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    Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Ritchie Craig,Smailagic Nadja,Noel-Storr Anna H,Takwoingi Yemisi,Flicker Leon,Mason Sam E,McShane Rupert The Cochrane database of systematic reviews BACKGROUND:According to the latest revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) (NINCDS-ADRDA) diagnostic criteria for Alzheimer's disease dementia of the National Institute on Aging and Alzheimer Association, the confidence in diagnosing mild cognitive impairment (MCI) due to Alzheimer's disease dementia is raised with the application of biomarkers based on measures in the cerebrospinal fluid (CSF) or imaging. These tests, added to core clinical criteria, might increase the sensitivity or specificity of a testing strategy. However, the accuracy of biomarkers in the diagnosis of Alzheimer's disease dementia and other dementias has not yet been systematically evaluated. A formal systematic evaluation of sensitivity, specificity, and other properties of plasma and CSF amyloid beta (Aß) biomarkers was performed. OBJECTIVES:To determine the accuracy of plasma and CSF Aß levels for detecting those patients with MCI who would convert to Alzheimer's disease dementia or other forms of dementia over time. SEARCH METHODS:The most recent search for this review was performed on 3 December 2012. We searched MEDLINE (OvidSP), EMBASE (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Web of Science and Conference Proceedings (ISI Web of Knowledge), PsycINFO (OvidSP), and LILACS (BIREME). We also requested a search of the Cochrane Register of Diagnostic Test Accuracy Studies (managed by the Cochrane Renal Group).No language or date restrictions were applied to the electronic searches and methodological filters were not used so as to maximise sensitivity. SELECTION CRITERIA:We selected those studies that had prospectively well defined cohorts with any accepted definition of cognitive decline, but no dementia, with baseline CSF or plasma Aß levels, or both, documented at or around the time the above diagnoses were made. We also included studies which looked at data from those cohorts retrospectively, and which contained sufficient data to construct two by two tables expressing plasma and CSF Aß biomarker results by disease status. Moreover, studies were only selected if they applied a reference standard for Alzheimer's dementia diagnosis, for example the NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. DATA COLLECTION AND ANALYSIS:We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. We assessed the identified full papers for eligibility and extracted data to create standard two by two tables. Two independent assessors performed quality assessment using the QUADAS-2 tool. Where data allowed, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic (ROC) curve. MAIN RESULTS:Alzheimer's disease dementia was evaluated in 14 studies using CSF Aß42. Of the 1349 participants included in the meta-analysis, 436 developed Alzheimer's dementia. Individual study estimates of sensitivity were between 36% and 100% while the specificities were between 29% and 91%. Because of the variation in assay thresholds, we did not estimate summary sensitivity and specificity. However, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary ROC curve. At the median specificity of 64%, the sensitivity was 81% (95% CI 72 to 87). This equated to a positive likelihood ratio (LR+) of 2.22 (95% CI 2.00 to 2.47) and a negative likelihood ratio (LR-) of 0.31 (95% CI 0.21 to 0.48).The accuracy of CSF Aß42 for all forms of dementia was evaluated in four studies. Of the 464 participants examined, 188 developed a form of dementia (Alzheimer's disease and other forms of dementia).The thresholds used were between 209 mg/ml and 512 ng/ml. The sensitivities were between 56% and 75% while the specificities were between 47% and 76%. At the median specificity of 75%, the sensitivity was estimated to be 63% (95% CI 22 to 91) from the meta-analytic model. This equated to a LR+ of 2.51 (95% CI 1.30 to 4.86) and a LR- of 0.50 (95% CI 0.16 to 1.51).The accuracy of CSF Aß42 for non-Alzheimer's disease dementia was evaluated in three studies. Of the 385 participants examined, 61 developed non-Alzheimer's disease dementia. Since there were very few studies and considerable variation between studies, the results were not meta-analysed. The sensitivities were between 8% and 63% while the specificities were between 35% and 67%.Only one study examined the accuracy of plasma Aß42 and the plasma Aß42/Aß40 ratio for Alzheimer's disease dementia. The sensitivity of 86% (95% CI 81 to 90) was the same for both tests while the specificities were 50% (95% CI 44 to 55) and 70% (95% CI 64 to 75) for plasma Aß42 and the plasma Aß42/Aß40 ratio respectively. Of the 565 participants examined, 245 developed Alzheimer's dementia and 87 non-Alzheimer's disease dementia.There was substantial heterogeneity between studies. The accuracy of Aß42 for the diagnosis of Alzheimer's disease dementia did not differ significantly (P = 0.8) between studies that pre-specified the threshold for determining test positivity (n = 6) and those that only determined the threshold at follow-up (n = 8). One study excluded a sample of MCI non-Alzheimer's disease dementia converters from their analysis. In sensitivity analyses, the exclusion of this study had no impact on our findings. The exclusion of eight studies (950 patients) that were considered at high (n = 3) or unclear (n = 5) risk of bias for the patient selection domain also made no difference to our findings. AUTHORS' CONCLUSIONS:The proposed diagnostic criteria for prodromal dementia and MCI due to Alzheimer's disease, although still being debated, would be fulfilled where there is both core clinical and cognitive criteria and a single biomarker abnormality. From our review, the measure of abnormally low CSF Aß levels has very little diagnostic benefit with likelihood ratios suggesting only marginal clinical utility. The quality of reports was also poor, and thresholds and length of follow-up were inconsistent. We conclude that when applied to a population of patients with MCI, CSF Aß levels cannot be recommended as an accurate test for Alzheimer's disease. 10.1002/14651858.CD008782.pub4
    RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial. Ahmed Heba A,Ishrat Tauheed,Pillai Bindu,Fouda Abdelrahman Y,Sayed Mohammed A,Eldahshan Wael,Waller Jennifer L,Ergul Adviye,Fagan Susan C Journal of neuroinflammation BACKGROUND:With the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as well as the number of individuals with vascular cognitive impairment/dementia (VCID). No specific FDA-approved treatments for VCID exist. Although clinical evidence supports that angiotensin receptor blockers (ARBs) prevent cognitive decline in older adults, whether ARBs have a similar effect on VCID after stroke is unknown. Moreover, these agents reduce BP, which is undesirable in the acute stroke period, so we believe that giving C21 in this acute phase or delaying ARB administration would enable us to achieve the neurovascular benefits without the risk of unintended and potentially dangerous, acute BP lowering. METHODS:The aim of our study was to determine the impact of candesartan (ARB) or compound-21 (an angiotensin type 2 receptor--AT2R--agonist) on long-term cognitive function post-stroke, in spontaneously hypertensive rats (SHRs). We hypothesized that AT2R stimulation, either directly with C21, or indirectly by blocking the angiotensin type 1 receptor (AT1R) with candesartan, initiated after stroke, would reduce cognitive impairment. Animals were subjected to a 60-min transient middle cerebral artery occlusion and randomly assigned to either saline/C21 monotherapy, for the full study duration (30 days), or given sequential therapy starting with saline/C21 (7 days) followed by candesartan for the remainder of the study (21 days). Outcome measures included sensorimotor/cognitive-function, amyloid-β determination, and histopathologic analyses. RESULTS:Treatment with RAS modulators effectively preserved cognitive function, reduced cytotoxicity, and prevented chronic-reactive microgliosis in SHRs, post-stroke. These protective effects were apparent even when treatment was delayed up to 7 days post-stroke and were independent of blood pressure and β-amyloid accumulation. CONCLUSION:Collectively, our findings demonstrate that RAS modulators effectively prevent cognitive impairment after stroke, even when treatment is delayed. 10.1186/s12974-018-1262-x
    Assessment of Plasma Amyloid-β42/40 and Cognitive Decline Among Community-Dwelling Older Adults. Giudici Kelly Virecoulon,de Souto Barreto Philipe,Guyonnet Sophie,Li Yan,Bateman Randall John,Vellas Bruno, JAMA network open Importance:Plasma measurement of amyloid-β (Aβ) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce. Objective:To investigate the associations between plasma Aβ42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns. Design, Setting, and Participants:This multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020. Exposure:Plasma Aβ42 and Aβ40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of Aβ assessment was defined as the baseline for this study. Main Outcomes and Measures:Cognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study-Activities of Daily Living. Mixed-effect linear regressions were performed. Results:A total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma Aβ42/40 (≤0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ε4 genotype, and MAPT intervention groups, low plasma Aβ42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: -0.20, 95% CI, -0.34 to -0.07; P = .004) and decline in MMSE score (adjusted between-group mean difference: -0.59; 95% CI, -1.07 to -0.11; P = .02) during the follow-up period compared with the group with an Aβ42/40 ratio greater than 0.107. Conclusions and Relevance:In this study, low plasma Aβ42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma Aβ42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement. 10.1001/jamanetworkopen.2020.28634
    Racial Disparity in Cerebrospinal Fluid Amyloid and Tau Biomarkers and Associated Cutoffs for Mild Cognitive Impairment. Garrett Stephanie L,McDaniel Darius,Obideen Malik,Trammell Antoine R,Shaw Leslie M,Goldstein Felicia C,Hajjar Ihab JAMA network open Importance:Prior evidence suggests that racial differences exist in tau biomarkers in mild cognitive impairment (MCI) and Alzheimer disease (AD). Whether this reported disparity is associated with a differential level of neurodegeneration and disease stage or with underlying mechanisms separate from amyloid or tau is unclear. Objectives:To compare cerebrospinal fluid (CSF) biomarkers in African American and white individuals with normal cognition and MCI, to estimate race-based cutoffs for these biomarkers that maximize diagnostic discrimination between normal cognition and MCI, and to study the association of demographic characteristics, cognitive performance, and common vascular risk factors with these differences. Design, Setting, and Participants:This case-control study conducted from March 1, 2016, through January 31, 2019, included participants in the Brain Stress Hypertension and Aging Research Program cohort undergoing baseline assessment. Participants were 50 years or older and recruited from the Atlanta, Georgia, area. Exposures:Self-reported race and cognitive status categorized using modified Petersen criteria and clinical consensus diagnosis. Main Outcomes and Measures:Levels of β-amyloid 1-42 (Aβ1-42), tau, and phosphorylated tau 181 (pTau181), the ratio of tau or pTau181 to Aβ1-42, and hippocampal volume on magnetic resonance imaging of the brain. Results:Data from 362 study participants were analyzed (mean [SD] age, 65.6 [7.9] years), of whom 152 (42.0%) were African American, 230 (63.5%) were women, and 189 (52.2%) had MCI. After adjustment for demographic characteristics and cognitive performance, lower mean (SE) levels were observed in African American vs white individuals with MCI for tau (52.40 [5.90] vs 78.98 [5.02] pg/mL; P = .001) and pTau181 (15.42 [2.06] vs 25.24 [1.75] pg/mL; P = .001) and a lower pTau181 to Aβ1-42 ratio (0.07 [0.02] vs 0.14 [0.01]; P = .003). There were no racial differences in the normal cognition group or in hippocampal volumes in the MCI group. Cutoffs for CSF biomarkers were higher for Aβ1-42 in African American relative to white individuals (208 [95% CI, 126-321] vs 197 [95% CI, 183-245] pg/mL) and lower for tau (51 [95% CI, 31-59] vs 59 [95% CI, 56-92] pg/mL) and pTau181 (12 [95% CI, 12-19] vs 20 [95% CI, 12-27] pg/mL) levels. Cutoffs for the pTau181 to Aβ1-42 ratio were 0.05 (95% CI, 0.03-0.12) for African American participants and 0.05 (95% CI, 0.05-0.13) for white participants. Conclusions and Relevance:This study found that African American individuals had lower levels of tau-based biomarkers that were not likely explained by the degree of disease stage or neurodegeneration reflected by hippocampal volumes. This study suggests that race is an important factor when interpreting CSF biomarkers, especially in the clinical diagnosis of prodromal AD. It appears that using the pTau181 to Aβ1-42 ratio may ameliorate these differences. 10.1001/jamanetworkopen.2019.17363
    Plasma Amyloid-β Levels, Cerebral Small Vessel Disease, and Cognition: The Rotterdam Study. Hilal Saima,Akoudad Saloua,van Duijn Cornelia M,Niessen Wiro J,Verbeek Marcel M,Vanderstichele Hugo,Stoops Erik,Ikram M Arfan,Vernooij Meike W Journal of Alzheimer's disease : JAD BACKGROUND:Plasma amyloid-β (Aβ) levels are increasingly studied as a potential, accessible marker of cognitive impairment and dementia. The most common plasma Aβ isoforms, i.e., Aβ1-40 and Aβ1-42 have been linked with risk of Alzheimer's disease. However, it remains under-explored whether plasma Aβ levels including novel Aβ1-38 relate to vascular brain disease and cognition in a preclinical-phase of dementiaObjective:To examine the association of plasma Aβ levels (i.e., Aβ1-38, Aβ1-40, and Aβ1-42) with markers of cerebral small vessel disease (SVD) and cognition in a large population-based setting. METHODS:We analyzed plasma Aβ1 levels in 1201 subjects from two independent cohorts of the Rotterdam Study. Markers of SVD [lacunes, white matter hyperintensity (WMH) volume] were assessed on brain MRI (1.5T). Cognition was assessed by a detailed neuropsychological battery. In each cohort, the association of Aβ levels with SVD and cognition was performed using regression models. Estimates were then pooled across cohorts using inverse variance meta-analysis with fixed effects. RESULTS:Higher levels of plasma Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-40/ Aβ1-42 ratio were associated with increasing lacunar and microbleeds counts. Moreover, higher levels of Aβ1-40 and Aβ1-40/ Aβ1-42 were significantly associated with larger WMH volumes. With regard to cognition, a higher level of Aβ1-38 Aβ1-40 and Aβ1-40/ Aβ1-42 was related to worse performance on cognitive test specifically in memory domain. CONCLUSION:Higher plasma levels of Aβ levels are associated with subclinical markers of vascular disease and poorer memory. Plasma Aβ levels thus mark the presence of vascular brain pathology. 10.3233/JAD-170458
    Plasma Amyloid Beta and Tau Levels Are Predictors of Post-stroke Cognitive Impairment: A Longitudinal Study. Chi Nai-Fang,Chao Shu-Ping,Huang Li-Kai,Chan Lung,Chen Yih-Ru,Chiou Hung-Yi,Hu Chaur-Jong Frontiers in neurology Post-stroke cognitive impairment (PSCI) is a common disease that may occur within 3 months after a stroke or even later. However, the mechanism of PSCI development is unclear. The present study investigated whether the levels of plasma amyloid beta-42 (Aβ42) and tau are associated with the onset of PSCI. Fifty-five patients admitted within 7 days of acute ischemic stroke were enrolled and followed up for 1 year. Montreal Cognitive Assessment (MoCA) was administered at 3 months and 1 year, and plasma Aβ42 and tau levels were determined using an ultrasensitive immunoassay (immunomagnetic reduction) within 7 days of the stroke event and 3 months later. In this study, 13 of 55 patients developed PSCI (MoCA score <23) at 3 months. Seven patients with PSCI at 3 months recovered to a cognitively normal state at 1 year, whereas seven cognitively normal patients developed PSCI at 1 year. The patients with PSCI at 1 year had a higher incidence of cognitive function deterioration between 3 months and 1 year compared with those without PSCI at 1 year. Plasma Aβ42 and tau levels at 3 months were lower in the patients with PSCI at 1 year than in those without PSCI (Aβ42: 15.1 vs. 17.2 pg/mL, = 0.013; tau: 16.7 vs. 19.9 pg/mL, = 0.018). Low education levels and pre-existing white matter disease were the most significant predictors of PSCI at 3 months, and poor cognitive performance at 3 months and low plasma Aβ42 and tau levels at 3 months were the most significant predictors of PSCI at 1 year. The pathogenesis of PSCI is complex and changes with time. Ischemia-induced Aβ42/tau pathology might be involved in PSCI development. 10.3389/fneur.2019.00715
    Elevation of Plasma Amyloid-β Level is More Significant in Early Stage of Cognitive Impairment: A Population-Based Cross-Sectional Study. Wang Jin,Qiao Fan,Shang Suhang,Li Pei,Chen Chen,Dang Liangjun,Jiang Yu,Huo Kang,Deng Meiying,Wang Jingyi,Qu Qiumin Journal of Alzheimer's disease : JAD BACKGROUND:Aggregation and deposition of amyloid-β (Aβ) in the brain is the main pathological change of Alzheimer's disease (AD). Decreased Aβ42 in the cerebrospinal fluid has been confirmed as a biomarker of AD; however, the relationship between plasma Aβ and cognitive impairment is currently unclear. OBJECTIVE:The aim was to explore the relationship between plasma Aβ and cognitive impairment in a cross-sectional study. METHODS:A total of 1,314 subjects (age above 40) from a village in the suburbs of Xi'an, China were enrolled between October 8, 2014 and March 30, 2015. A validated Chinese version of the Mini-Mental State Examination and neuropsychological battery were used to assess cognition. Levels of plasma Aβ42 and Aβ40 were tested using commercial enzyme-linked immunosorbent assay. Relationship of plasma Aβ and cognitive impairment was analyzed using logistic regression analysis. RESULTS:Of the enrolled subjects, 1,180 (89.80%) had normal cognition, 85 (6.47%) had possible cognitive impairment and 49 (3.73%) had probable cognitive impairment. Logistic regression analysis showed that the Aβ42/Aβ40 ratio (OR = 4.042, 95% CI: 1.248-11.098, p = 0.012) and plasma Aβ42 (OR = 1.036, 95% CI: 1.003-1.071, p = 0.031) was higher in the possible cognitive impairment than that in the normal cognition group. Furthermore, the plasma Aβ42/Aβ40 ratio was higher in the possible cognitive impairment group than that in the probable cognitive impairment group (OR = 0.029, 95% CI: 0.002-0.450, p = 0.011). CONCLUSIONS:Levels of plasma Aβ42 and Aβ42/Aβ40 ratio were elevated in patients with possible cognitive impairment, indicating that plasma Aβ42 and Aβ42/Aβ40 ratio increases may be more pronounced in early stage of cognitive impairment. 10.3233/JAD-180140
    High levels of plasma fibrinogen are related to post-stroke cognitive impairment. Liu Yuntao,Chen Huijun,Zhao Kai,He Weilei,Lin Shasha,He Jincai Brain and behavior INTRODUCTION:Studies have shown that high levels of the fibrinogen (FIB) are related to cognitive deficits. However, the relationship between fibrinogen and cognitive deficit after stroke remains unclear. Therefore, we explored the relationship between plasma fibrinogen and post-stroke cognitive impairment (PSCI). METHODS:This study is carried out in the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China. A total of 210 patients with acute ischemic stroke were enrolled in this study. Ultimately, 134 patients completed 3-month follow-up. Blood samples were collected at hospital admission. Cognitive function was evaluated 3 months after stroke. All patients underwent the Mini-Mental State Examination (MMSE) after 3 months. RESULTS:Higher levels of fibrinogen were observed in patients with post-stroke cognitive impairment compared with the non-PSCI group (p < .001). Additionally, elevated plasma fibrinogen levels were independently associated with PSCI (odds ratio [OR] = 2.000, 95% CI 1.062-3.770 p = .032). The plasma fibrinogen levels were negatively correlated with the 3-month MMSE scores (r = -.171, p = .048). In a multivariate linear regression, FIB was negatively associated with the 3-month MMSE scores after adjustment for the other variables (β = -0.782, p = .035). CONCLUSION:High levels of plasma fibrinogen were associated with the presence and severity of PSCI. 10.1002/brb3.1391
    Potential of serum metabolites for diagnosing post-stroke cognitive impairment. Liu Min,Zhou Kaige,Li Hailong,Dong Xin,Tan Guangguo,Chai Yifeng,Wang Weizhong,Bi Xiaoying Molecular bioSystems Cognitive impairment commonly accompanies clinical syndromes associated with stroke. The identification of laboratory markers of post-stroke cognitive impairment (PSCI) may help detect patients at increased risk of cognitive deterioration and determine the appropriate treatment regimes. A non-targeted metabolomics approach based on ultra-high performance liquid chromatography coupled with Q-TOF mass spectrometry was applied to study PSCI. The stroke patients were significantly distinguishable from the healthy subjects. Stroke patients could be well-stratified based on cognitive impairment. Several differential serum metabolites were further identified for post-stroke non-cognitive impairment (PSNCI) and PSCI patients, suggesting metabolic dysfunction in inflammation, neurotoxicity, bioenergetic homeostasis, oxidative stress, and apoptosis. In total, three serum metabolites (glutamine, kynurenine, and LysoPC(18:2)) were identified as candidate diagnostic biomarkers for PSCI, and their combined use yielded good diagnostic capacity for PSCI by receiver operating characteristic curves. The present metabolomics study provided a novel strategy for stratifying stroke patients with cognitive impairment using serum-based metabolite markers, which could be of great importance in understanding the pathological mechanisms and determining the appropriate treatment regimes of PSCI patients. 10.1039/c5mb00470e
    Midterm Blood Pressure Variability Is Associated with Poststroke Cognitive Impairment: A Prospective Cohort Study. Geng Shan,Liu Na,Meng Pin,Ji Niu,Sun Yong'an,Xu Yingda,Zhang Guanghui,He Xiaobing,Cai Zenglin,Wang Bei,Xu Bei,Li Zaipo,Niu Xiaoqin,Zhang Yongjin,Xu Bingchao,Zhou Xinyu,He Mingli Frontiers in neurology OBJECTIVE:The aim of this study was to investigate the relationship between blood pressure variability (BPV) and poststroke cognitive impairment (PSCI). METHODS:Seven-hundred ninety-six patients with acute ischemic stroke were included in this study. Midterm BPV was evaluated by calculating the SD and coefficient of variation (CV, 100 × SD/mean) of systolic blood pressure (SBP) and diastolic blood pressure during the 7 days after stroke onset. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) at admission and at all follow-up visits. Patients with MoCA scores <26 were considered to have PSCI. RESULTS:The incidence of PSCI reached its peak (72%) 3 months after stroke onset and decreased to 30.3% at 12 months poststroke. After adjusting for covariables, the increase in the prevalence of PSCI at 3 months was independently associated with increases in the CV of blood pressure during the 7 days after stroke [odds ratios and 95% CI for patients in the second to fifth quintiles of SBP CV were 2.28 (1.18, 4.39), 2.33 (1.18, 4.62), 2.69 (1.31, 5.53), and 4.76 (1.95, 11.67), respectively]. Sub-analysis of the MoCA scores revealed that the patients had impairments in visuoperceptual abilities and executive functions, as well as in naming and delayed recall ( < 0.05). CONCLUSION:Midterm BPV during the early phase of acute ischemic stroke is independently associated with PSCI, especially in the visuoperceptual, executive, and delayed recall domains. CLINICAL TRIAL REGISTRATION:http://www.chictr.org.cn, identifier ChiCTR-TRC-14004804. 10.3389/fneur.2017.00365
    Relationship between β-amyloid protein 1-42, thyroid hormone levels and the risk of cognitive impairment after ischemic stroke. Mao Lei,Chen Xiao-Han,Zhuang Jian-Hua,Li Peng,Xu Yi-Xin,Zhao Yu-Chen,Ma Yue-Jin,He Bin,Yin You World journal of clinical cases BACKGROUND:Post-stroke cognitive impairment (PSCI) is not only a common consequence of stroke but also an important factor for adverse prognosis of patients. Biochemical indicators such as blood lipids and blood pressure are affected by many factors, and the ability of evaluating the progress of patients with PSCI is insufficient. Therefore, it is necessary to find sensitive markers for predicting the progress of patients and avoiding PSCI. Recent studies have shown that β-amyloid protein 1-42 (Aβ1-42) and thyroid hormone levels are closely related to PSCI, which may be the influencing factors of PSCI, but there are few related studies. AIM:To investigate the relationship between serum levels of Aβ and thyroid hormones in acute stage and PSCI and its predicted value. METHODS:A total of 195 patients with acute cerebral infarction confirmed from June 2016 to January 2018 were enrolled in this study. Baseline data and serological indicators were recorded to assess cognitive function of patients. All patients were followed up for 1 year. Their cognitive functions were evaluated within 1 wk, 3 mo, 6 mo and 1 yr after stroke. At the end of follow-up, the patients were divided into PSCI and non-PSCI according to Montreal cognitive assessment score, and the relationship between biochemical indexes and the progression of PSCI was explored. RESULTS:Compared with patients with non-PSCI, the levels of Aβ1-42, triiodothyronine (T) and free thyroxin were lower in the patients with PSCI. Repeated measures analysis of variance showed that the overall content of Aβ1-42 and T in PSCI was also lower than that of the non-PSCI patients. Further analysis revealed that Aβ1-42 ( = 0.348), T ( = 0.273) and free thyroxin ( = 0.214) were positively correlated with disease progression ( < 0.05), suggesting that these indicators have the potential to predict disease progression and outcome. Cox regression analysis showed that Aβ1-42 and T were important factors of PSCI. Then stratified analysis showed that the lower the Aβ1-42 and T, the higher risk of PSCI in patients who were aged over 70, female and illiterate. CONCLUSION:Aβ1-42 and T3 have the ability to predict the progression of PSCI, which is expected to be applied clinically to reduce the incidence of PSCI and improve the quality of life of patients. 10.12998/wjcc.v8.i1.76
    The association between serum uric acid level and the risk of cognitive impairment after ischemic stroke. Sun Jing,Lv Xinhuang,Gao Xinxin,Chen Zewei,Wei Dianhui,Ling Yi,Zhang Junmei,Gu Qilu,Liu Jiaming,Chen Weian,Liu Suzhi Neuroscience letters Post-stroke cognitive impairment (PSCI) is a severe complication of stroke. Predicting PSCI is difficult because some risk factors for stroke, such as blood glucose level and blood pressure, are affected by many other elements. Although recent studies have shown that high serum uric acid (UA) levels are associated with cognitive dysfunction and may be a risk factor for PSCI, its impact remains unclear. Accordingly, the present study aimed to explore the association between serum UA level and PSCI. In total, 274 patients who experienced acute cerebral infarction, confirmed between January 2016 and December 2018, were enrolled. Baseline data and biological indicators were recorded. According to the Montreal Cognitive Assessment (MoCA) scores, patients were divided into two groups: PSCI and non-PSCI. Logistic regression analysis was used to determine possible risk factors for PSCI. Results demonstrated that serum UA levels were significantly higher in the PSCI group than in the non-PSCI group. Multivariable logistic analysis revealed that age, years of education, and UA level were independent risk factors for PSCI. PSCI patients were subdivided according to serum UA level: high and low. Hypertension history and homocysteine (Hcy) levels differed significantly between the high and low UA level groups. Further analysis revealed that a history of hypertension and Hcy demonstrated a certain correlation (r = 0.163, 0.162; P < 0.05), suggesting that serum UA level was an independent risk factor for PSCI. These findings indicate that serum UA level was correlated with PSCI in post-stroke patients and is anticipated to be used in clinical practice to reduce the incidence of PSCI. 10.1016/j.neulet.2020.135098
    Higher level of acute serum VEGF and larger infarct volume are more frequently associated with post-stroke cognitive impairment. Prodjohardjono Astuti,Vidyanti Amelia Nur,Susianti Noor Alia,Sudarmanta ,Sutarni Sri,Setyopranoto Ismail PloS one BACKGROUND:Serum vascular endothelial growth factor (VEGF) and infarct volume detected by brain imaging have been associated with stroke outcome. However, the relationship of these two variables with post-stroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between acute serum VEGF levels and infarct volume with PSCI in ischemic stroke patients. METHODS:Fifty-six first-ever ischemic stroke patients who were hospitalized in Dr. Sardjito General Hospital Yogyakarta, Indonesia were prospectively recruited. Serum VEGF level was taken on day 5 of stroke onset and measured by ELISA. Infarct volume was calculated manually from head CT scan by expert radiologist. PSCI was assessed after 3 months follow up by using Montreal Cognitive Assessment-Indonesian version (MoCA-INA). We performed a ROC curve analysis to determine the cut-off point of VEGF level and infarct volume. Multivariate logistic regression analysis was performed to measure the contribution of VEGF level and infarct volume to PSCI after controlling covariates (demographic and clinical data). RESULTS:The mean age of PSCI and non-PSCI patients was 61.63% ± 8.47 years and 58.67% ± 9.01 years, respectively (p = 0.221). No differences observed for vascular risk factors, infarct location, and NIHSS in both groups. Multivariate logistic regression showed that patients with higher VEGF level alone (≥519.8 pg/ml) were 4.99 times more likely to have PSCI than those with lower VEGF level (OR = 4.99, 95% CI = 1.01-24.7, p = 0.048). In addition, patients with larger infarct volume alone (≥0.054 ml) were also more frequently associated with PSCI (OR = 7.71, 95% CI = 1.39-42.91, p = 0.019). CONCLUSIONS:Acute ischemic stroke patients with higher serum VEGF level (≥519.8 pg/ml) and larger infarct volume (≥0.054 ml) were more likely to have PSCI 3 months after stroke. These findings may contribute to predict PSCI earlier and thus better prevention strategy could be made. 10.1371/journal.pone.0239370
    Plasma parameters and risk factors of patients with post-stroke cognitive impairment. Wu Ji-Xia,Xue Jian,Zhuang Lei,Liu Chun-Feng Annals of palliative medicine BACKGROUND:It is high of the incidence of stroke and dementia with the advent of an aging society. Post-stroke cognitive impairment is one of the common complications of stroke, which not only seriously affects the life quality of patients, but also significantly reduces the survival time of stroke patients. Moreover, it also brings in heavy burden to the family and society. The development of vascular dementia could be reduced by early intervention after stroke. Management of vascular risk factors could be an effective way to prevent dementia. This study aimed to investigate the plasma biochemical parameters of post-stroke cognitive impairment (PSCI) and its potential risk factors. METHODS:Four hundred eighty-seven consecutive patients with ischaemic stroke were included and followed up for 3 years. Among these patients, 132 cases were diagnosed as PSCI. The cognitive impairment of patients with PSCI was assessed by the Mini Mental State Examination and Montreal cognitive assessment scale. The plasma biochemical parameters and blood coagulation, as well as computed tomography and magnetic resonance imaging of all the patients after admission, were measured. RESULTS:Multivariate analyses revealed that increased age, carotid plaque, cerebral atrophy, white matter lesions (WML), alcohol use, smoking and history of systolic blood pressure ≥170 mmHg was highly associated with PSCI (P<0.05). Elevated homocysteine, low-density lipoprotein (LDL), and uric acid were also highly associated with PSCI. Logistic regression analysis identified five risk factors correlated with PSCI including alcohol use [odds ratio (OR): 5.138, 95% confidence interval (CI): 1.014-26.04, P=0.048], history of high systolic blood pressure (OR: 12.171, 95% CI: 3.339-44.363, P=0.001), carotid plaque (OR: 1.692, 95% CI: 1.032-2.796, P=0.040), cerebral atrophy (OR: 2.280, 95% CI: 1.294-4.001, P=0.004), and WML (OR: 3.155, 95% CI: 1.868-5.324, P=0.001). Three plasma biochemical parameters were also associated with PSCI including homocysteine (OR: 1.018, 95% CI: 0.944-1.042, P=0.010), and LDL (OR: 0.83, 95% CI: 0.6-1.148, P=0.051), and uric acid (OR: 1.00, 95% CI: 0.998-1.002, P=0.007). The area under the receiver operating curve for the risk factors of PSCI was 0.821 with the sensitivity of 76.3% and specificity of 71.9%. CONCLUSIONS:Elevated homocysteine, LDL, and uric acid were highly related to PSCI, which may help predict PSCI. These plasma biochemical parameters together with vascular risk factors, may improve the sensitivity for early detection of PSCI. 10.21037/apm.2019.12.05
    The relationship between inflammatory markers and post stroke cognitive impairment. Rothenburg Lana S,Herrmann Nathan,Swardfager Walter,Black Sandra E,Tennen Gayla,Kiss Alexander,Gladstone David J,Ween Jon,Snaiderman Abraham,Lanctôt Krista L Journal of geriatric psychiatry and neurology OBJECTIVE:To determine whether there is a relationship between inflammatory markers (serum C-reactive protein (CRP) and cytokines) and post stroke cognitive impairment (PSCI). METHODS:This was a cross-sectional observational study. Patients were recruited from 4 sources: (1) the acute stroke unit of a general hospital, (2) an outpatient stroke prevention clinic, (3) a stroke rehabilitation unit in a specialized geriatric hospital, or (4) a stroke rehabilitation unit of a rehabilitation hospital. Patients meeting National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (WHO-MONICA) project criteria for stroke were invited to participate in this study within the first 5 to 31 days post stroke. Patients with subarachnoid or intracranial hemorrhage, decreased level of consciousness, severe aphasia or dysarthria, or a significant acute medical, neurological, or psychiatric illness were excluded. Clinical assessments included the Mini-Mental State Examination (MMSE) for cognition, the National Institutes of Health Stroke Scale (NIHSS) for stroke severity, and the Center for Epidemiological Studies-Depression Scale (CES-D) for depressive symptoms. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum concentrations of CRP, interleukin 6 (IL-6), and interferon gamma (IFN-gamma). RESULTS:A total of 48 patients with ischemic stroke (age [mean +/- SD] 71.6 +/- 13.2 years, 54.2% male, MMSE 26.4 +/- 3.8, NIHSS 6.8 +/- 4.0) were recruited within their first month post stroke. Backward stepwise elimination linear regression showed that higher concentrations of serum CRP (beta(CRP) = -0.46, p( CRP) = 0.002) predicted lower post stroke global cognition ([MMSE], F1,44 = 11.31, P = .002), with age (P = .92), level of education (P = .22), infarct side (P = 0.49), IL-6 (P = 0.36), and IFN-gamma (P = .57) removed from the final model. CONCLUSIONS:A post stroke inflammatory response may be important in subacute, PSCI. 10.1177/0891988710373598
    [Neuroinflammatory, Neurodegenerative and Structural Brain Biomarkers of the Main Types of Post-Stroke Cognitive Impairment in Acute Period of Ischemic Stroke]. Kulesh A A,Drobakha V E,Nekrasova I V,Kuklina E M,Shestakov V V Vestnik Rossiiskoi akademii meditsinskikh nauk Background:Post-stroke cognitive impairment is a clinically heterogeneous condition, some types of which cannot be fully differentiated neuropsychologically that necessitates the active search for biomarkers. Aims:Analyze parameters of neuroinflammation and neurodegeneration in combination with neuroimaging markers in patients with different types of post-stroke cognitive impairment in acute ischemic stroke. Materials and Methods:In 72 patients we performed the assessment of cognitive status and distinguished 3 types: normal cognition, dysexecutive, and mixed cognitive impairment. In each group we determined the concentration of cytokines (IL-1β, IL-6, TNFα, IL-10) in liquor and serum, β-amyloid 1−40 in liquor and a number of MRI morphometric parameters and fractional anisotropy. Results:In all groups of patients we detected higher level ofIL-10 in serum compared with the control. Patients with dysexecutive cognitive impairment had higher concentration of IL-1β, IL-10 in liquor, IL-6 level in serum, lower fractional anisotropy of ipsilateral thalamus compared with patients with normal cognition and largest size of infarct. Patients with dysexecutive and mixed cognitive impairment had the higher area of leukoareosis and ventricular volume, reduced fractional anisotropy of contralateral cingulum compared with patients with normal cognition. Patients with mixed cognitive impairment characterized by lower fractional anisotropy of contralateral fronto-occipital fasciculus compared with patients with dysexecutive cognitive deficit. Conclusions:Serum and cerebrospinal fluid concentrations of cytokines studied in combination with MRI parameters particularly fractional anisotropy seems to be informative biomarkers of pathogenic types of PSCI. 10.15690/vramn685
    Association Between Small Vessel Disease Markers, Medial Temporal Lobe Atrophy and Cognitive Impairment After Stroke: A Systematic Review and Meta-Analysis. Wang Furu,Hua Sunyu,Zhang Yue,Yu Hongchang,Zhang Zhongshuai,Zhu Jiangtao,Liu Rong,Jiang Zhen Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association OBJECTIVES:Two-thirds of stroke survivors suffer from cognitive impairment, and up to one-third of them progress to dementia. However, the underlying pathogenesis is complex and controversial. Recent evidence has found that cerebral small vessel disease (SVD) markers and the Alzheimer's disease (AD) neuroimaging marker medial temporal lobe atrophy (MTLA), alone or in combination, contribute to the pathogenesis of poststroke cognitive impairment (PSCI). In the present systematic review and meta-analysis, we synthesized proof for these neuroimaging risk factors among stroke patients. MATERIALS AND METHODS:PUBMED, MEDLINE, EMBASE and the Cochrane Library were searched for studies investigating imaging predictors of cognitive impairment or dementia following stroke. Meta-analysis was conducted to compute the odds ratios (ORs). RESULTS:Thirteen studies were enrolled in the present study, and only ten of them, comprising 2713 stroke patients, were eligible for inclusion in the meta-analysis. MTLA was significantly correlated with PSCI (OR = 1.97, 95% CI: 1.48-2.62, I = 0.0%). In addition, white matter hyperintensities (WMH), as a neuroimaging marker of SVD, were associated with PSCI (OR = 1.17, 95% CI: 1.12-1.22, I = 0.0%). However, the presence of lacunar infarcts and enlarged perivascular spaces (EPVS) were not associated with the risk of PSCI. CONCLUSIONS:The findings of the present study suggest that MTLA and WMH were associated with an increased risk of PSCI. 10.1016/j.jstrokecerebrovasdis.2020.105460
    Matrix Metalloproteinase in Blood-Brain Barrier Breakdown in Dementia. Weekman Erica M,Wilcock Donna M Journal of Alzheimer's disease : JAD The neurovascular unit, which consists of astrocytic end-feet, neurons, pericytes, and endothelial cells, plays a key role in maintaining brain homeostasis by forming the blood-brain barrier and carefully controlling local cerebral blood flow. When the blood-brain barrier is disrupted, blood components can leak into the brain, damage the surrounding tissue and lead to cognitive impairment. This disruption in the blood-brain barrier and subsequent impairment in cognition are common after stroke and during cerebral amyloid angiopathy and Alzheimer's disease. Matrix metalloproteinases are proteases that degrade the extracellular matrix as well as tight junctions between endothelial cells and have been implicated in blood-brain barrier breakdown in neurodegenerative diseases. This review will focus on the roles of MMP2 and MMP9 in dementia, primarily post-stroke events that lead to dementia, cerebral amyloid angiopathy, and Alzheimer's disease. 10.3233/JAD-150759
    Serum tissue inhibitor of metalloproteinase-1 and risk of cognitive impairment after acute ischaemic stroke. Ge Jinzhuo,Li Ruyi,Yuan Pengcheng,Che Bizhong,Bu Xiaoqing,Shao Hancheng,Xu Tan,Ju Zhong,Zhang Jintao,Zhang Yonghong,Zhong Chongke Journal of cellular and molecular medicine The expression of tissue inhibitor metalloproteinase-1 (TIMP-1) significantly increased after acute cerebral ischaemia and involved in neurodegeneration. The purpose was to prospectively investigate the relationship between serum TIMP-1 with post-stroke cognitive impairment. Our participants were from an ancillary study of China Antihypertensive Trial in Acute Ischemic Stroke. 598 ischaemic stroke patients from seven participating hospitals were included. Cognitive impairment was evaluated using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at 3 months. 316 (52.84%) or 384 (64.21%) participants had cognitive impairment according to MMSE or MoCA, respectively. Compared with the first quartile of TIMP-1, the multivariate-adjusted odds ratios (95% confidence intervals) for the highest quartile were 1.80 (1.09-2.97) for cognitive impairment defined by MMSE and 2.55 (1.49-4.35) by MoCA. Multiple-adjusted spline regression models showed linear associations between TIMP-1 concentrations and cognitive impairment (P value for linearity < 0.01). The addition of TIMP-1 to models including conventional factors improved reclassification for cognitive impairment, as shown by net reclassification index or integrated discrimination improvement (P < 0.05). Participants with both higher TIMP-1 and matrix metalloproteinase-9 levels simultaneously had highest risk of cognitive impairment. Higher serum TIMP-1 levels were associated with increased risk of cognitive impairment after acute ischaemic stroke, independently of established risk factors. 10.1111/jcmm.15369
    The Determinants of Dementia After Stroke (DEDEMAS) Study: protocol and pilot data. Wollenweber Frank A,Zietemann Vera,Rominger Axel,Opherk Christian,Bayer-Karpinska Anna,Gschwendtner Andreas,Coloma Andrews Lisa,Bürger Katharina,Duering Marco,Dichgans Martin International journal of stroke : official journal of the International Stroke Society RATIONALE:About 20% of stroke patients develop dementia within a few months after their event, but the determinants and mechanisms of poststroke dementia are insufficiently understood. AIMS:To identify and characterize the determinants of cognitive impairment poststroke. DESIGN:Observational prospective study in patients with acute stroke and no prior dementia. Six hundred subjects will be characterized by detailed interview, standardized clinical examinations, biometric measures (intima-media thickness, waist-hip ratio, and ankle-brachial index), multimodal imaging (magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography (FDG-PET), amyloid-positron emission tomography (amyloid-PET), and retinal imaging), analysis of biomarkers derived from blood and cerebrospinal fluid, and detailed cognitive testing at repeat time points. Patients will be followed for five-years with a total of five personal visits and three telephone interviews. STUDY OUTCOMES:Primary end-point is the occurrence of poststroke dementia. Secondary end-points include poststroke cognitive impairment-no dementia, stroke recurrence, and death. Predictive factors for poststroke dementia will be identified by multiple Cox proportional-hazards model. RESULTS:Baseline characteristics of the first 71 patients (study inclusion between May 2011 and August 2012) are as follows: median age, 70 years (interquartile range, 65-75); female gender, 25 (35%); median National Institutes of Health Stroke Scale at admission, 2 (1-4); and etiological stroke subtypes according to TOAST classification, 15% large artery disease, 18% small vessel disease, 35% cardioembolic, and 32% undetermined or multiple competing etiologies. DISCUSSION:This study will provide insights into the mechanisms of poststroke dementia and hold the potential to identify novel diagnostic markers and targets for preventive therapies. The study is registered at http://www.clinicaltrials.gov (NCT01334749) and will be extended as a multicenter study starting 2013. 10.1111/ijs.12092
    Association between plasma immunoproteasome and 90-day prognosis after first-ever ischemic stroke. Chen Xing-Yong,Fu Ming,Wan Shao-Fen,Zhang Xu,Wang Yin-Zhou Neural regeneration research Many blood biomarkers are reportedly helpful for predicting post-stroke cognitive impairment (PSCI), but no biomarkers are widely used in clinical practice. The purpose of this study was to investigate the association between the plasma immunoproteasome and patients' 90-day prognosis after first-ever acute ischemic stroke. In our prospective, single-center study, 259 patients with first-ever acute ischemic stroke were enrolled from the Department of Neurology, Fujian Provincial Hospital, China, from March to September 2014. Of these, 27 patients (10.4%) had unfavorable outcomes as assessed by the Modified Rankin Scale (scores of 3-6). The National Institutes of Health Stroke Scale score on admission, plasma N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels, and immunopro-teasome subunit (low molecular mass peptide [LMP]2, LMP5, and LMP7) levels were significantly higher in the unfavorable outcome group than in the favorable outcome group. To predict unfavorable outcomes, the optimal cutoff points were National Institutes of Health Stroke Scale score > 12, NT-pro-BNP level > 1883.5 pg/mL, and LMP2 level > 841.4 pg/mL. Of the 193 patients that were able to complete the Mini-Mental State Examination at 90 days post-stroke, 66 patients (34.2%) had PSCI. Plasma levels of NT-pro-BNP and LMP2 were higher in patients with PSCI than in those without PSCI. To predict PSCI, the optimal cutoff values were age > 70.5 years and LMP2 level > 630.5 pg/mL. These findings indicate that plasma LMP2 may serve as a new prognostic biomarker of poor outcome and PSCI at 90 days after stroke. This study was approved by the Ethics Committee of Fujian Provincial Hospital, Provincial Clinical Medical College of Fujian Medical University (approval No. K2014-01-003) on January 15, 2014. 10.4103/1673-5374.295344
    Low and high circulating cortisol levels predict mortality and cognitive dysfunction early after stroke. Marklund N,Peltonen M,Nilsson T K,Olsson T Journal of internal medicine OBJECTIVE:Elevated cortisol levels are associated with confusion and poor outcome after stroke. Dehydroepiandrosterone sulphate (DS), the most abundant adrenal androgen may act as an anti-glucocorticoid. An altered regulation of these steroids may affect numerous brain functions, including neuronal survival. The purpose of this study was to investigate serum cortisol and DS levels and the cortisol/DS ratio early after stroke and relate our findings to the presence of disorientation and mortality. DESIGN:Patients with acute ischaemic stroke (n = 88, 56 men and 32 women) admitted to a stroke unit were investigated with repeated clinical assessments and scores for degree of confusion, extent of paresis and level of functioning. Serum cortisol (C) and DS were measured on day 1 and/or day 4. Data for 28-day and 1-year mortality are presented. A control group of 65 age-matched healthy individuals was used. Multivariate analyses of mortality rates in the different tertiles or sixtiles of serum cortisol were performed with logistic regression, adjusting for age, sex, diabetes and level of consciousness. RESULTS:There was no difference in serum cortisol levels on day 1 for stroke patients when compared with control group values. Initial cortisol levels were significantly higher in the patients with acute disorientation versus orientated patients (P < 0.05). Cortisol levels on day 1 were an independent predictor of 28-day mortality, and patients with low cortisol levels (<270 nmol L(-1)) and increased levels (>550 nmol L(-1)) both had an increased 1-year mortality. DS levels on day 1 were significantly elevated in stroke patients. CONCLUSION:Hypercortisolism is associated with cognitive dysfunction early after ischaemic stroke. High and low circulating cortisol levels are associated with increased mortality after stroke. DS levels were not associated with clinical outcome. 10.1111/j.1365-2796.2004.01334.x
    Fibrinogen concentrations predict long-term cognitive outcome in young ischemic stroke patients. Pedersen Annie,Stanne Tara M,Redfors Petra,Viken Jo,Samuelsson Hans,Nilsson Staffan,Jood Katarina,Jern Christina Research and practice in thrombosis and haemostasis Background:Cognitive impairment is frequent after stroke, and young patients may live with this consequence for a long time. Predictors of cognitive outcomes after stroke represent a current gap of knowledge. Objectives:To investigate levels of three hemostatic biomarkers as predictors of long-term cognitive function after stroke. Methods:This longitudinal study included consecutively recruited patients with ischemic stroke at 18-69 years (n = 268). Blood was collected 3 months after index stroke and analyzed for plasma concentrations of fibrinogen, von Willebrand factor (VWF) and tissue-type plasminogen activator (t-PA) antigen. Cognitive function 7 years after index stroke was assessed by the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS). Participants with stroke <50 years of age were also examined by the Trail Making Test A and B (n = 41). Associations between biomarker concentrations and cognitive scales were assessed in the whole group and in participants with stroke <50 years of age. Results:The hemostatic biomarkers fibrinogen, VWF and t-PA, were all correlated to total BNIS score, but these associations did not withstand adjustment for confounding factors in the whole group. However, in patients <50 years, we found an independent association between fibrinogen concentrations and total BNIS score (β= -.27, 95% confidence interval [CI], -0.47 to -0.07) and to performance on the Trail Making Test A (β= .31, 95% CI, 0.03-0.58). No such association was seen for the Trail Making Test B. Conclusion:High convalescent fibrinogen concentrations were associated with worse long-term cognitive outcomes in ischemic stroke <50 years of age. We propose further investigations of fibrinogen in relation to cognitive function in stroke in the young. 10.1002/rth2.12078
    [Association of serum lipoprotein-associated phospholipase A2 with vascular dementia after ischemic stroke]. Zhang Q L,Lu P,Zhang J W Zhonghua yi xue za zhi To study the relationship of serum lipoprotein-associated phospholipase A2 (Lp-PLA2) with vascular dementia (VD) after ischemic stroke. A total of 226 ischemic stroke patients who visited the People's Hospital of Zhengzhou University from June.2013 to Oct.2016 were included and divided into the VD group and the non-dementia group according to the degree of cognitive impairment.The non-dementia group were further divided into the normal cognition group and the vascular cognitive impairment no dementia(VCIND) group.The general information of all patients were collected and the serum Lp-PLA2, Hcy, hs-CRP and the blood lipid indexes were detected.The Logistic regression model was built to analyze the association of Lp-PLA2 with the VD, correlation analysis and ROC curve were conducted to analyze the correlation of Lp-PLA2 with the state of cognitive impairment and to generate the cutoff value respectively. The serum Lp-PLA2 in VD group[(221±84) ng/ml] was significant higher than the non-dementia group[(133±60) ng/ml], the Lp-PLA2 in VCIND group[(148±65) ng/ml] was significant higher than the normal cognition group[(114±48) ng/ml](<0.05). The result of Logistic regression showed that Lp-PLA2 was a significant risk factor of VD[((95%)=1.015(1.010-1.021)], and its level was negatively correlated with the score of cognitive function.The cutoff value of Lp-PLA2 between the VD and non-dementia was 164.65 ng/ml and was 120.8 ng/ml between the normal cognition group and VCIND group. Lp-PLA2 is a significant risk factor of VD after ischemic stroke. 10.3760/cma.j.issn.0376-2491.2018.15.010
    Cognitive decline after stroke: relation to inflammatory biomarkers and hippocampal volume. Kliper Efrat,Bashat Dafna Ben,Bornstein Natan M,Shenhar-Tsarfaty Shani,Hallevi Hen,Auriel Eitan,Shopin Ludmila,Bloch Sivan,Berliner Shlomo,Giladi Nir,Goldbourt Uri,Shapira Itzhak,Korczyn Amos D,Assayag Einor Ben Stroke BACKGROUND AND PURPOSE:Inflammation may contribute to cognitive impairment after stroke. Inflammatory markers are associated with hippocampal atrophy. We tested whether markers of inflammation, erythrocyte sedimentation rate (ESR), and serum levels of C-reactive protein are associated with reduced hippocampal volume and poor cognitive performance among stroke survivors. METHODS:We analyzed 368 consecutive cases from our prospective study of first-ever mild-moderate stroke patients. MRI, cognitive tests, and inflammatory markers were determined. Patients were reevaluated 6 and 12 months after the event. RESULTS:ESR remained unchanged in follow-up examinations, suggesting a chronic inflammation background in some patients. Higher levels of C-reactive protein and ESR were associated with worse performance in cognitive tests, particularly memory scores. This association was maintained for ESR (but not C-reactive protein) after adjustment for confounders (P=0.002). Patients with smaller hippocampi had inferior cognitive results. Moreover, in a multivariate regression model, higher ESR values (but not C-reactive protein) were related to reduced hippocampal volume (P=0.049). CONCLUSIONS:This report shows a strong relationship between ESR and hippocampal volume, as well as with cognitive performance among poststroke patients. This could plausibly relate to incipient cognitive decline via hippocampal pathways. 10.1161/STROKEAHA.111.000536
    Plasma β-Amyloids and Tau Proteins in Patients with Vascular Cognitive Impairment. Tang Sung-Chun,Yang Kai-Chien,Chen Chih-Hao,Yang Shieh-Yueh,Chiu Ming-Jang,Wu Chau-Chung,Jeng Jiann-Shing Neuromolecular medicine Increases in plasma of β-amyloids (Aβ) and tau proteins have been noted in patients with Alzheimer's dementia (AD). Our study investigated the associations of plasma Aβ and tau proteins with dementia in stroke patients. This cross-sectional study recruited 24 controls (mean age: 67.4 ± 7.5 years, 33.3% male), 27 stroke patients without dementia (mean age: 70.7 ± 6.9 years, 60.7% male), 34 stroke patients with dementia (mean age: 78.3 ± 5.3 years, 45.5% male, Clinical Dementia Ranking (CDR): 1.46 ± 0.63), and 21 AD patients (mean age: 77.1 ± 9.1 years, 42.9% male, CDR: 1.43 ± 0.60) from a medical center. Dementia was defined as a CDR scale score of ≥ 1. The plasma levels of Aβ-40, Aβ-42, and tau were analyzed using immunomagnetic reduction. One-way analysis of variance was used to compare the differences in measured protein levels between the groups. The results indicated that plasma levels of tau and Aβ-42, but not Aβ-40, in stroke patients were significantly higher than in the controls. After adjustment for age, sex, diabetes mellitus, hypertension, and hyperlipidemia, only plasma level of Aβ-42 remained significantly higher in stroke patients with dementia than in those without dementia (OR 1.85, 1.25-2.75, p = 0.002). In summary, our results suggest that plasma Aβ-42 is a potential biomarker for dementia in stroke patients. 10.1007/s12017-018-8513-y
    The Norwegian Cognitive impairment after stroke study (Nor-COAST): study protocol of a multicentre, prospective cohort study. Thingstad Pernille,Askim Torunn,Beyer Mona K,Bråthen Geir,Ellekjær Hanne,Ihle-Hansen Hege,Knapskog Anne Brita,Lydersen Stian,Munthe-Kaas Ragnhild,Næss Halvor,Pendlebury Sarah T,Seljeseth Yngve Muller,Saltvedt Ingvild BMC neurology BACKGROUND:Early and late onset post-stroke cognitive impairment (PCI) contributes substantially to disability following stroke, and is a high priority within stroke research. The aetiology for PCI is complex and related to the stroke itself, brain resilience, comorbid brain diseases, prestroke vulnerability and complications during the hospital stay. The aim of the Norwegian Cognitive Impairment After Stroke study (Nor-COAST) is to quantify and measure levels of cognitive impairments in a general Norwegian stroke population and to identify biological and clinical markers associated with prognosis for cognitive disorders following incident stroke. The study will be organised within five work packages: 1) Incidence and trajectories 2) Pathological mechanisms 3) Development of a risk score 4) Impact of physical activity and 5) Adherence to secondary prevention. METHODS:Nor-COAST is an ongoing multicentre (five participating hospitals), prospective, cohort study with consecutive inclusion during the acute phase and with follow-up at three and 18 months, and at three years. Inclusion criteria are stroke defined according to the WHO criteria. During the recruitment period from 18.05.2015 to 31.03.2017, 816 participants have been included. Cognitive impairment will be classified according to the DSM-5 criteria using a consensus group. Cognitive function is assessed by a standardised neuropsychological test battery, the Montreal Cognitive Assessment, Trail making A and B, ten-word immediate and delayed recall test, the Controlled Oral Word Association, Global Deterioration Scale and proxy based information by and the Ascertain Dementia 8 item informant questionnaire. Biomarkers include magnetic resonance imaging, routine blood samples and bio-banking. Clinical assessments include characteristics of the stroke, comorbidity, delirium, frailty and tests for cognitive and physical function, sensor based activity monitoring and adherence to secondary prophylaxis. DISCUSSION:Nor-COAST is the first Norwegian multicentre study to quantify burden of PCI that will provide reliable estimates in a general stroke population. A multidisciplinary approach aiming to identify biomarkers and clinical markers of overall prognosis will add new knowledge about risk profiles, including pre-stroke vulnerability and modifiable factors such as physical activity and secondary prophylaxis of relevance for clinical practice and later intervention studies. TRIAL REGISTRATION:ClinicalTrials.gov: NCT02650531 . Retrospectively registered January 8, 2016. First participant included May 18, 2015. 10.1186/s12883-018-1198-x
    Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability. Vilar-Bergua A,Riba-Llena I,Nafría C,Bustamante A,Llombart V,Delgado P,Montaner J Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Vascular dementia is the second most common type of dementia after Alzheimer’s disease (AD). Subcortical ischemic vascular disease refers to a form of vascular cognitive impairment characterized by the presence of diffuse white matter hyperintensities (WMHs) and multiple lacunar infarcts. These neuroimaging findings are mainly caused by cerebral small-vessel disease (cSVD) and relate to aging and cognitive impairment, but they can also be silent and highly prevalent in otherwise healthy individuals. We aimed to review studies on blood and cerebrospinal fluid (CSF) markers related to the presence of WMHs and lacunar infarcts that have been conducted in the past in large population-based studies and in high-risk selected patients (such as those with vascular risk factors, vascular cognitive impairment, or AD). Relevant associations with the presence and progression of cSVD have been described in the blood for markers related to inflammatory processes, endothelial damage and coagulation/fibrinolysis processes, etc. Also, different combinations of CSF markers might help to differentiate between etiologic types of dementia. In the future, to translate these findings into clinical practice and use biomarkers to early diagnosis and monitoring vascular cognitive impairment would require the replication of candidate markers in large-scale, multicenter, and prospectively designed studies. 10.1038/jcbfm.2015.68
    Aβ1-40 and Aβ1-42 Plasmatic Levels In Stroke: Influence of Pre-Existing Cognitive Status and Stroke Characteristics. Moulin Solene,Leys Didier,Schraen-Maschke Susanna,Bombois Stephanie,Mendyk Anne-Marie,Muhr-Tailleux Anne,Cordonnier Charlotte,Buee Luc,Pasquier Florence,Bordet Regis Current Alzheimer research Many stroke patients have pre-existing cognitive impairment. Plasma amyloid β peptides (Aβ) - possible biomarkers of Alzheimer's pathology - induce vascular dysfunction. Our objective was to evaluate factors influencing plasma Aβ1-40 and Aβ1-42 peptides in a cohort of stroke patients. In the Biostroke study (ClinicalTrials.gov Identifier: NCT00763217), we collected vascular risk factors, neuroimaging features and biological tests including Aβ1-40 and Aβ1-42. We used the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) to systematically assess the pre-existing cognitive status. Of 403 patients (371 ischemia), 25 met criteria for pre-existing dementia, 142 for pre-existing cognitive decline-no-dementia, and 236 had no PCoI. Aβ1-42 was independently associated with PCoI (odds ratio 0.973; 95% confidence interval: 0.950-0.996; p=0.024). Factors associated with plasma Aβ1- 40 were age, smoking and diabetes mellitus. After exclusion of hemorrhagic strokes, the results remained unchanged, but blood samples taken less than 12 hours after onset were associated with lower plasma Aβ1-40. Our results support a dissociated response of the 2 plasma Aβ peptides in stroke patients, plasma Aβ1-40 being involved in vascular aspects whereas Aβ1-42 might be involved in neurodegenerative processes. 10.2174/1567205012666151027141730
    Early biomarkers for post-stroke cognitive impairment. Qian Lai,Ding Lidong,Cheng Liqun,Zhu Xiaolei,Zhao Hui,Jin Jiali,Guan Dening,Zhang Bing,Chen Xuemei,Xu Yun Journal of neurology The aim of this study was to investigate whether some biomarkers could predict cognitive impairment after stroke. One hundred fifty-two first-ever stroke patients were recruited within 6-72 h after the onset of symptoms. Blood was drawn within 1 h after admission for determining biomarkers. Cognitive function was assayed 2 weeks after stroke. The patients were divided into four groups: stroke, vascular cognitive impairment with no dementia (VCIND), vascular dementia (VaD), and mixed dementia (MD). Forty healthy subjects were used as controls. The results indicated that lower soluble receptor levels for advanced glycation end products (sRAGE) and higher β-secretase enzyme (BACE1) and neprilysin (NEP) levels were found in the VCIND, VaD, and MD groups. In addition, the percentages of ε3/ε4 genotypes and ε4 alleles in the VCIND, VaD, and MD groups were higher than in the stroke group. Correlation analysis determined that sRAGE, BACE1, and NEP were significantly related to the results of neuropsychological assessments. Logistic regression analysis, however, suggested that only sRAGE and BACE1 changed ahead of cognitive impairment after stroke. In conclusion, only BACE1 and sRAGE, not NEP or APOE genotypes, may be biomarkers diagnosing post-stroke cognitive impairment. 10.1007/s00415-012-6465-y
    Post-stroke dementia - a comprehensive review. Mijajlović Milija D,Pavlović Aleksandra,Brainin Michael,Heiss Wolf-Dieter,Quinn Terence J,Ihle-Hansen Hege B,Hermann Dirk M,Assayag Einor Ben,Richard Edo,Thiel Alexander,Kliper Efrat,Shin Yong-Il,Kim Yun-Hee,Choi SeongHye,Jung San,Lee Yeong-Bae,Sinanović Osman,Levine Deborah A,Schlesinger Ilana,Mead Gillian,Milošević Vuk,Leys Didier,Hagberg Guri,Ursin Marie Helene,Teuschl Yvonne,Prokopenko Semyon,Mozheyko Elena,Bezdenezhnykh Anna,Matz Karl,Aleksić Vuk,Muresanu DafinFior,Korczyn Amos D,Bornstein Natan M BMC medicine Post-stroke dementia (PSD) or post-stroke cognitive impairment (PSCI) may affect up to one third of stroke survivors. Various definitions of PSCI and PSD have been described. We propose PSD as a label for any dementia following stroke in temporal relation. Various tools are available to screen and assess cognition, with few PSD-specific instruments. Choice will depend on purpose of assessment, with differing instruments needed for brief screening (e.g., Montreal Cognitive Assessment) or diagnostic formulation (e.g., NINDS VCI battery). A comprehensive evaluation should include assessment of pre-stroke cognition (e.g., using Informant Questionnaire for Cognitive Decline in the Elderly), mood (e.g., using Hospital Anxiety and Depression Scale), and functional consequences of cognitive impairments (e.g., using modified Rankin Scale). A large number of biomarkers for PSD, including indicators for genetic polymorphisms, biomarkers in the cerebrospinal fluid and in the serum, inflammatory mediators, and peripheral microRNA profiles have been proposed. Currently, no specific biomarkers have been proven to robustly discriminate vulnerable patients ('at risk brains') from those with better prognosis or to discriminate Alzheimer's disease dementia from PSD. Further, neuroimaging is an important diagnostic tool in PSD. The role of computerized tomography is limited to demonstrating type and location of the underlying primary lesion and indicating atrophy and severe white matter changes. Magnetic resonance imaging is the key neuroimaging modality and has high sensitivity and specificity for detecting pathological changes, including small vessel disease. Advanced multi-modal imaging includes diffusion tensor imaging for fiber tracking, by which changes in networks can be detected. Quantitative imaging of cerebral blood flow and metabolism by positron emission tomography can differentiate between vascular dementia and degenerative dementia and show the interaction between vascular and metabolic changes. Additionally, inflammatory changes after ischemia in the brain can be detected, which may play a role together with amyloid deposition in the development of PSD. Prevention of PSD can be achieved by prevention of stroke. As treatment strategies to inhibit the development and mitigate the course of PSD, lowering of blood pressure, statins, neuroprotective drugs, and anti-inflammatory agents have all been studied without convincing evidence of efficacy. Lifestyle interventions, physical activity, and cognitive training have been recently tested, but large controlled trials are still missing. 10.1186/s12916-017-0779-7
    Post-Stroke Cognitive Impairment: A Review Focusing on Molecular Biomarkers. Zhang Xinxin,Bi Xia Journal of molecular neuroscience : MN Post-stroke cognitive impairment (PSCI), as one of the major complications after stroke, refers to a series of syndromes from mild cognitive impairment to dementia caused by stroke. Stroke has been reported to increase the risk of cognitive impairment by at least five to eight times. The assessment of PSCI usually relies on neuropsychological tests, but the results of these tests are subjective and inaccurate, and can be insufficient for the diagnosis and prognosis of PSCI. In recent years, an increasing number studies have indicated that changes in the expression of biomarkers such as C-reactive protein (CRP), interleukin 6 (IL-6) and IL-10 in blood, urine and other body fluids are associated with cognitive decline after stroke. Therefore, the detection of biomarkers in circulating blood serum, plasma and cerebrospinal fluid (CSF) may improve the accuracy of diagnosis and prognosis in PSCI. This review aims to summarize the studies on potential molecular biomarkers of PSCI. 10.1007/s12031-020-01533-8
    Serum Matrix Metalloproteinase-9 and Cognitive Impairment After Acute Ischemic Stroke. Zhong Chongke,Bu Xiaoqing,Xu Tan,Guo Libing,Wang Xuemei,Zhang Jintao,Cui Yong,Li Dong,Zhang Jianhui,Ju Zhong,Chen Chung-Shiuan,Chen Jing,Zhang Yonghong,He Jiang Journal of the American Heart Association BACKGROUND:The impact of serum matrix metalloproteinases-9 (MMP-9) on cognitive impairment after ischemic stroke is unclear. We aimed to investigate the association between serum MMP-9 in the short-term acute phase of ischemic stroke and cognitive impairment at 3 months. METHODS AND RESULTS:Our study was based on a subsample from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke); a total of 558 patients with serum MMP-9 levels from 7 of 26 participating sites of the trial were included in this analysis. Cognitive impairment severity was categorized as severe, mild, or none (Mini-Mental State Examination score, <23, 23-26, or ≥27, respectively; Montreal Cognitive Assessment score, <20, 20-24, or ≥25, respectively). Cognitive impairment was defined as a score of <27 for Mini-Mental State Examination or <25 for Montreal Cognitive Assessment. According to Mini-Mental State Examination score, 143 participants (25.6%) had mild cognitive impairment and 153 (27.4%) had severe cognitive impairment at 3 months. After adjustment for age, National Institutes of Health stroke score, education, and other covariates, the odds ratio for the highest quartile of serum MMP-9 compared with the lowest quartile was 3.20 (95% confidence interval, 1.87-5.49) for cognitive impairment. Multiple-adjusted spline regression model showed a linear association between MMP-9 levels and cognitive impairment (<0.001 for linearity). Sensitivity and subgroup analyses further confirmed these results. Similar significant findings were observed when cognitive impairment was defined by Montreal Cognitive Assessment score. CONCLUSIONS:Increased serum MMP-9 levels in the short-term phase of ischemic stroke were associated with 3-month cognitive impairment, independently of established risk factors. 10.1161/JAHA.117.007776
    Serum Rheumatoid Factor Levels at Acute Phase of Ischemic Stroke are Associated with Poststroke Cognitive Impairment. Zhu Zhengbao,Chen Lihua,Guo Daoxia,Zhong Chongke,Wang Aili,Bu Xiaoqing,Xu Tan,Zhang Jianhui,Ju Zhong,Guo Libing,Zhang Jintao,Li Dong,Chen Chung-Shiuan,Chen Jing,Zhang Yonghong,He Jiang Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association BACKGROUND:The effect of serum rheumatoid factor (RF) on poststroke cognitive impairment remains unknown. We aimed to investigate the association of serum RF in the acute phase with cognitive impairment at 3 months after ischemic stroke onset. METHODS:Our study was based on a random sample from the China Antihypertensive Trial in Acute Ischemic Stroke, a total of 582 patients from 7 of 26 participating sites of the trial with serum RF levels were included in this analysis. Cognitive impairment was defined as Mini-Mental State Examination less than 27 or Montreal Cognitive Assessment less than 25. RESULTS:According to Mini-Mental State Examination score, the multivariate-adjusted odds ratio and 95% confidence interval of cognitive impairment for the highest tertile of serum RF was 1.79 (1.08-2.99) compared with the lowest tertile. Each standard deviation increase of log-transformed RF was associated with 33% (95% confidence interval: 7%-66%) increased risk of cognitive impairment, and a linear association between serum RF and risk of poststroke cognitive impairment was observed (P for linearity < .01). Adding log-transformed RF to a model containing conventional risk factors improved the predictive power for poststroke cognitive impairment (net reclassification improvement: 26.21%, P < .01; integrated discrimination index: 1.24%, P = .02). Similar significant findings were observed when cognitive function was defined by Montreal Cognitive Assessment score. CONCLUSIONS:Elevated serum RF levels in the acute phase were independently associated with 3-month cognitive impairment among ischemic stroke patients. Further studies are needed to replicate our findings and to clarify the potential mechanisms. 10.1016/j.jstrokecerebrovasdis.2018.12.049
    High Serum Levels of Malondialdehyde and 8-OHdG are both Associated with Early Cognitive Impairment in Patients with Acute Ischaemic Stroke. Liu Zhihua,Liu Yuntao,Tu Xinjie,Shen Huiping,Qiu Huihua,Chen Huijun,He Jincai Scientific reports Post-stroke cognitive impairment (PSCI) is an increasingly prevalent sequel after stroke that may associate with poor functional outcome and increased risk of recurrent stroke. We aimed to explore the relationship between oxidative stress biomarkers and the presence of PSCI. 193 first-ever acute ischaemic stroke patients were consecutively enrolled in the current study. The oxidative stress biomarkers malondialdehyde (MDA) and 8-hydroxydeoxyquanosine (8-OHdG) were measured within 24 h after admission. Cognition function was evaluated by the Mini-Mental State Examination (MMSE) at 1 month after stroke. Serum levels of 8-OHdG and MDA were both significantly higher in the PSCI (p < 0.001) compared with the non-PSCI group. Both the serum levels of both 8-OHdG and MDA were negatively correlated with the MMSE score. Receiver operating characteristic curve analysis was used to evaluate 8-OHdG and MDA as markers of a high risk of PSCI and produced area under curve values of 0.700 and 0.793. Adjusted logistic regression showed that serum 8-OHdG and MDA levels remained as independent markers of PSCI. High serum levels of malondialdehyde and 8-OHdG are associated with the presence of PSCI at 1 month after stroke. 10.1038/s41598-017-09988-3
    Hemoglobin, anemia, and poststroke cognitive impairment: A cohort study. He Weilei,Ruan Yiting,Yuan Chengxiang,Luan Xiaoqian,He Jincai International journal of geriatric psychiatry OBJECTIVES:Several studies have demonstrated that anemia was associated with cognitive impairment. The aim of this study was to explore the relationship between hemoglobin and cognitive impairment in patient with acute ischemic stroke. METHODS:In total, 326 patients with acute ischemic stroke were followed up for 1 month. The main outcome was the incidence and severity of poststroke cognitive impairment (PSCI) assessed by Mini-Mental State Examination (MMSE). The impact of hemoglobin levels and anemia on PSCI was assessed by multiple regression models controlling for potential confounders. RESULTS:During the 1-month follow-up, 193 (59.2%) patients developed PSCI. Anemia was independently associated with PSCI (OR = 3.637; 95% CI, 1.216-10.881; P = .021) after adjusting for demographics, vascular risk factors, stroke severity, and functional outcome. When the hemoglobin levels stratified into tertiles, higher hemoglobin levels were associated with better cognitive function. This result was however not significant after adjusting for the same confounders above. CONCLUSIONS:Low hemoglobin levels are associated with an increased risk of PSCI. Targeted interventions in this population may reduce the incidence of PSCI and require further evaluation. 10.1002/gps.5272
    Association of plasma trimethylamine-N-oxide levels with post-stroke cognitive impairment: a 1-year longitudinal study. Zhu Chen,Li Guangzong,Lv Zhiyu,Li Jing,Wang Xiangming,Kang Jie,Zhan Cheng Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology BACKGROUND AND AIMS:Post-stroke cognitive impairment (PSCI) is a clinical condition arising from stroke and causes significant changes to memory, thinking, and behavior. Trimethylamine-N-oxide (TMAO), the metabolite produced by gut microbiota, has mechanistic relevance to atherosclerotic diseases. This study aimed to investigate whether an association existed between elevated plasma TMAO levels and PSCI. METHODS:Consecutive patients with acute ischemic stroke were prospectively enrolled during Jan. 2017 to Dec. 2017. TMAO concentration was measured within 24 h after admission. PSCI was assessed using the Mini-Mental State Examination (MMSE) score after 1 year and defined as MMSE score ≤ 26. Binary logistic regression analysis was used to determine the contribution of TMAO level in the prediction of PSCI. RESULTS:Of the 256 patients studied (age, 67.1 ± 11.0 years; male, 54.3%), 86 (33.6%) patients were diagnosed as PSCI. The mean TMAO level was 5.6 ± 2.4 μM, with quartile level as follows: < 3.9 μM (first quartile), 3.9-5.1 μM (second quartile), 5.2-7.4 μM (third quartile), and > 7.4 μM (fourth quartile). After controlling for potential confounders, multivariable logistic analysis showed that higher level of plasma TMAO was an independent predictor for cognitive impairment in post-stroke patients (the quartile 1 was used as reference, the quartile 4 odds ratio, 3.304; 95% confidence intervals, 1.335-8.178; P = 0.010). CONCLUSIONS:This study demonstrated that increasing plasma level of TMAO may be associated with PSCI. 10.1007/s10072-019-04040-w
    Serum Retinoic Acid Level and The Risk of Poststroke Cognitive Impairment in Ischemic Stroke Patients. Hou Le,Ding Caixia,Chen Zhao,Liu Yuanyue,Shi Haishan,Zou Cong,Zhang Hui,Lu Zhiwei,Zheng Dong Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association BACKGROUND:Retinoic acid (RA), an active metabolite of vitamin A, possesses enormous protective effects on vascular systems. It may also be positively related to good functional outcome after ischemic stroke. However, whether circulating RA concentration is associated with poststroke cognitive impairment (PSCI) remains unclear. This study aimed to detect the association between RA level and PSCI among patients with first-ever acute ischemic stroke. METHODS:Two hundred and 61 consecutive patients were prospectively recruited during March 2018 and March 2019. Serum RA concentration was measured at admission for all patients. We also performed cognitive function examination using the Montreal Cognitive Assessment (MoCA) at admission and at every follow-up visit. Patients with MoCA score less than 26 were identified as developing PSCI. RESULTS:The median serum RA level was 2.0 ng/mL (interquartile range, 1.1-3.2 ng/mL) after admission. Patients diagnosed as PSCI at admission, 1-month and 3-month were 53 (20.3%), 91 (34.6%), and 141 (54.0%), respectively. Univariate analysis showed that reduced RA level was correlated with PSCI at 3-month (P = .003), but not at admission (P = .416) and 1-month poststroke (P = .117). After adjusting for all potential confounders, the odds ratio for the lowest tertile of RA, compared with the highest tertile, was 1.97 (95% confidence interval, 1.01-3.83, P = .046) for PSCI at 3 months. Furthermore, multiple-adjusted spline regression model further confirmed the dose-response relationships between RA level and 3-month PSCI (P < .001). CONCLUSIONS:Decreasing serum RA level might be associated with 3-month PSCI in ischemic stroke patients. 10.1016/j.jstrokecerebrovasdis.2019.104352
    Plasma Endostatin Levels at Acute Phase of Ischemic Stroke Are Associated with Post-Stroke Cognitive Impairment. Qian Sifan,Li Ruyi,Zhang Chenhuan,Zhang Rui,Guo Daoxia,Bu Xiaoqing,Wang Aili,Peng Hao,Chen Jing,Zhang Yonghong,He Jiang,Xu Tan,Zhong Chongke Neurotoxicity research The effect of plasma endostatin on cognitive impairment after ischemic stroke remains unclear. We conducted this study to explore the association between plasma endostatin in the acute phase of ischemic stroke and post-stroke cognitive impairment (PSCI). Baseline plasma endostatin levels were measured, and cognitive function status was assessed by Montreal cognitive assessment at 3 months among 613 ischemic stroke patients. PSCI was defined as Montreal cognitive assessment score less than 26. The association of endostatin with PSCI was analyzed by logistic regression model. The receiver operating characteristic curve was applied to explore the optimal cutoff value of plasma endostatin levels in predicting PSCI. In a multivariable-adjusted model, the odds ratio for the highest vs lowest quartile of endostatin was 2.01 (95% CI, 1.15-3.53) for PSCI. Restricted cubic spline regression model showed a linear dose-response association between endostatin and PSCI (p for linearity = 0.01). The optimal cut point of endostatin was 84.22 ng/mL; higher endostatin levels (≥ 84.22 ng/mL) were associated with increased risk of 2.17-fold for PSCI (adjusted odds ratio, 2.17; 95% CI, 1.44-3.26; p = 0.0002). Furthermore, adding endostatin to a model containing conventional factors led to significant reclassification for PSCI (net reclassification improvement, 0.20; p = 0.025; integrated discrimination improvement, 0.016; p = 0.002). Our findings showed that elevated plasma endostatin levels were associated with cognitive impairment at 3 months after acute ischemic stroke, independently of established conventional risk factors, suggesting that endostatin may be an important biomarker of cognitive impairment after ischemic stroke. 10.1007/s12640-020-00173-5
    Cytokine Response, Tract-Specific Fractional Anisotropy, and Brain Morphometry in Post-Stroke Cognitive Impairment. Kulesh Aleksey,Drobakha Viktor,Kuklina Elena,Nekrasova Irina,Shestakov Vladimir Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association BACKGROUND:Post-stroke cognitive impairment is a clinically heterogeneous condition and its types have a different course and prognosis. The aim of the present study is to address the roles of inflammation, white matter pathology, and brain atrophy in different neuropsychological types of cognitive impairment in the acute period of ischemic stroke. METHODS:In 92 patients, we performed an assessment of the cognitive status and measured concentrations of cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor-alpha, IL-10) in liquor and serum, as well as a number of magnetic resonance imaging (MRI) morphometric parameters and fractional anisotropy. The control group consisted of 14 individuals without cerebrovascular disease. RESULTS:All patients had a higher level of IL-10 in serum than the control group. Patients with dysexecutive cognitive impairment had a higher concentration of IL-1β and IL-10 in liquor, IL-6 level in serum, and a lower fractional anisotropy of the ipsilateral thalamus than patients with normal cognition. Patients with mixed cognitive impairment were characterized by a lower fractional anisotropy of contralateral fronto-occipital fasciculus, compared with patients with dysexecutive cognitive impairment. Patients with both dysexecutive and mixed cognitive deficit had a wide area of leukoaraiosis and a reduced fractional anisotropy of the contralateral cingulum, compared with patients without cognitive impairment. Also, we found numerous correlations between cognitive status and levels of cytokines, MRI morphometric parameters, and fractional anisotropy of certain regions of the brain. CONCLUSIONS:The concentrations of cytokines in serum and cerebrospinal fluid studied in combination with MRI morphometric parameters and fractional anisotropy appear to be informative biomarkers of clinical types of post-stroke cognitive impairment. 10.1016/j.jstrokecerebrovasdis.2018.02.004
    Multiple biomarkers covering several pathways improve predictive ability for cognitive impairment among ischemic stroke patients with elevated blood pressure. Zhu Zhengbao,Zhong Chongke,Guo Daoxia,Bu Xiaoqing,Xu Tan,Guo Libing,Liu Jiale,Zhang Jintao,Li Dong,Zhang Jianhui,Ju Zhong,Chen Chung-Shiuan,Chen Jing,He Jiang,Zhang Yonghong Atherosclerosis BACKGROUND AND AIMS:We aimed to evaluate the ability of multiple novel biomarkers representing several pathophysiological pathways to improve risk prediction of post-stroke cognitive impairment. METHODS:We conducted a prospective multicenter study in 638 ischemic stroke patients with elevated blood pressure based on a random subsample from China Antihypertensive Trial in Acute Ischemic Stroke and measured 12 circulating biomarkers in these participants. Cognitive impairment was assessed at 3 months after stroke with definitions of Mini-Mental State Examination (MMSE) score <27 or Montreal Cognitive Assessment (MoCA) score <25. RESULTS:According to MMSE score, 1 SD increase of rheumatoid factor (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.02-1.46), matrix metalloproteinase-9 (OR 1.47, 95% CI 1.22-1.77) and total homocysteine (OR 1.22, 95% CI 1.01-1.49) after log transformation was significantly associated with the risk of post-stroke cognitive impairment. The ORs associated with their simultaneously high levels were 4.89 (95% CI, 2.31-10.35; p<0.001) and 3.09 (95% CI, 1.60-5.98; p<0.001) for cognitive impairment and the severity of cognitive impairment, respectively. Adding these 3 biomarkers to conventional model significantly improved the risk prediction of cognitive impairment (C statistic 0.729 vs. 0.688, p = 0.004; net reclassification improvement = 33.67%, p < 0.001; integrated discrimination index = 4.61%; p < 0.001). Similar significant findings were observed when cognitive impairment was defined by MoCA score. CONCLUSIONS:Combination of rheumatoid factor, matrix metalloproteinase-9 and total homocysteine can improve the risk prediction of cognitive impairment among ischemic stroke patients with elevated blood pressure. Further studies are warranted to validate our findings and explore their roles as potential therapeutic targets. 10.1016/j.atherosclerosis.2019.05.028