Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease

The extracellular domain(p75ECD)of p75 neurotrophin receptor(p75NTR)antagonizes Aβ neurotoxicity and promotes Aβclearance in Alzheimer’s disease(AD).The impaired shedding of p75ECD is a key pathological process in AD,but its regulatory mechanism is largely unknown.This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD(p75ECD-NAbs)in AD patients and their effects on AD pathology.We found that the cerebrospinal fluid(CSF)level of p75ECD-NAbs was increased in AD,and negatively associated with the CSF levels of p75ECD.Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain,as well as worse cognitive functions than the control groups,which were immunized with Re-p75ECD(the reverse sequence of p75ECD)and phosphate-buffered saline,respectively.These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance,providing a novel insight into the role of autoimmunity and p75NTR in AD.

Clinical Research on Alzheimer's Disease: Progress and Perspectives

Alzheimer’s disease(AD), the most common type of dementia, is becoming a major challenge for global health and social care. However, the current understanding of AD pathogenesis is limited, and no early diagnosis and disease-modifying therapy are currently available. During the past year, significant progress has been made in clinical research on the diagnosis, prevention, and treatment of AD.In this review, we summarize the latest achievements,including diagnostic biomarkers, polygenic hazard score,amyloid and tau PET imaging, clinical trials targeting amyloid-beta(Ab), tau, and neurotransmitters, early intervention, and primary prevention and systemic intervention approaches, and provide novel perspectives for further efforts to understand and cure the disease.

Association of Polygenic Risk Score with Age at Onset and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease in a Chinese Cohort

To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer’s disease(sAD)and pathological biomarkers in cerebrospinal fluid(CSF),462 sAD patients and 463 age-matched cognitively normal(CN)controls were genotyped for 35 singlenucleotide polymorphisms(SNPs)that are significantly associated with sAD.Then,the alleles found to be associated with sAD were used to build polygenic risk score(PRS)models to represent the genetic risk.Receiver operating characteristic(ROC)analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset.We measured the CSF levels of Aβ42,Aβ42/Aβ40,total tau(T-tau),and phosphorylated tau(P-tau)in a subgroup(60 sAD and 200 CN participants),and analyzed their relationships with the PRSs.We found that 14 SNPs,including SNPs in the APOE,BIN1,CD33,EPHA1,SORL1,and TOMM40 genes,were associated with sAD risk in our cohort.The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls,and were able to predict the incidence rate of sAD and age at onset.Furthermore,the PRSs were correlated with the CSF levels of Aβ42,Aβ42/Aβ40,T-tau,and P-tau.Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD.As genetic risk profiles vary among populations,large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.

Efficacy and safety of early anticoagulation after endovascular treatment in patients with atrial fibrillation

Background The timing for initiating anticoagulant therapy in acute ischaemic stroke(AIS)patients with atrial fibrillation who recanalised after endovascular treatment(EVT)is unclear.The objective of this study was to evaluate the effect of early anticoagulation after successful recanalisation in AIS patients with atrial fibrillation.Methods Patients with anterior circulation large vessel occlusion and atrial fibrillation who were successfully recanalised by EVT within 24 hours after stroke in the Registration Study for Critical Care of Acute Ischemic Stroke after Recanalization registry were analysed.Early anticoagulation was defined as the initiation of unfractionated heparin(UFH)or low-molecular-weight heparin(LMWH)within 72 hours after EVT.Ultra-early anticoagulation was defined if it was initiated within 24 hours.The primary efficacy outcome was the score on the modified Rankin Scale(mRS)at day 90,and the primary safety outcome was symptomatic intracranial haemorrhage within 90 days.Results Overall,257 patients were enrolled,of whom 141(54.9%)initiated anticoagulation within 72 hours after EVT,including 111 within 24 hours.A significant shift towards better mRS scores at day 90 was associated with early anticoagulation(adjusted common OR 2.08(95%CI 1.27 to 3.41)).Symptomatic intracranial haemorrhage was comparable between patients treated with early and routine anticoagulation(adjusted OR 0.20(95%CI 0.02 to 2.18)).Comparison of different early anticoagulation regimens showed that ultra-early anticoagulation was more significantly associated with favourable functional outcomes(adjusted common OR 2.03(95%CI 1.20 to 3.44))and reduced the incidence of asymptomatic intracranial haemorrhage(OR 0.37(95%CI 0.14 to 0.94)).Conclusions In AIS patients with atrial fibrillation,early anticoagulation with UFH or LMWH after successful recanalisation is associated with favourable functional outcomes without increasing the risk of symptomatic intracranial haemorrhages.