Elevated Cerebral Blood Flow Research Articles

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.

Jumping at a chance to control cerebral blood flow in astronauts.

Jumping at a chance to control cerebral blood flow in astronauts.

Cerebral artery reactivity in young, adult, and aged APOE3 and APOE4 mice

Introduction Alzheimer's disease (AD) is the most common form of dementia and is the 6th leading cause of death in the US. Growing evidence supports a link between AD and cardiovascular disease (CVD). Variant isoforms of apolipoprotein E (APOE) are risk factors for both AD and CVD. The most common APOE isoform, APOE3, has neutral risk for developing AD, whereas APOE4 increases AD risk. In order to study APOE-mediated processes, cerebral vessels were isolated from mice expressing human-ApoE targeted replacement of APOE3 (B6.129P2-Apoetm2(APOE*3)Mae N8) and APOE4 (B6.129P2-Apoetm3(APOE*4)Mae N8)(Taconic Labs). Our objective was to determine whether allelic differences altered vascular function by assessing mechanical characteristics and vascular reactivity in the posterior cerebral artery (PCA) isolated from young (Y, 3mo), adult (A, 12mo) and aged (Aged, 18-22mo), homozygous APOE3 and APOE4, male and female mice. We hypothesize that APOE4 expression alters PCA structure/function compared to PCAs isolated from age matched APOE3 mice. Methods PCAs were rapidly isolated from age matched male and female, APOE3 and APOE4 mice, cleaned of connective tissue, cut into 5mm segments, and cannulated in an arteriograph chamber to assess mechanical characteristics and vascular reactivity (myogenic tone (MT) in the absence and presence of the non-specific NOS inhibitor, L-NAME). Active/passive wall tension, wall thickness, distensibility, stress/strain and MT was measured with stepwise increases in intraluminal pressure (10mm Hg to 140mm Hg). Results Our preliminary data suggests: PCAs from APOE3 and APOE4 mice exhibited similar MT. L-NAME inhibition of NOS unmasked MT in PCAs from APOE3 and APOE4 mice. L-NAME - induced MT was similar in Y, A and Aged APOE3 mice, where Y APOE4 mice exhibited greater L-NAME-induced tone than A and Aged (P<0.05). When challenged with 60mM [K+]o, all groups showed similar % constriction. Passive wall tension was similar in Y, A, and Aged APOE3 mice, where wall tension significantly decreased with aging in APOE4 mice (P<0.05). Wall thickness tended to increase with age in APOE3 mice, while wall thickness significantly decreased in aged APOE4 mice (P<0.05). Finally, Y APOE3 mice exhibited a rightward shift in stress vs strain, compared to A, and no difference was observed in vessels from A and Aged APOE3 mice. In contrast, PCAs from Y and A, APOE4 mice exhibited similar stress vs strain values. Interestingly, stress vs strain values in aged APOE4 PCAs were shifted to the left, and exhibited significantly different strain values for given values of stress at physiologically relevant pressures (P<0.05). Summary/Conclusions Our data suggests PCA vascular structure/function from APOE3 mice exhibit “normal” aging characteristics, whereas PCAs from APOE4 mice exhibit delayed changes in vascular structure/function. This data provides possible mechanisms for elevated cerebral blood flow in Y human and mice carrying the APOE4 allele vs aged matched APOE3.

Cerebral Hemodynamics and Executive Function in Sickle Cell Anemia.

Individuals with sickle cell anemia experience cognitive deficits, even in the absence of cerebral infarcts or strokes. This study tested the hypothesis that elevated cerebral blood flow and oxygen extraction fraction are associated with lower executive function in individuals with sickle cell anemia. Three-Tesla brain magnetic resonance imaging was performed, including anatomic, gray matter cerebral blood flow, and global oxygen extraction fraction imaging. Executive function was measured using the working memory index from an age-appropriate Wechsler battery and tasks from the National Institutes of Health Toolbox Cognition Battery. Bivariate and multivariate models were examined (significance: P<0.05). Fifty-four participants (age range=6-31 years) with sickle cell anemia were enrolled. Hematocrit was positively related to fluid cognition, cerebral blood flow was inversely related to working memory and inhibitory control, and oxygen extraction fraction was inversely related to processing speed. Associations remained significant in multivariate analyses controlling for age, income, and infarcts. Elevated cerebral blood flow and oxygen extraction fraction, markers of hemodynamic impairment, are associated with deficits in executive function in individuals with sickle cell anemia.

Elevated cerebral blood flow in patients with pure autonomic failure.

Pure autonomic failure (PAF) results from an impaired peripheral autonomic nervous system, and clinical symptoms present with orthostatic hypotension. While the impact on cardiovascular indices of orthostatic intolerance are well-characterized, more limited information is available regarding cerebral hemodynamic dysfunction in PAF. The objective of this study was to test the hypothesis that cerebral blood flow (CBF) is reduced in PAF, and to quantify the relationship between CBF and clinical indicators of disease severity, including peripheral supine arterial blood pressure. Participants with PAF (n = 17) and age- and sex-matched normotensive healthy controls (n = 17) were examined using established clinical rating scales, cardiovascular autonomic function tests, and 3T MRI measurements of CBF. CBF-weighted images were also used to determine the prevalence of venous hyperintensities from the major dural sinuses as evidence of abnormal capillary flow. Nonparametric tests and general linear models were used to evaluate differences and correlations between study variables. Gray matter CBF was higher in PAF (51.1 ± 13.4mL/100g/min) compared to controls (42.9 ± 6.5mL/100g/min, p = 0.007). Venous hyperintensities were more prevalent in PAF relative to controls, and the presence and degree of venous hyperintensities was associated with higher mean CBF (p = 0.027). In PAF participants, CBF and supine systolic blood pressure were inversely related (Spearman's rho = -0.545, p = 0.024). Findings suggest that PAF patients may exhibit elevated CBF and provide evidence that this condition exerts a hemodynamic impact in the central nervous system.

Cerebral blood flow and acute episodes of Leigh syndrome in neurometabolic disorders.

To investigate cerebral blood flow (CBF) in acute episodes of Leigh syndrome compared with basal state in patients carrying pathogenic mitochondrial disease gene variants responsible for neurometabolic disorders. Arterial spin labelling (ASL) magnetic resonance imaging (MRI) sequences were used to measure CBF in 27 patients with mitochondrial respiratory chain enzyme deficiencies, ascribed to pathogenic variants of reported disease genes who were undergoing either urgent neuroimaging for acute episodes of Leigh syndrome (Group I: 15 MRI, seven females, eight males; mean age 7y; range 7mo-14y) or routine brain MRI (Group II: 15 MRI, eight females, seven males; mean age 5y 2mo; range 2mo-12y). Patients displayed markedly increased CBF in the striatum (2.8-fold greater, p<0.001 [1.05-2.53]) during acute episodes of Leigh syndrome compared to basal conditions. Detection of elevated CBF preceded identification of structural MRI lesions in four out of 15 cases. Our results suggest that increased CBF is an overt hallmark of Leigh syndrome episodes and ASL MRI sequences should facilitate early diagnosis of acute episodes of Leigh syndrome, especially during the first attack in young children, when structural MRI is insufficiently informative.

Temporal Changes in Brain Perfusion in Neuronal Intranuclear Inclusion Disease.

We herein report a patient with neuronal intranuclear inclusion disease (NIID) who presented with encephalitis-like episodes. A neurological examination revealed a disturbance of consciousness without any evidence of encephalitis or epilepsy on laboratory tests. Brain perfusion single-photon emission computed tomography revealed an elevated cerebral blood flow during the encephalitis-like episode and reduced cerebral blood flow in the chronic phase with clinical recovery. This report suggests that the cerebral blood flow of patients with NIID can change over the clinical course. Encephalitis-like episodes of NIID should thus be considered in the differential diagnosis of acute disturbance of consciousness.

Neuroimaging of Cerebral Blood Flow and Sodium in Women with Lipedema.

Lipedema is characterized by pain, fatigue, and excessive adipose tissue and sodium accumulation of the lower extremities. This case-control study aims to determine whether sodium or vascular dysfunction is present in the central nervous system. Brain magnetic resonance imaging was performed at 3 T in patients with lipedema (n = 15) and control (n = 18) participants matched for sex, age, race, and BMI. Standard anatomical imaging and intracranial angiography were applied to evaluate brain volume and vasculopathy, respectively; arterial spin labeling and sodium magnetic resonance imaging were applied to quantify cerebral blood flow (CBF) (milliliters per 100 grams oftissue/minute) and brain tissue sodium content (millimoles per liter), respectively. A Mann-Whitney U test (significance criteria P < 0.05) was applied to evaluate group differences. No differences in tissue volume, white matter hyperintensities, intracranial vasculopathy, or tissue sodium content were observed between groups. Gray matter CBF was elevated (P = 0.03) in patients with lipedema (57.2 ± 9.6 mL per 100 g/min) versus controlparticipants (49.8 ± 9.1 mL per 100 g/min). Findings provide evidence that brain sodium and tissue fractions are similar between patients with lipedema and control participants and that patients with lipedema do not exhibit abnormal radiological indicators of intracranial vasculopathy or ischemic injury. Potential explanations for elevated CBF are discussed in the context of the growing literature on lipedema symptomatology and vascular dysfunction.

Carotid Artery Reactivity in Young, Adult, and Aged APOE3 and APOE4 Mice

IntroductionAlzheimer’s disease (AD) is the most common form of dementia and is the 6th leading cause of death in the US. Growing evidence supports a link between AD and cardiovascular disease (CVD). Interestingly, variant isoforms of apolipoprotein E (APOE) are risk factors for both AD and CVD. The most common APOE isoform, APOE3, has a neutral risk for developing AD, whereas APOE4 increases AD risk. In order to study APOE‐mediated processes in large arteries, carotid arteries (CAs) were isolated from mice expressing human‐ ApoE targeted replacement of APOE3 (B6.129P2‐Apoetm2(APOE*3)Mae N8) and APOE4 (B6.129P2‐Apoetm3(APOE*4)Mae N8)(Taconic Labs). Our objective was to determine whether allelic expression alters CA vascular function by assessing mechanical characteristics and vascular reactivity in the left main CA isolated from young (Y, 3mo), adult (A, 12mo) and aged (Aged, 18–22mo), homozygous APOE3 and APOE4, male and female mice. We hypothesize that APOE4 expression alters CA vascular reactivity, along with vascular structure compared to CAs isolated from age matched APOE3 mice.MethodsCAs were rapidly isolated from age matched male and female, APOE3 and APOE4 mice, cleaned of connective tissue, cut into 8mm segments, and cannulated in an arteriograph chamber to assess vascular reactivity via myogenic tone (MT) and phenylephrine (PE)‐induced constriction in the absence and presence of the non‐specific NOS inhibitor, L‐NAME. In addition, passive wall tension, arterial wall thickness, vascular distensibility, and arterial stress/strain were measured at intraluminal pressures ranging from 10mm Hg to 140mm Hg for assessment of age‐related changes in arterial structure/function.ResultsCAs from APOE3 and APOE4 mice did not exhibit MT in the absence or presence of L‐NAME. PE‐induced constriction in CA from APOE3 mice tended to decrease with age, while PE‐induced constriction in CA from A APOE4 mice were significantly greater than PE‐induced constriction in CAs from Y (P&lt;0.05) or Aged (P&lt;0.05) mice. In the presence of L‐NAME, PE‐induced constrictions were significantly increased in all mice at all ages (P&lt;0.05). Wall thickness was similar in Y, A and Aged APOE3 and APOE 4 mice. Finally, CA from Y APOE3 mice exhibited a rightward shift in stress vs strain, compared to CAs from A and Aged mice. In contrast, CAs from Y and A, APOE4 mice exhibited similar stress vs strain values. Stress vs strain values in Aged APOE4 CAs were significantly shifted to the left of CA from A APOE4 mice suggesting greater arterial stiffening in Aged APOE4 mice at physiologically relevant intraluminal pressures (P&lt;0.05).Summary/ConclusionsThese data suggest that CA vascular structure/function in APOE3 mice exhibit “normal” aging characteristics, whereas CAs from APOE4 mice exhibit “delayed” age related changes in arterial stiffening, which may contribute to elevated cerebral blood flow in Y human and mice carrying the APOE4 allele vs aged matched APOE3.Support or Funding InformationFundingABRC/ADHS18‐205211 (DME, JVE, CJ, TBJ), Biomedical Sciences Program (LJS, RGP, DME), Biomedical Sciences Start‐up Funds (DME)

Cerebrovascular reactivity to carbon dioxide is not influenced by variability in the ventilatory sensitivity to carbon dioxide.

What is the central question of this study? Do differing magnitudes of ventilation influence cerebrovascular CO2 reactivity and the cerebral blood flow response to increases in arterial carbon dioxide? What is the main finding and its importance? While a greater ventilation, through voluntary hyperventilation, is associated with a higher anterior cerebral blood flow during carbon dioxide breathing, this elevated cerebral blood flow is due to a higher blood pressure and not ventilation per se. A greater ventilation, through voluntary hyperventilation, does not influence global or posterior cerebral blood flow during carbon dioxide breathing. Cerebrovascular reactivity to carbon dioxide is not influenced by an individual's ventilatory sensitivity to carbon dioxide. Recent work demonstrated an influence of ventilation on cerebrovascular reactivity to CO2 ; however, the concomitant influence of changes in mean arterial blood pressure (MAP) on ventilation-induced differences in cerebral blood flow (CBF) has yet to be examined in this context. Healthy participants (n=15; 25±3years of age; 179±6cm height; 74±10kg weight; 3 female) underwent end-tidal forcing to increase their partial pressure of end-tidal CO2 by +3, +6 and +9mmHg above baseline in 5-min sequential steps while maintaining iso-oxia. This protocol was then repeated twice, with participants hyperventilating and hypoventilating by ∼30% compared to the first trial. Intra-cranial and extra-cranial CBF were measured using ultrasound. The MAP (finger photo-plethysmography) was higher during the hyperventilation and hypoventilation trials compared to normal ventilation (main effects, P<0.05 for both). While internal carotid artery blood flow was higher during the hyperventilation trial compared to normal ventilation (P=0.01), this was due to a higher MAP, as indicated by analysis of conductance values (P=0.68) or inclusion of MAP in covariate analysis (P=0.11). Global CBF (P=0.11) and vertebral artery blood flow (P=0.93) were unaffected by the magnitude of ventilation. Further, CO2 reactivity was not affected by the different breathing trials (P>0.05 for all). Retrospective analysis of a larger data set (n=53) confirmed these observations and demonstrated no relationships between the ventilatory and global CBF response to hypercapnia (r2 =0.04; P=0.14). Therefore, when differences in MAP are accounted for, cerebrovascular CO2 reactivity (assessed via end-tidal forcing) is independent of the magnitude of ventilation.

Cerebral Oxygen Delivery and Metabolic Rate in Chronically Anemic Subjects

Introduction: In subjects with chronic anemia syndromes, such as sickle cell disease and major thalassemia, cerebral blood flow (CBF) has been shown to increase in compensation for the decreased oxygen content. In previous works using pseudo-continuous arterial spin labeling, our laboratory has demonstrated the phenomenon of venous outflow suggestive of physiological arteriovenous shunting in anemic subjects with high CBF and short microvascular transit time (Bush et al., 2018). In this study, we evaluated CBF, oxygen delivery (DO2), oxygen extraction fraction (OEF) and cerebral metabolic rate (CMRO2) in three subject groups: sickle cell disease (SCD), non-sickle anemia (ACTL) and healthy controls (CTL). We hypothesize that even though DO2 is preserved in the presence of chronic anemia, due to physiological shunting, OEF and CMRO2 are impaired in anemic subjects compared to controls. Methods: Three study groups of 50 SCD subjects, 27 ACTL subjects and 44 healthy controls were tested (Table 1). Oxygen content, DO2, OEF and CMRO2 were computed from the hemoglobin level, CBF from phase contrast MRI and venous saturation from TRUST MRI. Results: Table 2 shows the global DO2, OEF and CMRO2. As expected, anemic patients had approximately 50% higher CBF but similar DO2 levels compared to healthy controls. Despite normal delivery, both CMRO2 and OEF are significantly decreased in SCD and ACTL subjects. Resting DO2, whether entered as CBF and O2 content separately or as their product, was the strongest predictor of the brain's metabolic rate, explaining approximately 21% of the variation in baseline CMRO2. Even after controlling for the variations in delivery, our subjects still demonstrated significant differences based on disease state, with the lowest CMRO2 in SCD patients, followed by ACTL and then healthy controls (p&lt;0.01). After correcting for both DO2 and disease state, CMRO2 was independent of transfusion status, age, sex, hemolytic indices, fetal hemoglobin levels and mean corpuscular volume but remained directly proportional to hemoglobin (p=0.01) and platelets (p=0.01) with a combined r2=0.62. Discussion: Using a larger cohort, our results recapitulated the compensatory hyperemic response previously described in anemic subjects. Despite the ability to maintain a normal level of oxygen supply to the brain, these anemic patients had significantly lower cerebral metabolism, consistent with reports from two other laboratories (Vaclavu et al., 2019; Croal et al., 2019). We postulate that poor oxygen utilization is caused by non-nutritive perfusion or physiological arteriovenous shunting. This phenomenon has been previously characterized in SCD and other anemias with high CBF and reduced microvascular transit times. Microvascular oxygen unloading requires sufficient transit time in the capillaries network for efficient oxygen extraction, but transit times had been demonstrated to be significantly shorter in the presence of anemia due to compensatory hyperemia. In chronic anemia syndromes, the elevated CBF that preserves normal DO2 shortens transit times and impairs oxygen unloading, leading to a decrease in OEF and CMRO2 in both SCD and ACTL subjects. The predictors of baseline CMRO2 yielded interesting insights into the physiological impact of chronic anemia on cerebral oxygen availability and utilization. In acute normovolemic anemia, CMRO2 is preserved despite declining O2 carrying capacity. However, in our chronically anemic cohort, CMRO2 was strongly proportional to resting DO2; this result suggests that there is a divergence in physiological responses to acute versus chronic anemia. While DO2 was the strongest predictor of CMRO2, disease state, hemoglobin level and platelets remained in the multivariate model, confirming the roles of anemia, inflammation, and disease-specific factors in the modulating CMRO2. In summary, this report demonstrates impaired cerebral oxygen supply-demand matching in chronically anemic subjects. Cerebral hyperemia appears to simultaneously preserve DO2 while diminishing OEF and CMRO2. This observation may explain why absolute hemoglobin level remains the strongest predictor of poor neurovascular outcome in SCD patients, and raises questions regarding the proper hemoglobin target level for hydroxyurea and chronic transfusion therapy. Disclosures Coates: celgene: Consultancy, Honoraria, Other: steering committee of clinical study; vifor: Consultancy, Honoraria; agios pharma: Consultancy, Honoraria; apo pharma: Consultancy, Honoraria, Speakers Bureau. Wood:National Institutes of Health: Research Funding; Philips Healthcare: Research Funding; BluebirdBio: Consultancy; Celgene: Consultancy; BiomedInformatics: Consultancy; Imago Biosciences: Consultancy; Apopharma: Consultancy; WorldcareClinical: Consultancy.

Association of Endothelial Biomarkers with Cerebral MRI Perfusion Analysis in Patients with Sickle Cell Disease

Introduction Sickle cell disease (SCD) is associated with silent cerebral infarcts (SCI) which are related to neurocognitive damage. One of the major causes of SCI is the impaired cerebral oxygenation, which makes cerebral blood flow (CBF) an essential parameter to measure. Previous hemodynamic studies have shown elevated CBF and reduced cerebrovascular reserve (CVR) in patients with SCD (Helton 2015; Václavů 2018). CVR is known as the increase of CBF in response to vasoactive stimulus, relative to the baseline. The reduced CVR renders SCD patients susceptible to cerebral ischemia, especially under hypotensive or hypoxic conditions. Possible factors contributing to microvascular damage and thus reduced CVR include hemoglobin S polymerization, neutrophil activation and endothelial activation and adhesion. Previous studies examined the role of these factors in patients with SCD (Sins 2017; Al Najjar 2017). However, the association between the endothelial biomarkers and hemodynamic parameters is unknown in adult patients with SCD. In this study, we investigated the correlation between CBF and CVR and the adhesion molecules including sVCAM-1, sP-selectin, VWF-Ag and ADAMTS13. Additionally, we studied the association of these endothelial biomarkers with standard laboratory parameters. Methods This study was performed in accordance with the Declaration of Helsinki and was approved by the Review Board of Amsterdam UMC. For this study, 33 steady state patients with SCD (mean age 32.1 ± 10.7, 64% male, 29 HbSS, 4 HbSß) and 10 healthy volunteers (mean age 36,4 ± 15.9, 60% male, 2 HbAS, 8 HbAA) were included. Hematologic laboratory parameters were assessed using standard laboratory procedures. Plasma levels of sVCAM-1 and sP-selectin were determined using ELISA (R&amp;D Systems, USA) and ADAMTS13 and VWF-Ag were measured with the INNOVANCE assay (Siemens Healthcare Diagnostics). For the CBF measurements, pseudo-continuous arterial spin labelling (pCASL) was acquired at 3T MRI (Philips Healthcare, The Netherlands). CBF was measured before and after acetazolamide (vasoactive stimulus) administration and subsequently CVR was calculated using the following equation: CVR = (CBFafter - CBFbefore) / CBFbefore x 100% Plasma levels of endothelial biomarkers were compared between groups using ANOVA test. Correlation between the parameters were measured using single regression model where p&lt;0.05 was considered as statistically significant. Results sVCAM-1 levels and VWF-Ag were significantly higher in SCD patients compared to healthy controls (p &lt; 0.01 and p = 0.01). ADAMTS13 and sP-selectin were not significantly different between the two groups (p = 0.06 and p = 0.33). sVCAM-1 was significantly associated with CBF, and parameters of hemolysis LDH and bilirubin in SCD patients (Fig. 1A and 2C). Negative correlation was observed between sVCAM-1 and hemoglobin (Fig. 1B). The relationship between sVCAM-1 and hemodynamic and laboratory parameters are shown in Table 1. No significant correlation was found between sVCAM-1, hemodynamic and standard laboratory parameters in healthy controls. VWF-Ag, ADAMTS13 and sP-selectin were not significantly associated with hemodynamic MRI parameters. Discussion Our results show elevated sVCAM-1 levels in sickle cell patients, strongly related to CBF. sVCAM-1 is an adhesion molecule and elevated plasma levels are found in patients with endothelial activation due to inflammation or atherosclerosis (Cook-Mills 2013; Cybulsky 2001). Previous studies showed elevated levels in sickle cell disease but no correlation with parameters of cerebral perfusion have been demonstrated yet (Antwi-Boasiako 2018; Kato 2005). The strong correlation with CBF is mostly related to the chronic hemolysis given the association found with hemoglobin levels and markers of hemolysis like LDH and bilirubin. In contrast to sVCAM-1, no such relation was found with other markers of endothelial activation such as VWF activity and sP-selectin levels. No correlation between endothelial markers and the CVR was demonstrated, suggesting that endothelial damage itself may not related to the impaired cerebral vasodilatation in response to a vasoactive stimulus. Conclusion Endothelial adhesion molecule sVCAM-1 showed a strong correlation with CBF and parameters of hemolysis, suggesting a relation between the hemolytic damage of endothelial cells and impaired cerebral perfusion. Disclosures Nur: Novartis Pharmaceuticals: Consultancy.

Normal Cerebral Oxygen Consumption Despite Elevated Cerebral Blood Flow in Adolescents With Bipolar Disorder: Putative Neuroimaging Evidence of Anomalous Energy Metabolism

Background: Regional cerebral blood flow (CBF) is reportedly altered in both adolescents and adults with bipolar disorder (BD). Whether these CBF differences are part of an overall imbalance in cerebral energy homeostasis remains unknown. Therefore, we examined global cerebral metabolic rate of oxygen consumption (CMRO2) as a physiological index of brain metabolism in adolescents with and without BD. Methods: One hundred and fifteen adolescents (mean age 17.3 ± 1.4 years), including 58 BD (type I, II, or not otherwise specified [NOS]) and 57 age-matched healthy controls (HCs) participated in this magnetic resonance imaging (MRI) study. Global estimates for venous blood oxygenation (Yv) and grey matter CBF were measured using T2-relaxation-under-spin-tagging (TRUST) and arterial spin labeling (ASL) MRI, respectively. CMRO2 was calculated using the Fick principle of arteriovenous difference to test for a group difference. We also examined CMRO2 in relation to mood states (i.e. euthymic, depressed, or hypomanic/mixed). Results: Although CBF was significantly higher in BD compared to HCs, there was no group difference in global CMRO2, nor Yv. Meanwhile, Yv significantly decreased with age, and females tended to have greater CBF and CMRO2 in comparison to males. Lastly, there was no significant association between CMRO2 and mood states. Conclusions: Our results indicate a potential mismatch between cerebral blood supply and oxygen metabolism in BD, suggesting inefficiency in energy homeostasis in the brain. Mapping CMRO2 would provide the spatial resolution to investigate regional alterations in metabolism, particularly in the brain regions where CBF is increased.

UBC-Nepal Expedition: Haemoconcentration underlies the reductions in cerebral blood flow observed during acclimatization to high altitude.

What is the central question of this study? The aim was to evaluate the degree to which increases in haematocrit alter cerebral blood flow and cerebral oxygen delivery during acclimatization to high altitude. What is the main finding and its importance? Through haemodilution, we determined that, after 1week of acclimatization, the primary mechanism contributing to the cerebral blood flow response during acclimatization is an increase in haemoglobin and haematocrit. The remaining contribution to the cerebral blood flow response during acclimatization is likely to be attributable to ventilatory acclimatization. At high altitude, an increase in haematocrit (Hct) is achieved through altitude-induced diuresis and erythropoiesis, both of which result in increased arterial oxygen content. Given the impact of alterations in Hct on oxygen content, haemoconcentration has been hypothesized to mediate, in part, the attenuation of the initial elevation in cerebral blood flow (CBF) at high altitude. To test this hypothesis, healthy men (n=13) ascended to 5050m over 9days without the aid of prophylactic acclimatization medications. After 1week of acclimatization at 5050m, participants were haemodiluted by rapid saline infusion (2.10±0.28l) to return Hct towards pre-acclimatization values. Arterial blood gases, Hct, global CBF (duplex ultrasound) and haemodynamic variables were measured after initial arrival at 5050m and after 1week of acclimatization at high altitude, before and after the haemodilution protocol. After 1week at 5050m, the Hct increased from 42.5±2.5 to 49.6±2.5% (P<0.001), and it was subsequently reduced to 45.6±2.3% (P<0.001) after haemodilution. Global CBF decreased from 844±160 to 619±136mlmin-1 (P=0.033) after 1week of acclimatization and increased to 714±204mlmin -1 (P=0.045) after haemodilution. Despite the significant changes in Hct, and thus oxygen content, cerebral oxygen delivery was unchanged at all time points. Furthermore, these observations occurred in the absence of any changes in mean arterial blood pressure, cardiac output, arterial blood pH or oxygen saturation pre- and posthaemodilution. These data highlight the influence of Hct in the regulation of CBF and are the first to demonstrate experimentally that haemoconcentration contributes to the reduction in CBF during acclimatization to altitude.

PF742 CEREBRAL OXYGEN METABOLISM MEASUREMENTS WITH MRI IN ADULTS WITH SICKLE CELL DISEASE

Background:MRI studies have demonstrated a high prevalence of silent cerebral infarcts (SCI) in both children and adults with sickle cell disease (SCD). SCI are associated with cognitive impairment and lesion progression in adults with SCD. Disrupted oxygen transport can contribute to cerebral ischemic lesions, despite the compensatory elevation in cerebral blood flow (CBF) in SCD. Investigating the cerebral metabolic rate of oxygen (CMRO2) may therefore give insight into the hemodynamic etiology of SCI in SCD patients. We hypothesized that CMRO2 is reduced in adult patients with SCD as a result of chronic anemia and that vasodilation can improve CMRO2 by generating an increase in blood and oxygen flow.Aims:The purpose of this study was to measure CBF and OEF to compute CMRO2 and to measure the response to vasodilation with acetazolamide.Methods:We included adults with SCD (HbSS or HbSb0‐thalassaemia), and age‐, sex‐, and race‐matched controls. Exclusion criteria were contraindications to MRI and acetazolamide, and a clinical history of a cerebrovascular event or neurologic disease affecting cerebral autoregulation.The MRI protocol comprised fluid‐attenuated inversion recovery (FLAIR) for anatomy and lesions, T2‐prepared tissue relaxation with inversion recovery (T2‐TRIR) for oxygenation and T1 of blood, and pseudo continuous arterial spin labelling (pCASL) for cerebral blood flow. Paired tests were used to assess statistical significance of changes from baseline to post‐acetazolamide conditions. P &lt; .05 was considered significant. Variables were summarized by means and standard deviations.Results:Hb was lower in patients compared to controls (8.8 ± 1.4 vs 13.7 ± 1.3 g/dL, P &lt; .001). Oxygen delivery was similar in patients compared to controls (371 ± 70 vs 368 ± 39 μmol O2/100 g/min, P = .832), due to compensatory elevated CBF in patients versus controls (73 ± 16 vs 46 ± 4 mL/100 g/min, P &lt; .001). OEF was lower in patients compared to controls (27.1 ± 4.4 vs 35.3 ± 3.6 %, P = .001). SCD patients had lower CMRO2 compared to controls (99.7 ± 24.2 vs 126.6 ± 18.9 μmol O2/100 g/min, P = .003) (Figure 2). Cerebrovascular reserve was lower in patients versus controls (43.1 ± 12.5 vs 67.0 ± 20.0%, P = .003). After acetazolamide, CMRO2 did not change significantly in the healthy controls (P = .844), but declined in SCD patients (P = .036), showing that the ACZ challenge was indeed isometabolic in controls but not in patients. Finally, we found that increased CBF after ACZ was accompanied by a drop in OEF in patients with SCD (P &lt; .001) as well as in controls (P = .003).Summary/Conclusion:Our findings support our hypothesis that SCD patients have reduced CMRO2. This indicates that in this chronic condition, CMRO2, and therefore likely also neuronal function, have adapted to chronic low oxygen availability. Heterogeneous flow distribution could be the reason for the reduced CMRO2 we observed in patients with SCD, whereby oxygen shunted to the venous side without delivering oxygen to the brain tissue, and this was exacerbated by acetazolamide. We conclude that CMRO2 does not adjust quickly to transient changes in oxygen availability at the microvascular level despite the increase in CBFimage

Neuroimaging endophenotypes of type 2 diabetes mellitus: a discordant sibling pair study.

Type 2 diabetes mellitus (T2DM) is characterized by notable familial aggregation involving common variants of many genes, and its heritability leads to a high prevalence in the siblings of affected individuals compared with the general population. Endophenotypes are objective, heritable, quantitative traits that appear to reflect the genetic risk for polygenic disorders at more biologically tractable levels. Based on a sibling pair design, we aimed to find the neuroimaging endophenotypes of T2DM and investigate the role of inherent neurological disorders in the pathogenesis and deterioration of T2DM. Twenty-six pairs of diagnosed T2DM patients with unaffected siblings and 26 unrelated controls were included in this study. Both high-resolution structural MRI and three-dimensional pseudo-continuous arterial spin labelling (3D-pCASL) MRI data were acquired with a 3.0 T MRI system. Voxel-based morphometry (VBM) analysis was performed on the structural T1W images, and cerebral blood flow (CBF) maps were obtained. All data were processed with the SPM8 package under the MATLAB 7.6 operation environment. The T2DM patients and their unaffected siblings shared significant atrophy in the right inferior/middle temporal gyrus, and left insula, in addition to elevated CBF in the right prefrontal lobe. Several regions with abnormal CBF in siblings, including the right inferior/middle temporal gyrus, left insula, left operculum, right supramarginal gyrus, right prefrontal lobe, and bilateral anterior cingulate cortex, also presented significant atrophy in T2DM patients. The shared brain regions with grey matter (GM) loss and CBF increases may serve as neuroimaging endophenotypes of T2DM, and the regions with abnormal CBF in siblings indicate an increased risk for T2DM.

Cerebral blood flow augmentation using a cardiac-gated intracranial pulsating balloon pump in a swine model of elevated ICP.

Augmenting brain perfusion or reducing intracranial pressure (ICP) dose is the end target of many therapies in the neuro-critical care unit. Many present therapies rely on aggressive systemic interventions that may lead to untoward effects. Previous studies have used a cardiac-gated intracranial balloon pump (ICBP) to model hydrocephalus or to flatten the ICP waveform. The authors sought to sought to optimize ICBP activation parameters to improve cerebral physiological parameters in a swine model of raised ICP. The authors developed a cardiac-gated ICBP in which the volume, timing, and duty cycle (time relative to a single cardiac cycle) of balloon inflation could be altered. They studied the ICBP in a swine model of elevated ICP attained by continuous intracranial fluid infusion with continuous monitoring of systemic and cerebral physiological parameters, and defined two specific protocols of ICBP activation. Eleven swine were studied, 3 of which were studied to define the optimal timing, volume, and duty cycle of balloon inflation. Eight swine were studied with two defined protocols at baseline and with ICP gradually raised to a mean of 30.5 mm Hg. ICBP activation caused a consistent modification of the ICP waveform. Two ICBP activation protocols were used. Balloon activation protocol A led to a consistent elevation in cerebral blood flow (8%-25% above baseline, p < 0.00001). Protocol B resulted in a modest reduction of ICP over time (8%-11%, p < 0.0001) at all ICP levels. Neither protocol significantly affected systemic physiological parameters. The preliminary results indicate that optimized protocols of ICBP activation may have beneficial effects on cerebral physiological parameters, with minimal effect on systemic parameters. Further studies are warranted to explore whether ICBP protocols may be of clinical benefit in patients with brain injuries with increased ICP.

Pendulum Study: Active Visual Tracking Elicits Non‐Selective Elevations in Cerebral Blood Flow

Neurovascular coupling (NVC) describes the effective matching of cerebral blood flow (CBF) to regions of neuro‐metabolic demand. There is increasing interest to assess human NVC for both basic research and its potential role in vascular‐cognitive impairment. The clinical utility of NVC relies on a standardized protocol for which the driving metabolic demands are highly‐selective. Various research groups deploy divergent strategies to elicit visual NVC responses, including inactive processes (visual grating), passive visual tracking (target with predictable motion) and active visual tracking (target with unpredictable motion). These strategies differ in degree of cognitive and metabolic demand and may elicit different NVC responses, thus precluding study comparison.The present NVC assessment evaluated temporal and regional responsiveness of blood flow (transcranial Doppler) to the visual cortex [via the posterior cerebral artery (PCA)] and blood pressure (Finapres NOVA) during visual stimulation in 19 healthy subjects while also measuring middle cerebral artery (MCA) blood flow. Visual stimulation included 10 cycles of 30‐seconds with eyes‐closed, followed by 30‐seconds with eyes‐open tracking a moving computerized target. Each subject completed three trials of passive tracking and three trials of active tracking (114 NVC protocols, 1140 individual hyperemias). A custom eye‐scanning apparatus followed eye motion to quantify visual target‐tracking vigilance. Additional custom software was used to quantify NVC.The data demonstrated that active tracking elicited greater NVC responses compared to passive tracking. Specifically, there was 26% greater change in the mean elevation of PCA blood velocity (p=&lt;0.000) and 13% greater peak NVC response (p&lt;0.01). The MCA response was also greater during active tracking (mean response 111% greater, peak response 41% greater; both p&lt;0.001). Visual target‐tracking vigilance was linearly correlated to the degree of hyperemia in the MCA and PCA, as well blood pressure during NVC.It was observed that active and passive visual tracking elicit different NVC responses and cannot be reliably compared. That PCA and MCA responses were greater with active tracking suggests an elevated global CBF (i.e. not selective to regions perfused by the PCA) that may result from recruitment of brain centres responsible for sustained attention and executive function. In other words, active tracking leads to non‐selective elevations in global CBF and greater target‐tracking vigilance impacts the NVC response. These findings are a critical step to better understand and standardize the evaluation of NVC in humans and for potential clinical deployment of NVC assessments.Support or Funding InformationNatural Sciences and Engineering Research Council; Alberta Innovates Research Studentship; NSERC; CIHR; Libin Cardiovascular Institute; Hotchkiss Brain Institute; Compute CanadaThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Altered amplitude of low-frequency fluctuation and regional cerebral blood flow in females with primary dysmenorrhea: a resting-state fMRI and arterial spin labeling study.

Purpose: The current study aimed to explore the central mechanism of primary dysmenorrhea (PD) by investigating the alterations in resting state amplitude of low-frequency fluctuation (ALFF) and regional cerebral blood flow (CBF) between PD patients and healthy controls (HCs).Patients and methods: A total of 34 female subjects including 20 PD patients and 14 HCs underwent resting-state functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling technique (ASL) MRI during menstrual phase. Subsequently, the differences in ALFF and CBF were compared in the two groups. The visual analog scores for pain (VAS-P) and for anxiety (VAS-A) were applied to assess cramping pain and related symptoms in PD patients. Finally, Pearson’s correlation analysis was performed to analyze relationships between the neuroimaging findings and clinical characteristics.Results: Compared to HCs, PD patients had decreased ALFF in the right cerebellum posterior lobe, right middle temporal gyrus, right parahippocampal gyrus, right hippocampus, right brainstem and left parietal lobe. In addition, elevated CBF values were observed in the right inferior frontal gyrus, right precentral gyrus, and right superior temporal gyrus. There was no significant correlation between ALFF, CBF values and clinical characteristics including onset age of dysmenorrhea, VAS-A, and VAS-P in PD patients.Conclusion: The preliminary alterations of ALFF and CBF values in PD patients were observed in different pain-related brain regions, which were involved in multiple dimensions of pain and pain modulation. The combination of rs-fMRI and ASL MRI might provide complementary information for a better understanding of the central mechanism in PD.

Machine learning-based prediction of clinical pain using multimodal neuroimaging and autonomic metrics.

Although self-report pain ratings are the gold standard in clinical pain assessment, they are inherently subjective in nature and significantly influenced by multidimensional contextual variables. Although objective biomarkers for pain could substantially aid pain diagnosis and development of novel therapies, reliable markers for clinical pain have been elusive. In this study, individualized physical maneuvers were used to exacerbate clinical pain in patients with chronic low back pain (N = 53), thereby experimentally producing lower and higher pain states. Multivariate machine-learning models were then built from brain imaging (resting-state blood-oxygenation-level-dependent and arterial spin labeling functional imaging) and autonomic activity (heart rate variability) features to predict within-patient clinical pain intensity states (ie, lower vs higher pain) and were then applied to predict between-patient clinical pain ratings with independent training and testing data sets. Within-patient classification between lower and higher clinical pain intensity states showed best performance (accuracy = 92.45%, area under the curve = 0.97) when all 3 multimodal parameters were combined. Between-patient prediction of clinical pain intensity using independent training and testing data sets also demonstrated significant prediction across pain ratings using the combined model (Pearson's r = 0.63). Classification of increased pain was weighted by elevated cerebral blood flow in the thalamus, and prefrontal and posterior cingulate cortices, and increased primary somatosensory connectivity to frontoinsular cortex. Our machine-learning approach introduces a model with putative biomarkers for clinical pain and multiple clinical applications alongside self-report, from pain assessment in noncommunicative patients to identification of objective pain endophenotypes that can be used in future longitudinal research aimed at discovery of new approaches to combat chronic pain.