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Backgrounds Freezing of gait (FOG) and cognitive impairment are serious symptoms of Parkinson’s disease (PD). Understanding the association between FOG and cognition may help formulate specific interventions for PD individuals. Objectives We aimed to investigate the associations of cognitive impairment in different domains with FOG status using multiple neuropsychological tests. Methods Two cohorts including 691 and 104 participants were recruited from Parkinson’s progression markers initiative (PPMI) and central China, respectively. All participants underwent FOG assessment and neuropsychological tests, and 595 individuals from PPMI and 51 from central China were enrolled for longitudinal observation. Cross-sectional and longitudinal associations between cognition and FOG status were evaluated using multivariable-adjusted models. Results Worse cognitive performances were observed in patients with FOG compared to those without FOG in both cohorts (β = − 0.020, p p Conclusions FOG is a risk factor for cognitive decline in PD, which emphasizes the need for early detection and monitoring of cognitive changes and interventions on cognitive impairments in PD patients with FOG.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons (DA) and the accumulation of Lewy body deposits composed of alpha-Synuclein (α-Syn), which act as antigenic epitopes to drive cytotoxic T-cell responses in PD. Increased T helper 17 (Th17) cells and dysfunctional regulatory T cells (Tregs) have been reported to be associated with the loss of DA in PD. However, the mechanism underlying the Th17/Treg imbalance remains unknown.Here, we examined the percentage of Th17 cells, the percentage of Tregs and the α-Syn level and analysed their correlations in the peripheral blood of PD patients and in the substantia nigra pars compacta (SNpc) and spleen of MPTP-treated mice and A53 transgenic mice. We assessed the effect of α-Syn on the stability and function of Tregs and the differentiation of Th17 cells and evaluated the role of retinoid-related orphan nuclear receptor (RORγt) upregulation in α-Syn stimulation in vivo and in vitro.We found that the α-Syn level and severity of motor symptoms were positively correlated with the increase in Th17 cells and decrease in Tregs in PD patients. Moreover, α-Syn stimulation led to the loss of Forkhead box protein P3 (FOXP3) expression in Tregs, accompanied by the acquisition of IL-17A expression. Increased Th17 differentiation was detected upon α-Syn stimulation when naïve CD4Together, our data suggest that α-Syn promotes the transcription of RORC in circulating CD4

BACKGROUND This study aimed to investigate the risk factors and patterns of cerebral microbleeds (CMBs) in Parkinson disease (PD) and the impact of CMBs on cognitive function and quality of life (QoL). MATERIAL AND METHODS Patients with PD that underwent susceptibility-weighted imaging were recruited and divided into CMB-free, lobar-CMB, deep-CMB, and mixed-CMB groups according to CMB location. Motor function (MDS-UPDRS III), cognitive abilities (MoCA, MMSE), and QoL (PDQ-39) were compared among groups. The risk factors for CMBs in patients with PD and the association between CMBs and cognition and QoL were analyzed using multivariable logistic regression models and linear regression models. RESULTS Among the 209 patients with PD, 42 (20.1%) had CMBs. Lobar, deep, and mixed CMBs were observed in 15 (35.7%), 17 (40.5%), and 10 (23.8%) patients, respectively. A higher frequency of hypertension was independently associated with deep CMBs (odds ratio [OR]=4.379, 95% CI: 1.405-13.643, P=0.011). The deep-CMB and mixed-CMB groups had lower MoCA scores and MMSE scores than the CMB-free group, especially in domains of naming, attention, and orientation (P0.05). Additionally, the presence of CMBs was associated with lower MMSE (R²=0.140, ß=-0.301, P0.001) and MoCA (R²=0.104, ß=-0.289, P0.001) and higher PDQ-39 (R²=0.052, ß=0.227, P0.05) scores, while the association between CMBs and PDQ-39 disappeared after adjustment of MMSE or MoCA as a covariate. CONCLUSIONS The results suggest that hypertension was associated with the occurrence of deep CMBs. Comorbidity with CMBs may impair cognitive function and indirectly reduce the QoL in patients with PD.

Yayuan Liu,1,&ast; Lizhi Lu,1,&ast; Xuemin Cheng,1 Qixiong Qin,1 Yunfei Wei,2 Dacheng Wang,3 Haihua Li,4 Guohui Li,5 Hongbin Liang,6 Shengyu Li,7 Zhijian Liang1 1Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, People’s Republic of China; 2Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi Province, People’s Republic of China; 3Department of Neurology, The Ninth Affiliated Hospital of Guangxi Medical University, Beihai, 536000, Guangxi Province, People’s Republic of China; 4Department of Neurology, Fusui County People’s Hospital, Chongzuo, 532100, Guangxi Province, People’s Republic of China; 5Department of Neurology, Wuzhou Red Cross Hospital, Wuzhou, 543002, Guangxi Province, People’s Republic of China; 6Department of Neurology, Cenxi People’s Hospital, Cenxi, 543200, Guangxi Province, People’s Republic of China; 7Department of Neurology, The Affiliated Wuming Hospital of Guangxi Medical University, Nanning, 530100, Guangxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhijian Liang, Department of Neurology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi, 530000, People’s Republic of China, Tel +86-771-5330705, Fax +86-771-5352627, Email liangzhijian@gxmu.edu.cnPurpose: To investigate independent risk factors for esophageal cancer-related ischemic stroke (ECIS) and to use them to develop an index of ECIS to help clinicians identify patients at high risk for ECIS or to identify ECIS from other types of ischemic stroke.Methods: We retrospectively enrolled active esophageal cancer (EC) patients with acute ischemic stroke (ECIS group) and patients with active EC without ischemic stroke (EC group), age- and sex-matched with ECIS patients, at seven centers from January 2011 to December 2020. Clinical data and laboratory and imaging findings were collected. Univariate and multivariate analyses were performed to analyze the independent risk factors for ECIS. Optimal cutoffs for sensitivities and specificities were obtained by Youden’s J statistic following a receiver operator characteristic (ROC) analysis of each risk factor and the product of the risk factors.Results: A total of 91 ECIS patients and 91 EC patients were included. Elevated levels of carcinoembryonic antigen (CEA) [odds ratio (OR) = 0.105, 95% confidence interval (CI): 1.051– 1.174, P < 0.001], D-dimer (DD) (OR = 0.003, 95% CI: 1.002– 1.004, P < 0.001), and neutrophil count (OR = 0.857, 95% CI: 1.628– 3.407, P < 0.001) were independent risk factors for ECIS. The area under the curve (AUC) of each independent risk factor and the product of the three independent risk factors were calculated by a receiver operator characteristic (ROC) curve, and the cutoff value from the largest AUC was called the ECIS index.Conclusion: It was suggested that elevated plasma DD and CEA levels and increased neutrophils in EC patients may altogether contribute to the development of ECIS. The index of ECIS may facilitate clinicians to identify patients at high risk for ECIS or to identify ECIS from other etiologic types of ischemic stroke.Keywords: independent risk factors, carcinoembryonic antigen, D-dimer, neutrophil count

This retrospective study was designed to investigate the independent risks and specific biomarker for breast cancer-related ischemic stroke (BCRS).Clinical features and laboratory findings were compared between BCRS group and breast cancer group without stroke, and further multivariate analyses were performed to predict independent risks factors for BCRS patients. A receiver operator characteristic (ROC) curve analysis was configured to estimate the diagnostic efficacy of each independent risk and the product of these risks and to obtain the optimal cut-off value of diagnosis, which was termed the BCRS Index.BCRS patients had elevated plasma D-dimer and CA153 levels and platelet-to-lymphocyte ratio (PLR), as well as more patients received endocrine therapy (allEndocrine therapy, as well as elevated plasma D-dimer and CA153 levels and PLR values may be independent risks for BCRS. Furthermore, BCRS Index should be served as a novel specific biomarker for BCRS, which is useful to distinguish BCRS for clinicians.

Background: The occurrence of ischemic stroke in patients with non-Hodgkin lymphoma (NHL) is not well understood. This study aimed to determine independent risk factors to identity ischemic stroke in non-Hodgkin lymphoma-associated ischemic stroke (NHLAIS) patients. Methods: This retrospective study was conducted on NHLAIS patients and age- and gender-matched NHL patients. We collected clinical data of patients in both groups and used multiple logistic regression analysis to identify independent risk factors for NHLAIS. A receiver operating characteristic (ROC) analysis was used to establish an identification model based on potential risk factors of NHLAIS. Results: Sixty-three NHLAIS patients and 63 NHL patients were enrolled. Stage III/IV (58/63, 92.1%) and multiple arterial infarcts (44/63, 69.8%) were common among NHLAIS patients. Notably, NHLAIS patients had higher levels of serum fibrinogen (FIB), D-dimer, and ferritin (SF) and prolonged thromboplastin time and prothrombin time (PT) compared with NHL patients (all p < 0.05). Elevated FIB, D-dimer, and SF and prolonged PT were independent risk factors for NHLAIS. The area under the ROC curve of the identification model of NHLAIS patients was largest compared to that of other risk factors (0.838, 95% confidence interval: 0.759–0.899) (p < 0.05). Conclusion: This study reveals that elevated serum FIB, D-dimer, and SF and prolonged PT are potential independent risk factors of NHLAIS. The identification model established in this study may help monitor NHL patients who are at high risk of developing NHLAIS.

strongBACKGROUND/strongIschemic stroke in cancer patients is associated with poor prognosis. However, the specific biomarkers of cancer-associated ischemic stroke (CaIS) have not been well defined.strongMATERIAL AND METHODS/strongA retrospective study was conducted on PCaIS patients. Clinical data and laboratory and imaging findings were collected. Multivariable logistic regression analysis was used to analyze the independent risk factors for PCaIS. A multiple model combining the independent risk factors of PCaIS was developed using the receiver operating characteristic (ROC) and area under the ROC curve (AUC).strongRESULTS/strongA total of 83 PCaIS patients and 83 prostate cancer (PCa) patients were included. PCaIS patients had higher levels of D-dimer, neutrophil-to-lymphocyte ratio (NLR), and total prostate-specific antigen (T-PSA). In the multivariate analysis, D-dimer [OR=1.001, 95% CI: 1.00,1.00,iP/i=0.002], NLR [OR=1.12, 95% CI: 1.04,1.22,iP/i=0.005], and T-PSA [OR=6.275, 95% CI: 2.57,15.31,iP/i0.001] were independent risk factors of PCaIS. Additionally, the AUC of the multiple model of PCaIS was 0.815 (95% CI, 0.750-0.869), with sensitivity of 81.71% and specificity of 70.21%.strongCONCLUSIONS/strongElevated levels of D-dimer and T-PSA and increased NLR are independent risk factors of PCaIS. The multiple model of PCaIS can be a specific biomarker and is a reliable predictor of development of PCaIS.

BACKGROUND Alzheimer disease (AD) is a typical progressive and destructive neurodegenerative disease that has been studied extensively. However, genetic features and molecular mechanisms underlying AD remain unclear. Here we used bioinformatics to investigate the candidate nuclear genes involved in the molecular mechanisms of AD. MATERIAL AND METHODS First, we used Gene Expression Omnibus (GEO) database to obtain the expression profiles of the mRNAs from hippocampus microarray and identify differentially expressed genes (DEGs) the plier algorithm. Second, functional annotation and visualization of the DEGs were conducted by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Finally, BioGRID, IntAct, STRING, and Cytoscape were utilized to construct a protein-protein interaction (PPI) network. Hub genes were analytically obtained from the PPI network and the microRNA (miRNA)-target network. RESULTS Two hippocampus microarrays (GSE5281 and GSE48350) were obtained from the GEO database, comprising 161 and 253 cases separately. Among these, 118 upregulated genes and 694 downregulated genes were identified. The upregulated DEGs were mainly involved in positive regulation of transcription from RNA polymerase II promoter, positive regulation of cartilage development, and response to wounding. The downregulated DEGs were enriched in chemical synaptic transmission, neurotransmitter secretion, and learning. By combining the results of PPI and miRNA-target network, 8 genes and 2 hub miRNAs were identified, including YWHAZ, DLG4, AGAP2, EGFR, TGFBR3, PSD3, RDX, BRWD1, and hsa-miR-106b-5p and hsa-miR-93-5p. These target genes are highly enriched in various key pathways, such as amyloid-beta formation, regulation of cardiocyte differentiation, and actin cytoskeleton reorganization. CONCLUSIONS In this study, YWHAZ, DLG4, AGAP2, EGFR, TGFBR3, PSD3, RDX, and BRWD1 were identified as candidate genes for future molecular studies in AD, which is expected to improve our understanding of its cause and potential molecular mechanisms. Nuclear genes, DEGs, and related networks identified by integrated bioinformatics analysis may serve as diagnostic and therapeutic targets for AD.

BACKGROUND The combined effects of bilateral corticospinal tract (CST) reorganization and interhemispheric functional connectivity (FC) reorganization on motor recovery of upper and lower limbs after stroke remain unknown. MATERIAL AND METHODS A total of 34 patients underwent magnetic resonance imaging (MRI) examination at weeks 1, 4, and 12 after stroke, with a control group of 34 healthy subjects receiving 1 MRI examination. Interhemispheric FC in the somatomotor network (SMN) was calculated using the resting-state functional MRI (rs-fMRI). Fractional anisotropy (FA) of bilateral CST was recorded as a measure of reorganization obtained from diffusion tensor imaging (DTI). After intergroup comparisons, multiple linear regression analysis was used to explore the effects of altered FA and interhemispheric FC on motor recovery. RESULTS Interhemispheric FC restoration mostly occurred within 4 weeks after stroke, and FA in ipsilesional remained CST consistently elevated within 12 weeks. Multivariate linear regression analysis showed that the increase in both interhemispheric FC and ipsilesional CST-FA were significantly correlated with greater motor recovery from week 1 to week 4 following stroke. Moreover, only increased FA of ipsilesional CST was significantly correlated with greater motor recovery during weeks 4 to 12 after stroke compared to interhemispheric FC. CONCLUSIONS Our results show dynamic structural and functional reorganizations following motor stroke, and structure reorganization may be more related to motor recovery at the late subacute phase. These results may play a role in guiding neurological rehabilitation.

Objective To investigate the independent risk factors and potential predictors of bladder cancer-related ischemic stroke (BCRIS). Methods This was a multi-center retrospective study including patients with active bladder cancer and acute ischemic stroke without traditional stroke risk factors (BCRIS group), and sex- and age-matched patients with active bladder cancer alone (control group). Data were collected between January 2006 and December 2018. Uni- and multivariate analyses were performed to identify independent risk factors for BCRIS. The predictive performance of these risk factors was assessed using receiver operating characteristic (ROC) curves. Results Records were retrospectively reviewed from 60 BCRIS patients and 120 bladder cancer controls. Univariate analysis revealed that serum D-dimer and carcinoembryonic antigen (CEA) levels and the platelet and neutrophil counts were significantly higher in BCRIS patients compared with controls. Multivariate analysis identified the three above-mentioned variables as independent risk factors for BCRIS. The product of all three factors gave the largest area under the ROC curve. Conclusions Elevated serum D-dimer and CEA levels and increased platelet count were independent risk factors for BCRIS, and the cut-off value based on the product of the three independent risk factors (≥2,640,745.29) could serve as a potential predictor of BCRIS.

Lung cancer related hypercoagulability could increase the risk of ischemic stroke. Routine coagulation tests may have limited capacity in evaluating hypercoagulability. The aim of this study was to investigate the ability of thromboelastography (TEG) in the identification of hypercoagulability in patients with lung cancer and cryptogenic ischemic stroke (LCIS). Between January 2016 and December 2018, whole citrated blood from LCIS patients (n = 35) and age- and gender-matched lung cancer patients and healthy volunteers were used for TEG and routine coagulation tests. The coagulation indicator and clinical data were compared among the 3 groups. There were 27/35 (77.14%) on TEG and 18/35 (51.43%) on routine coagulation tests of LCIS patients who had evidence of hypercoagulability. The detection rate of hypercoagulability by TEG in LCIS patients was higher than routine coagulation tests ( P = 0.018). Comparing with lung cancer patients and healthy controls, LCIS patients have a significantly higher maximum amplitude (MA), fibrinogen, and D-dimer. Multivariate analysis showed that D-dimer and MA were significantly associated with ischemic stroke in lung cancer patients. ROC curve showed that the area under the curve of TEG (0.790 ± 0.048, 95% CI: 0.697-0.864) was significantly higher than routine coagulation tests (0.673 ± 0.059, 95% CI: 0.572-0.763) ( P = 0.04) in identifying hypercoagulability in LCIS patients. Therefore, TEG could identify hypercoagulability in LCIS patients and healthy controls. Identification of hypercoagulability in lung cancer patients by TEG may be helpful to prevent the occurrence of LCIS.

AIM To investigate the specific biomarkers and potential pathogenesis of colorectal cancer-related ischemic stroke (CRCIS). METHODS A retrospective study was conducted on CRCIS patients (colorectal cancer patients with ischemic stroke without conventional stroke risk factors) registered at seven centers between January 2007 and December 2017. Clinical data and laboratory and imaging findings were compared with age- and sex- matched patients with colorectal cancer (CRC) without ischemic stroke that were admitted to the same hospital during the same period. Univariate and multivariate analyses were performed to analyze the independent risk factors for CRCIS. A receiver operator characteristic curve was configured to calculate the optimal cut-off value of the products of the independent risk factors for CRCIS. RESULTS A total of 114 CRCIS patients and 114 CRC patients were included. Multiple lesions in multiple vascular territories were common in CRCIS patients (71, 62.28%). The levels of plasma D-dimer, carcinoembryonic antigen (CEA), cancer antigen 125, and neutrophil count were significantly higher in CRCIS patients than in CRC patients. Multiple logistic regression analysis revealed that plasma D-dimer levels [odds ratio (OR) = 1.002, 95% confidence interval (CI): 1.001-1.003, P < 0.001], CEA levels (OR = 1.011, 95%CI: 1.006-1.015, P < 0.001), and neutrophil count levels (OR = 1.626, 95%CI: 1.268-2.087, P < 0.001) were independent risk factors for CRCIS. In addition, receiver operator characteristic curve revealed that the area under curve for the products of plasma D-dimer, CEA, and neutrophil count was 0.889 ± 0.022 (95%CI: 0.847-0.932, P < 0.001), and the optimal cut-off value for the product was 252.06, which was called the CRCIS Index, with a sensitivity of 86.0% and specificity of 79.8%. CONCLUSION Hypercoagulability induced by elevated CEA and neutrophils may be an important cause of CRCIS. The CRCIS index, which serves as a biomarker of CRCIS, needs further study.

To investigate the pathogenesis of somatic solid cancer-related cerebral venous sinus thrombosis (CVST). A total of 174 patients with CVST were recruited from the hospital between January 2006 and December 2017 and divided into two groups: (1) somatic cancer-related CVST group, defined as active somatic solid cancer patients with acute CVST; (2) cancer group (CG), defined as active somatic solid cancer patients without CVST. The cancer group patients were age and gender-matched somatic cancer-related CVST group patients. In addition, the types and amount distribution of cancer in cancer group were also matched with somatic cancer-related CVST group patients. Compared to cancer group patients, somatic cancer-related CVST group patients had more intracranial metastasis, a higher platelet count, higher plasma D-dimer, carcinoembryonic antigen (CEA) and cancer antigen (CA) 125 levels, a greater platelet to lymphocyte ratio (PLR), and a greater platelet to neutrophil ratio (PNR). The risk for CVST in somatic cancer-related CVST group patients increased independently by 0.7% (odds ratio [OR] 1.007; 95% confidence interval [CI] 1.000, 1.015; P = .047) with a 1 ng/ml increase in D-dimer levels, by 4.6% (OR 1.046; 95% CI 1.011, 1.083; P = .010) with a 1 U/ml increase in CEA, by 2.7% (OR 1.027; 95% CI 1.003, 1.051; P = .025) with a 1 U/ml increase in CA125, and by 10.6% (OR 1.106; 95% CI 1.002, 1.220; P = .045) with a 1 unit increase in PNR. It was suggested that together impacts of elevated plasma D-dimer, CA125, CEA levels, and a greater PNR may lead to hypercoagulability and to trigger the development of cancer-related CVST.