Shani Shenhar-Tsarfaty

Interleukin‐6 as an early predictor for one‐year survival following an ischaemic stroke/transient ischaemic attack

Background Early biomarkers for survival in an acute ischaemic stroke/transient ischaemic attack might serve as a useful tool for the clinician. Several studies have highlighted the role of inflammatory biomarkers as an early signal for acute ischaemic stroke prognosis. Aims This study examines the potential advantage of using high-sensitivity interleukin-6 as a possible biomarker at the early stages of acute stroke for identifying patients at a high risk for 12-month mortality. Methods Inflammatory biomarkers and neurological scores were determined in 250 patients following mild to moderate acute ischaemic stroke within 24 h of hospital admission. Outcome data on mortality were collected after 12 months. The signal detection methodology was used to identify subgroups that were at a high risk for 12-month mortality. Results Twelve months following the event, 234 of the 250 stroke patients survived. Signal detection identified predictors that distinguished individuals likely to die from those with a better recovery prediction. Plasma interleukin-6 concentration emerged as the optimal predictor, with a cut point of 6·47pg/ml, χ2 (I, N = 250) = 20·5, P<0·001. Interleukin-6 above 6·47 pg/ml during the acute phase predicted subsequent non-survival (P = 0·006, odds ratio 8·0). Conclusions This study demonstrates the clinical potential of using high-sensitivity interleukin-6 as an early signal for acute ischaemic stroke survival and suggests a clear cut point for patients at a high risk who might benefit from closer clinical surveillance and/or administration of therapeutic interventions.

Cognitive State following Stroke: The Predominant Role of Preexisting White Matter Lesions

Background and purpose Stroke is a major cause of cognitive impairment and dementia in adults, however the role of the ischemic lesions themselves, on top of other risk factors known in the elderly, remains controversial. This study used structural equation modeling to determine the respective impact of the new ischemic lesions volume, preexisting white matter lesions and white matter integrity on post stroke cognitive state. Methods Consecutive first ever mild to moderate stroke or transient ischemic attack patients recruited into the ongoing prospective TABASCO study underwent magnetic resonance imaging scans within seven days of stroke onset and were cognitively assessed one year after the event using a computerized neuropsychological battery. The volumes of both ischemic lesions and preexisting white matter lesions and the integrity of the normal appearing white matter tissue were measured and their contribution to cognitive state was assessed using structural equation modeling path analysis taking into account demographic parameters. Two models were hypothesized, differing by the role of ischemic lesions volume. Results Structural equation modeling analysis of 142 patients confirmed the predominant role of white matter lesion volume (standardized path coefficient βu200a=u200a−0.231) and normal appearing white matter integrity (βu200a=u200a−0.176) on the global cognitive score, while ischemic lesions volume showed no such effect (βu200a=u200a0.038). The model excluding the ischemic lesion presented better fit to the data (comparative fit index 0.9 versus 0.092). Conclusions Mild to moderate stroke patients with preexisting white matter lesions are more vulnerable to cognitive impairment regardless of their new ischemic lesions. Thus, these patients can serve as a target group for studies on cognitive rehabilitation and neuro-protective therapies which may, in turn, slow their cognitive deterioration.

Butyrylcholinesterase interactions with amylin may protect pancreatic cells in metabolic syndrome.

The metabolic syndrome (MetS) is a risk factor for type 2 diabetes mellitus (T2DM). However, the mechanisms underlying the transition from MetS to T2DM are unknown. Our goal was to study the potential contribution of butyrylcholinesterase (BChE) to this process. We first determined the hydrolytic activity of BChE in serum from MetS, T2DM and healthy individuals. The ‘Kalow’ variant of BChE (BChE‐K), which has been proposed to be a risk factor for T2DM, was genotyped in the last two groups. Our results show that in MetS patients serum BChE activity is elevated compared to T2DM patients and healthy controls (Pu2002< 0.001). The BChE‐K genotype showed similar prevalence in T2DM and healthy individuals, excluding this genotype as a risk factor for T2DM. However, the activity differences remained unexplained. Previous results from our laboratory have shown BChE to attenuate the formation of β‐amyloid fibrils, and protect cultured neurons from their cytotoxicity. Therefore, we next studied theu2002in vitrou2002interactions between recombinant human butyrylcholinesterase and amylin by surface plasmon resonance, Thioflavine T fluorescence assay and cross‐linking, and used cultured pancreatic β cells to test protection by BChE from amylin cytotoxicity. We demonstrate that BChE interacts with amylin through its core domain and efficiently attenuates both amylin fibril and oligomer formation. Furthermore, application of BChE to cultured β cells protects them from amylin cytotoxicity. Taken together, our results suggest that MetS‐associated BChE increases could protect pancreatic β‐cellsu2002in vivou2002by decreasing the formation of toxic amylin oligomers.

Association of the -757T>C polymorphism in the CRP gene with circulating C-reactive protein levels and carotid atherosclerosis

INTRODUCTIONnC-reactive protein (CRP) is an inflammatory protein that may play a role in the pathogenesis of atherosclerosis. CRP gene single nucleotide polymorphisms (SNPs) have been shown to be associated with CRP concentration; however, their independent effect on atherosclerosis has not been yet established. We aimed to determine whether the 5-flanking -757T>C CRP gene polymorphism is associated with CRP concentration and carotid atherosclerosis.nnnMETHODSnWe genotyped the -757T>C CRP gene SNP and determined the concentration of serum CRP, the intima-media thickness (IMT) of the common carotid artery and the existence of plaque/s in 612 apparently healthy men and women aged 66+/-10 years.nnnRESULTSnCarriers of the CRP -757C allele presented with higher IMT and higher CRP concentrations (p=0.002, p=0.042, respectively). After adjustment for vascular risk factors, linear regression analysis showed an independent effect of CRP -757C allele on carotid IMT, beyond serum CRP concentrations. This SNP was also associated with carotid plaque occurrence (O.R. 1.74, 95% CI 1.1-2.77, p=0.002).nnnCONCLUSIONSnThe present study provides evidence that a genetic variant of CRP gene is associated with carotid atherosclerosis, independently of traditional vascular risk factors. Further large-scale genomic studies are required, which may identify the genetic vulnerable subjects to develop atherosclerosis.

Cognitive Assessment in Proximity to Acute Ischemic Stroke/Transient Ischemic Attack: Comparison of the Montreal Cognitive Assessment Test and MindStreams Computerized Cognitive Assessment Battery

Background/Aims: Even mild stroke survivors may sometimes experience residual cognitive damage. No consensus has emerged about which cognitive test is most appropriate for the diagnosis of poststroke cognitive impairment. We aim to compare a computerized battery of neuropsychological tests for memory, attention and executive functions (MindStreams®) with the Montreal Cognitive Assessment (MoCA) to detect mild-to-moderate cognitive impairments in poststroke patients. Methods: Subjects enrolled to the TABASCO (Tel Aviv Brain Acute Stroke Cohort) study, a prospective study which includes consecutive first-ever mild-to-moderate stroke patients, were included. All participants underwent neurological and cognitive evaluations. Results: A total of 454 patients with transient ischemic attack (TIA) or stroke are reported. Their mean MoCA and MindStreams scores were lower than normal; however, the TIA group presented significantly better scores using either method. The correlation between the MoCA and the computerized global score was 0.6 (p < 0.001). A significant correlation was found between the subcategory scores (executive function, memory and attention). However, the MoCA identified many more subjects with low scores (<26) compared to the MindStreams (70.6 vs. 15.7%). Conclusion: Our results demonstrate that either of the modalities alone is sensitive enough for identifying subtle cognitive impairment and none picks up substantially more cognitive losses than the other in patients with cerebrovascular disease.

Cognitive state following mild stroke: A matter of hippocampal mean diffusivity

The hippocampus is known to play a vital role in learning and memory and was demonstrated as an early imaging marker for Alzheimers disease (AD). However, its role as a predictor for mild cognitive impairment and dementia following stroke is unclear. The main purpose of this study was to examine the associations between hippocampal volume, mean diffusivity (MD) and connectivity and cognitive state following stroke. Eighty three consecutive first ever mild to moderate stroke or transient ischemic attack (TIA) survivors from our ongoing prospective TABASCO (Tel Aviv Brain Acute Stroke Cohort) study underwent magnetic resonance imaging scans within 7 days of stroke onset. Hippocampal volume was measured from T1 weighted images, hippocampal mean diffusivity was calculated from diffusion tensor imaging and connectivity was calculated from resting state fMRI. Global cognitive assessments were evaluated during hospitalization and 6 and 12 months later using a computerized neuropsychological battery. Multiple linear regression analysis was used to test which of the hippocampi measurements best predict cognitive state. All three imaging parameters were significantly correlated to each other (|rs| >0.3, Psu2009<u20090.005), and with cognitive state 6 and 12 months after the event. Multiple regression analyses demonstrated the predictive role of hippocampal mean diffusivity (βu2009=u2009−0.382, Pu2009=u20090.026) on cognitive state, above and beyond that of volume and connectivity of this structure. To our knowledge, the combination of hippocampal volume, mean diffusivity and connectivity in first ever post stroke or TIA patients has not yet been considered in relation to cognitive state. The results demonstrate the predictive role of hippocampal mean diffusivity, suggesting that these changes may precede and contribute to volumetric and connectivity changes in the hippocampi, potentially serving as a marker for early identification of patients at risk of developing cognitive impairment or dementia.

Exercise-induced albuminuria is related to metabolic syndrome.

Microalbuminuria (MA) is a known marker for endothelial dysfunction and future cardiovascular events. Exercise-induced albuminuria (EiA) may precede the appearance of MA. Associations between EiA and metabolic syndrome (MS) have not been assessed so far. Our aim was to investigate this association in a large sample of apparently healthy individuals with no baseline albuminuria. This was a cross-sectional study of 2,027 adults with no overt cardiovascular diseases who took part in a health survey program and had no baseline MA. Diagnosis of MS was based on harmonized criteria. All patients underwent an exercise test (Bruce protocol), and urinary albumin was measured before and after the examination. Urinary albumin-to-creatinine ratio (ACR) values before and after exercise were 0.40 (0.21-0.89) and 1.06 (0.43-2.69) mg/g for median (interquartile range) respectively. A total of 394 (20%) subjects had EiA; ACR rose from normal rest values (0.79 mg/g) to 52.28 mg/g after exercise (P < 0.001); this effect was not shown for the rest of the study population. EiA was related to higher prevalence of MS (13.8% vs. 27.1%, P < 0.001), higher metabolic equivalents (P < 0.001), higher baseline blood pressure (P < 0.001), and higher levels of fasting plasma glucose, triglycerides, and body mass index (P < 0.001). Multivariate binary logistic regression model showed that subjects with MS were 98% more likely to have EiA (95% confidence interval: 1.13-3.46, P = 0.016). In conclusion, EiA in the absence of baseline MA is independently related to MS.

Wide‐range C‐reactive protein efficacy in acute ischemic stroke patients

Objectiveu2002–u2002 To compare the recently introduced wide‐range C‐reactive protein (wr‐CRP) with the widely used high‐sensitivity Behring Dade method (hs‐CRP) in acute stroke/transient ischemic attack (TIA) patients.

High hair cortisol concentrations predict worse cognitive outcome after stroke: Results from the TABASCO prospective cohort study

BACKGROUND AND PURPOSEnThe role of stress-related endocrine dysregulation in the development of cognitive changes following a stroke needs further elucidation. We explored this issue in a longitudinal study on stroke survivors using hair cortisol concentrations (HCC), a measure of integrated long-term cortisol levels.nnnMETHODSnParticipants were consecutive cognitively intact first-ever mild-moderate ischemic stroke/transient ischemic attack (TIA) survivors from the Tel Aviv Brain Acute Stroke Cohort (TABASCO) study. They underwent 3T magnetic resonance imaging (MRI) scanning and were cognitively assessed at admission, and at 6, 12 and 24 months post-stroke. Scalp hair samples were obtained during the initial hospitalization.nnnRESULTSnFull data on baseline HCC, MRI scans and 2 years neuropsychological assessments were available for 65 patients. Higher HCC were significantly associated with a larger lesion volume and with worse cognitive results 6, 12 and 24 months post-stroke on most of the neurocognitive tests. 15.4% of the participants went on to develop clinically significant cognitive decline in the follow-up period, and higher HCC at baseline were found to be a significant risk factor for this decline, after adjustment for age, gender, body mass index and APOE e4 carrier status (HR=6.553, p=0.038).nnnCONCLUSIONSnOur findings suggest that individuals with higher HCC, which probably reflect higher long-term cortisol release, are prone to develop cognitive decline following an acute stroke or TIA.

Sex difference in the risk for exercise-induced albuminuria correlates with hemoglobin A1C and abnormal exercise ECG test findings

BackgroundAlbuminuria is an established marker for endothelial dysfunction and cardiovascular risk in diabetes and prediabetes. Exercise induced albuminuria (EiA) appears earlier and may be a more sensitive biomarker for renal endothelial damage. We sought to examine the association between EiA, parameters of the metabolic syndrome, A1C levels, exercise ECG test results and sex related differences in a large cohort of healthy, pre-diabetic and diabetic subjects.MethodsA total of 3029 participants from the Tel-Aviv Medical Center Inflammation Survey cohort (mean age 46xa0years, 73% men) were analyzed. Multiple physiologic and metabolic parameters including A1C were collected and albuminuria was measured in all subjects before and immediately after completing an exercise ECG test.ResultsExercise increased urinary albumin to creatinine ratio (ΔEiA) by 2.8 (0–13.6) mg/g for median (IQR) compared to rest albuminuria (pxa0<xa00.001). An increase in ΔEiA was observed with accumulating parameters of the metabolic syndrome. ΔEiA showed significant interaction with sex and A1C levels; i.e. women with A1Cxa0>xa06.5% had an increased risk of higher ΔEiA (pxa0<xa00.001). Using a cutoff of ΔEiAxa0>xa013xa0mg/g (top quartile) we found that women with ΔEiAxa0>xa013xa0mg/g were at greater risk for abnormal exercise ECG findings, (ORxa0=xa02.7, pxa0=xa00.001).ConclusionExercise promotes excessive urinary albumin excretion in dysmetabolic patients. In women, a significant correlation exists between ΔEiA and A1C levels. A cutoff of ΔEiAxa0>xa013xa0mg/g in women may be used to identify populations at risk for abnormal exercise ECG test findings and perhaps increased cardiovascular risk. Future studies will be needed to further validate the usefulness of ΔEiA as a biomarker for cardiovascular risk in women with and without diabetes.