Outcome and safety of intracardiac echocardiography guided left atrial appendage closure within zero-fluoroscopy atrial fibrillation ablation procedures.

BACKGROUND: Simultaneous atrial fibrillation (AF) catheter ablation and left atrial appendage closure (LAAC) are sometimes recommended for both rhythm control and stroke prevention. However, the advantages of intracardiac echocardiography (ICE) guidance for this combined procedure have been scarcely reported. We aim to evaluate the clinical outcomes and safety of ICE-guided LAAC within a zero-fluoroscopy catheter ablation procedure. METHODS AND RESULTS: From April 2019 to April 2020, 56 patients with symptomatic AF underwent concomitant catheter ablation and LAAC. ICE with a multi-angled imaging protocol mimicking the TEE echo windows was used to guide LAAC. Successful radiofrequency catheter ablation and LAAC were achieved in all patients. Procedure-related adverse event rate was 3.6%. During the 12-month follow-up, 75.0% of patients became free of arrhythmia recurrences and oral anticoagulants were discontinued in 96.4% of patients. No ischemic stroke occurred despite two cases of device-related thrombosis versus an expected stroke rate of 4.8% based on the CHA2 DS2 -VASc score. The overall major bleeding events rate was 1.8%, which represented a relative reduction of 68% versus an expected bleeding rate of 5.7% based on the HAS-BLED score of the patient cohort. The incidence of iatrogenic atrial septal defect secondary to single transseptal access dropped from 57.9% at 2 months to 4.2% at 12 months TEE follow-up. CONCLUSION: The combination of catheter ablation and LAAC under ICE guidance was safe and effective in AF patients with high stroke risk. ICE with our novel protocol was technically feasible for comprehensive and systematic assessment of device implantation.

Serum human epididymis protein 4 levels in the prediction of the recurrence of atrial fibrillation after catheter ablation.

The aim of this study is to assess serum human epididymis protein 4 (HE-4) levels as a biomarker for predicting the recurrence of atrial fibrillation (AF) after catheter ablation. This was a prospective observational study that enrolled one hundred eighty-four consecutive nonvalvular AF patients (65 persistent, 119 paroxysmal) who were eligible for their first ablation. Multiple Cox proportional hazards models and Kaplan-Meier curve analyses were used to test the association between serum HE-4 levels and AF recurrence after catheter ablation. During the 12-month follow-up, we observed that 47 patients (25.5%) experienced AF recurrence. Patients were divided into tertiles of HE-4 level (T1: < 50 pmol/L; T2: ≥ 50 pmol/L). The AF recurrence rate of higher serum HE-4 level patients was significantly increased (34.6% vs 13.8%, P < 0.001). Generalized additive models were used to visually assess functional relationships between the serum HE-4 levels and the risk of AF recurrence. When stratified with serum levels as the cut-off value, Kaplan-Meier analysis showed that patients with serum HE-4 levels (> 50 pmol/L) had a significantly increased risk of AF recurrence. In addition, multivariate Cox proportional hazard modelling revealed that HE-4 (≥ 50 pmol/L) (HR 2.65; 95% CI 1.34, 5.27, P = 0.005) was independent predictors of AF recurrence. Serum HE-4 levels in patients with AF are associated with postoperative recurrence of AF, and high HE-4 levels are an independent predictor of AF recurrence after ablation.

Efficacy and Safety of Adjunctive Substrate Modification During Pulmonary Vein Isolation for Atrial Fibrillation: A Meta-Analysis.

BACKGROUND: The efficacy and safety of adjuvant substrate modification (SM; either linear ablation [LA] or complex fractionated atrial electrogram [CFAE] ablation) in addition to pulmonary vein isolation (PVI) for the treatment of symptomatic, drug-refractory atrial fibrillation (AF), have still not been clarified and need further assessment. METHOD: We systematically searched the PubMed, MEDLINE, and Cochrane databases for studies comparing PVI with adjunctive SM versus PVI alone for treatment of drug-refractory AF. RESULTS: Twenty-six (26) studies including 3,409 patients (1,975 PVI + SM; 1,434 PVI alone) were included for further analysis. Atrial fibrillation/atrial tachycardia-free survival of patients with PVI + SM was comparable with that of PVI alone (relative risk [RR], 1.06; 95% confidence interval [CI], 0.98-1.14; p = 0.143). In line with this, the primary clinical outcomes were robust, irrespective of additional LA (RR, 1.07; 95% CI, 0.97-1.18; p = 0.194) or CFAE ablation (RR, 1.04; 95% CI, 0.93-1.16; p = 0.534). Adjuvant SM is associated with longer procedural time (weighted mean difference, 20.72; 95% CI, 10.25-31.20; p = 0.0) and fluoroscopy time (weighted mean difference, 6.66; 95% CI, 1.74-11.58; p = 0.000); surprisingly, it presented similar procedure-related complications as PVI alone during AF catheter ablation (RR, 1.01; 95% CI, 0.68-1.50; p = 0.946). CONCLUSIONS: Adjuvant LA or CFAE ablation do not provide incremental benefit over PVI alone. Although substrate-based ablation markedly prolonged procedural and fluoroscopic duration, there was no evidence of increased risk of procedure-related complications.

Young Patients with Unknown Stroke and Little P Wave in ECG.

Here we report two young patients with atrial fibrillation/atrial flutter complicated with cardiogenic cerebral embolism. Electrophysiological study revealed a large area of low-voltage zone or area of electric silence in both sides of the atrium during restoration of sinus rhythm, and the echocardiogram showed loss of mechanical function of the atrium. The electrical-mechanical dysfunction of the atrium was considered to be the cause of embolic event in this type of patient who was "very low" stroke risk atrial fibrillation or atrial flutter. The idiopathic, fibrotic atrial cardiomyopathy may be underlying in these patients.

Haplodeficiency of activin receptor-like kinase 4 alleviates myocardial infarction-induced cardiac fibrosis and preserves cardiac function.

Cardiac fibrosis (CF), a repairing process following myocardial infarction (MI), is characterized by abnormal proliferation of cardiac fibroblasts and excessive deposition of extracellular matrix (ECM) resulting in inevitable resultant heart failure. TGF-ß (transforming growth factor-ß)/ALK5 (Activin receptor-like kinase 5)/Smad2/3/4 pathways have been reported to be involved in the process. Recent studies have implicated both activin and its specific downstream component ALK4 in stimulating fibrosis in non-cardiac organs. We recently reported that ALK4 is upregulated in the pressure-overloaded heart and its partial inhibition attenuated the pressure overload-induced CF and cardiac dysfunction. However, the role of ALK4 in the pathogenesis of MI-induced CF, which is usually more severe than that induced by pressure-overload, remains unknown. Here we report: 1) In a wild-type mouse model of MI, ALK4 upregulation was restricted in the fibroblasts of the infarct border zone; 2) In contrast, ALK4+/- mice with a haplodeficiency of ALK4 gene, showed a significantly attenuated CF in the border zone, with a smaller scar size, a preserved cardiac function and an improved survival rate post-MI; 3) Similarly to pressure-overloaded heart, these beneficial effects might be through a partial inactivation of the Smad3/4 pathway but not MAPK cascades; 4) The apoptotic rate of the cardiomyocytes were indistinguishable in the border zone of the wild-type control and ALK4+/- mice; 5) Cardiac fibroblasts isolated from ALK4+/- mice showed reduced migration, proliferation and ECM synthesis in response to hypoxia. These results indicate that partial inhibition of ALK4 may reduce MI-induced CF, suggesting ALK4 as a novel target for inhibition of unfavorable CF and for preservation of LV systolic function induced by not only pressure-overload but also MI.

Role of contact force-guided radiofrequency catheter ablation for treatment of atrial fibrillation: A systematic review and meta-analysis.

INTRODUCTION: CF-sensing catheter emerged as a novel ablation technology and was increasingly used in clinical practice. Nonetheless, available evidence of efficacy and safety comparison between CF-guided RF catheter ablation and non-CF-guided ablation for treatment of AF was still lacking. METHODS AND RESULTS: Twenty-two eligible studies were included after systematic review through the MEDLINE, Google Scholar, the Cochrane Library and PubMed databases. AF/atrial tachycardia-free survival was markedly improved in CF-guided catheter ablation compared with non-CF-guided ablation at a median 12-month follow-up (RR: 1.12, 95% CI: 1.06-1.19, P = 0.000, fixed). Notably, CF-guided catheter ablation presented a robust survival benefit for treatment of paroxysmal AF (RR: 1.10, 95% CI: 1.03-1.18, P = 0.005, fixed), but not persistent AF (RR: 1.07, 95% CI: 0.89-1.28, P = 0.466, fixed). Moreover, procedure time (WMD: -23.87, 95% CI: -33.83 to -13.91, P = 0.000, random), fluoroscopy time (WMD: -7.78, 95% CI: -13.93 to -1.63, P = 0.013, random) and RF time (WMD: -3.98, 95% CI: -7.78 to -0.17, P = 0.040, random) were significantly reduced in CF-guided catheter ablation. The incidence of procedure-related complications did not differ between these two technologies (RR: 0.83, 95% CI: 0.59 to 1.16, P = 0.271, fixed). CONCLUSION: CF-guided RF catheter ablation was associated with a significant AF/atrial tachycardia-free survival benefit compared with non-CF-guided ablation in patients with paroxysmal AF rather than persistent AF. In addition, CF-guided ablation strategy also reduced the procedure time, fluoroscopy time, as well as RF time despite no distinct effect on the alleviation of procedure-related complications.

Role of adenosine-guided pulmonary vein isolation in patients undergoing catheter ablation for atrial fibrillation: a meta-analysis.

AIMS: Adenosine had been reported to unmask dormant conduction and thus identify pulmonary vein at risk of reconnection. However, the role of adjunctive adenosine infusion after pulmonary vein isolation (PVI) on long-term arrhythmia-free survival was still contentious. The purpose of the present meta-analysis was to assess the association of adenosine testing with long-term ablation success in patients with atrial fibrillation (AF) (i.e. freedom from AF recurrence). METHODS AND RESULTS: We systematically searched the electronic databases and finally included 10 studies, with 1771 patients undergoing adenosine-guided PVI and 1787 patients undergoing conventional PVI. In comparison to conventional PVI alone, adenosine-guided PVI improved the arrhythmia-free survival by 17% during a median follow-up of 12 months [relative risk (RR): 1.17; 95% confidence interval (CI): 1.07 to 1.27; P = 0.014]. Patients undergoing adenosine-guided PVI had similar fluoroscopy time to those who undergoing conventional PVI [weighted mean difference (WMD): 1.76; 95% CI: -5.66 to 9.17; P = 0.64], despite longer procedure time (WMD: 20.6; 95% CI: 0.70 to 40.50; P = 0.042). CONCLUSION: From the available data of clinical studies, adenosine-guided PVI was associated with an increased arrhythmia-free survival when compared with conventional PVI in patients undergoing catheter ablation for AF.

Cryoablation vs. radiofrequency ablation for treatment of paroxysmal atrial fibrillation: a systematic review and meta-analysis.

AIMS: Cryoablation is a promising alternative technique to RF ablation for treating paroxysmal AF with encouraging results. However, data about the efficacy and safety comparison between cryoablation and RF ablation is still lacking. METHODS AND RESULTS: We systematically search the PubMed, the Cochrane Library, MEDLINE and Google Scholar databases, and finally identify 16 eligible studies including 7195 patients (2863 for cryoablation; 4332 for RF ablation). Freedom from AF/atrial tachycardial replase is slightly higher in cryoablation than RF ablation during a median 12 months of follow-up, with no statistical significant (RR: 1.05, 95% CI: 0.98-1.13, P = 0.159). In cryoablation, the procedure time is substantially shortened (WMD: -27.66, 95% CI: -45.24 to - 10.08, P = 0.002), whereas the fluoroscopy time is identical to RF ablation (WMD: -0.37, 95% CI: -2.78 to 2.04, P = 0.763). Procedure-related adverse events in cryoablation are parallel with that in RF ablation (RR: 1.08, 95% CI: 0.86-1.35, P = 0.159). CONCLUSIONS: Compared with RF ablation, cryoablation present a comparable long-term AF/atrial tachycardial-free survival and procedure-related adverse events. Meanwhile, cryoablation markedly shorten the procedure time, nonetheless, with negligible impact on the fluoroscopy time.

Oxidative Stress-Induced Afterdepolarizations and Protein Kinase C Signaling.

BACKGROUND: Hydrogen peroxide (H2O2)-induced oxidative stress has been demonstrated to induce afterdepolarizations and triggered activities in isolated myocytes, but the underlying mechanisms remain not fully understood. We aimed to explore whether protein kinase C (PKC) activation plays an important role in oxidative stress-induced afterdepolarizations. METHODS: Action potentials and ion currents of isolated rabbit cardiomyocytes were recorded using the patch clamp technique. H2O2 (1 mM) was perfused to induce oxidative stress and the specific classical PKC inhibitor, Gö 6983 (1 µM), was applied to test the involvement of PKC. RESULTS: H2O2 perfusion prolonged the action potential duration and induced afterdepolarizations. Pretreatment with Gö 6983 prevented the emergence of H2O2-induced afterdepolarizations. Additional application of Gö 6983 with H2O2 effectively suppressed H2O2-induced afterdepolarizations. H2O2 increased the late sodium current (INa,L) (n = 7, p < 0.01) and the L-type calcium current (ICa,L) (n = 5, p < 0.01), which were significantly reversed by Gö 6983 (p < 0.01). H2O2 also increased the transient outward potassium current (Ito) (n = 6, p < 0.05). However, Gö 6983 showed little effect on H2O2-induced enhancement of Ito. CONCLUSIONS: H2O2 induced afterdepolarizations via the activation of PKC and the enhancement of ICa,L and INa,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations.

Dual-specificity phosphatase 14 protects the heart from aortic banding-induced cardiac hypertrophy and dysfunction through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway.

Dual-specificity phosphatase 14 (Dusp14), an important negative modulator of mitogen-activated protein kinase (MAPK) signaling pathways, has been implicated in inflammatory immune response, cancers, cell differentiation and proliferation. The role of Dusp14 in chronic pressure overload-induced cardiac hypertrophy has not been explored. Here we have shown that Dusp14-/- knockout mice and cardiac-specific Dusp14 transgenic mice were generated and subjected to aortic banding (AB) for 4 weeks. Our results demonstrated that genetic loss of Dusp14 significantly aggravated cardiac hypertrophy, fibrosis, ventricular dilation and dysfunction, whereas transgenic cardiac-specific Dusp14 overexpression significantly attenuated AB-induced cardiac dysfunction and remodeling. In vitro, adenoviral overexpression of constitutive Dusp14 blocked angiotensin II-induced hypertrophic growth of cardiomyocytes, while Dusp14 knockdown led to opposite effects. Mechanistically, excessive phosphorylation of TAK1, P38MAPK and JNK1/2 was evidenced in Dusp14-/- knockout mice post-AB and inactivation of TAK1-P38MAPK and -JNK1/2 signaling using TAK1 inhibitor 5Z-7-ox shares similar antihypertrophic effect as Dusp14 overexpression. Moreover, we show that Dusp14 directly interacted with TAK1. Results from present experiments indicate that Dusp14 protects the heart from AB-induced cardiac hypertrophy and dysfunction possibly through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway. Future studies are warranted to test the feasibility of overexpressing Dusp14 as a therapeutic strategy to attenuate cardiac hypertrophy and failure.

Catheter Ablation of Idiopathic Epicardial Ventricular Arrhythmias Originating from the Vicinity of the Coronary Sinus System.

Catheter Ablation of Idiopathic Epicardial Ventricular Arrhythmias. Idiopathic epicardial ventricular arrhythmias (IEVAs) originating from the vicinity of the coronary sinus system are not uncommon, accounting for about 9% of idiopathic ventricular arrhythmia cases. IEVAs share clinical presentation and electrophysiological characteristics with ventricular arrhythmias arising from the right ventricular outflow tract possibly as manifestations of cAMP-mediated triggered activity and delayed after-depolarizations. Detailed analysis of standard 12-lead electrocardiogram morphology by using unique variables and algorithms allows clinicians to predict probable location of epicardial foci and informs optimal catheter ablation strategy. Epicardial mapping and ablation through the coronary sinus and its branches is effective and safe, and increasingly favored. However, it is important because of the common perivascular origin of IEVAs to perform coronary angiography prior to or after ablation and to select the appropriate ablation energy form to avoid serious complications.

A systematic review and meta-analysis of cognitive behavioral and psychodynamic therapy for depression in Parkinson's disease patients.

Numerous practice guidelines have recommended cognitive behavioral therapy (CBT) and psychodynamic therapy as a treatment of choice for depression in Parkinson's disease (PD). However, no recent meta-analysis has examined the effects of brief psychotherapy (which includes both CBT and psychodynamic therapy) for adult depression in PD. We decided to conduct such a systematic review and meta-analysis. We included randomized controlled trials (RCTs) examining the effects of brief psychotherapy compared with control groups, other support nursing, or pharmacotherapy. The quality of included studies was strictly evaluated. Twelve studies including 766 patients met all inclusion criteria. The result showed that brief psychotherapy could evidently improve the HAMD (p < 0.00001) and Moca scale (p = 0.006). There was no statistical significance in PDQ-39 scale (p = 0.31). In the subgroup analysis by types of brief psychotherapy, the efficacy of psychodynamic psychotherapy was better than CBT (SMD = -2.02 vs SMD = -0.90) for the outcome measure according to HAMD scale. Meanwhile, we found brief psychotherapy in China was more effective than in US (SMD = -1.54 vs SMD = -1.23), and in low quality studies was more efficacious than in high quality studies (SMD = -1.50 vs SMD = -1.33). Time of brief psychotherapy treatment above 6 weeks was superior to studies with less than 6 weeks treatment. We found brief psychotherapy is probable effective in the management of depression in PD patients. But one reason to undermine the validity of findings is high clinical heterogeneity and low methodological quality of the included trials.

Levodopa alone compared with levodopa-sparing therapy as initial treatment for Parkinson's disease: a meta-analysis.

To assess the long-term use of L-dopa alone vs L-dopa-sparing therapy, as initial treatment, provides the most efficient long-term control of symptoms and best quality of life for people with early Parkinson's disease (PD). PubMed; Google scholar; Cochrane Central Register of Controlled Trials and the Web of Science were searched for randomised, placebo-controlled trials (RCTs) on L-dopa alone and L-dopa sparing as initial treatment in early PD patients. We used a random effects model rather than a fixed effects model because of this takes into account heterogeneity between multi-studies. Eleven RCTs were included. The results showed that L-dopa alone could evidently improve the UPDRS part I (p = 0.005), part II (p < 0.0001), part III (p < 0.0001) and UPDRS total score (p = 0.004) compared with L-dopa-sparing therapy in PD patients. Meanwhile, a reduced risk of dyskinesia (p < 0.0001, RR = 1.88, 95 % CI 1. 37-2.59) and wearing-off phenomenon (p < 0.00001, RR = 1.36, 95 % CI 1. 20-1.55) in patients treated initially with L-dopa-sparing therapy compared to L-dopa has been consistently reported. What is more, we found more patients on aL-dopa-sparing therapy were more than triple as likely to discontinue treatment prematurely due to adverse events than L-dopa treatment patients (43.7 vs 15.8 %). L-Dopa alone is the most effective medication available for treating the motor symptoms of PD patients, despite the greater incidence of involuntary movements. Meanwhile, more patients on dopamine agonists or MAOBI were more likely to discontinue treatment prematurely than L-dopa alone treatment patients within the long follow-up period.

The role of left atrium posterior wall isolation in patients undergoing catheter ablation for atrial fibrillation.

The posterior left atrium (LAPW) is an important substrate for initiation and maintenance of atrial fibrillation (AF). While it has been proposed as a potential target for preventing recurrence of atrial tachyarrhythmias, it remains unclear whether electrical silence of LAPW offers additional benefits over pulmonary vein isolation (PVI) alone. We conducted a systematic review of PubMed, Medline, Embase, and Cochrane databases and identified 21 eligible studies, encompassing 1514 patients assigned to PVI + posterior wall isolation (PWI) group and 1629 patients assigned to PVI group. Over a median follow-up of 12 months, adjunctive PWI significantly improved the atrial tachyarrhythmia-free survival by 14 % in comparison to PVI alone [relative risk (RR): 1.14, 95 % confidence interval (CI): 1.04 to 1.25, p = 0.004]. This improvement was mainly attributed to a pronounced benefit for patients with persistent AF. In addition, patients undergoing PVI + PWI had a longer procedure time [weighted mean difference (WMD): 23.85, 95 % CI: 12.68 to 35.01, p < 0.001], ablation time (WMD: 9.27, 95 % CI: 5.19 to 13.54, p < 0.001), and a nearly negligible increase in fluoroscopic exposure (WMD: 2.69, 95 % CI: -0.23 to 5.62, p = 0.071). There was no increased risk of procedure-related complications between these approaches (RR: 1.06, 95 % CI: 0.71 to 1.57, p = 0.787). Compared with PVI alone, PWI adjunctive to PVI exhibited a higher procedure success of sinus rhythm maintenance in persistent AF during an index catheter ablation. Meanwhile, elongated procedure time and ablation time did not compromise the safety of extensive ablation strategy with additional PWI.

Ivabradine inhibits the production of proinflammatory cytokines and inducible nitric oxide synthase in acute coxsackievirus B3-induced myocarditis.

The role of ß-adrenergic stimulation on viral myocarditis has been investigated in animal models. The beneficial action of the ß-blocker carvedilol in murine viral myocarditis can be explained partly by the resulting heart rate reduction and the inhibition of proinflammatory cytokine production. The modulation of myocardial necrosis and contractile dysfunction by proinflammatory cytokines may be partially mediated by the production of nitric oxide (NO). The selective I(f) current inhibitor ivabradine reduces the heart rate without affecting cardiac contractility and has been shown to be cardioprotective in failing hearts. However, little is known about the effects of ivabradine in viral myocarditis, and in particular, its effects on inducible NO synthase (iNOS) have not been investigated. This study was therefore designed to examine the effects of ivabradine in murine viral myocarditis. In a coxsackievirus B3 murine myocarditis model, the effects of ivabradine and carvedilol on the myocardial histopathological changes and fibrosis, NO production, iNOS protein and cytokine levels were studied. Both ivabradine and carvedilol similarlyattenuated myocardial lesions and fibrosis, inhibited NO synthesis by iNOS, and decreased the production of TNF-α and IL-6. These results show that ivabradine has a therapeutic benefit in murine CVB3-induced myocarditis. The beneficial effects of ivabradine in viral myocarditis are partially mediated by the inhibition of both the production of proinflammatory cytokines and the synthesis of NO by iNOS.

The protective effect of vagus nerve stimulation against myocardial ischemia/reperfusion injury: pooled review from preclinical studies.

Aims: Myocardial ischemia-reperfusion (I/R) injury markedly undermines the protective benefits of revascularization, contributing to ventricular dysfunction and mortality. Due to complex mechanisms, no efficient ways exist to prevent cardiomyocyte reperfusion damage. Vagus nerve stimulation (VNS) appears as a potential therapeutic intervention to alleviate myocardial I/R injury. Hence, this meta-analysis intends to elucidate the potential cellular and molecular mechanisms underpinning the beneficial impact of VNS, along with its prospective clinical implications. Methods and Results: A literature search of MEDLINE, PubMed, Embase, and Cochrane Database yielded 10 articles that satisfied the inclusion criteria. VNS was significantly correlated with a reduced infarct size following myocardial I/R injury [Weighed mean difference (WMD): 25.24, 95% confidence interval (CI): 32.24 to 18.23, p < 0.001] when compared to the control group. Despite high heterogeneity (I2 = 95.3%, p < 0.001), sensitivity and subgroup analyses corroborated the robust efficacy of VNS in limiting infarct expansion. Moreover, meta-regression failed to identify significant influences of pre-specified covariates (i.e., stimulation type or site, VNS duration, condition, and species) on the primary estimates. Notably, VNS considerably impeded ventricular remodeling and cardiac dysfunction, as evidenced by improved left ventricular ejection fraction (LVEF) (WMD: 10.12, 95% CI: 4.28; 15.97, p = 0.001) and end-diastolic pressure (EDP) (WMD: 5.79, 95% CI: 9.84; -1.74, p = 0.005) during the reperfusion phase. Conclusion: VNS offers a protective role against myocardial I/R injury and emerges as a promising therapeutic strategy for future clinical application.

Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer's Disease Continuum.

Purpose: Biomarkers used for predicting longitudinal cognitive change in Alzheimer's disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Patients and Methods: A total of 430 subjects including, 96 cognitive normal (CN) with amyloid ß (Aß)-negative, 54 CN with Aß-positive, 195 mild cognitive impairment (MCI) with Aß-positive, and 85 AD with amyloid-positive (Aß-positive are identified by CSF Aß42/Aß40 < 0.138). Aß burden was evaluated by CSF and plasma Aß42/Aß40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer's Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline. Results: Baseline CSF Aß42/Aß40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline. Conclusion: Our study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.

Discerning the Role of Blood Brain Barrier Dysfunction in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease. The predominant characteristics of AD are the accumulation of amyloid-ß (Aß) and hyperphosphorylated tau in the brain. Blood brain barrier (BBB) dysfunction as one of the causative factors of cognitive impairment is increasingly recognized in the last decades. However, the role of BBB dysfunction in AD pathogenesis is still not fully understood. It remains elusive whether BBB dysfunction is a consequence or causative fact of Aß pathology, tau pathology, neuroinflammation, or other conditions. In this review, we summarized the major findings of BBB dysfunction in AD and the reciprocal relationships between BBB dysfunction, Aß pathology, tau pathology, and neuroinflammation. In addition, the implications of BBB dysfunction in AD for delivering therapeutic drugs were presented. Finally, we discussed how to better determine the underlying mechanisms between BBB dysfunction and AD, as well as how to explore new therapies for BBB regulation to treat AD in the future.

Alzheimer's disease susceptibility locus in CD2AP is associated with increased cerebrospinal fluid tau levels in mild cognitive impairment.

INTRODUCTION: Rs9296559 within CD2-associated protein (CD2AP) has been identified as a susceptibility locus for Alzheimer's disease (AD). Recent studies indicated that CD2AP functioned as a regulator of endocytic trafficking to modulate the ß-amyloid (Aß) generation in neurons. Moreover, knockdown of cindr, the Drosophila ortholog of CD2AP, enhanced tau-induced neurodegeneration, implying CD2AP also participated in tau pathology. However, the role of rs9296559 in regulating Aß and tau metabolism in AD was still unclear. METHODS: Here, the associations of rs9296559 with CSF Aß1-42, p-tau, and t-tau were performed using a linear regression model in a total of 543 cognitive normal (CN), mild cognitive impairment (MCI), and AD subjects from the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort. The results were replicated in an independent cohort consisting of 198 Chinese subjects recruited from our hospital. RESULTS: In the ADNI cohort, CC + TC genotypes significantly increased CSF t-tau and p-tau levels in MCI patients but did not alter CSF tau levels in AD. This association was also observed in the replication cohort. Moreover, there was no association between rs9296559 and CSF Aß1-42 level at different disease statuses in the two cohorts. CONCLUSION: Our findings showed that rs9296559 was associated with higher CSF t-tau and p-tau levels in MCI, supporting that CD2AP modified AD risk by altering tau-related neurodegeneration in the early stage of the AD continuum. To the best of our knowledge, this is the first study to evaluate the association between CD2AP genotypes and AD CSF biomarkers.