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

BACKGROUND AND PURPOSE: The 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. METHODS: Participants 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. RESULTS: Full 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). CONCLUSIONS: Our 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.

Intensified vmPFC surveillance over PTSS under perturbed microRNA-608/AChE interaction.

Trauma causes variable risk of posttraumatic stress symptoms (PTSS) owing to yet-unknown genome-neuronal interactions. Here, we report co-intensified amygdala and ventromedial prefrontal cortex (vmPFC) emotional responses that may overcome PTSS in individuals with the single-nucleotide polymorphism (SNP) rs17228616 in the acetylcholinesterase (AChE) gene. We have recently shown that in individuals with the minor rs17228616 allele, this SNP interrupts AChE suppression by microRNA (miRNA)-608, leading to cortical elevation of brain AChE and reduced cortisol and the miRNA-608 target GABAergic modulator CDC42, all stress-associated. To examine whether this SNP has effects on PTSS and threat-related brain circuits, we exposed 76 healthy Israel Defense Forces soldiers who experienced chronic military stress to a functional magnetic resonance imaging task of emotional and neutral visual stimuli. Minor allele individuals predictably reacted to emotional stimuli by hyperactivated amygdala, a hallmark of PTSS and a predisposing factor of posttraumatic stress disorder (PTSD). Despite this, minor allele individuals showed no difference in PTSS levels. Mediation analyses indicated that the potentiated amygdala reactivity in minor allele soldiers promoted enhanced vmPFC recruitment that was associated with their limited PTSS. Furthermore, we found interrelated expression levels of several miRNA-608 targets including CD44, CDC42 and interleukin 6 in human amygdala samples (N=7). Our findings suggest that miRNA-608/AChE interaction is involved in the threat circuitry and PTSS and support a model where greater vmPFC regulatory activity compensates for amygdala hyperactivation in minor allele individuals to neutralize their PTSS susceptibility.

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.

Atherosclerosis and arteriosclerosis parameters in stroke patients associate with paraoxonase polymorphism and esterase activities.

BACKGROUND AND PURPOSE: Polymorphic paraoxonase (PON1) variants can variably prevent low- and high-density lipoprotein oxidation, but their role in provoking atherosclerosis remained unclear. We addressed this issue by profiling PON1 polymorphisms and enzymatic activities, and assessing atherosclerosis and cerebral arteriosclerosis severity in post-stroke patients. METHODS: Carotid artery intima-media-thickness (IMT), cerebral white matter lesions (WML), serum PON1 -108C/T, Q192R and L55M polymorphisms, and PON and acetylcholinesterase (AChE) enzyme activities were determined in 237 patients. RESULTS: Genetic variation at the PON1 locus showed a strong influence on PON1 activity in ischaemic stroke patients, but lacked direct influence on IMT. Stroke patients with PON1 QQ192 or MM55 genotypes demonstrated lower PON and arylesterase activities at both Day 1 and 12 months post-stroke than patients with either RQ/RR192 or LM/LL55 genotypes (P < 0.001). Furthermore, patients with carotid atherosclerosis and/or cerebral arteriosclerosis expressed as IMT, carotid plaques and WML had lower 12 months PON1 activity than patients without (P = 0.02, P = 0.027 and P = 0.001, respectively), and PON and AChE hydrolysis rates were more tightly correlated in patients carrying the PON1 192R compared with the 192QQ allele, in a gene dose-dependent manner (P < 0.001). CONCLUSION: Our findings show inverse PON1 activity-carotid atherosclerosis and -cerebral arteriosclerosis association in stroke patients: the lower the PON1 activity the more progressed is the atherosclerotic process and the weaker is the association with AChE activity. Extending previous PON1 genetic studies in stroke populations, our study emphasizes the PON1 activity as a potential anti-atherogenic element and proposes involvement of cholinesterase activities in its effects.

Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFκB pathway.

Post-traumatic anxiety notably involves inflammation, but its causes and functional significance are yet unclear. Here, we report that failure of the innate immune system Toll-like receptor 9 (TLR9) to limit inflammation is causally involved with anxiety-associated inflammation and that peripheral administration of specific oligonucleotide activators of TLR9 may prevent post-traumatic consequences in stressed mice. Suggesting involvement of NFκB-mediated enhancement of inflammatory reactions in the post-traumatic phenotype, we found association of serum interleukin-1ß increases with symptoms severity and volumetric brain changes in post-traumatic stress disorder patients. In predator scent-stressed mice, the moderate NFκB-activating oligonucleotides mEN101 and its human ortholog BL-7040, but not the canonic NFκB activator oligonucleotide ODN1826, induced anxiolytic effects. In stressed mice, peripherally administered mEN101 prevented delayed stress-inducible serum interleukin-1ß increases while limiting stress-characteristic hippocampal transcript modifications and the anxiety-induced EGR1-mediated neuronal activation. Attesting to the TLR9 specificity of this response, BL-7040 suppressed NFκB-mediated luciferase in transfected cells co-expressing TLR9, but not other TLRs. Furthermore, TLR9-/- mice were mEN101 and BL-7040 resistant and presented unprovoked anxiety-like behavior and anxiety-characteristic hippocampal transcripts. Our findings demonstrate functional relevance of TLR9 in protecting stressed mammals from overreacting to traumatic experiences and suggest using oligonucleotide-mediated peripheral TLR9 activation to potentiate the innate immune system and prevent post-traumatic inflammation and anxiety.

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 6.47 pg/ml, chi(2) (l, 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.

Triggered C-reactive protein (CRP) concentrations and the CRP gene -717A>G polymorphism in acute stroke or transient ischemic attack.

C-reactive protein (CRP) increases following an acute stroke/transient ischemic attack (TIA), but the increment level varies among patients. We analyzed CRP concentrations during an acute stroke/TIA in relation to the CRP gene -717A>G polymorphism. Six months following an acute ischemic stroke/TIA, basal concentrations of CRP were measured in 507 controls and 219 patients and were found to be unassociated with the CRP -717A>G polymorphism. However, during the acute phase of stroke/TIA, individuals with the AG/GG genotype had significantly elevated CRP concentrations as opposed to those with the AA genotype (2.02 +/- 1.59 vs. 1.73 +/- 1.69 mg/l, P = 0.027). In addition, significant 3.22-fold increments in CRP concentrations was noted in individuals carrying the -717G allele when comparing the acute phase with the basal state of each patient and averaging the results. CRP -717A>G polymorphism is associated with triggered CRP concentrations during acute stroke/TIA. These findings might shed more light on the mechanisms of CRP elevation in acute ischemic stroke/TIA.

Wide-range C-reactive protein efficacy in acute ischemic stroke patients.

OBJECTIVE: 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. MATERIALS AND METHODS: A total of 119 consecutive patients admitted to a tertiary medical center with acute ischemic stroke/TIA were included in the study. Venous blood was obtained for both assays during the first 24 h, 3-5 days, as well as 3-6 months thereafter. RESULTS: A highly significant correlation (r=0.994, P<0.0001) was found between the two methods even when analyzed at three different time points. In addition, a similar correlation was noted between these two assays and other commonly used biomarkers, including white blood cell count, Westergren's sedimentation rate and quantitative fibrinogen. CONCLUSION: Real-time, on-line and low-cost wr-CRP assay is a reasonable alternative to the Behring Dade hs-CRP method in acute stroke/TIA patients.