on a 60% high-fat diet displayed no significant differences in body weight, fat mass, glucose homeostasis, or lipid metabolism. Macrophage Lxrα promoted Arl7 expression, enhanced cholesterol efflux, and reduced foam cell formation in an Arl7 LXRE-dependent manner. In contrast, Lxrα reduced macrophage activation, inflammatory cytokine expression, and efferocytosis independent of Arl7 LXRE. Western diet-fed Ldlr-/- mice reconstituted with transgenic BMDMs revealed that macrophage Lxrα reduced atherosclerotic plaque formation independent of Arl7 LXRE. CONCLUSION: Lxrα's anti-atherosclerotic effects in Ldlr-/- mice are not primarily attributable to Lxrα's influence on Arl7 expression. This evidence suggests that Lxrα's effects on plaque inflammation may be more critical to in vivo atherogenesis than its effects on macrophage cholesterol efflux and foam cell development.

Protein and mRNA Delivery Enabled by Cholesteryl-Based Biodegradable Lipidoid Nanoparticles.

Developing safe and efficient delivery systems for therapeutic biomacromolecules is a long-standing challenge. Herein, we report a newly developed combinatorial library of cholesteryl-based disulfide bond-containing biodegradable cationic lipidoid nanoparticles. We have identified a subset of this library which is effective for protein and mRNA delivery in vitro and in vivo. These lipidoids showed comparable transfection efficacies but much lower cytotoxicities compared to the Lpf2k in vitro. In vivo studies in adult mice demonstrated the successful delivery of genome engineering protein and mRNA molecules in the skeletal muscle (via intramuscular injection), lung and spleen (via intravenous injection), and brain (via lateral ventricle infusion).

Preventive effect on endothelial surface layer damage of Fusu agent in LPS-induced acute lung injury in rats.

Acute lung injury (ALI) is one of major causes of morbidity and mortality in intensive care. In pathophysiological events of ALI, endothelial surface layer (ESL) injury can result in capillary leakage as the initial event. The "Fusu agent", a traditional Chinese medicine, can inhibit inflammatory factors, attenuate lung capillary leak as seen in our previous study. This study was aimed to explore the molecular mechanism of Fusu agent treatment with ALI. Consistent with previous studies, we found that Fusu agent has the protective effect on LPS-induced ALI model rats. Further investigation demonstrated that heparanase activation is necessary for the LPS-induced ALI model to aggravate ESL loss. Fusu agent can inhibit heparanase activation and heparan sulfate proteoglycans' (HSPGs) degradation to mitigate the ESL injury. Furthermore, TNF-α and intercellular adhesion molecule-1 (ICAM-1) were significantly reduced upon Fusu agent pre-treatment to inhibit inflammatory cell influx and neutrophil adhesion in ALI. These findings shed light on the pharmacologic basis for the clinical application of traditional Chinese medicine in treating ALI.

Enteral nutrition feeding in Chinese intensive care units: a cross-sectional study involving 116 hospitals.

BACKGROUND: There is a lack of large-scale epidemiological data on the clinical practice of enteral nutrition (EN) feeding in China. This study aimed to provide such data on Chinese hospitals and to investigate factors associated with EN delivery. METHODS: This cross-sectional study was launched in 118 intensive care units (ICUs) of 116 mainland hospitals and conducted on April 26, 2017. At 00:00 on April 26, all patients in these ICUs were included. Demographic and clinical variables of patients on April 25 were obtained. The dates of hospitalization, ICU admission and nutrition initiation were reviewed. The outcome status 28 days after the day of investigation was obtained. RESULTS: A total of 1953 patients were included for analysis, including 1483 survivors and 312 nonsurvivors. The median study day was day 7 (IQR 2-19 days) after ICU entry. The proportions of subjects starting EN within 24, 48 and 72 h after ICU entry was 24.8% (84/352), 32.7% (150/459) and 40.0% (200/541), respectively. The proportion of subjects receiving > 80% estimated energy target within 24, 48, 72 h and 7 days after ICU entry was 10.5% (37/352), 10.9% (50/459), 11.8% (64/541) and 17.8% (162/910), respectively. Using acute gastrointestinal injury (AGI) 1 as the reference in a Cox model, patients with AGI 2-3 were associated with reduced likelihood of EN initiation (HR 0.46, 95% CI 0.353-0.599; p < 0.001). AGI 4 was significantly associated with lower hazard of EN administration (HR 0.056; 95% CI 0.008-0.398; p = 0.004). In a linear regression model, greater Sequential Organ Failure Assessment scores (coefficient - 0.002, 95% CI - 0.008 to - 0.001; p = 0.024) and male gender (coefficient - 0.144, 95% CI - 0.203 to - 0.085; p < 0.001) were found to be associated with lower EN proportion. As compared with AGI 1, AGI 2-3 was associated with lower EN proportion (coefficient - 0.206, 95% CI - 0.273 to - 0.139; p < 0.001). CONCLUSIONS: The study showed that EN delivery was suboptimal in Chinese ICUs. More attention should be paid to EN use in the early days after ICU admission.

Association of sleep duration with excess risk of dementia among shift workers in the UK biobank: a population-based cohort study.

BACKGROUND: Shift work was associated with elevated dementia risk. Definitive guidelines for sleep duration among shift workers have not been proposed. We aimed to identify sleep durations associated with elimination of excess dementia risk in shift workers. METHODS: 285,213 dementia-free UK Biobank participants at baseline, aged 38-71 years, were enrolled between 2006 and 2010 and followed up through 2022 in this cohort study. Cox proportional hazards models were used to examine the associations between shift work, sleep duration, and risk of dementia. RESULTS: The 285,213 participants included 49,079 shift workers and 236,134 non-shift workers. Over a median follow-up of 13.8 years, 1887 dementia cases were documented. Current shift workers had significantly higher dementia risk than non-shift workers (hazard ratio [HR] 1.26; 95% CI 1.11-1.42). However, this excess risk was eliminated in shift workers with 8 h of sleep (HR 1.02; 95% CI 0.80-1.29). Analysis of shift work frequency indicated that "sometimes" and "usually/always" shift work were associated with increased dementia risk compared to that of non-shift workers, but excess dementia risk was eliminated in members of either frequency group receiving 8 h of sleep ("sometimes", HR 1.05; 95% CI 0.75-1.48; "usually/always", HR 0.98; 95% CI 0.70-1.35). Both "non-night shift" and "night shift" workers showed increased dementia risk compared to non-shift workers. Workers with 8 h of sleep mitigated the excess risk (HR 1.13; 95% CI 0.84-1.53 and HR 0.86; 95% CI 0.59-1.26, respectively). CONCLUSION: 8-h sleep may eliminate excess dementia risk among shift workers, suggesting a potentially effective dementia prevention guideline for shift workers.

ATAK complex (adrenaline, takotsubo, anaphylaxis, and kounis hypersensitivity-associated coronary syndrome) related to latamoxef administration-a case report.

Background: Adrenaline, stress cardiomyopathy, allergic reactions, and Kounis syndrome (Adrenaline, Takotsubo, Anaphylaxis, Kounis Complex, ATAK) constitute a complex clinical syndrome often associated with endogenous or exogenous adrenaline. Due to its rapid onset, severity, and treatment challenges, it warrants significant attention from clinicians. This article reports a case of Type II Kounis syndrome combined with stress cardiomyopathy (ATAK) triggered by a latamoxef-induced allergy. Case report: A 67-year-old male patient with an acute exacerbation of chronic obstructive pulmonary disease was admitted to the respiratory department for treatment. The day before discharge, after receiving a latamoxef infusion for 27 min, the patient developed wheezing, dyspnea, chills, profuse sweating, and an elevated body temperature, necessitating transfer to the ICU for monitoring and treatment. The ECG suggested a suspected myocardial infarction, while bedside echocardiography showed a left ventricular ejection fraction of 40%, segmental dysfunction of the left ventricle, and apical rounding. Emergency coronary angiography revealed 50% segmental eccentric stenosis in the mid-segment of the left anterior descending branch and right coronary artery. The final diagnosis was Type II Kounis Syndrome combined with stress cardiomyopathy due to a latamoxef-induced allergy, i.e., ATAK. Despite aggressive treatment, the patient succumbed to severe cardiogenic shock on the third day in the ICU. Conclusion: ATAK is a critical condition that progresses rapidly. For patients experiencing severe allergic reactions, monitoring biomarkers such as Troponin and ECG changes is crucial for timely recognition. If a patient is diagnosed with Kounis syndrome, caution should be exercised in using adrenaline to prevent ATAK.

Global research progress of endothelial cells and ALI/ARDS: a bibliometric analysis.

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory conditions with complex pathogenesis, in which endothelial cells (ECs) play a key role. Despite numerous studies on ALI/ARDS and ECs, a bibliometric analysis focusing on the field is lacking. This study aims to fill this gap by employing bibliometric techniques, offering an overarching perspective on the current research landscape, major contributors, and emerging trends within the field of ALI/ARDS and ECs. Methods: Leveraging the Web of Science Core Collection (WoSCC) database, we conducted a comprehensive search for literature relevant to ALI/ARDS and ECs. Utilizing Python, VOSviewer, and CiteSpace, we performed a bibliometric analysis on the corpus of publications within this field. Results: This study analyzed 972 articles from 978 research institutions across 40 countries or regions, with a total of 5,277 authors contributing. These papers have been published in 323 different journals, spanning 62 distinct research areas. The first articles in this field were published in 2011, and there has been a general upward trend in annual publications since. The United States, Germany, and China are the principal contributors, with Joe G. N. Garcia from the University of Arizona identified as the leading authority in this field. American Journal of Physiology-Lung Cellular and Molecular Physiology has the highest publication count, while Frontiers in Immunology has been increasingly focusing on this field in recent years. "Cell Biology" stands as the most prolific research area within the field. Finally, this study identifies endothelial glycocalyx, oxidative stress, pyroptosis, TLRs, NF-κB, and NLRP3 as key terms representing research hotspots and emerging frontiers in this field. Conclusion: This bibliometric analysis provides a comprehensive overview of the research landscape surrounding ALI/ARDS and ECs. It reveals an increasing academic focus on ALI/ARDS and ECs, particularly in the United States, Germany, and China. Our analysis also identifies several emerging trends and research hotspots, such as endothelial glycocalyx, oxidative stress, and pyroptosis, indicating directions for future research. The findings can guide scholars, clinicians, and policymakers in targeting research gaps and setting priorities to advance the field.

Associations of Multimorbidity with Cerebrospinal Fluid Biomarkers for Neurodegenerative Disorders in Early Parkinson's Disease: A Cross-sectional and Longitudinal Study.

OBJECT: The study aims to determine whether multimorbidity status is associated with cerebrospinal fluid (CSF) biomarkers for neurodegenerative disorders. METHODS: A total of 827 patients were enrolled from the Parkinson's Progression Markers Initiative (PPMI) database, including 638 patients with early-stage Parkinson's disease (PD) and 189 healthy controls (HCs). Multimorbidity status was evaluated based on the count of long-term conditions (LTCs) and the multimorbidity pattern. Using linear regression models, cross-sectional and longitudinal analyses were conducted to assess the associations of multimorbidity status with CSF biomarkers for neurodegenerative disorders, including α-synuclein (αSyn), amyloid-ß42 (Aß42), total tau (t-tau), phosphorylated tau (p-tau), glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL). RESULTS: At baseline, the CSF t-tau (p = 0.010), p-tau (p = 0.034), and NfL (p = 0.049) levels showed significant differences across the three categories of LTC counts. In the longitudinal analysis, the presence of LTCs was associated with lower Aß42 (ß < -0.001, p = 0.020), and higher t-tau (ß = 0.007, p = 0.026), GFAP (ß = 0.013, p = 0.022) and NfL (ß = 0.020, p = 0.012); Participants with tumor/musculoskeletal/mental disorders showed higher CSF levels of t-tau (ß = 0.016, p = 0.011) and p-tau (ß = 0.032, p = 0.044) than those without multimorbidity. CONCLUSION: Multimorbidity, especially severe multimorbidity and the pattern of mental/musculoskeletal/ tumor disorders, was associated with CSF biomarkers for neurodegenerative disorders in early-stage PD patients, suggesting that multimorbidity might play a crucial role in aggravating neuronal damage in neurodegenerative diseases.

ANU-ADRI scores, tau pathology, and cognition in non-demented adults: the CABLE study.

BACKGROUND: It has been reported that the risk of Alzheimer's disease (AD) could be predicted by the Australian National University Alzheimer Disease Risk Index (ANU-ADRI) scores. However, among non-demented Chinese adults, the correlations of ANU-ADRI scores with cerebrospinal fluid (CSF) core biomarkers and cognition remain unclear. METHODS: Individuals from the Chinese Alzheimer's Biomarker and LifestyLE (CABLE) study were grouped into three groups (low/intermediate/high risk groups) based on their ANU-ADRI scores. The multiple linear regression models were conducted to investigate the correlations of ANU-ADRI scores with several biomarkers of AD pathology. Mediation model and structural equation model (SEM) were conducted to investigate the mediators of the correlation between ANU-ADRI scores and cognition. RESULTS: A total of 1078 non-demented elders were included in our study, with a mean age of 62.58 (standard deviation [SD] 10.06) years as well as a female proportion of 44.16% (n = 476). ANU-ADRI scores were found to be significantly related with MMSE (ß = -0.264, P < 0.001) and MoCA (ß = -0.393, P < 0.001), as well as CSF t-tau (ß = 0.236, P < 0.001), p-tau (ß = 0.183, P < 0.001), and t-tau/Aß42 (ß = 0.094, P = 0.005). Mediation analyses indicated that the relationships of ANU-ADRI scores with cognitive scores were mediated by CSF t-tau or p-tau (mediating proportions ranging from 4.45% to 10.50%). SEM did not reveal that ANU-ADRI scores affected cognition by tau-related pathology and level of CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2). CONCLUSION: ANU-ADRI scores were associated with cognition and tau pathology. We also revealed a potential pathological mechanism underlying the impact of ANU-ADRI scores on cognition.

Mapping the vast landscape of multisystem complications of COVID-19: Bibliometric analysis.

Background: With the rapid global spread of COVID-19, it has become evident that the virus can lead to multisystem complications, leading to a significant increase in related publications. Bibliometrics serves as a valuable tool for identifying highly cited literature and research hotspots within specific areas. Objective: The aim of this study is to identify current research hotspots and future trends in COVID-19 complications. Methods: The dataset was obtained from the Web of Science Core Collection, covering COVID-19 complications from December 8, 2019, to October 31, 2022. Various aspects, including publication general information, authors, journals, co-cited authors, co-cited references, research hotspots, and future trends, were subjected to analysis. Visual analysis was conducted using VOSviewer, The Online Analysis Platform of Literature Metrology, and Charticulator. Results: There were 4597 articles in the study. The top three countries with the most published articles are the USA (n = 1350, 29.4 %), China (n = 765, 16.6 %), and Italy (n = 623, 13.6 %). USA and China have the closest collaborative relationship. The institute with the largest number of publications is Huazhong University of Science and Technology, followed by Harvard Medical School. Nevertheless, half of the top 10 institutes belong to the USA. "Rezaei, Nima" published 13 articles and ranked first, followed by "Yaghi, Shadi" with 12 articles and "Frontera, Jennifer" with 12 articles. The journal with the largest number of publications is "Journal of Clinical Medicine". The top 3 co-cited authors are "Zhou, Fei", "Guan, Wei-Jie", "Huang, Chaolin". The top 3 co-cited references addressed COVID-19's clinical features in China and noticed that COVID-19 patients had a wide range of complications. We also list four research hotspots. Conclusions: This study conducted a bibliometric visual analysis of the literature on COVID-19 complications and summarized the current research hotspots. This study may provide valuable insights into the complications of COVID-19.

Associations between cardiometabolic multimorbidity and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study.

BACKGROUND: Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD. METHODS: This study included 1464 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed. RESULTS: A total of 1464 individuals (mean age, 61.80 years; age range, 40-89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: ß = 0.165, P = 0.037) and neuronal injury (CSF T-tau: ß = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aß42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses. CONCLUSIONS: The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.