Publications by authors named "Qiang Dong"

471 Publications

Clopidogrel with aspirin in High-risk patients with Acute Non-disabling Cerebrovascular Events II (CHANCE-2): rationale and design of a multicentre randomised trial.

Stroke Vasc Neurol 2021 May 5. Epub 2021 May 5.

Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: In patients with a minor ischaemic stroke or transient ischaemic attack (TIA), separate trials have shown that dual antiplatelet therapy with clopidogrel plus aspirin (clopidogrel-aspirin) or ticagrelor plus aspirin (ticagrelor-aspirin) are more effective than aspirin alone in stroke secondary prevention. However, these two sets of combination have not been directly compared. Since clopidogrel was less effective in stroke patients who were loss-of-function (LOF) allele carriers, whether ticagrelor-aspirin is clinically superior to clopidogrel-aspirin in this subgroup of patients with stroke is unclear.

Aim: To describe the rationale and design considerations of the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE-2) trial.

Design: CHANCE-2 is a randomised, double-blind, double-dummy, placebo-controlled, multicentre trial that compares two dual antiplatelet strategies for minor stroke or TIA patients who are allele carriers: ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily on days 2-90) or clopidogrel (300 mg loading dose on day 1 followed by 75 mg daily on days 2-90), plus open-label aspirin with a dose of 75-300 mg on day 1 followed by 75 mg daily on day 2-21. All will be followed for 1 year.

Study Outcomes: The primary efficacy outcome is any stroke (ischaemic or haemorrhagic) within 3 months and the primary safety outcome is any severe or moderate bleeding event within 3 months.

Discussion: The CHANCE-2 trial will evaluate whether ticagrelor-aspirin is superior to clopidogrel-aspirin for minor stroke or TIA patients who are LOF allele carriers.

Trial Registration Number: NCT04078737.
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http://dx.doi.org/10.1136/svn-2020-000791DOI Listing
May 2021

Serum Neurofilament Dynamics Predicts Cognitive Progression in de novo Parkinson's Disease.

J Parkinsons Dis 2021 Apr 30. Epub 2021 Apr 30.

Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

Background: Neurofilament light (NfL) can reflect the extent of neuron/axon damage, thus providing an opportunity to examine the severity and progression of the diseases with such damage.

Objective: Whether serum NfL can be used as an indicator to monitor the cognitive progress of de novo Parkinson's disease (PD) remains unclear.

Methods: In this research, 144 healthy controls and 301 de novo PD patients from Parkinson's Progression Markers Initiative (PPMI) were recruited. Linear mixed effects models were used to examine the associations of baseline/longitudinal serum NfL with cognitive decline. Cox regression was used to detect cognitive progression in PD participants.

Results: We found PD patients had higher serum NfL than controls at baseline (p = 0.031), and NfL increase was faster in PD group (p < 0.001). Both baseline serum NfL and its rate of change predicted measurable cognitive decline in early PD (MoCA, β= -0.014, p < 0.001; β= -0.002, p < 0.001, respectively). Additionally, we observed that NfL levels were also able to predict progression in different diagnostic groups and Amyloid- PD and Amyloid+PD groups. After an average follow-up of 6.37±1.84 years, the baseline NfL of the third tertile of high concentrations was associated with a future high risk of PD dementia (adjusted HR 6.33, 95% CI 2.62-15.29, p < 0.001).

Conclusion: In conclusion, our results indicated that the serum NfL concentration could function as an easily accessible biomarker to monitor the severity and progression of cognitive decline in PD.
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http://dx.doi.org/10.3233/JPD-212535DOI Listing
April 2021

Retroperitoneal or transperitoneal approach in robot-assisted partial nephrectomy, which one is better?

Cancer Med 2021 May 1. Epub 2021 May 1.

Department of Urology, West China Hospital, Sichuan University, Chengdu, China.

Purpose: To systematically assess the perioperative outcomes of retroperitoneal (RP) and transperitoneal (TP) approaches in robot-assisted partial nephrectomy (RAPN), we conducted an updated meta-analysis.

Methods: A literature retrieval of multi-database including PubMed, Web of Science, Embase, Cochrane Library, and CNKI was performed to identify eligible comparative studies from the inception dates to January 2021. Perioperative outcomes included operative time (OT), estimated blood loss (EBL), warm ischemia time (WIT), postoperative length of stay (PLOS), positive surgical margin (PSM), and complications (major complications and overall complications). Outcomes of data were pooled and analyzed with Review Manager 5.4.1.

Results: Twenty-one studies involving a total of 2482 RP and 3423 TP approach RAPN patients met the inclusion criteria. Operating time (OT) (weighted mean difference [WMD] -16.60; 95% confidence interval [CI] -23.08, -10.12; p < 0.01) and PLOS (WMD -0.46 days; 95% CI -0.69, -0.23; p < 0.01) were shorter in RP-RAPN. Besides, lower EBL (WMD -21.67; 95% CI -29.74, -13.60; p < 0.05) was also found in RP-RAPN. Meanwhile, no significant differences were found in other outcomes.

Conclusions: RP-RARN was superior to TP-RAPN in patients undergoing RAPN in terms of OT, PLOS, and estimated blood loss. Besides these two approaches have no significant differences in PSMs or perioperative complications.
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http://dx.doi.org/10.1002/cam4.3888DOI Listing
May 2021

Teaching Video NeuroImages: Optic Ataxia as the Presenting Sign of the Heidenhain Variant of Creutzfeldt-Jakob Disease.

Neurology 2021 Apr 26. Epub 2021 Apr 26.

Department of Neurology, Huashan Hospital, Fudan University.

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http://dx.doi.org/10.1212/WNL.0000000000012057DOI Listing
April 2021

Teaching NeuroImages: Parkinsonism Presenting With Watershed Pattern Lesions.

Neurology 2021 Apr 26. Epub 2021 Apr 26.

Department of Neurology, Huashan Hospital, Fudan University

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http://dx.doi.org/10.1212/WNL.0000000000012056DOI Listing
April 2021

Associations of healthy lifestyles with cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: the CABLE study.

Alzheimers Res Ther 2021 Apr 19;13(1):81. Epub 2021 Apr 19.

Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12th Wulumuqi Zhong Road, Shanghai, 200040, China.

Objective: We aimed to investigate the associations between healthy lifestyles and Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF).

Methods: A total of 1108 cognitively intact individuals from Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were examined to evaluate the associations of AD biomarkers with healthy lifestyle factors, including no current smoking, no harmful drinking, absence of social isolation, and regular physical activity. The participants were categorized into groups of favorable, intermediate, and unfavorable lifestyles according to the lifestyle factors. The associations between overall lifestyle and CSF biomarkers were also analyzed.

Results: Among cognitively intact older adults, those having more social engagement had lower CSF tau (p = 0.009) and p-tau (p < 0.001) than those who had social isolation. Regular physical activity was associated with higher CSF Aβ42 (p = 0.013) and lower levels of CSF tau (p = 0.036) and p-tau (p = 0.007). However, no significant associations were found of smoking status or alcohol intake with CSF biomarkers. When the overall lifestyle of the participants was evaluated by all the four lifestyle factors, favorable lifestyle profiles were related to lower levels of CSF tau (p < 0.001) and p-tau (p < 0.001).

Conclusions: These findings suggest that healthy lifestyles had a beneficial effect on AD pathology among cognitively intact elders.
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http://dx.doi.org/10.1186/s13195-021-00822-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056495PMC
April 2021

Transperitoneal versus retroperitoneal approaches of pyeloplasty in management of ureteropelvic junction obstruction: A meta-analysis.

Asian J Surg 2021 Apr 15. Epub 2021 Apr 15.

Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China. Electronic address:

The aim of this study was to evaluate the benefits and safety of transperitoneal and retroperitoneal pyeloplasty for ureteropelvic junction obstruction by a meta-analysis. We searched the databases including PubMed, Cochrane Library and Embase database from their inception to December 1st, 2020. Relevant literatures comparing retroperitoneal pyeloplasty with transperitoneal pyeloplasty were identified. A meta-analysis was conducted with Revman 5.3. The main outcomes included success rate, operative time, hospital stay, conversion rate of open surgery, overall complications, and detailed postoperative complications/indicators. 15 studies with 1881 patients were included. The results revealed that there were no significant differences between two approaches in success rate [OR = 1.51, 95%CI (0.94, 2.41), p = 0.09], hospital stay [MD = 0.21, 95%CI (-0.12, 0.54), p = 0.21] and overall complications [OR = 1.07, 95%CI (0.76, 1.50), p = 0.69]. The retroperitoneal approach was associated with longer operative time [MD = -26.91, 95%CI (-40.97, -12.84), p < 0.001], higher conversion rate [OR = 0.23, 95%CI (0.11, 0.47), p < 0.001] than the transperitoneal approach. As for the detailed postoperative complications/indicators, there were no significant differences between two approaches in the urinary leak, mild hematuria, fever, UPJO recurrence, infection and subcutaneous emphysema, as well as split renal function, renal pelvis anteroposterior diameter. The funnel plots showed that there were no obvious publication biases in our analysis. Therefore, we concluded that transperitoneal and retroperitoneal approaches had similar benefits and safety in success rate, hospital stay, overall complications and detailed postoperative complications/indicators. However, retroperitoneal was associated with longer operative time and higher conversion rate than transperitoneal approach. With the limitations of our study, additional high-quality studies are still essential for further evaluation.
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http://dx.doi.org/10.1016/j.asjsur.2021.03.022DOI Listing
April 2021

Red and processed meat consumption and cancer outcomes: Umbrella review.

Food Chem 2021 Mar 27;356:129697. Epub 2021 Mar 27.

Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address:

The purpose of this umbrella review was to evaluate the quality of evidence, validity and biases of the associations between red and processed meat consumption and multiple cancer outcomes according to existing systematic reviews and meta-analyses. The umbrella review identified 72 meta-analyses with 20 unique outcomes for red meat and 19 unique outcomes for processed meat. Red meat consumption was associated with increased risk of overall cancer mortality, non-Hodgkin lymphoma (NHL), bladder, breast, colorectal, endometrial, esophageal, gastric, lung and nasopharyngeal cancer. Processed meat consumption might increase the risk of overall cancer mortality, NHL, bladder, breast, colorectal, esophageal, gastric, nasopharyngeal, oral cavity and oropharynx and prostate cancer. Dose-response analyses revealed that 100 g/d increment of red meat and 50 g/d increment of processed meat consumption were associated with 11%-51% and 8%-72% higher risk of multiple cancer outcomes, respectively, and seemed to be not correlated with any benefit.
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http://dx.doi.org/10.1016/j.foodchem.2021.129697DOI Listing
March 2021

A Novel ITM2B Mutation Associated with Familial Chinese Dementia.

J Alzheimers Dis 2021 Mar 30. Epub 2021 Mar 30.

Department of Neurology and Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, China.

Mutations in ITM2B have been found to be associated with familial Danish dementia (FDD) and familial British dementia (FBD). Here, we describe a patient with dementia caused by a novel ITM2B p. *267Leuext *11 mutation. The patient presented with dementia, ataxia, deafness, and paraplegia. Amyloid PET and Tau PET showed abnormal deposition of amyloid and tau protein in brain. Summarized from previous 26 FBD and FDD cases, the clinical phenotype of ITM2B; p. *267Leuext *11 mutation in ITM2B is different from the features of FBD and FDD. Our findings increased genetic knowledge of familial dementia and extend the ethnic distribution of ITM2B mutations.
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http://dx.doi.org/10.3233/JAD-210176DOI Listing
March 2021

Left Ventricular Ejection Fraction and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Normal Older Adults: The CABLE Study.

J Alzheimers Dis 2021 Apr 1. Epub 2021 Apr 1.

Department of Neurology, Qingdao Municipal Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, China.

Background: Heart failure has been considered as a potential modifiable risk factor for cognitive impairment and dementia. Left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, has also been associated with cognitive aging. However, the effect of LVEF on Alzheimer's disease (AD) pathology is still less known.

Objective: We aimed to investigate the associations of LVEF with cerebrospinal fluid (CSF) biomarkers for AD in cognitively normal elders.

Methods: A total of 423 cognitively normal individuals without heart failure were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Participants were divided into low LVEF group (50%≤LVEF <  60%) and high LVEF group (LVEF≥60%). The associations of LVEF with CSF AD biomarkers including CSF amyloid-β 42 (Aβ 42), total-tau (t-tau), and phosphorylated tau (p-tau) were analyzed using multivariate linear regression models.

Results: Participants with low LVEF had higher levels of CSF t-tau (β= -0.009, p = 0.006) and t-tau/Aβ 42 ratios (β= -0.108, p = 0.026). Subgroup analyses showed that the associations only existed in female and middle-aged groups (<  65 years old). Besides, participants with low LVEF had higher levels of CSF p-tau (β= -0.002, p = 0.043) in middle-aged group.

Conclusion: In conclusion, our findings revealed the associations between LVEF and AD pathology, which may provide new insights into AD prevention through maintaining cardiac function.
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http://dx.doi.org/10.3233/JAD-201222DOI Listing
April 2021

Serum Uric Acid May Aggravate Alzheimer's Disease Risk by Affecting Amyloidosis in Cognitively Intact Older Adults: The CABLE Study.

J Alzheimers Dis 2021 Mar 30. Epub 2021 Mar 30.

Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, China.

Background: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear.

Objective: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD.

Methods: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-β [Aβ], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models.

Results: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aβ1 - 42 (p = 0.019) and Aβ1 - 42/Aβ1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aβ1 - 42 (p = 0.009) and t-Tau/Aβ1 - 42 (p = 0.043) were increased with the highest (>  75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them.

Conclusion: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.
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http://dx.doi.org/10.3233/JAD-201192DOI Listing
March 2021

Evaluation relationships between subjective wellbeing, personality traits, and Alzheimer's disease: A two-sample Mendelian randomization study.

J Psychiatr Res 2021 May 25;137:498-505. Epub 2021 Mar 25.

Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address:

Objective: Observational studies have suggested that subjective wellbeing and personality traits link to risk of Alzheimer's disease (AD), but it is unclear if these associations are causal.

Methods: We performed two-sample Mendelian randomization to assess potential causality. Genetic associations were obtained from the largest genome-wide association studies in Social Science Genetic Association Consortium (N = 298,420), Genetics of Personality Consortium (N = 81,036), and four independent consortia of AD (N = 455,258). We run the inverse variance weighted (IVW) approach as one primary analysis. A Bonferroni-corrected threshold of p < 8.33 × 10 was considered significant, and p values between 8.33 × 10 and 0.05 were considered to be suggestive of an association.

Results: The suggestive association with decreased risk of AD was noted for a genetically predicted 1-SD increase in subjective wellbeing (odds ratio = 0.963, 95% confidence interval = 0.930-0.997; p = 0.032). Genetically predicted greater neuroticism was significantly associated with lower subjective wellbeing (β = -0.077; p = 0.004). No putative personality traits were significantly associated with AD risk after correction for multiple tests, including agreeableness (β = -0.0010; p = 0.477), conscientiousness (β = 0.0018; p = 0.270), openness (β = 0.0004; p = 0.738), neuroticism (β = -0.0098; p = 0.262), or extraversion (β = 0.0120; p = 0.262).

Conclusions: Subjective wellbeing may independently reduce the risk of AD. Residual confounding is likely to be responsible for the previous observational relationships between personality traits and AD.
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http://dx.doi.org/10.1016/j.jpsychires.2021.03.033DOI Listing
May 2021

Dl-3-n-Butylphthalide Alleviates Demyelination and Improves Cognitive Function by Promoting Mitochondrial Dynamics in White Matter Lesions.

Front Aging Neurosci 2021 8;13:632374. Epub 2021 Mar 8.

Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.

White matter lesions (WMLs) are a type of cerebrovascular disorder accompanied by demyelination and cognitive decline. Dl-3-n-butylphthalide (D1-NBP) is a neuroprotective drug used for the treatment of ischemic cerebrovascular diseases, although the function of DI-NBP on WML is still not clear. This study aims to investigate whether DI-NBP affects cognitive function and ameliorates demyelination in a model of WML. The bilateral carotid artery stenosis (BCAS) mouse model and brain slice cultures with low glucose and low oxygen (LGLO) treatment were adopted. The Dl-NBP was administered intragastrically for 28 days after BCAS or added at a dose of 50 μm for 48 h after LGLO. Spatial learning and memory were evaluated by an eight-arm radial maze. Demyelination was detected using a TEM. Mitochondrial dynamics were assessed by time-lapse imaging in the cultured brain slices. The function of the synapse was evaluated by the patch clamp technique. In BCAS mice, obvious demyelination and cognitive decline were observed, while both were significantly relieved by a high-dose D1-NBP treatment (100 mg/kg). Along with demyelination, mitochondrial accumulation in the axons was significantly increased in the BCAS mice model, but with the treatment of a high-dose D1-NBP, mitochondrial accumulation was mitigated, and the anterograde/retrograde transport of mitochondria was increased. Following the improved anterograde/retrograde transport of mitochondria, the synapse activity was significantly upregulated while the reactive oxygen species (ROS) generation was remarkably decreased in the cultured brain slices. In addition, we identified syntaphilin (SNPH) as the downstream target of D1-NBP. The overexpression of SNPH mediated the effects of D1-NBP in mitigating axonal mitochondrial accumulation. In conclusion, the D1-NBP treatment significantly relieved demyelination and improved spatial learning and memory in the WML model by promoting mitochondrial dynamics. These neuroprotective effects of D1-NBP were mediated by inhibiting the mitochondrial arching protein, SNPH, which provided a potential therapeutic target for WML.
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http://dx.doi.org/10.3389/fnagi.2021.632374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982723PMC
March 2021

Blood biomarkers related to osteonecrosis of femoral head by internal fixation after Garden I femoral neck fracture: a cohort study.

Injury 2021 Feb 17. Epub 2021 Feb 17.

Orthopaedics Institute, Tianjin hospital, Tianjin University, NO.406, Jiefang South Road, Hexi District, Tianjin, 300211, Peoples Republic of China; Department of Traumatic Orthopaedics, Tianjin hospital, Tianjin University, NO.406, Jiefang South Road, Hexi District, Tianjin, 300211, Peoples Republic of China. Electronic address:

Background: Internal fixation is currently considered the gold standard in treatment for femoral neck fractures in adults. However, osteonecrosis of the femoral head (ONFH) after internal fixation would occur in quite proportion of patients with femoral neck fracture, even in Garden I femoral neck fracture. The purpose of this study was to determine the association between the blood biomarkers (serum albumin, pre-albumin, total protein and total lymphocyte count) and ONFH following internal fixation of Garden I femoral neck fracture in adults.

Method: This is a single center cohort study, in which each patient who sustained a Garden I femoral neck fracture had been treated with internal fixation, and had adequate preoperative blood examinations. The serum albumin was categorized as ≥ 40g/L or < 40g/L. The pre-albumin was categorized as ≥ 22mg/dL or < 22mg/dL. The total protein was categorized as ≥ 65g/L or < 65 g/L. The total lymphocyte count was categorized as ≥1.1× 10 /L or <1.1×10 /L. Multivariate cox proportional hazards analysis was used to assess the association between blood markers and the osteonecrosis of femoral head during the 2-years follow-up period controlling the confounders.

Result: A total of 10 cases of ONFH were identified. Multivariate Cox regression analysis revealed that low total lymphocyte count and hypertension state were significant independent risk factors for ONFH after internal fixation for Garden I femoral head fractures.

Conclusion: Blood biomarkers were potential predictors for ONFH after internal fixation Garden I femoral neck fractures. We suggest that routine laboratory tests might can be used to assist surgeons to identify patients at great risk of ONFH.
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http://dx.doi.org/10.1016/j.injury.2021.02.042DOI Listing
February 2021

Social Networks and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.

J Alzheimers Dis 2021 Mar 15. Epub 2021 Mar 15.

Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

Background: Although social networks are deemed as moderators of incident Alzheimer's disease (AD), few data are available on the mechanism relevant to AD pathology.

Objective: We aimed to investigate whether social networks affect metabolism of cerebrospinal fluid (CSF) AD biomarkers during early stage and identify modification effects of genetic factor and subjective cognitive decline (SCD).

Methods: We studied participants from the Chinese Alzheimer's disease Biomarker and Lifestyle (CABLE) database who received cognition assessments and CSF amyloid-β (Aβ 1-42 and Aβ 1-40) and tau proteins (total-tau [T-tau] and phosphorylated-tau [P-tau]) measurements. The social networks were measured using self-reported questionnaires about social ties. Linear regression models were used.

Results: Data were analyzed from 886 cognitively intact individuals aged 61.91 years (SD = 10.51), including 295 preclinical AD participants and 591 healthy controls. Social networks were mostly associated with CSF indicators of AD multi-pathologies (low P-tau/Aβ 1-42 and T-tau/Aβ 1-42 and high Aβ 1-42/Aβ 1-40). Significant differences of genetic and cognitive status were observed for CSF indicators, in which associations of social network scores with CSF P-tau and indicators of multi-pathologies appeared stronger in APOE 4 carriers (versus non-carriers) and participants with SCD (versus controls), respectively. Alternatively, more pronounced associations for CSF T-tau (β= -0.005, p <  0.001), Aβ 1-42/Aβ 1-40 (β= 0.481, p = 0.001), and T-tau/Aβ 1-42 (β= -0.047, p <  0.001) were noted in preclinical AD stage than controls.

Conclusion: These findings consolidated strong links between social networks and AD risks. Social networks as a modifiable lifestyle probably affected metabolisms of multiple AD pathologies, especially among at-risk populations.
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http://dx.doi.org/10.3233/JAD-201426DOI Listing
March 2021

Deficiency in Neuroserpin Exacerbates CoCl Induced Hypoxic Injury in the Zebrafish Model by Increased Oxidative Stress.

Front Pharmacol 2021 2;12:632662. Epub 2021 Mar 2.

Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.

Protective strategy against hypoxic-ischemic (H/I) induced injury has been intensively discussed. Neuroserpin, an inhibitor for tissue plasminogen activator (tPA), has been proved a vital neuroprotective agent in cerebral ischemia mouse model and oxygen-glucose deprivation and reoxygenation (OGD/R) cell model. Neuroserpin is a promising therapeutic hint for neonatal hypoxic-ischemia injury. Here, we established a neuroserpin deficient zebrafish to study its role in CoCl chemically induced hypoxic injury. CoCl exposure was beginning at the embryonic stage. Development defects, neuronal loss, and vascular malformation was assessed by imaging microscopy. Neuroserpin deficient zebrafish showed more development defects, neuronal loss and vascular malformation compared to wide-type. Apoptosis and oxidative stress were evaluated to further identify the possible mechanisms. These findings indicate that neuroserpin could protective against CoCl induced hypoxic injury by alleviating oxidative stress.
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http://dx.doi.org/10.3389/fphar.2021.632662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960655PMC
March 2021

iTRAQ-based comparative proteome analyses of different growth stages revealing the regulatory role of reactive oxygen species in the fruiting body development of .

PeerJ 2021 3;9:e10940. Epub 2021 Mar 3.

Key Laboratory of Standardization of Chinese Medicine, Ministry of Education; Key Laboratory of Systematic Research, Development and Utilization of Chinese Medicine Resources in Sichuan Province-Key Laboratory Breeding Base founded by Sichuan Province, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.

In this study, using an isobaric tags for relative and absolute quantitation (iTRAQ ) approach coupled with LC-MS / MS and bioinformatics, the proteomes were analyzed for the crucial three stages covering the fruiting body development of , including sclerotium (ST), primordium (PR) and mature fruiting body (MF), with a focus on fruiting body development-related proteins and the potential mechanisms of the development. A total of 1,875 proteins were identified. Principal Component Analysis (PCA) demonstrated that the protein patterns between PR and MF were more similar than ST. Differentially accumulated proteins (DAPs) analysis showed that there were 510, 173 and 514 DAPs in the comparisons of ST vs. PR, PR vs. MF and ST vs. MF, respectively. A total of 62 shared DAPs were identified and primarily enriched in proteins related to 'carbon transport and mechanism', 'the response to oxidative stress', 'antioxidative activity' and 'translation'. KEGG and GO databases showed that the DAPs were enriched in terms of 'primary metabolisms (amino acid/fatty acid/energy metabolism)', 'the response to oxidative stress' and 'peroxidase'. Furthermore, 34 DAPs involved in reactive oxygen species (ROS) metabolism were identified and clustered across the three stages using hierarchical clustering implemented in hCluster R package . It was suggested that their roles and the underlying mechanisms may be stage-specific. ROS may play a role in fungal pathogenicity in ST, the fruit-body initiation in PR, sexual reproduction and highland adaptation in MF. Crucial ROS-related proteins were identified, such as superoxide dismutase (SOD, T5A6F1), Nor-1 (T5AFX3), electron transport protein (T5AHD1), histidine phosphotransferase (HPt, T5A9Z5) and Glutathione peroxidase (T5A9V1). Besides, the accumulation of ROS at the three stages were assayed using 2,7-dichlorofuorescin diacetate (DCFH-DA) stanning. A much stronger ROS accumulation was detected at the stage MF, compared to the stages of PR and ST. Sections of ST and fruit-body part of MF were stained by DCFH-DA and observed under the fluorescencemicroscope, showing ROS was distributed within the conidiospore and ascus. Besides, SOD activity increased across the three stages, while CAT activity has a strong increasement in MF compared to the stages of ST and PR. It was suggested that ROS may act in gradient-dependent manner to regulate the fruiting body development. The coding region sequences of six DAPs were analyzed at mRNA level by quantitative real-time PCR (qRT-PCR). The results support the result of DAPs analysis and the proteome sequencing data. Our findings offer the perspective of proteome to understand the biology of fruiting body development and highland adaptation in , which would inform the big industry of this valuable fungus.
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http://dx.doi.org/10.7717/peerj.10940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936569PMC
March 2021

Incident cerebral microbleeds and hypertension defined by the 2017 ACC/AHA Guidelines.

Ann Transl Med 2021 Feb;9(4):314

Department of Neurology, National Clinical Research Centre for Aging and Medicine, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.

Background: The cut-off for hypertension was lowered to blood pressure (BP) over 130/80 mmHg in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline. Whether the new definition of hypertension remains a potent risk factor of cerebral microbleeds (CMBs) is uncertain. We aimed to analyze the relationship between the new definition of hypertension and incident CMBs in a 7-year longitudinal community study.

Methods: This study is a sub-study of the Shanghai Aging Study (SAS). A total of 317 participants without stroke or dementia were included at baseline (2009-2011), and were invited to repeated clinical examinations and cerebral magnetic resonance imaging (MRI) at follow-up (2016-2018). CMBs at baseline and follow-up were evaluated on T2*-weighted gradient recalled echo (GRE) and susceptibility-weighted angiography (SWAN) sequence of MRI. We classified baseline BP into four categories: normal BP, elevated systolic BP, stage 1 hypertension and stage 2 hypertension according to the ACC/AHA guideline. We assessed the associations between BP categories and incident CMBs by generalized linear models.

Results: A total of 159 participants (median age, 67 years) completed follow-up examinations with a mean interval of 6.9 years. Both stage 1 and stage 2 hypertension at baseline were significantly related with a higher risk of incident CMBs (IRR 2.77, 95% CI, 1.11-6.91, P=0.028; IRR 3.04, 95% CI, 1.29-7.16, P=0.011, respectively), indicating dose-response effects across BP categories. Participants with ≥5 incident CMBs or incident CMBs in the deep locations all had baseline stage 1 and 2 hypertension.

Conclusions: Participants with baseline stage 1 and stage 2 hypertension had a significantly higher risk of incident CMBs in this 7-year longitudinal community cohort.
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http://dx.doi.org/10.21037/atm-20-5142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944264PMC
February 2021

Metabolically healthy obesity and risk of stroke: a meta-analysis of prospective cohort studies.

Ann Transl Med 2021 Feb;9(3):197

Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.

Background: Metabolic healthy obesity (MHO) is a unique subgroup of overweight and obese individuals with normal metabolic characteristics. Its association with the risk of stroke remains unclear. We aimed to examine the risk of stroke in MHO individuals and the further associations between stroke and metabolic abnormalities under different bodyweight conditions.

Methods: We systematically searched PubMed, Embase and Cochrane Library from December 1946 to January 2019, and only included prospective cohort studies. Random effects models were used to evaluate the pooled risk ratios (RR) and 95% confidence intervals (95% CI) of incident stroke.

Results: A total of eight studies comprising 4,256,888 participants were included in the meta-analysis. MHO individuals had an increased risk of stroke compared with metabolically healthy normal weight (MH-NW) individuals (RR =1.17, 95% CI: 1.11-1.23). However, the stroke risk of metabolically healthy overweight individuals was the same (RR =1.02, 95% CI: 0.84-1.23). All groups with unhealthy metabolism had a similarly elevated risk: normal weight (RR =1.83, 95% CI: 1.57-2.14), overweight (RR =1.93, 95% CI: 1.44-2.58), and obesity (RR =2.00, 95% CI: 1.40-2.87).

Conclusions: The meta-analysis confirms a positive association between MHO phenotype and the risk of stroke. Individuals with metabolic abnormalities under different bodyweight conditions are at elevated risk.
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http://dx.doi.org/10.21037/atm-20-4387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940916PMC
February 2021

Factors for incidence risk and prognosis in non-small-cell lung cancer patients with synchronous brain metastasis: a population-based study.

Future Oncol 2021 Mar 12. Epub 2021 Mar 12.

Department of Ultrasound, The 941st Hospital of the PLA Joint Logistic Support Force, Xining, 810007, China.

We aimed to investigate the epidemiology of synchronous brain metastasis (SBM) in non-small-cell lung cancer (NSCLC) patients. Logistic regression and Cox regression were used to identify the related factors of SBM incidence and cancer-specific survival (CSS). A nomogram for predicting CSS was developed and validated. The incidence of SBM in NSCLC patients was 12.58%. The median CSS was 5 months. Patients with younger age, female gender, and adenocarcinoma had higher odd ratios for developing SBM. In addition, a nomogram was developed based on significant factors from Cox regression. The validation of the nomogram showed that it had good calibration and discrimination. SBM was highly prevalent in NSCLC patients, who also had poor survival.
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http://dx.doi.org/10.2217/fon-2021-0103DOI Listing
March 2021

Identification of geographical origins of Panax notoginseng based on HPLC multi-wavelength fusion profiling combined with average linear quantitative fingerprint method.

Sci Rep 2021 Mar 4;11(1):5126. Epub 2021 Mar 4.

Development and Utilization of Chinese Medicine Resources Key Laboratory Breeding Base, Key Laboratory of Systematic Research, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.

The aim of this study was to establish a method for geographical origins identification of Panax notoginseng (P. notoginseng) based on abundant chromatographic spectral information. Characteristic fingerprints of P. notoginseng extracts samples were generated by Multi-wavelength Fusion Profiling (MWFP) method based on the HPLC fingerprints established at three wavelengths of 203 nm, 270 nm and 325 nm. The samples grouping results calculated with the averagely linear quantified fingerprint method (ALQFM) and the unsupervised statistical methods based on fusion fingerprints matches with the geographical origins. The Multi-wavelength Fusion Profiling (MWFP) method has been successfully applied to identification of geographical origins of P. notoginseng and shows the advantages compared with single-channel fingerprints. In addition, eight physiologically active components, including four saponins, two flavones and two amino acids, were identified from the most relevant ingredients of P. notoginseng geographical origins by fusion fingerprint-efficacy relationship analysis. Besides the recognized active saponins, other categories of active ingredients such as flavonoids and amino acids should be paid attention to in the producing areas identification or the quality judgment of P. notoginseng.
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http://dx.doi.org/10.1038/s41598-021-84589-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933339PMC
March 2021

Differences between primary peritoneal serous carcinoma and advanced serous ovarian carcinoma: a study based on the SEER database.

J Ovarian Res 2021 Feb 27;14(1):40. Epub 2021 Feb 27.

Department of Oncology, Qijiang Hospital of the First Affiliated Hospital of Chongqing Medical University, Qijiang, Chongqing, 401420, China.

Objective: This study aimed to compare clinical features and overall survival (OS) between patients with primary peritoneal serous carcinoma (PPSC) and those with advanced serous ovarian carcinoma (ASOC) and to identify prognostic factors.

Methods: Patients diagnosed with PPSC and ASOC from 2010 to 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were enrolled. Pearson's chi-square test was used to compare clinical features. The primary endpoint was OS. The Kaplan-Meier method and log-rank test were used to perform the survival analysis. Propensity score matching was also conducted. Univariate, multivariate and subgroup analyses were performed using the Cox proportional hazards model.

Results: A total of 708 PPSC patients and 7610 ASOC patients were enrolled. The clinical features of PPSC patients were noticeably different from those of ASOC patients. The survival analysis showed that PPSC patients had poorer outcomes than ASOC patients. Even after the clinical features were balanced, PPSC patients still had poorer survival. Univariate and multivariate analyses indicated that older age, higher tumor grade and advanced American Joint Committee on Cancer stage were adverse prognostic factors in both groups, while surgery and chemotherapy were protective factors. A subgroup analysis demonstrated that most factors favored ASOC patients. The total distant metastasis rates of PPSC and ASOC were similar. Liver or lung metastasis was common, but bone and brain metastases were rare. A higher proportion of liver metastasis was observed in the ASOC group.

Conclusion: The clinical features and survival outcomes between PPSC patients and ASOC patients are clearly different, and PPSC is more aggressive than ASOC.
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http://dx.doi.org/10.1186/s13048-021-00788-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916278PMC
February 2021

Spatiotemporal trends in stroke burden and mortality attributable to household air pollution from solid fuels in 204 countries and territories from 1990 to 2019.

Sci Total Environ 2021 Jun 13;775:145839. Epub 2021 Feb 13.

Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai 200438, China; Fudan University Taizhou Institute of Health Sciences, Taizhou 225312, Jiangsu, China. Electronic address:

Exposure to household air pollution from solid fuels (HAP) is associated with stroke. However, few studies have assessed stroke burden attributable to HAP globally and made comparisons across countries. We aimed to estimate the spatiotemporal trends in stroke burden and mortality attributable to household air pollution from solid fuels (HAP) in 204 countries and territories from 1990 to 2019. Data on stroke burden and mortality attributable to HAP from 1990 to 2019 were obtained from Global Burden of Disease Study 2019. We estimated the numbers and age-standardized rates (ASRs) of stroke disability-adjusted life years (DALYs) and mortality (ASDR and ASMR) by sex, age, and subtype, at global, regional, and national levels. Estimated annual percentage change (EAPC) was calculated to evaluate the temporal trends in ASDR and ASMR from 1990 to 2019. In 2019, globally, 14.7 million DALYs and 0.6 million deaths were caused by stroke attributable to HAP. The corresponding ASDR and ASMR increased with age, were highest in males and for intracerebral hemorrhage, with highest ASRs in the low sociodemographic index (SDI) regions and Solomon Islands, and varied greatly at the national level. From 1990 to 2019, the corresponding EAPCs in ASDR and ASMR were -4.00 (95% confidence interval [CI]: -4.21 to -3.80) and -4.12 (95% CI: -4.37 to -3.87), respectively. Stroke burden attributable to HAP decreased in all age groups. Females had a lower decreasing trend in ASDR and ASMR, compared with males. The decline was more significant for subarachnoid hemorrhage, while proportions of ischemic stroke in the numbers of stroke burden increased worldwide and in all SDI regions. Although most of countries and territories were in a decreasing trend in ASRs over the past three decades, Zimbabwe and Philippines showed an undesirable increased trend. Stroke burden attributable to HAP is still pronounced in males, old-age populations, low-income countries, and for intracerebral hemorrhage. Despite its decreasing spatiotemporal trends in most countries, continued efforts on HAP control are needed to reduce related stroke burden, especially in those countries with increased trends.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145839DOI Listing
June 2021

Role of Blood Pressure Management in Stroke Prevention: A Systematic Review and Network Meta-Analysis of 93 Randomized Controlled Trials.

J Stroke 2021 Jan 31;23(1):1-11. Epub 2021 Jan 31.

Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

Background And Purpose: The present study aimed to compare the efficacy and tolerability of different blood pressure (BP)-lowering strategies.

Methods: Randomized controlled trials that compared various antihypertensive treatments and stroke outcomes were included. Eligible trials were categorized into three scenarios: single or combination antihypertensive agents against placebos; single or combination agents against other agents; and different BP-lowering targets. The primary efficacy outcome was the risk reduction pertaining to strokes. The tolerability outcome was the withdrawal of drugs, owing to drug-related side effects (PROSPERO registration number CRD42018118454 [20/12/2018]).

Results: The present study included 93 trials (average follow-up duration, 3.3 years). In the pairwise analysis, angiotensin-converting enzyme inhibitors (ACEis) and beta-blockers (BBs) were inferior to calcium channel blockers (CCBs) (odds ratio [OR], 1.123; 95% confidence interval [CI], 1.008 to 1.252) (OR, 1.261; 95% CI, 1.116 to 1.425) for stroke prevention, BB was inferior to angiotensin II receptor blockers (ARB) (OR, 1.361; 95% CI, 1.142 to 1.622), and diuretics were superior to ACEi (OR, 0.871; 95% CI, 0.771 to 0.984). The combination of ACEi+CCB was superior to ACEi+diuretic (OR, 0.892; 95% CI, 0.823 to 0.966). The network meta-analysis confirmed that diuretics were superior to BB (OR, 1.34; 95% CI, 1.11 to 1.58), ACEi+diuretic (OR, 1.47; 95% CI, 1.02 to 2.08), BB+CCB (OR, 2.05; 95% CI, 1.05 to 3.79), and renin inhibitors (OR, 1.87; 95% CI, 1.25 to 2.75) for stroke prevention. Regarding the tolerability profile, the pairwise analysis revealed that ACEi was inferior to CCB and less tolerable, compared to the other treatments.

Conclusions: Monotherapy using diuretics, CCB, or ARB, and their combinations could be employed as first-line treatments for stroke prevention in terms of efficacy and tolerability.
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http://dx.doi.org/10.5853/jos.2020.02698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900391PMC
January 2021

What Is the "Optimal" Target Mismatch Criteria for Acute Ischemic Stroke?

Front Neurol 2020 13;11:590766. Epub 2021 Jan 13.

Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.

We aimed to compare Perfusion Imaging Mismatch (PIM) and Clinical Core Mismatch (CCM) criteria in ischemic stroke patients to identify the effect of these criteria on selected patient population characteristics and clinical outcomes. Patients from the INternational Stroke Perfusion Imaging REgistry (INSPIRE) who received reperfusion therapy, had pre-treatment multimodal CT, 24-h imaging, and 3 month outcomes were analyzed. Patients were divided into 3 cohorts: endovascular thrombectomy (EVT), intravenous thrombolysis alone with large vessel occlusion (IVT-LVO), and intravenous thrombolysis alone without LVO (IVT-nonLVO). Patients were classified using 6 separate mismatch criteria: PIM-using 3 different measures to define the perfusion deficit (Delay Time, Tmax, or Mean Transit Time); or CCM-mismatch between age-adjusted National Institutes of Health Stroke Scale and CT Perfusion core, defined as relative cerebral blood flow <30% within the perfusion deficit defined in three ways (as above). We assessed the eligibility rate for each mismatch criterion and its ability to identify patients likely to respond to treatment. There were 994 patients eligible for this study. PIM with delay time (PIM-DT) had the highest inclusion rate for both EVT (82.7%) and IVT-LVO (79.5%) cohorts. In PIM positive patients who received EVT, recanalization was strongly associated with achieving an excellent outcome at 90-days (e.g., PIM-DT: mRS 0-1, adjusted OR 4.27, = 0.005), whereas there was no such association between reperfusion and an excellent outcome with any of the CCM criteria (all > 0.05). Notably, in IVT-LVO cohort, 58.2% of the PIM-DT positive patients achieved an excellent outcome compared with 31.0% in non-mismatch patients following successful recanalization ( = 0.006). PIM-DT was the optimal mismatch criterion in large vessel occlusion patients, combining a high eligibility rate with better clinical response to reperfusion. No mismatch criterion was useful to identify patients who are most likely response to reperfusion in non-large vessel occlusion patients.
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http://dx.doi.org/10.3389/fneur.2020.590766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874100PMC
January 2021

Sequential tirofiban infusions combined with endovascular treatment may improve outcomes in acute ischemic stroke - a meta-analysis.

Aging (Albany NY) 2021 02 11;13(4):5426-5441. Epub 2021 Feb 11.

Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.

In this meta-analysis, we explored whether tirofiban could safely improve outcomes when combined with endovascular therapy in acute ischemic stroke with large vessel occlusion. We searched the PubMed, EMBASE, Web of Science, and The Cochrane Library databases from January 2000 to October 2019 for relevant RCTs/non-RCTs. A total of 13 trials involving 2584 patients, of whom 893 (34.5%) received tirofiban, were ultimately included in the meta-analysis. The results suggested that tirofiban improved patient independence at 90 days (51.2% vs 42.4%; OR 1.26; =0.02) without increasing the risk of symptomatic intracranial hemorrhage (OR 1.01; =0.96) or mortality (OR 0.86; =0.09). There was no association between the use of tirofiban and recanalization rate (OR 1.35; =0.11). Subgroup analysis showed that a loading dose followed by maintenance doses, but not a single dose, of tirofiban increased favorable 90-day functional outcomes (OR 1.49; =0.0008). Moreover, low maintenance doses may be more effective than high maintenance doses (OR 1.41; =0.02). These results suggest that adjunctive tirofiban treatment administered as a loading dose followed by low-dose maintenance may improve functional outcomes of endovascular therapy in acute ischemic stroke.
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http://dx.doi.org/10.18632/aging.202473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950282PMC
February 2021

Social Isolation, Social Interaction, and Alzheimer's Disease: A Mendelian Randomization Study.

J Alzheimers Dis 2021 ;80(2):665-672

Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.

Background: Social isolation and social interaction have been suggested to be associated with Alzheimer's disease. However, the causality cannot be unambiguously assessed as traditional epidemiological methods are easily subject to unmeasured confounders and potential bias.

Objective: To examine bidirectional relationships between social isolation, social interaction, and Alzheimer's disease using Mendelian randomization method for assessing potential causal inference.

Methods: This bidirectional two-sample Mendelian randomization study used independent genetic variants associated with social isolation and social interaction (n = 302,567-487,647), and Alzheimer's disease (n = 455,258). MR analyses were performed using the inverse-variance-weighted (IVW) as the main MR analytical method to estimate the causal effect. For sensitivity analyses, we applied weighted median, MR Egger to further assess the credibility of the causal effect.

Results: Of the five types of social engagement examined in our study, only one showed evidence of an association with the risk of Alzheimer's disease. Attendance at a gym or sports club (IVW OR per SD change: 0.670; 95% CI: 0.463-0.970; p = 0.034) was inversely associated with the risk of Alzheimer's disease. We also found that AD may reduce the attendance at religious group (IVW OR per SD change: 1.017; 95% CI: 1.005-1.030; p = 0.004).

Conclusion: This study suggests that regular attendance at a gym or sports club is causally associated with reduced risk of Alzheimer's disease. Further studies are warranted to elucidate potential mechanisms.
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http://dx.doi.org/10.3233/JAD-201442DOI Listing
January 2021

Genetically determined blood pressure, antihypertensive medications, and risk of Alzheimer's disease: a Mendelian randomization study.

Alzheimers Res Ther 2021 02 9;13(1):41. Epub 2021 Feb 9.

Department of Neurology and Institute of Neurology, WHO Collaborating Center for Research and Training in Neurosciences, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

Background: Observational studies suggest that the use of antihypertensive medications (AHMs) is associated with a reduced risk of Alzheimer's disease (AD); however, these findings may be biased by confounding and reverse causality. We aimed to explore the effects of blood pressure (BP) and lowering systolic BP (SBP) via the protein targets of different AHMs on AD through a two-sample Mendelian randomization (MR) approach.

Methods: Genetic proxies from genome-wide association studies of BP traits and BP-lowering variants in genes encoding AHM targets were extracted. Estimates were calculated by inverse-variance weighted method as the main model. MR Egger regression and leave-one-out analysis were performed to identify potential violations.

Results: There was limited evidence that genetically predicted SBP/diastolic BP level affected AD risk based on 400/398 single nucleotide polymorphisms (SNPs), respectively (all P > 0.05). Suitable genetic variants for β-blockers (1 SNP), angiotensin receptor blockers (1 SNP), calcium channel blockers (CCBs, 45 SNPs), and thiazide diuretics (5 SNPs) were identified. Genetic proxies for CCB [odds ratio (OR) = 0.959, 95% confidence interval (CI) = 0.941-0.977, P = 3.92 × 10] and overall use of AHMs (OR = 0.961, 95% CI = 0.944-0.978, P = 5.74 × 10, SNPs = 52) were associated with a lower risk of AD. No notable heterogeneity and directional pleiotropy were identified (all P > 0.05). Additional analyses partly support these results. No single SNP was driving the observed effects.

Conclusions: This MR analysis found evidence that genetically determined lowering BP was associated with a lower risk of AD and CCB was identified as a promising strategy for AD prevention.
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http://dx.doi.org/10.1186/s13195-021-00782-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874453PMC
February 2021

Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer's disease.

Transl Psychiatry 2021 Feb 2;11(1):89. Epub 2021 Feb 2.

Department of Neurology and Institute of Neurology, WHO Collaborating Center for Research and Training in Neurosciences, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

The bridging integrator 1 (BIN1) gene is the second most important susceptibility gene for late-onset Alzheimer's disease (LOAD) after apolipoprotein E (APOE) gene. To explore whether the BIN1 methylation in peripheral blood changed in the early stage of LOAD, we included 814 participants (484 cognitively normal participants [CN] and 330 participants with subjective cognitive decline [SCD]) from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Then we tested associations of methylation of BIN1 promoter in peripheral blood with the susceptibility for preclinical AD or early changes of cerebrospinal fluid (CSF) AD-related biomarkers. Results showed that SCD participants with significant AD biological characteristics had lower methylation levels of BIN1 promoter, even after correcting for covariates. Hypomethylation of BIN1 promoter were associated with decreased CSF Aβ42 (p = 0.0008), as well as increased p-tau/Aβ42 (p = 0.0001) and t-tau/Aβ42 (p < 0.0001) in total participants. Subgroup analysis showed that the above associations only remained in the SCD subgroup. In addition, hypomethylation of BIN1 promoter was also accompanied by increased CSF p-tau (p = 0.0028) and t-tau (p = 0.0130) in the SCD subgroup, which was independent of CSF Aβ42. Finally, above associations were still significant after correcting single nucleotide polymorphic sites (SNPs) and interaction of APOE ɛ4 status. Our study is the first to find a robust association between hypomethylation of BIN1 promoter in peripheral blood and preclinical AD. This provides new evidence for the involvement of BIN1 in AD, and may contribute to the discovery of new therapeutic targets for AD.
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http://dx.doi.org/10.1038/s41398-021-01218-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854626PMC
February 2021

Association of Plasma Neurofilament Light With Small Vessel Disease Burden in Nondemented Elderly: A Longitudinal Study.

Stroke 2021 Mar 1;52(3):896-904. Epub 2021 Feb 1.

Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, China (X.-N.S., H.-Q.L., M.C., Q.D., J.-T.Y.).

Background And Purpose: Neurofilament light chain (NfL) is a promising predictive biomarker of active axonal injury and neuronal degeneration diseases. We aimed to evaluate if an increase in plasma NfL levels could play a monitoring role in the progression of cerebral small vessel disease (CSVD) among the nondemented elders, which are highly prevalent in elderly individuals and associated with an increased risk of stroke and dementia.

Methods: The study included 496 nondemented participants from the Alzheimer disease neuroimaging initiative database. All participants underwent plasma NfL measurements and 3.0-Tesla magnetic resonance imaging of the brain; 387 (78.0%) underwent longitudinal measurements. The number of cerebral microbleeds, lacunar infarcts, and volumetric white matter hyperintensities, as well as Fazekas scores, were measured. Cross-sectional and longitudinal associations between CSVD burden and NfL levels were evaluated using multivariable-adjusted models.

Results: Plasma NfL was higher in the moderate-severe CSVD burden group (45.2±16.0 pg/mL) than in the nonburden group (34.3±15.1 pg/mL; odds ratio [OR]=1.71 [95% CI, 1.24-2.35]) at baseline. NfL was positively associated with the presence of cerebral microbleeds (OR=1.29 [95% CI, 1.01-1.64]), lacunar infarcts (OR=1.43 [95% CI, 1.06-1.93]), and moderate-severe white matter hyperintensities (OR=1.67 [95% CI, 1.24-2.25]). Longitudinally, a higher change rate of NfL could predict more progression of CSVD burden (OR=1.38 [95% CI, 1.08-1.76]), white matter hyperintensities (OR=1.41 [95% CI, 1.10-1.79]), and lacunar infarcts (OR=1.99 [95% CI, 1.42-2.77]).

Conclusions: Plasma NfL level is a valuable noninvasive biomarker that supplements magnetic resonance imaging scans and possibly reflects the severity of CSVD burden. Furthermore, high plasma NfL levels tend to represent an increased CSVD risk, and dynamic increases in NfL levels might predict a greater progression of CSVD.
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http://dx.doi.org/10.1161/STROKEAHA.120.030302DOI Listing
March 2021