Hematocrit, hemoglobin and red blood cells are associated with vascular function and vascular structure in men.

High and low hematocrit (Hct) and hemoglobin (Hb) levels are associated with the risk of cardiovascular disease. The purpose of this study was to determine the relationships of Hct, Hb and red blood cells (RBCs) with vascular function and structure. We measured flow-mediated vasodilation (FMD), nitroglycerin-induced vasodilation (NID), brachial intima media thickness (IMT), and brachial-ankle pulse wave velocity (baPWV) in 807 men. The subjects were divided into six groups according to the levels of Hct, Hb and RBCs. NID was highest in the 46.0-48.9% Hct group among the six groups according to Hct levels. Brachial IMT was lowest in the 46.0-48.9% Hct group among the six groups. There were no significant differences in FMD and baPWV among the six groups. We used 46.0-48.9% Hct as a reference to define the lower tertile. The adjusted odds ratio of being in the low tertile of NID was significantly higher in the < 42.9% and ≥ 49.0% Hct groups. Adjusted odds ratio of being in the low tertile of brachial IMT was significantly lower in the < 39.9% Hct groups. Similar results were obtained for Hb and RBCs. Low and high levels of Hct, Hb and RBCs were associated with vascular smooth muscle dysfunction, and low Hct levels were associated with abnormal vascular structure. Increases in the levels of Hct, Hb and RBCs within normal ranges may have beneficial effects on the vasculature.

Effect of Active and Passive Mechanical Thromboprophylaxis and Consensual Effect on the Venous Blood Flow Velocity Among Hemiparetic Patients.

Our aim was to measure the venous blood flow velocity (VBFV) in case of hemiparetic patients, after passive and active thromboembolic methods, as well as the consensual effect in the hemiparetic limb following the active venous exercises in the healthy limb. We examined 215 patients, with the median age of 58.0 (55.0-63.0) years. The VBFV was measured with a HADECO BIDOP ES-100 V II type Doppler ultrasound device, using an 8 MHz head, on the femoral vein at the level of the hip joint. For statistical analysis, SPSS version 22 was used. After passive movement, on the hemiparetic side, compared to the value in resting state, the VBFV significantly (12.6; 11.6-13.5 cm/s; P < .001) increased. Following active venous exercises performed on the healthy side, the VBFV significantly (18.0; 15.6-19.6 cm/s; P < .001) increased compared to the value in resting state. Following the active venous exercises performed on the healthy side, the VBFV measured on the hemiparetic side (consensual effect) was significantly (15.1 [14.1-16.5] cm/s; P < .001) higher than the value on the hemiparetic side in resting state. Active and passive mechanical thromboprophylaxis methods can be effective. Movements of the healthy limb significantly increase the VBFV in the inactive limb, and patients can perform it themselves several times a day.

Early diagnosis of trisomy 21, trisomy 18 and trisomy 13 using nuchal translucency thickness and ductus venosus blood flow waveform in West China.

Abnormal nuchal translucency (NT) thickness and ductus venosus (DV) blood flow have been associated with trisomy 21, 18 and 13. However, the association of abnormal DV with these aneuploidies varies among clinical studies. The present study examined the possibility of using NT combined with DV for the early diagnosis of the three aforementioned aneuploidies in the Western Chinese population, focusing on three aspects: Biological pathway analysis, theoretical statistical analysis and clinical data analysis from 1,962 first­trimester pregnant women from Western China. The pathway and statistical analyses performed suggested the reliability of integrating NT and DV in the prediction of the three aneuploidies. The clinical data analysis suggested that integrating NT and DV, compared with NT alone, resulted in increased predictive power (34.09 vs. 22.45%), better rejection probability (0.21 vs. 0.44%), increased specificity (96.71 vs. 94.07%) and increased sensitivity (89.47 vs. 80.49%). The present results suggested the reliability of integrating NT and DV for the early diagnosis of trisomy 21, 18 and 13 for the Western Chinese population. The present results provided novel statistical analyses to the field of prenatal diagnosis in the Western Chinese population.

Analysis of chaotic and noise processes in a fluctuating blood flow using the Allan variance technique.

OBJECTIVE: The aim of this work was to develop a novel technique for digital processing of Doppler ultrasound blood flow sensor data from noisy blood flow velocity waveforms. METHODS: To evaluate the fluctuating blood flow parameters, various nonlinear dynamics methods and algorithms are often being used. Here, for identification of chaotic and noise components in a fluctuating coronary blood flow, for the first time the Allan variance technique was used. Analysis of different types of noises (White, Brownian, Flicker) was carried out and their strong correlation with fractality of time series (the Hurst exponent) was revealed. RESULTS: Based on a specialized software realizing the developed technique, numerical experiments with real clinical data were carried out. Recommendations for identification of noisy patterns of coronary blood flow in normal and pathological states were developed. CONCLUSION: The methodology gives us the possibility for the more detailed quantitative and qualitative analysis of a noisy fluctuating blood flow data.

Altered aortic shape in bicuspid aortic valve relatives influences blood flow patterns.

AIMS: Bicuspid aortic valve (BAV) is known to exhibit familial inheritance and is associated with aortopathy and altered aortic haemodynamics. However, it remains unclear whether BAV-related aortopathy can be inherited independently of valve morphology. METHODS AND RESULTS: Four-dimensional flow magnetic resonance imaging for the in vivo assessment of thoracic aortic 3D blood flow was performed in 24 BAV relatives with trileaflet aortic valves (age = 40 ± 14 years) and 15 healthy controls (age = 37 ± 10 years). Data analysis included aortic dimensions, shape (round/gothic/cubic), and 3D blood flow characteristics (semi-quantitative vortex/helix grading and peak velocities). Cubic and gothic aortic shapes were markedly more prevalent in BAV relatives compared with controls (38 vs. 7%). Ascending aorta (AAo) vortex flow in BAV relatives was significantly increased compared with controls (grading = 1.5 ± 1.0 vs. 0.6 ± 0.9, P = 0.015). Aortic haemodynamics were influenced by aortic shape: peak velocities were reduced for gothic aortas vs. round aortas (P = 0.003); vortex flow was increased for cubic aortas in the AAo (P < 0.001) and aortic arch (P = 0.004); vortex and helix flows were elevated for gothic aortas in the AAo and descending aorta (P = 0.003, P = 0.029). Logistic regression demonstrated significant associations of shape with severity of vortex flow in AAo (P < 0.001) and aortic arch (P = 0.016) in BAV relatives. CONCLUSION: BAV relatives expressed altered aortic shape and increased vortex flow despite the absence of valvular disease or aortic dilatation. These data suggest a heritable component of BAV-related aortopathy affecting aortic shape and aberrant blood flow, independent of valve morphology.

Mitochondrial DNA damage and vascular function in patients with diabetes mellitus and atherosclerotic cardiovascular disease.

OBJECTIVE: Prior studies demonstrate mitochondrial dysfunction with increased reactive oxygen species generation in peripheral blood mononuclear cells in diabetes mellitus. Oxidative stress-mediated damage to mitochondrial DNA promotes atherosclerosis in animal models. Thus, we evaluated the relation of mitochondrial DNA damage in peripheral blood mononuclear cells s with vascular function in patients with diabetes mellitus and with atherosclerotic cardiovascular disease. APPROACH AND RESULTS: We assessed non-invasive vascular function and mitochondrial DNA damage in 275 patients (age 57 ± 9 years, 60 % women) with atherosclerotic cardiovascular disease alone (N = 55), diabetes mellitus alone (N = 74), combined atherosclerotic cardiovascular disease and diabetes mellitus (N = 48), and controls age >45 without diabetes mellitus or atherosclerotic cardiovascular disease (N = 98). Mitochondrial DNA damage measured by quantitative PCR in peripheral blood mononuclear cells was higher with clinical atherosclerosis alone (0.55 ± 0.65), diabetes mellitus alone (0.65 ± 1.0), and combined clinical atherosclerosis and diabetes mellitus (0.89 ± 1.32) as compared to control subjects (0.23 ± 0.64, P < 0.0001). In multivariable models adjusting for age, sex, and relevant cardiovascular risk factors, clinical atherosclerosis and diabetes mellitus remained associated with higher mitochondrial DNA damage levels (ß = 0.14 ± 0.13, P = 0.04 and ß = 0.21 ± 0.13, P = 0.002, respectively). Higher mitochondrial DNA damage was associated with higher baseline pulse amplitude, a measure of arterial pulsatility, but not with flow-mediated dilation or hyperemic response, measures of vasodilator function. CONCLUSIONS: We found greater mitochondrial DNA damage in patients with diabetes mellitus and clinical atherosclerosis. The association of mitochondrial DNA damage and baseline pulse amplitude may suggest a link between mitochondrial dysfunction and excessive small artery pulsatility with potentially adverse microvascular impact.

Manejo de las muestras para test inmunohistoquímicos, moleculares y genéticos en el cáncer de mama / Management of samples for immunohistochemical, molecular and genetic tests in breast cancer

Las determinaciones inmunohistoquímicas y moleculares en las muestras tisulares son métodos utilizados para establecer factores pronósticos y predictivos en el cáncer de mama. Para que estas técnicas sean lo más eficaces posible se requiere de un correcto manejo de los especímenes, lo que incluye controles preanalíticos como el del tiempo de isquemia, una correcta fijación, tallado e inclusión en parafina, así como la adecuada selección de la representación del tumor que se someterá a estudio. La precisión en todos estos pasos repercutirá en un resultado óptimo de la técnica inmunohistoquímica o molecular aplicada (AU)

Molecular and immunohistochemical analysis of tissue samples are useful tools to establish prognostic and predictive factors in breast cancer. The efficiency of these techniques is based on a correct management of surgical specimens which includes pre-analytic controls such time of ischemia, appropriate fixation, gross manipulation and paraffin embedding. It is also important the right selection of tumor representation for study submission. The accuracy of all these steps will affect in the optimal result of the immunohistochemical and molecular test applied (AU)

Morphological and Biomechanical Differences in the Elastase and AngII apoE(-/-) Rodent Models of Abdominal Aortic Aneurysms.

An abdominal aortic aneurysm (AAA) is a potentially fatal cardiovascular disease with multifactorial development and progression. Two preclinical models of the disease (elastase perfusion and angiotensin II infusion in apolipoprotein-E-deficient animals) have been developed to study the disease during its initiation and progression. To date, most studies have used ex vivo methods to examine disease characteristics such as expanded aortic diameter or analytic methods to look at circulating biomarkers. Herein, we provide evidence from in vivo ultrasound studies of the temporal changes occurring in biomechanical parameters and macromolecules of the aortic wall in each model. We present findings from 28-day studies in elastase-perfused rats and AngII apoE(-/-) mice. While each model develops AAAs specific to their induction method, they both share characteristics with human aneurysms, such as marked changes in vessel strain and blood flow velocity. Histology and nonlinear microscopy confirmed that both elastin and collagen, both important extracellular matrix molecules, are similarly affected in their levels and spatial distribution. Future studies could make use of the differences between these models in order to investigate mechanisms of disease progression or evaluate potential AAA treatments.

Flow-dependent expression of ectonucleotide tri(di)phosphohydrolase-1 and suppression of atherosclerosis.

The ability of cells to detect and respond to nucleotide signals in the local microenvironment is essential for vascular homeostasis. The enzyme ectonucleotide tri(di)phosphohydrolase-1 (ENTPD1, also known as CD39) on the surface of leukocytes and endothelial cells metabolizes locally released, intravascular ATP and ADP, thereby eliminating these prothrombotic and proinflammatory stimuli. Here, we evaluated the contribution of CD39 to atherogenesis in the apolipoprotein E-deficient (ApoE-deficient) mouse model of atherosclerosis. Compared with control ApoE-deficient animals, plaque burden was markedly increased along with circulating markers of platelet activation in Cd39+/-Apoe-/- mice fed a high-fat diet. Plaque analysis revealed stark regionalization of endothelial CD39 expression and function in Apoe-/- mice, with CD39 prominently expressed in atheroprotective, stable flow regions and diminished in atheroprone areas subject to disturbed flow. In mice, disturbed flow as the result of partial carotid artery ligation rapidly suppressed endothelial CD39 expression. Moreover, unidirectional laminar shear stress induced atheroprotective CD39 expression in human endothelial cells. CD39 induction was dependent upon the vascular transcription factor Krüppel-like factor 2 (KLF2) binding near the transcriptional start site of CD39. Together, these data establish CD39 as a regionalized regulator of atherogenesis that is driven by shear stress.

Genetic influence on left ventricular structure and function: a Korean twin and family study.

Genetic factors have been suggested to be one of the determinants of the variation of left ventricular (LV) structure and function. However, the heritability range of LV structure varies across studies and the influence of genetics on LV function is not well established, especially in Asian populations. Study subjects were 1,642 healthy Korean adults from 426 families, consisting of 298 pairs of monozygotic twins, 62 pairs of dizygotic twins, one set of triplets, 567 siblings, and 354 parents. LV structure and function were measured by M-mode and 2D echocardiography, and conventional and tissue Doppler imaging (TDI). Pairwise intra-class correlations for various familial relationships and heritability were estimated for LV structure and function. The heritability of LV mass, LV ejection fraction (LVEF), left atrial volume index, the ratio between early and late diastolic velocity of mitral inflow (E/A ratio), and the ratio between early diastolic velocity of mitral inflow and early diastolic mitral annular velocities (E/Ea ratio) was 0.44, 0.27, 0.44, 0.25, and 0.33, respectively. Bivariate genetic analysis showed that LV structural and functional traits had significant genetic correlations with cardiovascular risk factors. Additive genetic correlation (ρG) of LV mass with body mass index, systolic blood pressure, and high density lipoprotein cholesterol were 0.49, 0.42, and -0.15 respectively. LVEF (ρG = 0.33) and left atrial volume index (ρG = 0.24) also had a significant genetic correlation with systolic blood pressure. These findings support the theory that genetic factors have significant influence on these traits and necessitate further work to identify the specific genes involved.

Proliferation following tetraploidization regulates the size and number of erythrocytes in the blood flow during medaka development, as revealed by the abnormal karyotype of erythrocytes in the medaka TFDP1 mutant.

BACKGROUND: For the delivery of oxygen, the correct size/number of erythrocytes is required for proper blood flow. RESULTS: By combined analyses of wild-type (WT) medaka and the kyoho (kyo) mutant, we found proliferation-mediated adaptation for size/number of erythrocytes in the blood flow during medaka development. Before the start of heart beating in the WT medaka, the karyotype of erythrocytes was 2N-4N. After the start of blood flow, the karyotype changed to 4N-8N with tetraploidization, and the cell size became larger. After the start of intersegmental and pharyngeal blood flow, the erythrocytes became smaller. The medaka mutant kyo showed erythrocytes of large size, and positional cloning of kyo demonstrated the candidate gene TFDP1, indicating higher polyploidization due to arrest in S-phase in erythrocytes of the kyo mutant. CONCLUSIONS: From our findings, we uncovered a previously unrecognized system for the regulation of the size/number in the blood flow:proliferation of erythrocytes following tetraploidization during embryonic development.

Inhibition of 14q32 MicroRNAs miR-329, miR-487b, miR-494, and miR-495 increases neovascularization and blood flow recovery after ischemia.

RATIONALE: Effective neovascularization is crucial for recovery after cardiovascular events. OBJECTIVE: Because microRNAs regulate expression of up to several hundred target genes, we set out to identify microRNAs that target genes in all pathways of the multifactorial neovascularization process. Using www.targetscan.org, we performed a reverse target prediction analysis on a set of 197 genes involved in neovascularization. We found enrichment of binding sites for 27 microRNAs in a single microRNA gene cluster. Microarray analyses showed upregulation of 14q32 microRNAs during neovascularization in mice after single femoral artery ligation. METHODS AND RESULTS: Gene silencing oligonucleotides (GSOs) were used to inhibit 4 14q32 microRNAs, miR-329, miR-487b, miR-494, and miR-495, 1 day before double femoral artery ligation. Blood flow recovery was followed by laser Doppler perfusion imaging. All 4 GSOs clearly improved blood flow recovery after ischemia. Mice treated with GSO-495 or GSO-329 showed increased perfusion already after 3 days (30% perfusion versus 15% in control), and those treated with GSO-329 showed a full recovery of perfusion after 7 days (versus 60% in control). Increased collateral artery diameters (arteriogenesis) were observed in adductor muscles of GSO-treated mice, as well as increased capillary densities (angiogenesis) in the ischemic soleus muscle. In vitro, treatment with GSOs led to increased sprout formation and increased arterial endothelial cell proliferation, as well as to increased arterial myofibroblast proliferation. CONCLUSIONS: The 14q32 microRNA gene cluster is highly involved in neovascularization. Inhibition of 14q32 microRNAs miR-329, miR-487b, miR-494, and miR-495 provides a promising tool for future therapeutic neovascularization.

Comparison of efficacy of the disease-specific LOX1- and constitutive cytomegalovirus-promoters in expressing interleukin 10 through adeno-associated virus 2/8 delivery in atherosclerotic mice.

The development of gene therapy vectors for treating diseases of the cardiovascular system continues at a steady pace. Moreover, in the field of gene therapy the utility of "disease-specific promoters" has strong appeal. Many therapeutic genes, including transforming growth factor beta 1 or interleukin 10, are associated to adverse effects. The use of a disease-specific promoter might minimize toxicity. The lectin-like oxidized low density lipoprotein receptor 1 is a marker of cardiovascular disease and a potential therapeutic target. The lectin-like oxidized low density lipoprotein receptor 1 is known to be up-regulated early during disease onset in a number of cell types at the sites where the disease will be clinically evident. In this study an adeno-associated virus-2 DNA vector (AAV2) using the AAV8 capsid, and containing the full length The lectin-like oxidized low density lipoprotein receptor 1 promoter, was generated and assayed for its ability to express human interleukin 10 in low density lipoprotein receptor knockout mice on high cholesterol diet. The cytomegalovirus early promoter was used for comparison in a similarly structured vector. The two promoters were found to have equal efficacy in reducing atherogenesis as measured by aortic systolic blood velocity, aortic cross sectional area, and aortic wall thickness. This is the first head-to-head comparison of a constitutive with a disease-specific promoter in a therapeutic context. These data strongly suggest that the use of a disease-specific promoter is appropriate for therapeutic gene delivery.

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 <24 years. Homozygosity for alpha-thalassaemia 3·7 deletion was significantly associated with reduced mean CBFv compared to wild-type (ß-coefficient -16·1 cm/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.

Association of body mass index with arterial stiffness and blood pressure components: a twin study.

RATIONALE: Obesity, blood pressure and arterial stiffness are heritable traits interconnected to each other but their possible common genetic and environmental etiologies are unknown. METHODS: We studied 228 monozygotic and 150 dizygotic twin pairs aged 18-82 years from Italy, Hungary and the United States, of which 45 monozygotic and 38 dizygotic pairs were discordant for body mass index (BMI; intrapair difference (Δ) in BMI ≥ 3 kg/m(2)). Blood pressure components and arterial stiffness were measured by TensioMed Arteriograph. RESULTS: Hypertension was more prevalent among obese than non-obese individuals (55% vs. 29%, p < 0.001). Age-, sex- and country-adjusted heritability estimates were high for hemodynamic measures (45%-58%) and BMI (78%). According to bivariate Cholesky decomposition, phenotypic correlations between BMI and blood pressure components (r = -0.15 to 0.24, p < 0.05) were largely explained by additive genetic factors (65%-77%) with the remaining explained by the unique environment. When controlling for genetic factors within all monozygotic pairs, ΔBMI was significantly correlated with Δbrachial systolic blood pressure (SBP) and diastolic blood pressure (DBP), Δmean arterial pressure, and Δaortic SBP (r = 0.15-0.17, p < 0.05). For the same measures, heavier co-twins of BMI-discordant monozygotic pairs had significantly higher values than their leaner counterparts (p < 0.05). CONCLUSION: Blood pressure components are moderately correlated with BMI, largely because of shared genetic factors. However, for the association of BMI with brachial SBP and DBP, aortic SBP and mean arterial pressure, acquired, modifiable factors were also found to be important.

Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice.

Recent studies have challenged the prevailing view that reduced mitochondrial function and increased oxidative stress are correlated with reduced longevity. Mice carrying a homozygous knockout (KO) of the Surf1 gene showed a significant decrease in mitochondrial electron transport chain Complex IV activity, yet displayed increased lifespan and reduced brain damage after excitotoxic insults. In the present study, we examined brain metabolism, brain hemodynamics, and memory of Surf1 KO mice using in vitro measures of mitochondrial function, in vivo neuroimaging, and behavioral testing. We show that decreased respiration and increased generation of hydrogen peroxide in isolated Surf1 KO brain mitochondria are associated with increased brain glucose metabolism, cerebral blood flow, and lactate levels, and with enhanced memory in Surf1 KO mice. These metabolic and functional changes in Surf1 KO brains were accompanied by higher levels of hypoxia-inducible factor 1 alpha, and by increases in the activated form of cyclic AMP response element-binding factor, which is integral to memory formation. These findings suggest that Surf1 deficiency-induced metabolic alterations may have positive effects on brain function. Exploring the relationship between mitochondrial activity, oxidative stress, and brain function will enhance our understanding of cognitive aging and of age-related neurologic disorders.

The role of noninvasive and invasive diagnostic imaging techniques for detection of extra-cranial venous system anomalies and developmental variants.

The extra-cranial venous system is complex and not well studied in comparison to the peripheral venous system. A newly proposed vascular condition, named chronic cerebrospinal venous insufficiency (CCSVI), described initially in patients with multiple sclerosis (MS) has triggered intense interest in better understanding of the role of extra-cranial venous anomalies and developmental variants. So far, there is no established diagnostic imaging modality, non-invasive or invasive, that can serve as the "gold standard" for detection of these venous anomalies. However, consensus guidelines and standardized imaging protocols are emerging. Most likely, a multimodal imaging approach will ultimately be the most comprehensive means for screening, diagnostic and monitoring purposes. Further research is needed to determine the spectrum of extra-cranial venous pathology and to compare the imaging findings with pathological examinations. The ability to define and reliably detect noninvasively these anomalies is an essential step toward establishing their incidence and prevalence. The role for these anomalies in causing significant hemodynamic consequences for the intra-cranial venous drainage in MS patients and other neurologic disorders, and in aging, remains unproven.

Effect of mild cognitive impairment and APOE genotype on resting cerebral blood flow and its association with cognition.

Using whole-brain pulsed arterial spin labeling magnetic resonance imaging, resting cerebral blood flow (CBF) was measured in 20 mild cognitive impairment (MCI; 11 ɛ3 and 9 ɛ4) and 40 demographically matched cognitively normal (CN; 27 ɛ3 and 13 ɛ4) participants. An interaction of apolipoprotein (APOE) genotype (ɛ3 and ɛ4) and cognitive status (CN and MCI) on quantified gray-matter CBF corrected for partial volume effects was found in the left parahippocampal and fusiform gyri (PHG/FG), right middle frontal gyrus, and left medial frontal gyrus. In the PHG/FG, CBF was elevated for CN ɛ4 carriers but decreased for MCI ɛ4 carriers. The opposite pattern was seen in frontal regions: CBF was decreased for CN ɛ4 carriers but increased for MCI ɛ4 carriers. Cerebral blood flow in the PHG/FG was positively correlated with verbal memory for CN ɛ4 adults (r=0.67, P=0.01). Cerebral blood flow in the left medial frontal gyrus was positively correlated with verbal memory for MCI ɛ4 adults (r=0.70, P=0.05). Findings support dynamic pathophysiologic processes in the brain associated with Alzheimer's disease risk and indicate that cognitive status and APOE genotype have interactive effects on CBF. Correlations between CBF and verbal memory suggest a differential neurovascular compensatory response in posterior and anterior cortices with cognitive decline in ɛ4 adults.