Publications by authors named "Jeremiasz Jagiella"

23 Publications

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4C Mortality Score correlates with in-hospital functional outcome after COVID-19-associated ischaemic stroke.

Neurol Neurochir Pol 2021 May 5. Epub 2021 May 5.

Department of Neurology, Jagiellonian University Medical College, Krakow, Poland.

Aim Of The Study: The 4C Mortality Score was created to predict mortality in hospitalised patients with COVID-19 and has to date been evaluated only in respiratory system disorders. The aim of this study was to investigate its application in patients with COVID-19-associated acute ischaemic stroke (AIS).

Clinical Rationale For Study: COVID-19 is a risk factor for AIS. COVID-19-associated AIS results in higher mortality and worse functional outcome. Predictors of functional outcome in COVID-19-associated AIS are required.

Materials And Methods: This was a retrospective observational study of patients with AIS hospitalised in seven neurological wards in Małopolska Voivodship (Poland) between August and December 2020. We gathered data concerning the patients' age, sex, presence of cardiovascular risk factors, type of treatment received, and the presence of stroke-associated infections (including pneumonia, urinary tract infection and infection of unknown source). We calculated 4C Mortality Score at stroke onset, and investigated whether there was a correlation with neurological deficit measured using the National Health Institute Stroke Scale (NIHSS) and functional outcome assessed using the modified Rankin Scale (mRS) at discharge.

Results: The study included 52 patients with COVID-19-associated AIS. The 4C Mortality Score at stroke onset correlated with mRS (rs = 0.565, p < 0.01) at discharge. There was also a statistically significant difference in the mean 4C Mortality Score between patients who died and patients who survived the stroke (13.08 ± 2.71 vs. 9.85 ± 3.47, p = 0.04).

Conclusions And Clinical Implications: 4C Mortality Score predicts functional outcome at discharge in COVID-19-associated AIS patients.
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http://dx.doi.org/10.5603/PJNNS.a2021.0037DOI Listing
May 2021

Prognostic Significance of Stroke-Associated Infection and other Readily Available Parameters in Acute Ischemic Stroke Treated by Intravenous Thrombolysis.

J Stroke Cerebrovasc Dis 2021 Feb 15;30(2):105525. Epub 2020 Dec 15.

Department of Neurology, Jagiellonian University Medical College, Jakubowskiego 2 Str., 30-688 Krakow, Poland. Electronic address:

Objectives: The impact of contracting stroke-associate infection (SAI) that requires antibiotic treatment after an acute ischemic stroke (AIS) treated with alteplase remains unclear. We studied the profiles of SAI in patients with AIS treated with alteplase toward identifying predictive factors and prognostic implications at 90 days post-stroke.

Methods: We analyzed 33 parameters readily available within 24 hours after AIS: demographics, risk factors, and several clinical and biochemical parameters. Outcome measures were mRS ≤ 2 and mortality 90 days post-stroke.

Results: 83 (23.6%) of 352 patients developed SAI. Multivariate logistic regression analysis showed that atrial fibrillation, mRS above 0 pre-stroke, lower delta NIHSS (the difference between NIHSS score measured upon admission and 24 hours after later), CRP≥10 mg/L, and elevated WBC count affected SAI risk (model including CRP levels and WBC count) and atrial fibrillation, mRS above 0 pre-stroke, lower delta NIHSS, HT, and elevated fibrinogen levels affected SAI risk (model excluding CRP levels and WBC count). 231 patients (74.1%) had mRS ≤ 2 at day 90. Multivariate logistic regression analysis showed that younger age, no hypertension, mRS=0 pre-stroke, higher delta NIHSS, no HT, no SAI, and CRP<10 mg/L, were associated with mRS≤2 at day 90. 54 (15.3%) patients died within 90 days. Multivariate logistic regression analysis showed that pre-stroke mRS>0, lower delta NIHSS, HT, CRP≥10 mg/L, lower triglyceride levels affected the risk of death within 90 days.

Conclusions: Several markers available within 24 hours post-stroke were predictive of SAI that requires antibiotic treatment. SAI affects long-term outcome but not mortality.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105525DOI Listing
February 2021

Mechanical thrombectomy for acute ischaemic stroke during therapeutic anticoagulation: long-term outcomes.

Neurol Neurochir Pol 2020 17;54(6):538-543. Epub 2020 Nov 17.

Neurology Department, Jagiellonian University, Krakow, Poland.

Aim Of Study: Mechanical thrombectomy (MT) is one of the aetiological treatment options recommended for anticoagulated patients with acute ischaemic stroke (AIS). We analysed its long-term outcomes using the modified Rankin Score (mRS) or mortality on day 90.

Clinical Rationale For The Study: Data describing the anticoagulant efficacy and safety of MT in patients with AIS is limited.

Materials And Methods: This study included 291 patients with AIS (49% women, mean [SD] age 66 [15] years) who underwent MT in the Comprehensive Stroke Centre in Krakow, Poland. Data describing demographics, stroke risk factors, NIHSS on admission, postprocedural thrombolysis in cerebral infarction score, 24-hour postprocedural haemorrhagic transformation (ECASS-2) as seen on computed tomography, and time between stroke onset and groin puncture was collected. The outcome measure was the mRS on day 90 after stroke onset (a favourable outcome was defined as an mRS not exceeding 2 points; an unfavourable outcome was death).

Results: Thirty-seven patients (13%) were on therapeutic anticoagulation during MT. Univariate analysis showed that anticoagulated patients were older and more likely to have been diagnosed with hypertension, ischaemic heart disease, or atrial fibrillation. The patient groups did not differ in terms of clot location, postprocedural thrombolysis in cerebral infarction score, haemorrhagic transformation on computed tomography, or mRS on day 90. Multivariate logistic regression analysis showed that younger age, male sex, no history of diabetes mellitus, lower NIHSS score on admission, shorter time between stroke onset and groin puncture, and better recanalisation were associated with favourable outcomes at day 90, and that therapeutic anticoagulation was not (OR, 1.00; 95%CI, 0.46-2.15; p = 0.99). Anticoagulation did not affect mortality at day 90 (OR, 1.28; 95%CI, 0.56-2.92; p = 0.55).

Conclusion And Clinical Implications: In anticoagulated patients with AIS, MT does not affect long-term outcomes.
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http://dx.doi.org/10.5603/PJNNS.a2020.0088DOI Listing
January 2021

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.

Ann Neurol 2020 07 7;88(1):56-66. Epub 2020 May 7.

Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.

Objective: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH.

Methods: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses.

Results: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively.

Interpretation: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.
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http://dx.doi.org/10.1002/ana.25740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523882PMC
July 2020

Time from stroke onset to groin puncture affects rate of recanalisation after mechanical thrombectomy: a real-life single centre experience.

Neurol Neurochir Pol 2020 3;54(2):156-160. Epub 2020 Apr 3.

Neurology Department, Jagiellonian University, Krakow, Poland.

Aim Of The Study: We investigated whether the time elapsed between stroke onset and groin puncture (SO-GP) affects the rate of recanalisation as measured by the Thrombolysis in Cerebral Infarction (TICI) scale.

Clinical Rationale For The Study: There is no doubt that the effectiveness of thrombolysis in acute ischaemic stroke (AIS) is time-dependent. There is growing evidence that there is a correlation between SO-GP time and rate of recanalisation in patients treated by mechanical thrombectomy (MT).

Materials And Methods: This study was performed in patients treated in the Comprehensive Stroke Centre in Krakow that covers 3.5 million inhabitants. The following data was collected for this study: demographics, stroke risk factors, transportation (directly from home or via another hospital), admission NIHSS, IV rt-PA administration prior to MT, the number of passes used during MT, and SO-GP time. The favourable outcome measure was TICI 2b or 3.

Results: 223 patients (48.4% females; mean age: 66.0 ± 16.6 years) with anterior circulation strokes were treated by MT; 64.6% arrived directly from home. Mean admission NIHSS was 15.6 ± 5.3. IV rtPA was administered in 68.6% of patients. At least two thrombectomy passes were required in 20.6% of cases. Median SO-GP time was 240 minutes (IQR range: 180-305 minutes). Grade 3 or 2b TICI scores were obtained in 70.4% of patients. Univariate logistic regression showed that among all studied parameters, only NIHSS affected the rate of recanalisation, but in a multivariate logistic regression model, the only parameter that affected the rate of recanalisation was the SO-GP time (OR = 0.76; 95% CI: 0.60-0.98, p = 0.03).

Conclusions And Clinical Implications: We suggest that SO-GP time affects the rate of recanalisation in patients with MT.
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http://dx.doi.org/10.5603/PJNNS.a2020.0024DOI Listing
July 2020

Fasting Hyperglycemia and Long-term Outcome in Patients with Acute Ischemic Stroke Treated with Mechanical Thrombectomy.

J Stroke Cerebrovasc Dis 2020 May 19;29(5):104774. Epub 2020 Mar 19.

Jagiellonian University Medical College, Department of Neurology, Krakow, Poland; University Hospital in Krakow, Poland.

Background: Little is known about the prognostic role of fasting glucose after mechanical thrombectomy (MT).

Aims: We investigated whether fasting glucose on the next day after MT was associated with long-term outcome in acute ischemic stroke patients according to diabetes.

Methods: We retrospectively analyzed 181 consecutive patients with acute anterior circulation ischemic stroke who underwent MT in 2 comprehensive stroke centers in Poland. Glucose levels were evaluated on admission and on the next day after MT. Fasting hyperglycemia (FHG) was defined as the glucose level above 5.5 mmol/L. Unfavorable outcome was defined as modified Rankin scale (mRS) of 3-6 at day 90 from stroke onset.

Results: Patients with FHG had higher mRS at 3-month follow-up compared with those without FHG (3.71 ± 2.56 versus 1.87 ± 2.22, P < .001). In the subgroup analyses, FHG was associated with poor neurological outcome in the group without diabetes (3.74 ± 2.52 versus 1.81 ± 3.74, P < .001) but not with diabetes (3.64 ± 2.67 versus 2.30 ± 3.74, P= .11). Patients without diabetes who had FHG were older, had higher glucose on admission, higher prevalence of atrial fibrillation, cardioembolic stroke etiology and bleeding brain complications compared with the group with normal fasting glucose. After adjustment for potential confounders, fasting glucose (odds ratio [OR] 1.46; 95% CI 1.19-1.79, P < .001), age (OR 1.06; 95% CI 1.02-1.10, P = .001), successful reperfusion (OR 0.09; 95% CI 0.04-0.22, P < .001) and baseline NIHSS score (OR 1.18; 95% CI 1.08-1.29, P < .001) were predictors of mRS 3-6 at 3-month follow-up in the whole group. In the subgroup without diabetes, fasting glucose (OR 1.57; 95% CI 1.17-2.11, P = .002), age (OR 1.05; 95% CI 1.01-1.08, P = .008), successful reperfusion (OR 0.11; 95% CI 0.04-0.30, P < .001) and baseline NIHSS score (OR 1.14; 95% CI 1.04-1.26, P = .011) were independent predictors of unfavorable 3-month outcome.

Conclusions: Fasting glucose on the next day after MT in patients with acute ischemic stroke is an independent risk factor for worse 3-month outcome.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104774DOI Listing
May 2020

Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis.

JAMA Neurol 2019 04;76(4):480-491

Department of Neurology, Baltimore Veterans Administration Medical Center and University of Maryland School of Medicine, Baltimore.

Importance: Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations.

Objective: To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH.

Design, Setting, And Participants: This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study.

Main Outcomes And Measures: Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies.

Results: In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE ε2 and ε4 did not show an association with nonlobar ICH risk in any race/ethnicity.

Conclusions And Relevance: APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
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http://dx.doi.org/10.1001/jamaneurol.2018.4519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459133PMC
April 2019

AQP4 tag SNPs in patients with intracerebral hemorrhage in Greek and Polish population.

Neurosci Lett 2019 03 19;696:156-161. Epub 2018 Dec 19.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece; Department of Neurology, Medical School, University of Cyprus, Nicosia, Cyprus.

Backround: A relatively small number of genetic variants are implicated to pathophysiology of intracerebral hemorrhage (ICH). Aquaporin-4 (AQP4) has been reported to be implicated in the pathophysiological processes of ICH development.

Objective: To examine the role of AQP4 gene region polymorphisms on the ICH risk.

Methods: A total of 250 Greek and 193 Polish patients with primary ICH and 250 and 322 respective controls were enrolled, forming two independent cohorts in order to validate any significant effect. With logistic regression analyses, 7 AQP4 tag single nucleotide polymorphisms (SNPs) were examined for association with ICH risk, lobar/non-lobar ICH risk, and 6-month disability after ICH. Cox regression analysis was applied in order to the effect of AQP4 SNPs on ICH age of onset be tested. Correction for multiple comparisons was applied.

Results: Multivariate logistic regression analysis showed that rs3875089 in the Greek cohort and rs3763043, rs335931 in the Polish cohort had a significant influence on the risk of ICH, lobar and non-lobar ICH. Regarding the age of onset, rs3875089 in the Greek cohort and rs3763043, rs11661256 in the Polish cohort were found to significantly alter the age of onset of ICH and its subtypes. However, all of the above associations did not survive the Bonferroni correction (p-value >0.007). Finally, AQP4 tag SNPs were not found to have any significant effect on long-term disability after ICH.

Conclusions: In conclusion, the present study provides an indication that AQP4 gene variants may affect susceptibility to primary ICH and may influence the ICH age of onset.
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http://dx.doi.org/10.1016/j.neulet.2018.12.025DOI Listing
March 2019

Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

Brain 2017 Oct;140(10):2663-2672

Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA, USA.

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.
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http://dx.doi.org/10.1093/brain/awx220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841027PMC
October 2017

Genetic variants in CETP increase risk of intracerebral hemorrhage.

Ann Neurol 2016 11 19;80(5):730-740. Epub 2016 Oct 19.

Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.

Objective: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.

Methods: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.

Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10 ) with no heterogeneity across studies (I  = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10 ).

Interpretation: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.
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http://dx.doi.org/10.1002/ana.24780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115931PMC
November 2016

Integrins AV and B8 Gene Polymorphisms and Risk for Intracerebral Hemorrhage in Greek and Polish Populations.

Neuromolecular Med 2017 Mar 30;19(1):69-80. Epub 2016 Jul 30.

Laboratory of Neurogenetics, Department of Neurology, Faculty of Medicine, University of Thessaly, University Hospital of Larissa, Biopolis, Mezourlo Hill, 41100, Larissa, Greece.

Α limited number of genetic variants have been linked to the development of intracerebral hemorrhage (ICH). Ιntegrin AV and/or B8-deficient mice were found to develop ICH. The present candidate gene association study was designed to investigate possible influence of integrin AV (ITGAV) and integrin B8 (ITGB8) gene region polymorphisms on the risk of ICH. 1015 participants (250 Greek and 193 Polish patients with primary ICH and 250 Greek and 322 Polish controls) were included in the study. Using logistic regression analyses, 11 tag single nucleotide polymorphisms (SNPs) for ITGAV and 11 for ITGB8 gene were tested for associations with ICH risk, lobar ICH risk and non-lobar ICH after adjustment for age, gender, history of hypertension and country of origin. Linear regression models were used to test the effect of tag SNPs on the ICH age of onset. Correction for multiple comparisons was carried out. The rs7565633 tag SNP of the ITGAV gene was independently associated with the risk of lobar ICH in the codominant model of inheritance [odds ratio (95 % confidence interval (CI)) 0.56 (0.36-0.86), p = 0.0013]. Furthermore, heterozygous individuals of the rs10251386 and the rs10239099 of the ITGB8 gene had significantly lower age of ICH onset compared to the wild-type genotypes [regression coefficient (b) -3.884 (95 % CI -6.519, -1.249), p = 0.0039 and b = -4.502 (95 % CI -7.159, -1.845), p = 0.0009, respectively]. The present study provides preliminary indication for an influence of ITGAV gene tag SNP in the development of lobar ICH and of ITGB8 gene variants in the age of ICH onset.
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http://dx.doi.org/10.1007/s12017-016-8429-3DOI Listing
March 2017

Catalase activity in blood fractions of patients with sporadic ALS.

Pharmacol Rep 2014 Aug 24;66(4):704-7. Epub 2014 Apr 24.

Jagiellonian University Medical College, Department of Neurology, Kraków, Poland. Electronic address:

Background: Oxidative stress may be a key element in pathogenesis of sporadic amyotrophic lateral sclerosis (sALS). Several studies proved that markers of peroxidation of lipids, proteins or nucleic acids are increased in postmortem tissue of sALS patients. However, much less is known about enzymatic antioxidant defense mechanism in sALS.

Objectives: The aim of the study was to assess catalase (CAT) activity that is implicated in the defense against oxidative stress, in three blood fractions, i.e. erythrocytes, plasma and serum of sALS patients and healthy controls.

Methods: Altogether 46 sALS patients and 54 controls were enrolled in the study. CAT activity was estimated using a commercially available assay kit.

Results: CAT activity in erythrocytes of sALS patients was significantly decreased compared to neurologically healthy controls (p=0.04), whereas CAT activity in plasma and serum was similar in both studied groups.

Conclusions: CAT activity in erythrocytes, in contrast to other blood fractions is reduced in sALS cases as compared to controls, which may indirectly indicate that antioxidant defense system in erythrocytes is involved in pathogenesis of sALS.
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http://dx.doi.org/10.1016/j.pharep.2014.02.021DOI Listing
August 2014

The FGA Thr312Ala polymorphism and risk of intracerebral haemorrhage in Polish and Greek populations.

Neurol Neurochir Pol 2014 23;48(2):105-10. Epub 2014 Jan 23.

Department of Neurology, Jagiellonian University Medical College, Krakow, Poland.

Background And Purpose: Spontaneous intracerebral haemorrhage (ICH) is the most fatal form of stroke with the highest morbidity and disability rate of all stroke types. Recent data suggest that the genetic background has a sizeable and mostly undiscovered effect on the brain haemorrhage risk. Since the coagulation system is crucial to ICH pathology, we studied the significance of the FGA Thr312Ala polymorphism in two European populations.

Materials And Methods: We genotyped 550 and 224 controls as well as 261 and 242 stroke patients in Polish and Greek populations, respectively. The ICH diagnosis was confirmed by computed tomography. The FGA Thr312Ala polymorphism was analysed using real-time polymorphism chain reaction.

Results: Both crude and multivariable regression analyses showed that the studied polymorphism is a protective factor in the Polish population under the dominant and additive models of inheritance. Those results did not replicate in the Greek population. The meta-analysis of results from the Polish and the Greek populations proved that FGA Thr312Ala polymorphism affects the risk of ICH in the dominant model of inheritance.

Conclusions: The FGA Thr312Ala polymorphism affects a risk for ICH in the Polish but not in the Greek population. An advanced meta-analysis of well-designed studies with a significant number of cases might provide useful information of novel polymorphisms, including the FGA Thr312Ala polymorphism, and their role in ICH pathology.
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http://dx.doi.org/10.1016/j.pjnns.2013.12.004DOI Listing
August 2014

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.

Am J Hum Genet 2014 Apr 20;94(4):511-21. Epub 2014 Mar 20.

Department of Neurology, Medical University of Graz, Graz 8036, Austria; Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz 8036, Austria.

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
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http://dx.doi.org/10.1016/j.ajhg.2014.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980413PMC
April 2014

The β-fibrinogen -455G/A gene polymorphism and the risk of ischaemic stroke in a Polish population.

Neurol Neurochir Pol 2013 Mar-Apr;47(2):152-6

Department of Neurology, Jagiellonian University Medical College, ul. Botaniczna 3, 31-503 Krakow, Poland.

Background And Purpose: Ischaemic stroke is considered to be multifactorial and interactions between environmental and genetic factors play an important role. Although vascular risk factors are well known, the genetic ones are still undiscovered. In the present study, we assessed the significance of the β-fibrinogen -455G/A gene polymorphism and the risk of ischaemic stroke in a Polish population.

Material And Methods: 426 ischaemic stroke patients classified according to stroke aetiologies (small vessel disease, large vessel disease or cardioembolic stroke) and 234 controls were included in the study. The association of the β-fibrinogen genotypes with ischaemic stroke was tested using logistic regression analysis under dominant, recessive or additive models of inheritance.

Results: The allele and genotype distributions of the β-fibrinogen -455G/A gene polymorphism did not differ significantly between patients and controls (patients: G - 75%, GG - 56.6%, GA - 36.8%, AA - 6.6%; controls: G - 73.7%, GG - 57.3%, GA - 32.9%, AA - 9.8%; p > 0.05, χ2). In addition, logistic regression analysis adjusted for the known risk factors, i.e. hypertension, ischaemic heart disease, myocardial infarction, hypercholesterolaemia, diabetes mellitus and smoking, did not show a role of the studied polymorphism in ischaemic stroke.

Conclusions: The β-fibrinogen -455G/A gene polymorphism is not a risk factor for ischaemic stroke in a Polish population.
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http://dx.doi.org/10.5114/ninp.2013.34462DOI Listing
August 2013

Heritability estimates identify a substantial genetic contribution to risk and outcome of intracerebral hemorrhage.

Stroke 2013 Jun 4;44(6):1578-83. Epub 2013 Apr 4.

Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge St, CPZN-6818, Boston, MA 02114, USA.

Background And Purpose: Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome.

Methods: We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality.

Results: ICH risk heritability was estimated at 29% (SE, 11%) for non-APOE loci and at 15% (SE, 10%) for APOE. Heritability for 90-day ICH mortality was 41% for non-APOE loci and 10% (SE, 9%) for APOE. Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non-APOEloci and at 12% (SE, 4%) for APOE.

Conclusions: Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified.
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http://dx.doi.org/10.1161/STROKEAHA.111.000089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684199PMC
June 2013

Burden of risk alleles for hypertension increases risk of intracerebral hemorrhage.

Stroke 2012 Nov 28;43(11):2877-83. Epub 2012 Aug 28.

Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, and Department of Epidemiology, Harvard School of Public Health, 185 Cambridge Street; CPZN-6818, Boston, MA 02114, USA.

Background And Purpose: Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN.

Methods: We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables.

Results: No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score.

Conclusions: Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN.
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http://dx.doi.org/10.1161/STROKEAHA.112.659755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479325PMC
November 2012

Fibrin clot properties in acute stroke: what differs cerebral hemorrhage from cerebral ischemia?

Stroke 2012 May 16;43(5):1412-4. Epub 2012 Feb 16.

Department of Neurology, Jagiellonian University, Krakow, Poland.

Background And Purpose: Fibrin clot formation is important in acute intracerebral hemorrhage (ICH). We investigated plasma fibrin clot characteristics in acute ICH compared with acute ischemic stroke (IS) and nonstroke conditions.

Methods: In the 3 studied groups, we analyzed plasma fibrin clot phenotype and its association with clinical stroke presentation.

Results: Compared with controls, in patients with acute strokes, fibrin clots presented with lower clot permeability, longer lysis time, and higher maximum clot absorbance (for all, P<0.001). In ICH patients compared with IS patients, only lysis time was shorter by 13% (P<0.001). In the ICH group, neurological deficit correlated significantly (P<0.05) with clot compaction, and the rate of increase in d-dimers released from clots, whereas initial hematoma volume correlated with lag phase of fibrin formation on turbidimetry and compaction (P<0.05).

Conclusions: In both types of acute strokes, fibrin clot properties are altered: denser fibrin clots are relatively resistant to lysis. In acute ICH, fibrin clots are more susceptible to tissue plasminogen activator-mediated lysis compared with in IS, which might affect ICH pathogenesis.
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http://dx.doi.org/10.1161/STROKEAHA.111.646729DOI Listing
May 2012

APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study.

Lancet Neurol 2011 Aug 6;10(8):702-9. Epub 2011 Jul 6.

Hemorrhagic Stroke Research Group, Massachusetts General Hospital, Boston, MA, USA.

Background: Carriers of APOE ε2 and ε4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome.

Methods: We investigated the association of APOE ε2 and ε4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE ε4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH.

Findings: For patients with lobar ICH, carriers of the APOE ε2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2·5×10(-5)), in both replication phases (p=0·008 in Europeans and p=0·016 in African-Americans), and in the meta-analysis (p=3·2×10(-8)). In the meta-analysis, each copy of APOE ε2 increased haematoma size by a mean of 5·3 mL (95% CI 4·7-5·9; p=0·004). Carriers of APOE ε2 had increased mortality (odds ratio [OR] 1·50, 95% CI 1·23-1·82; p=2·45×10(-5)) and poorer functional outcomes (modified Rankin scale score 3-6; 1·52, 1·25-1·85; p=1·74×10(-5)) compared with non-carriers after lobar ICH. APOE ε4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1·08, 0·86-1·36; p=0·52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality.

Interpretation: Vasculopathic changes associated with the APOE ε2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the ε2 variant might allow identification of those at increased risk of mortality and poor functional outcomes.

Funding: US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.
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http://dx.doi.org/10.1016/S1474-4422(11)70148-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153411PMC
August 2011

The rs2200733 variant on chromosome 4q25 is a risk factor for cardioembolic stroke related to atrial fibrillation in Polish patients.

Neurol Neurochir Pol 2011 Mar-Apr;45(2):148-52

Uniwersytet Jagielloński, Collegium Medicum, Katedra i Klinika Neurologii, ul. Botaniczna 3, 31-503 Kraków.

Background And Purpose: A few single nucleotide polymorphisms (SNPs) on chromosome 4q25, associated with atrial fibrillation (AF), are risk factors for ischaemic stroke. We studied the significance of the SNP rs2200733 on chromosome 4q25 in different types of cardioembolic (CE) stroke.

Material And Methods: We genotyped 428 controls and 301 CE stroke patients, among whom 197 (65.4%) presented with high risk sources of embolism (CE stroke related to AF) and 104 with medium risk sources (CE stroke unrelated to AF). The SNP rs2200733 was analysed using real-time polymorphism chain reaction.

Results: Both univariate and multivariate regression analyses showed that the studied variant affected risk of all CE strokes or CE strokes related to AF in recessive and additive mo-dels. The two types of CE stroke differed significantly in demographics and distribution of vascular risk factors.

Conclusions: The SNP rs2200733 on chromosome 4q25 is a risk factor for CE stroke related to AF only.
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http://dx.doi.org/10.1016/s0028-3843(14)60026-8DOI Listing
July 2011

Angiotensin-converting enzyme tag single nucleotide polymorphisms in patients with intracerebral hemorrhage.

Pharmacogenet Genomics 2011 Mar;21(3):136-41

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Objectives: Studies investigating the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the risk of intracerebral hemorrhage (ICH) have provided conflicting results. Moreover, it is possible that the ACE I/D polymorphism may not represent the functional variant of the gene. The objective of this study was to clarify the influence of the ACE gene region on the risk of ICH by genotyping tag polymorphisms along ACE gene in two independent ethnically different cohorts.

Methods: We included 250 Greek and 169 Polish unrelated patients with ICH and 250 Greek and 322 Polish normal controls in the study. To cover the majority of the genetic variability across the extended ACE gene region, we identified five tag single nucleotide polymorphisms (rs4343, rs4461142, rs7221780, rs8066276, rs8066114) from the HapMap using a pairwise tagging approach and an r2 greater than or equal to 0.8. Single nucleotide polymorphisms and haplotypes were analyzed for associations with ICH risk, ICH subtype (lobar/nonlobar), and age of disease onset using logistic and Cox regression models. Correction for multiple comparisons was carried out.

Results: In the Polish cohort, we observed a trend toward an association between the rs4461142 and the age of ICH onset (hazard ratio 0.50, 95% confidence interval 0.27-0.90, P=0.02). A common haplotype (GTCTC) also showed a trend for increased ICH risk in the Polish cohort (odds ratio 0.19, 95% confidence interval 0.04-0.85, P=0.02). These results were not replicated in the Greek cohort.

Conclusions: Our results did not provide clear evidence for a role of ACE gene in the development of ICH.
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http://dx.doi.org/10.1097/FPC.0b013e328343ab15DOI Listing
March 2011

Variants at APOE influence risk of deep and lobar intracerebral hemorrhage.

Ann Neurol 2010 Dec;68(6):934-43

Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.

Objective: Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied.

Methods: We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification.

Results: Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 × 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 × 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 × 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes.

Interpretation: APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied.
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http://dx.doi.org/10.1002/ana.22134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058266PMC
December 2010

Common mitochondrial sequence variants in ischemic stroke.

Ann Neurol 2011 Mar 13;69(3):471-80. Epub 2010 Sep 13.

Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA.

Objective: Rare mitochondrial mutations cause neurologic disease, including ischemic stroke and MRI white matter changes. We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV).

Methods: In this multicenter, mitochondrial genome-wide association study (GWAS), 2284 ischemic stroke cases and 1728 controls from the International Stroke Genetics Consortium were genotyped for 64 mitochondrial single nucleotide polymorphisms (SNPs). Imputation resulted in 144 SNPs, which were tested in each cohort and in meta-analysis for ischemic stroke association. A genetic score of all mitochondrial variants was also tested in association with ischemic stroke.

Results: No individual SNP reached adjusted significance in meta-analysis. A genetic score comprised of the summation of contributions from individual variants across the mitochondrial genome showed association with ischemic stroke in meta-analysis (odds ratio [OR] = 1.13, p < 0.0001) with minimal heterogeneity (I(2) = 0.00). This ischemic stroke score was robust to permutation, and was also associated with WMHV in 792 nested case individuals with ischemic stroke (p = 0.037).

Interpretation: In this mitochondrial GWAS of ischemic stroke, a genetic score comprised of the sum of all common variants in the mitochondrial genome showed association with ischemic stroke. In an independent analysis of a related trait, this same score correlated with WMHV in stroke cases. Despite this aggregate association, no individual variant reached significance. Substantially larger studies will be required to identify precise sequence variants influencing cerebrovascular disease.
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http://dx.doi.org/10.1002/ana.22108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003764PMC
March 2011