Higher Cerebral Blood Flow Velocity Research Articles

Peculiarities of angiospasm and ischemic complications in ruptures of cerebral arterial aneurysms against the background of occlusive-stenotic lesions of cerebral arteries

Objective – to determine the effect of occlusive-stenotic lesions of cerebral arteries on angiospasm and ischemic complications in patients with ruptured arterial aneurysms against the background of occlusive-stenotic lesions of cerebral arteries. Materials and methods. A retrospective study of the medical histories of 1,147 patients with cerebral artery aneurysms from 2006 to 2022 was conducted. 63 patients were included in the study group because they met the following criteria: surgical treatment; rupture of saccular aneurysms (SAs); the presence of occlusive-stenotic lesions was proven using instrumental examination methods. Patients of the control group had to meet the following criteria: surgical treatment; rupture of SAs; the absence of occlusive-stenotic lesions was proven by means of instrumental examination methods; the gender and age distribution had to match the study group. Of the 126 patients included in this study, there were 76 men (60.32%) and 50 women (39.68%). The age of the patients varied from 31 to 77 years. The average age of patients- 55.9±0.76 years; men – 54.3±0.94 years, women – 58.3±1.19 years. Results. A percentage predominance of patients with high cerebral blood flow velocity (>200 cm/s, which is equal to the velocity with severe grade III vasospasm of the cerebral arteries) in the study group (32.56%) compared with the control group (24.24%) was revealed. Conclusions. The predominance of men among patients of the study group (60.32%) was established. The average age of men with occlusive-stenotic lesions was younger than that of women (men – 54.3±0.94 years, women – 58.3±1.19 years). The difference in age is the largest in the 2nd subgroup of the study group where the severity of stenosis is 50-75% (men - 48.3 years; women - 62 years). Ruptures of arterial aneurysms of the middle cerebral artery occur more often in the presence of stenoses (study group - 25.4%, control group - 12.7%). The neurological status of patients with a hemorrhagic stroke, as a result of the rupture of an arterial aneurysm, is significantly aggravated by occlusive-stenotic lesions due to the occurrence of chronic brain ischemia. The worst prognosis for life and health was in men with a ruptured arterial aneurysm against the background of a 50-75% stenotic lesion and severe vasospasm of the cerebral arteries.

Age-specific sex-differences in cerebral blood flow velocity in relation to haemoglobin levels.

Cerebral blood flow (CBF) declines with age and abnormalities in CBF are associated with age-related cerebrovascular disease and neurodegeneration. Women have higher CBF than men, although this sex-difference diminishes to some extent with age in healthy subjects. The physiological drivers of these age/sex differences are uncertain, but might be secondary to age and sex-differences in haemoglobin (Hb) level. Hb levels are inversely correlated with CBF, are lower in women, and decline with age in men, but the interrelations between these factors have not been explored systematically either in healthy subjects or across the full age-range in patients with vascular risk factors. We aimed to determine the age-specific interrelations between sex, Hb, and CBF velocity in a large cohort of patients with cerebrovascular disease. In patients with a recent transient ischaemic attack or minor stroke (Oxford Vascular Study) and no ipsilateral or contralateral stenosis of the carotid or intracranial arteries, we related peak-systolic velocity (PSV) and other parameters on transcranial Doppler ultrasound (TCD) of the middle cerebral artery to sex, age, Hb and vascular risk factors. Of 958 eligible subjects (mean age/SD = 68.04/14.26, 53.2% male), younger women (age < 55 years) had higher CBF velocities than men (mean sex difference in PSV at age < 55 years = 16.31 cm/s; p < 0.001), but this difference declined with age (interaction p < 0.001), such that it was no longer significant at age 75-84 (∆PSV = 3.26 cm/s; p = 0.12) and was reversed at age ⩾ 85 (∆PSV = -7.42 cm/s; p = 0.05). These changes mirrored trends in levels of Hb, which were higher in men at age < 55 (∆Hb = 1.92 g/dL; p < 0.001), but steadily decreased with age in men but not in women (interaction p < 0.001), with no residual sex-difference at age ⩾ 85 (∆Hb = 0.12 g/dL; p = 0.70). There was an inverse correlation between Hb and PSV in both women and men (both p ⩽ 0.01), and the sex-difference in PSV at age < 55 was substantially diminished after adjustment for Hb (∆PSV = 6.92; p = 0.036; ∆PSV = 5.92, p = 0.13 with further adjustment for end-tidal CO2). In contrast, the sex difference in PSV was unaffected by adjustment for systolic and diastolic blood pressure, heart rate, and vascular risk factors (history of hypertension, diabetes, hyperlipidaemia and smoking). CBF velocity is strongly correlated with Hb level at all ages, and sex-differences in CBF velocity appear to be explained in major part by age-related sex-differences in Hb.

Abstract 15140: Cerebral Hemodynamics During Left Ventricular Assist Device Speed Titration

Introduction: Left ventricular assist device (LVAD) speed may be titrated to optimize cardiopulmonary hemodynamics, but the impact on cerebral blood flow remains poorly understood. Hypothesis: Here, we monitored cerebral hemodynamics during ramp studies, to test the hypothesis that LVAD speed correlates with cerebral blood flow and cerebral autoregulation. Methods: Patients with HeartMate3 LVADs underwent ramp study for optimization, during which cerebral blood flow velocity (CBFv) was continuously monitored by transcranial Doppler (TCD), and blood pressure was continuously monitored by finger plethysmography. Mx index was used a measure of autoregulation which correlates blood pressure and CBFv (i.e. high Mx index indicates poor autoregulation). The treating cardiologist determined the optimal speed based on cardiopulmonary dynamics (other speeds were categorized as sub-optimal). Results: Of 23 patients, 5 did not undergo speed changes. At least two speeds were explored in the remaining 18 patients. When comparing the lowest and highest speeds for each patient, higher speeds resulted in higher CBFv (p=0.02; Figure 1a ), but no change in autoregulation (p=0.38; Figure 1b ). However, when comparing the optimal and suboptimal LVAD speeds, CVFv was similar (p=0.89; Figure 2a ,), whereas the optimal speed was associated with a trend toward favorable autoregulation (p=0.09; Figure 2b ). Conclusions: Cerebral blood flow velocity is sensitive to LVAD speed titration, and cardiopulmonary optimization may improve cerebral autoregulation. A larger cohort and a broader range of speeds may further clarify the impact of speed titration on cerebral hemodynamics.

Early stellate ganglion block for improvement of postoperative cerebral blood flow velocity after aneurysmal subarachnoid hemorrhage: results of a pilot randomized controlled trial.

Stellate ganglion block (SGB) is a commonly used sympathetic nerve block technique that may have benefits for patients with aneurysmal subarachnoid hemorrhage (aSAH) in the early stage. Cerebral vasospasm (CVS), one of the most common complications of aSAH, is accompanied by an abnormal increase in cerebral blood flow velocity (CBFV) and neurological dysfunction. In this pilot study the authors sought to determine the feasibility of early SGB for CVS in aSAH patients by observing the incidence of symptomatic CVS. Prior to receiving surgical treatment, patients with aSAH were randomly assigned to the SGB group or the non-SGB group. The primary outcome was the incidence of symptomatic CVS within 14 ± 2 days after the onset of aSAH. As a higher CBFV is often associated with CVS and a poor prognosis, the mean CBFV of the middle cerebral artery was observed immediately after surgery and on postoperative days 1, 2, 3, 5, and 7. Other secondary outcomes included transcranial Doppler (TCD)/CTA-type CVS, delayed cerebral ischemia during hospitalization, new cerebral infarction within 3 months, adverse events (AEs), and clinical prognosis. Symptomatic CVS occurred in 40% of patients in the non-SGB group and in 20% in the SGB group (RR 0.50, 95% CI 0.22-1.16). Continuous TCD sonography revealed that the postoperative mean CBFV was lower in the SGB group than in the non-SGB group (F = 3.608, p = 0.02). In addition, the percentages of patients with CVS evaluated by TCD (TCD-CVS) and total new infarctions within 3 months were also significantly lower than those in patients with CVS (TCD-CVS 36.7% vs 70%, RR 0.52, 95% CI 0.31-0.89, and total new infarctions 26.7% vs 53.3%, RR 0.50, 95% CI 0.25-0.99). In terms of AEs and mortality, there were no significant differences between the two groups. This pilot study demonstrated for the first time, to the authors' knowledge, that early SGB is feasible and has the potential to reduce the risk of CVS and improve the prognosis of aSAH. This method may be a new treatment for patients with aSAH that may have more advantages than traditional therapeutic drugs and is worth further study. Clinical trial registration no.: NCT04691271 (ClinicalTrials.gov).

Neutrophil-to-lymphocyte ratio is associated with increased cerebral blood flow velocity in acute bacterial meningitis

In community-acquired bacterial meningitis (CABM) intracranial vascular alterations are devastating complications which are triggered by neuroinflammation and result in worse clinical outcome. The Neutrophil-to-Lymphocyte ratio (NLR) represents a reliable parameter of the inflammatory response. In this study we analyzed the association between NLR and elevated cerebral blood flow velocity (CBFv) in CABM-patients. This study included all (CABM)-patients admitted to a German tertiary center between 2006 and 2016. Patients’ demographics, in-hospital measures, neuroradiological data and clinical outcome were retrieved from institutional databases. CBFv was assessed by transcranial doppler (TCD). Patients’, radiological and laboratory characteristics were compared between patients with/without elevated CBFv. Multivariate-analysis investigated parameters independently associated with elevated CBFv. Receiver operating characteristic(ROC-)curve analysis was undertaken to identify the best cut-off for NLR to discriminate between increased CBFv. 108 patients with CABM were identified. 27.8% (30/108) showed elevated CBFv. Patients with elevated CBFv and normal CBFv, respectively had a worse clinical status on admission (Glasgow Coma Scale: 12 [9–14] vs. 14 [11–15]; p = 0.005) and required more often intensive care (30/30 [100.0%] vs. 63/78 [80.8%]; p = 0.01).The causative pathogen was S. pneumoniae in 70%. Patients with elevated CBFv developed more often cerebrovascular complications with delayed cerebral ischemia (DCI) within hospital stay (p = 0.031). A significantly higher admission-NLR was observed in patients with elevated CBFv (median [IQR]: elevated CBFv:24.0 [20.4–30.2] vs. normal CBFv:13.5 [8.4–19.5]; p < 0.001). Multivariate analysis, revealed NLR to be significantly associated with increased CBFv (Odds ratio [95%CI] 1.042 [1.003–1.084]; p = 0.036). ROC-analysis identified a NLR of 20.9 as best cut-off value to discriminate between elevated CBFv (AUC = 0.713, p < 0.0001, Youden's Index = 0.441;elevated CBFv: NLR ≥ 20.9 19/30[63.5%] vs. normal CBFv: NLR > 20.9 15/78[19.2%]; p < 0.001). Intracranial vascular complications are common among CABM-patients and are a risk factor for unfavorable outcome at discharge. Elevated NLR is independently associated with high CBFv and may be useful in predicting patients’ prognosis.

Association of alpha-thalassemia and Glucose-6-Phosphate Dehydrogenase deficiency with transcranial Doppler ultrasonography in Nigerian children with sickle cell anemia.

BackgroundStroke is a devastating complication of sickle cell anemia (SCA) and can be predicted through abnormally high cerebral blood flow velocity using transcranial Doppler Ultrasonography (TCD). The evidence on the role of alpha‐thalassemia and glucose‐6‐phosphate dehydrogenase (G6PD) deficiency in the development of stroke in children with SCA is conflicting. Thus, this study investigated the association of alpha‐thalassemia and G6PD(A−) variant with abnormal TCD velocities among Nigerian children with SCA.MethodsOne hundred and forty‐one children with SCA were recruited: 72 children presented with normal TCD (defined as the time‐averaged mean of the maximum velocity: < 170 cm/s) and 69 children with abnormal TCD (TAMMV ≥ 200 cm/s). Alpha‐thalassemia (the α‐3.7 globin gene deletion) was determined by multiplex gap‐PCR, while G6PD polymorphisms (202G > A and 376A > G) were genotyped using restriction fragment length polymorphism—polymerase chain reaction.ResultsThe frequency of α‐thalassemia trait in the children with normal TCD was higher than those with abnormal TCD: 38/72 (52.8%) [α‐/ α α: 41.7%, α ‐/ α ‐: 11.1%] versus 21/69 (30.4%) [α‐/ α α: 27.5%, α ‐/ α ‐: 2.9%], and the odds of abnormal TCD were reduced in the presence of the α‐thalassemia trait [Odds Ratio: 0.39, 95% confidence interval: 0.20–0.78, p = 0.007]. However, the frequencies of G6PDA− variant in children with abnormal and normal TCD were similar (11.6% vs. 15.3%, p = 0.522).ConclusionOur study reveals the protective role of α‐thalassemia against the risk of abnormal TCD in Nigerian children with SCA.

Double-blinded, placebo-controlled crossover trial to determine the effects of midodrine on blood pressure during cognitive testing in persons with SCI.

Study Design:Clinical trial.Objectives:Individuals with spinal cord injury (SCI) above T6 experience impaired descending cortical control of the autonomic nervous system which predisposes them to hypotension. However, treatment of hypotension is uncommon in the SCI population because there are few safe and effective pharmacological options available. The primary aim of this investigation was to test the efficacy of a single dose of midodrine (10 mg), compared to placebo, to increase and normalize systolic blood pressure (SBP) between 110–120 mmHg during cognitive testing in hypotensive individuals with SCI. Secondary aims were to determine the effects of midodrine on cerebral blood flow velocity (CBFv) and global cognitive function.Setting:United States clinical research laboratory.Methods:Forty-one healthy hypotensive individuals with chronic (≥ 1-year post-injury) SCI participated in this 2-day study.Seated SBP, CBFv, cognitive performance were monitored before and after administration of identical encapsulated tablets, containing either midodrine or placebo.Results:Compared to placebo, midodrine increased SBP (4±13 vs. 18±24 mmHg, respectively; p<0.05); however, responses varied widely with midodrine (−15.7 to +68.6 mmHg). Further, the proportion of SBP recordings within the normotensive range did not improve during cognitive testing with midodrine compared to placebo. Although higher SBP was associated with higher CBFv (p=0.02), global cognitive function was not improved with midodrine.Conclusions:The findings indicate that midodrine increases SBP and may be beneficial in some hypotensive patients with SCI; however, large heterogeneity of responses to midodrine suggest careful monitoring of patients following administration.

Carotid artery blood flow velocities during open-heart surgery and its association with delirium: A prospective, observational pilot study.

The aim of this prospective observational single-centre pilot study was to evaluate the association between alterations in carotid artery blood flow velocities during cardiac surgery and postoperative delirium.Carotid artery blood flow velocity was determined perioperatively at 5 different timepoints by duplex sonography in 36 adult cardiac surgical patients. Delirium was assessed using the Confusion Assessment Method for the ICU and the Intensive Care Delirium Screening Checklist. Additionally, blood flow velocities in the middle cerebral arteries, differences in regional cerebral tissue oxygenation and quantity and quality of microemboli were measured.Delirium was detected in 7 of 36 patients. After cardiopulmonary bypass carotid artery blood flow velocities increased by +23 cm/second (95% confidence interval (CI) 9-36 cm/second) in non-delirious patients compared to preoperative values (P = .002), but not in delirious patients (+3 cm/second [95% CI -25 to 32 cm/second], P = .5781). Middle cerebral artery blood flow velocities were higher at aortic de-cannulation in non-delirious patients (29 cm/second [inter-quartile range (IQR), 24-36 cm/second] vs 12 cm/second [IQR, 10-19 cm/second]; P = .017). Furthermore, brain tissue oxygenation was higher in non-delirious patients during surgery.Our results suggest that higher cerebral blood flow velocities after aortic de-clamping and probably also improved brain oxygenation might be beneficial to prevent postoperative delirium.

Cerebral Infarcts and Cerebrovascular Disease in Neurologically Intact Tanzanian Children with Sickle Cell Anaemia

Introduction:Children and adolescents with sickle cell anemia (SCA) without history of neurological manifestations remain at risk of stroke and require cost effective screening as evidence-based stroke prevention interventions are developed. Although there are data on the prevalence of Transcranial Doppler (TCD) abnormality, there are relatively few studies on the prevalence of silent cerebral infarction (SCI) on magnetic resonance imaging (MRI) and vasculopathy on MR angiography (MRA), paricularly in Africa, where the burden of disease is greatest. In this study in Africa, we determined the prevalence of SCI on MRI and cerebral vasculopathy on MRA, and explored associations with age, sex, internal carotid/middle cerebral artery (ICA/MCA) and basilar cerebral blood flow velocities (CBFV) on TCD, and hematological variables.Patients and methods:We prospectively studied children with homozygous SCA (HbSS) without prior clinically overt stroke or TIA or seizures. Clinical information and blood for full blood count was collected for all patients. All were offered TCD using non-imaging equipment (Compumedics) and MRI and MRA of intracranial arteries on a Philips 1.5 Tesla scanner. MRA was graded as 1 Turbulence, 2 Stenosis, 3 Occlusion, 4 Occlusion with collaterals (moyamoya). Imaging was reviewed by 2 neuroradiologists (MJ and DS) and consensus was reached.Results:Within a period of 12 months, 395 children with SCA were recruited. Mean age was 12.7+/-4 (range 5-19 years); 199 (50.4%) were male. Mean hemoglobin was 7.6±1.1 (range 4.1-13.5) g/dl. 381 had TCD, of whom 227 (57%) have had brain MRI and MRA so far.Only 14/395 (3.5%) of patients had abnormal CBFV, 8 (2%) with maximum CBFV <50 cm/sec, 3 with CBFV 150-169 cm/sec, 1 with conditional (170-199 cm/sec) and 2 (0.5%) with abnormal CBFV (>200cm/sec).Prevalence of silent cerebral infarction was 29% (65/227) and was similar in males (30%; 34/114) and females (28%; 31/110) but was lower in children aged <9 years (20%; 10/51) than in those aged 10-14 years (33%; 27/83) or those aged 15-19 years (32%; 28/89); this was not significant (p=0.2).The prevalence of cerebral vasculopathy on MRA, defined as stenosis (Grade 2), occlusion (Grade 3) or occlusion with collaterals (moyamoya; Grade 4), was 9% (20/227). The internal carotid and/or middle cerebral artery was affected in all 20 and the anterior cerebral artery was affected in 7 patients. Vasculopathy was not observed on MRA in the posterior cerebral artery and no patients had moyamoya. An additional 9 (4%) patients had turbulence (Grade 1) in at least one artery on MRA.SCI were more common in those with MRA vasculopathy Grades 2-3 (12/64; 19%) and in those with Grade 1 Turbulence (2/9; 22%) than in those with normal MRA (8/165; 5%) (p<0.05). Patients with Grade 1 Turbulence had higher ICA/MCA CBFv (mean 122+/-36 cm/sec) than those with normal MRA (mean 101+/-25 cm/sec) or Grades 2-3 (mean 109+/-21 cm/sec) vasculopathy. The difference in those with Grade 1 turbulence compared with those with normal MRA was significant (mean difference 20 cm/sec, 95% confidence intervals 1, 39 cm/sec; p=0.037). Basilar velocity was also significantly higher in those with Grade 1 turbulence (87+/-21 cm/sec) than in those with normal MRA (76+/-14 cm/sec) and those with Grade 2-3 vasculopathy (80+/-11 cm/sec)(mean difference 11.5 cm/sec, 95% confidence intervals 0.3, 22.6 cm/sec; p=0.043). Basilar velocity weakly correlated with hemoglobin (r=-0.18) but the relationships between hemoglobin and ICA/MCA CBFV or either presence of SCI or MRA abnormality were not significant.Conclusions:The prevalence of SCI on MRI is high in children with SCA without neurological history living in Africa even when TCD CBFV is normal. Children and adolescents with all grades of vasculopathy on MRA are at higher risk of brain parenchymal injury. The lack of association between SCI and hemoglobin may be related to the relatively severe anemia in our African study. As MRA contrast depends on velocity of blood flowing in vessels, it is not surprising that Grade 1 turbulence on MRA appears to reflect high CBFV on TCD. Importantly, high TCD velocity and Grade 1 turbulence may reflect the potentially reversible early stages in the development of SCA vasculopathy when cerebral blood flow is high before stenosis and occlusion supervene. TCD is operator dependent and there may be a case for MRI and MRA screening if follow-up shows that these measures predict stroke. DisclosuresNo relevant conflicts of interest to declare.

Abstract TP115: Cerebral Hemodynamic Changes in Military Personnel With Long-term Effects of Concussions

Service members (SMs) suffer from repeated exposure to concussions or mild TBI, which can disrupt cerebral blood flow. This effect is seen in the acute phase of TBI, but the development of vascular wall abnormalities, which can lead to luminal narrowing and abnormally elevated cerebral blood flow velocities (CBFV), has not been studied in the post concussive phase. The purpose of this study was to evaluate the transcranial Doppler (TCD) determined incidence of abnormal cerebral hemodynamics in patients with long-term effects of mTBI. Material and Methods: TCD recordings of mean CBFV in cm/sec and Pulsatility Indices (PI) were recorded from 431 SMs (9 females; ages 24-54, mean age 39.2 ± 6.4 years) who were admitted to the National Intrepid Center of Excellence 4-week Interdisciplinary Outpatient Program. TCD data were analyzed to determine whether SMs exhibited abnormal CBFV s in the middle cerebral artery, internal carotid artery (ICA), and basilar artery. All subjects consented to protocol #362504 prior to any data collection or analysis. Two standard deviation from the mean CBFV in any direction labeled as an abnormal and PI was assumed normal with values between 0.7 and 0.9 Patients with one or more vessels with abnormal CBFV’s and PI’s were labeled as abnormal. Results: Average time since last TBI was 5.1 ± 3.4 years. We observed abnormal CBFV values in 33% of SMs. 149 (35%) and 48 (11%) demonstrated abnormally high CBFV and PIs in one or more vessels, respectively. Abnormal CBFV was observed most frequently in the ICA (48%). Majority of studied patients had patchy pattern of abnormal data presented in one or few vessels. The presence of abnormal cerebral hemodynamics was inversely related to the time since the last mTBI exposure: the likelihood of abnormal CBFV values deceased with increasing time since last head injury was sustained but was still present. Conclusions: Our data reveal that a large proportion of SMs have elevated CBFVs following mTBI exposure in many years after last mTBI. We believe that head injuries due to combat and training blast and blunt force trauma exposure cause early atherosclerotic or fibrotic changes in the large vessel walls of the Circle of Willis, which results in vascular lumen narrowing and increased CBFV’s.

Genome Wide Association Study of Sickle Cell Disease Individuals with Stroke Risk

INTRODUCTIONSickle cell disease (SCD) is characterized by the hemoglobin S (HbS) presence associated with other hemoglobin variants, as found in the hemoglobin SC disease (HbSC), or with globin chain synthesis defects, and sickle cell anemia (SCA) is the most severe form of SCD. Among clinical manifestations in SCD it has been highlight the stroke, which is the main cause of death among patients. Recent studies have associated the presence of gene polymorphisms with the stroke risk in SCA individuals. Several genetic markers have been previously associated with stroke risk, but many of the results remain controversial once they could not completely elucidate the effect of individuals' genetic heterogeneity in the stroke development. Thus, we sought to investigate genetic polymorphisms through genome-wide association among SCD patients with stroke risk. METHODSWe selected four SCA individuals and four HbSC individuals based on the transcranial Doppler (TCD) values in according to the velocities described by Adams et al and Deane et al respectively. Patients were matched by sex and age and are followed in the Pediatric Cerebrovascular Disease Outpatient Center at the Hospital Universitario Professor Edgard Santos of the Universidade Federal da Bahia. This study was approved by the Research Board of the Secretaria de Saúde do Estado da Bahia, and all experimental protocol were performed in accordance with the ethical standards of national research committee and with the Helsinki Declaration of 1975 and its later amendments. TCD was performed in all subjects included in the study, and the highest velocity found was assessed in the middle cerebral arteries and distal intracranial internal carotid. Genomic DNA was extracted from peripheral blood and the DNA concentration was evaluated and used for SNP analysis in an Illumina Human Omni5-4 v.1.1 BeadChip kit, and raw intensities were analyzed in GenomeStudio Software. We select SNPs showing different genotypes when individuals were pairwise compared according to TCD velocities such is showed in the Figure 1. We evaluate the SNPs using SNPnexus online tool and the UCSC, SIFT and POLYPHEN categories. The next step consisted of running these selected SNPs in the NHGRI-EBI Catalog of published genome-wide association studies with p-values < 1.0 x 10-5. Additionally, we used STRING database to construct a network of protein-protein interactions. RESULTSUsing the UCSC category, we selected 3698, 3851 and 3528 unique SNPs in coding regions in non-synonymous for corresponding amino acid change for the three comparisons of SCA individuals respectively: abnormal TCD vs normal TCD, abnormal TCD vs conditional TCD and abnormal TCD vs conditional high TCD. Using the SIFT and POLYPHEN categories we selected the SNPs with a highly confident prediction to be damaging and SNPs predicted to be probably damaging, and we found 551, 505 and 598 unique SNPs and 424, 393 and 425 unique SNPs, in TCD-SCA individuals respectively. The next step was to select the common SNPs to perform Genome-wide association study (GWAS) classification. The same strategy used for TCD-SCA was performed to TCD-HbSC groups of individuals. We identified 3654, 3722 and 3847 as unique non-synonymous SNPs predicted by UCSC to be located in genomic coding regions respectively. Using the SIFT category 429, 447 and 418 unique SNPs were found in the TCD-HbSC groups of individuals respectively. PolyPhen classification was used and we found 517, 539 and 508 unique SNPs in the TCD-HbSC groups respectively. The next step was to perform GWAS classification. Results obtained utilizing the GWAS showed that each pair of individuals had a different number of SNPs identified (Table 1). The network of protein-protein interactions for the three conditions of SCA individuals and HbSC individuals are shown in the Figure 2. CONCLUSIONSWe suggest that the DOCK6 rs2278426, TYR rs1042602, CYP4F2 rs2108622, MST1 rs3197999, OR51B5/6 rs5006884, THADA rs7578597, FUT2 rs602662, MTHFR rs1801133, TSEN15 rs1046934, CFB rs12614 and ABCG5 rs6756629SNPs may be candidate variants to be further investigated in HbSC individuals with high speed of cerebral blood flow. We suggest that the SLCO1B1 rs4149056, PRIM1 rs2277339, APOB rs676210, TYK2 rs12720356, TSEN15 rs1046934, CYP4F2 rs2108622 and MST1 rs3197999 as candidate SNPs to be further investigated in SCA with high cerebral blood flow velocities. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Biomarkers of Disease Severity Predict Neurocognitive Functioning in Pediatric SCD

Introduction: Research clearly documents the increased risk of silent and overt strokes in pediatric patients with sickle cell disease (SCD), as well as the associated neurocognitive deficits in domains such as working memory (WM) and attention regulation. However, less research has examined the effects of biomarkers of SCD severity, such as cerebral blood flow velocity (CBFV), hemoglobin, and blood pressure, on neurocognitive functioning. This investigation aimed to explore the utility of using biomarkers to predict caregiver-reported neurocognitive and behavioral functioning in pediatric SCD.Methods: Fifty-nine children with SCD ages 7-16 (M = 10.44, SD = 2.87, 42% male) enrolled in a larger study of the feasibility and efficacy of a computerized cognitive training program. As part of this study, a primary caregiver completed the Behavior Rating Inventory of Executive Function (BRIEF) and Conners-3, both caregiver-reported measures of behavioral, attentional, and emotional functioning in children and adolescents. Scores on the BRIEF and Conners-3 are both represented with T scores, where higher scores reflect greater problems. Complete blood count (CBC) and vital signs were extracted from patients' medical charts if results had been documented within 45 days of date caregivers completed the BRIEF and Conners-3. Transcranial Doppler (TCD) ultrasonography results were extracted if a TCD had been performed within 12 months of the testing date.Results: Mean hemoglobin was 9.05 (SD = 1.33), mean hematocrit was 25.84 (SD = 3.71), mean systolic blood pressure was 107.43 (SD = 8.89), and mean diastolic blood pressure was 63.69 (SD = 9.49). TCD results revealed a mean right middle cerebral artery (MCA) CBFV of 206.00 (SD = 21.30), left MCA CBFV of 127.84 (SD = 22.40), right distal cerebral artery (DiCA) CBFV of 86.44 (SD = 23.00), and left DiCA CBFV of100.45 (SD = 27.28). Bivariate Pearson correlations and linear regression analyses were conducted to examine the relationships between biomarkers (e.g., CBFV, blood pressure, CBC results) and caregiver-reported neurocognitive and behavioral functioning. Modest correlations were observed between CBC results (e.g., hemoglobin, hematocrit) and caregiver-rated cognitive and behavioral outcomes; though, these relationships were no longer significant after controlling for age and gender in subsequent regression analyses. However, higher left DiCA velocities significantly predicted more problems on the BRIEF Working Memory and Initiate subdomains (R2 = .569, b = 0.442, p < .001; R2 = .746, b = .466, p < .001, respectively). Additionally, higher left DiCA velocities significantly predicted more caregiver-rated problems on the BRIEF Organization of Materials and Plan/Organize scales (R2= .447, b = 0.191, p = .049; R2 = .377, b = 0.372, p = .00), respectively. TCD and blood pressure results also significantly predicted scores on the caregiver-reported Connors-3 Executive Functioning subscale, with higher left DiCA (R2 = .432, b = 0.446, p = .001) and systolic BP (R2 = .196, b = 0.859,p =.003) predicting more problems with executive functioning.Conclusion: Certain biomarkers of SCD severity appear to have a detectable and direct influence on neurocognitive and behavioral functioning in pediatric SCD. TCD results, specifically left DiCA CBFV, and systolic blood pressure significantly predicted scores on the BRIEF and Conners-3, two caregiver-reported measures of neurocognitive and behavioral functioning. More specifically, higher CBFV and systolic blood pressure were predictive of more caregiver-rated problems with working memory, executive functioning, and organizational skills. These cognitive and behavioral domains are of particular importance in children, who depend on such skills to learn and succeed academically. Progressive disease-related neurocognitive deficits may contribute to long-term difficulties in academic achievement, social functioning, and vocational attainment. Biomarkers of SCD severity, such as CBFV and blood pressure, may be useful indicators of worsening neurocognitive status and signal the need for preventative care to protect neurological integrity and preserve quality of life in pediatric patients with SCD. DisclosuresNo relevant conflicts of interest to declare.

The Effect of Neuroticism on Vigilance Performance

Selecting for vigilance assignments remains an important factor in human performance research. Recent research using personality measures as selection criteria has revealed mixed results in the predictive utility of personality on vigilance performance. The current study revisits the potential relationship between vigilance performance and one personality facet, trait neuroticism, in light of two opposing theories. The first theory suggests that neuroticism reduces vigilance performance due to an increase in self-referential worry. The second posits that neurotics can compensate for increased worry and other distractions by allocating increased attentional effort to the task, resulting in similar or improved performance. Neuroticism was assessed using the neuroticism facet of the NEO-PI-R. Using Transcranial Doppler Sonography, cerebral blood flow velocity (CBFV) was measured during completion of a 12-minute abbreviated vigilance task. Performance and CBFV data indicate that 1) high and low neuroticism participants displayed similar performance, and 2) a higher neuroticism score is associated with higher CBFV levels in the first period and a greater CBFV decrement over time on task. The association between neuroticism and high CBFV levels indicates that these individuals were recruiting additional cognitive resources in order to achieve similar performance to participants who are lower in neuroticism. Results are discussed in terms of theories that suggest that high levels of neuroticism can result in similar performance by allowing for increased on-task effort allocation at the cost of increased resource expenditure.

Haptoglobin, alpha‐thalassaemia and glucose‐6‐phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania

Transcranial Doppler ultrasonography measures cerebral blood flow velocity (CBFv) of basal intracranial vessels and is used clinically to detect stroke risk in children with sickle cell anaemia (SCA). Co-inheritance in SCA of alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) polymorphisms is reported to associate with high CBFv and/or risk of stroke. The effect of a common functional polymorphism of haptoglobin (HP) is unknown. We investigated the effect of co-inheritance of these polymorphisms on CBFv in 601 stroke-free Tanzanian SCA patients aged <24years. Homozygosity for alpha-thalassaemia 3·7 deletion was significantly associated with reduced mean CBFv compared to wild-type (β-coefficient -16·1cm/s, P=0·002) adjusted for age and survey year. Inheritance of 1 or 2 alpha-thalassaemia deletions was associated with decreased risk of abnormally high CBFv, compared to published data from Kenyan healthy control children (Relative risk ratio [RRR]=0·53 [95% confidence interval (CI):0·35-0·8] & RRR=0·43 [95% CI:0·23-0·78]), and reduced risk of abnormally low CBFv for 1 deletion only (RRR=0·38 [95% CI:0·17-0·83]). No effects were observed for G6PD or HP polymorphisms. This is the first report of the effects of co-inheritance of common polymorphisms, including the HP polymorphism, on CBFv in SCA patients resident in Africa and confirms the importance of alpha-thalassaemia in reducing risk of abnormal CBFv.

Cerebral blood flow velocity in early-onset neonatal sepsis and its clinical significance

Chorioamnionitis is a known risk factor for neurological damage in newborns. The present study aimed at assessing the changes in cerebral blood flow velocity (CBFV) in early-onset neonatal sepsis (EONS) and determining its predictive value as well as prognostic significance. Inborn neonates with antenatal risk factors for chorioamnionitis were followed up for development of EONS, diagnosed by presence of clinical signs along with positive blood culture and/or elevated interleukin-6 (IL-6) concentrations (≥50pg/mL) in umbilical cord blood. Comparison group was formed by asymptomatic neonates who had risk factors for chorioamnionitis but did not develop EONS and cord blood IL-6 concentrations were <50pg/mL. CBFV (resistance and pulsatility indices, peak systolic flow velocity, and vascular diameter) of internal carotid, vertebral, and middle cerebral arteries was assessed by transcranial Doppler ultrasonography within 24h of birth. The babies were kept under clinical and radiological follow-up for a minimum period of 6months. Data were analyzed by SPSS 16.0. Final study group contained 55 neonates with sepsis and 35 asymptomatic control neonates. Blood culture was positive in 27 babies of the sepsis group with a preponderance of Gram-negative bacterial isolation. Significantly lower resistance, vasodilatation, and higher blood flow were noted in all the cerebral arteries of the sepsis group. Increase in CBFV was correlated with elevated IL-6 concentrations. CBFV parameters showed significant predictive accuracy as early diagnostic markers of EONS. Among the sepsis group, 14 patients showed signs of intracranial hemorrhage during the hospital stay of which four expired and six showed signs of ventricular dilatation during follow-up. These patients had significantly higher CBFV compared to those who survived. Assessment of CBFV at early hours of birth can be adopted as an additional bedside, non-invasive investigation with immediate diagnostic and late prognostic significance.

Risk factors for high cerebral blood flow velocity and death in Kenyan children with Sickle Cell Anaemia: role of haemoglobin oxygen saturation and febrile illness

High cerebral blood flow velocity (CBFv) and low haemoglobin oxygen saturation (SpO2) predict neurological complications in sickle cell anaemia (SCA) but any association is unclear. In a cross-sectional study of 105 Kenyan children, mean CBFv was 120 ± 34·9 cm/s; 3 had conditional CBFv (170–199 cm/s) but none had abnormal CBFv (>200 cm/s). After adjustment for age and haematocrit, CBFv ≥150 cm/s was predicted by SpO2 ≤ 95% and history of fever. Four years later, 10 children were lost to follow-up, none had suffered neurological events and 11/95 (12%) had died, predicted by history of fever but not low SpO2. Natural history of SCA in Africa may be different from North America and Europe.

Low cerebral blood flow velocity and head circumference in infants with severe hypoxic ischemic encephalopathy and poor outcome

To evaluate long-term changes in cerebral blood flow velocity (CBFV) and head circumference in asphyxiated infants. CBFV was measured in 83 asphyxiated and 115 healthy term infants in anterior and middle cerebral, basilar and internal carotid artery (ICA) up to the age of 60-149 days. The psychomotor development and head circumference was followed for 18 months. RESULTS. Mean CBFV was increased (p < 0.05) during the first days after asphyxia in infants with severe hypoxic-ischemic encephalopathy (HIE) (n = 25) compared to control group or infants with mild to moderate HIE (n = 58) with maximum values found at the age of 36-71.9 h: in ICA (mean [95% CI]) 31.2 (25.5-36.6) cm/s in severe HIE infants compared to 13.0 (12.2-13.9) cm/s in controls. Decreased (p < 0.0001) mean CBFV developed in severe HIE infants by the age of 21-59 days: in ICA 14.1 (11.5-16.8) cm/s compared to 22.9 (21.4-24.4) cm/s in controls. Infants with severe HIE had similar mean height but lower head circumferences compared to controls (p < 0.05) at the age of 21-59 days. The high mean CBFV found in infants with severe HIE during the first days after asphyxia is temporary and low CBFV and head circumference develops by the age of 21-59 days.

Effect of halothane anesthesia on cerebral blood flow velocity in children

The effects of halothane on the cerebral circulation were studied in 23 children during general anaesthesia. Blood flow velocity in one middle cerebral artery was recorded continuously by transcranial Doppler sonography. Furthermore arterial blood pressure, pulse rate, endtidal CO2partial pressure and endtidal halothane concentration were recorded. Mean flow velocities/mean arterial blood pressures were 79 cm x s-1/65 mmHg; 86 cm x s-1/61 mmHg; 78 cm x s-1/54 mmHg and 67 cm x s-1/48 mmHg with 1; 1.5; 2 and 2.5 per cent endtidal halothane concentrations, respectively. Endtidal CO2-partial pressure and pulse rate remained constant throughout the study. The higher cerebral blood flow velocities seen with 1.5 per cent halothane compared with 1 per cent can be explained by an increase in cerebral blood flow. The lower cerebral blood flow velocities and arterial blood pressure with 2.5 per cent halothane compared with 1.5 per cent indicate impaired cerebral autoregulation. However, cerebral blood flow appeared to be sufficient even with low arterial blood pressures.

Cerebral perfusion and oxygenation after the Norwood procedure: Comparison of right ventricle–pulmonary artery conduit with modified Blalock–Taussig shunt

The proposed physiologic advantage of the modified Norwood procedure using a right ventricle-pulmonary artery conduit to supply pulmonary blood flow, compared with a modified Blalock-Taussig shunt, is reduced runoff from the systemic-to-pulmonary circulation during diastole, resulting in a higher diastolic blood pressure and improved systemic perfusion. We hypothesized that the modified Norwood procedure is associated with improved cerebral perfusion and oxygenation. Transcranial Doppler sonography and near-infrared spectroscopy were performed in neonates undergoing the Norwood procedure with either a modified Blalock-Taussig shunt (n = 14) or right ventricle-pulmonary artery conduit (n = 13). Diastolic blood pressure was significantly higher in the right ventricle-pulmonary artery group at 6 hours after bypass (46 +/- 7 vs 40 +/- 4 mm Hg; P = .03), on postoperative day 1 (45 +/- 6 vs 37 +/- 5 mm Hg; P = .002), and on postoperative day 2 (46 +/- 7 vs 37 +/- 4 mm Hg; P = .001). Cerebral diastolic blood flow velocity did not differ significantly between groups at any time point or over time, but cerebral systolic blood flow velocity was higher over time in the Blalock-Taussig group (P = .01). No significant differences in regional cerebral oxygen saturation were found between groups at baseline or after bypass. Blood flow velocities and cerebral oxygen saturation did not differ significantly according to use of regional low-flow perfusion. The higher diastolic blood pressure after the modified Norwood procedure is not associated with higher cerebral blood flow velocities or regional cerebral oxygen saturation. This may imply an equal vulnerability to the cerebral injury associated with hemodynamic instability in the early postoperative period.

Cerebral Blood Flow Velocities Measured by Transcranial Doppler Ultrasonography in Children with Sickle Cell Disease in Africa.

Background: Sickle cell anemia (SCA) is one of the commonest monogenic disorders, with 90% of the world's population living in sub-Saharan Africa. Cerebrovascular accident (CVA) is a major cause of morbidity, but its clinical prediction in resource rich countries has allowed effective primary and secondary prevention. Measurements of time-averaged maximum of the mean (TAMM) cerebral blood flow velocity (CBFv) in the internal carotid/middle cerebral (ICA/MCA) arteries by Transcranial Doppler (TCD) ultrasonography and of mean overnight oxyhemoglobin saturation (SpO2) have been useful in predicting CVA. The criteria used in Western populations may not be appropriate to children living in Africa.Aims: The aims of this study were to evaluate the TAMM CBFv in patients with SCA in Kilifi district hospital, Kenya, to assess risk factors associated with high ICA/MCA TAMM CBFv and to examine any association with neurological complications.Study design: This was a cross sectional descriptive study, where TCD ultrasonography was performed on all SCA patients attending the outpatient clinic at CGMR-C, Kilifi, Kenya in 2002. Previous data from 1990 and follow-up data from 2004 were included.Results: In 140 patients with SCA, aged 3 months to 16 years, the median ICA/MCA TAMM CBFv was 116cm/sec (SD 38, range 0–219 cms/s) compared with 97 (SD 24, range 46–190) cm/sec in 142 controls aged 2 months to 14 years (p=0.0001). 28 SCA patients (20%) had TAMM CBFv greater than and 16 (11%) had TAMM CBFv less than 2 standard deviations from the mean for controls in one or both ICA/MCA's, but only seven (5%) had a velocity above 170 cm/sec (one >200cm/sec), with the highest proportion of patients aged between 5–9 years (p=0.02). In only two of the patients with low velocities, both with previous CVA, was there no ultrasound signal from either side. 45 (32%) SCA patients had a second TCD after 2 years (two after 14 years). Of the 21 restudied who had high TAMM CBFv at baseline, 14 remained high and 2 became low. Of the 15 restudied who had low TAMM CBFv at baseline, 14 remained low and none became high. Patients with abnormal TCD had lower daytime SpO2 oxygen saturation (p=0.01) and hematocrit (p=0.05). Abnormal TCD was also associated with lower haemoglobin level, red blood cell count and higher white cell count, but not significantly. Neurological abnormalities included history of convulsions in 25 (18%) and history of CVA in 5 (4%). Of those with CVA, maximum TAMM CBFv on either side were 157, 156, 108, 0 and 0; the last patient subsequently died. Three patients who had convulsions in the interim attended for follow-up TCD; compared with those without seizures there was a trend for a greater increase in TAMM CBFv in these patients (p=0.06).Conclusion: Compared with the developed world, in Africa a smaller proportion of patients with SCA have conditional or abnormal TCDs or CVA, although convulsions are common. The proportion of those with low velocities, perhaps due to ICA/MCA occlusion with moyamoya, may increase with time. Further population-based studies in a birth cohort will determine whether cerebrovascular disease is rare or lethal and, together with imaging and neuropsychology, will establish whether abnormal TCD predicts neurological events in Africa.