Regulation Of Cerebral Perfusion Research Articles

Nasal turbinate lymphatic obstruction: a proposed new paradigm in the etiology of essential hypertension.

Hypertension affects an estimated 1.3 billion people worldwide and is considered the number one contributor to mortality via stroke, heart failure, renal failure, and dementia. Although the physiologic mechanisms leading to the development of essential hypertension are poorly understood, the regulation of cerebral perfusion has been proposed as a primary cause. This article proposes a novel etiology for essential hypertension. Our hypothesis developed from a review of nuclear medicine scans, where the authors observed a significantly abnormal increase in nasal turbinate vasodilation in hypertensive patients using quantitative region of interest analysis. The authors propose that nasal turbinate vasodilation and resultant blood pooling obstruct the flow of cerebrospinal fluid passing through nasal turbinate lymphatics, thereby increasing intracranial pressure. The authors discuss the glymphatic/lymphatic clearance system which is impaired with age, and at which time hypertension also develops. The increased intracranial pressure leads to compensatory hypertension via Cushing's mechanism, i.e., the selfish brain hypothesis. The nasal turbinate vasodilation, due to increased parasympathetic activity, occurs simultaneously along with the well-established increased sympathetic activity of the cardiovascular system. The increased parasympathetic activity is likely due to an autonomic imbalance secondary to the increase in worldwide consumption of processed food. This hypothesis explains the rapid worldwide rise in essential hypertension in the last 50 years and offers a novel mechanism and a new paradigm for the etiology of essential hypertension. This new paradigm offers compelling evidence for the modulation of parasympathetic nervous system activity as a novel treatment strategy, specifically targeting nasal turbinate regulation, to treat diseases such as hypertension, idiopathic intracranial hypertension, and degenerative brain diseases. The proposed mechanism of essential hypertension presented in this paper is a working hypothesis and confirmatory studies will be needed.

The Dynamic Relationship Between Cortical Oxygenation and End-Tidal CO 2 Transient Changes Is Impaired in Mild Cognitive Impairment Patients.

Background: Recent studies have utilized data-based dynamic modeling to establish strong association between dysregulation of cerebral perfusion and Mild Cognitive Impairment (MCI), expressed in terms of impaired CO2 dynamic vasomotor reactivity in the cerebral vasculature. This raises the question of whether this is due to dysregulation of central mechanisms (baroreflex and chemoreflex) or mechanisms of cortical tissue oxygenation (CTO) in MCI patients. We seek to answer this question using data-based input-output predictive dynamic models.Objective: To use subject-specific data-based multivariate input-output dynamic models to quantify the effects of systemic hemodynamic and blood CO2 changes upon CTO and to examine possible differences in CTO regulation in MCI patients versus age-matched controls, after the dynamic effects of central regulatory mechanisms have been accounted for by using cerebral flow measurements as another input.Methods: The employed model-based approach utilized the general dynamic modeling methodology of Laguerre expansions of kernels to analyze spontaneous time-series data in order to quantify the dynamic effects upon CTO (an index of relative capillary hemoglobin saturation distribution measured via near-infrared spectroscopy) of contemporaneous changes in end-tidal CO2 (proxy for arterial CO2), arterial blood pressure and cerebral blood flow velocity in the middle cerebral arteries (measured via transcranial Doppler). Model-based indices (physio-markers) were computed for these distinct dynamic relationships.Results: The obtained model-based indices revealed significant statistical differences of CO2 dynamic vasomotor reactivity in cortical tissue, combined with “perfusivity” that quantifies the dynamic relationship between flow velocity in cerebral arteries and CTO in MCI patients versus age-matched controls (p = 0.006). Significant difference between MCI patients and age-matched controls was also found in the respective model-prediction accuracy (p = 0.0001). Combination of these model-based indices via the Fisher Discriminant achieved even smaller p-value (p = 5 × 10–5) when comparing MCI patients with controls. The differences in dynamics of CTO in MCI patients are in lower frequencies (<0.05 Hz), suggesting impairment in endocrine/metabolic (rather than neural) mechanisms.Conclusion: The presented model-based approach elucidates the multivariate dynamic connectivity in the regulation of cerebral perfusion and yields model-based indices that may serve as physio-markers of possible dysregulation of CTO during transient CO2 changes in MCI patients.

Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans.

AimsNeuronal nitric oxide synthase (nNOS) is highly expressed within the cardiovascular and nervous systems. Studies in genetically modified mice suggest roles in brain blood flow regulation while dysfunctional nNOS signalling is implicated in cerebrovascular ischaemia and migraine. Previous human studies have investigated the effects of non-selective NOS inhibition but there has been no direct investigation of the role of nNOS in human cerebrovascular regulation. We hypothesized that inhibition of the tonic effects of nNOS would result in global or localized changes in cerebral blood flow (CBF), as well as changes in functional brain connectivity.Methods and resultsWe investigated the acute effects of a selective nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), on CBF and brain functional connectivity in healthy human volunteers (n = 19). We performed a randomized, placebo-controlled, crossover study with either intravenous SMTC or placebo, using magnetic resonance imaging protocols with arterial spin labelling and functional resting state neuroimaging. SMTC infusion induced an ∼4% decrease in resting global CBF [−2.3 (−0.3, −4.2) mL/100g/min, mean (95% confidence interval, CI), P = 0.02]. In a whole-brain voxel-wise factorial-design comparison of CBF maps, we identified a localized decrease in regional blood flow in the right hippocampus and parahippocampal gyrus following SMTC vs. placebo (2921 voxels; T = 7.0; x = 36; y = −32; z = −12; P < 0.001). This was accompanied by a decrease in functional connectivity to the left superior parietal lobule vs. placebo (484 voxels; T = 5.02; x = −14; y = −56; z = 74; P = 0.009). These analyses adjusted for the modest changes in mean arterial blood pressure induced by SMTC as compared to placebo [+8.7 mmHg (+1.8, +15.6), mean (95% CI), P = 0.009].ConclusionsThese data suggest a fundamental physiological role of nNOS in regulating regional CBF and functional connectivity in the human hippocampus. Our findings have relevance to the role of nNOS in the regulation of cerebral perfusion in health and disease.

Determining the Role of ApoE4 in Age-Related Cerebrovascular Decline

Cerebrovascular decline occurs during aging and may be critical during prodromal phases of Alzheimer’s disease (AD). The E4 allele of apolipoprotein E (APOE4) is the greatest genetic risk factor for AD and decreased longevity and studies suggest APOE4 increases risk for age-dependent cerebrovascular damage. To study the relationship between APOE4 and age-related cerebrovascular decline, male and female C57BL/6J (B6) mice carrying combinations of APOE alleles including APOE4 (risk) and APOE3 (neutral), as well as B6 controls were assessed at a variety of ages from 4 to 24 mos for cognitive ability, biometrics and cerebrovascular health including i) PET/MRI using 64Cu-PTSM (perfusion) and 18F-FDG (metabolism), ii) transcriptional profiling and iii) immunofluorescence. Despite no cognitive decline, male APOE4 mice showed hypo-perfusion and hypo-metabolism by 12 mos, while female APOE4 mice showed an uncoupled hyper-perfusion and hypo-metabolism phenotype. Transcriptional profiling showed differential expression of genes involved in regulation of cerebral perfusion, glucose transportation and metabolism in APOE4 mice. An age-dependent blood brain barrier compromise was also apparent in the brains of female APOE4 mice. Physical activity reduces risk for human AD and our data shows exercise improves cerebrovascular health in mice. However, the effects to cerebrovascular health in individuals carrying genetic risk factors such as APOE4 are not known. To determine whether exercise can overcome APOE4-dependent cerebrovascular damage, APOE mice are being exercised from 2-4 and to 2-12 mos. Transcriptional profiling and immunofluorescence will determine whether the benefits of exercise to the cerebrovasculature are modulated by genetic risk factors such as APOE4.

Pathophysiology of white matter perfusion in Alzheimer’s disease and vascular dementia

Little is known about the contributors and physiological responses to white matter hypoperfusion in the human brain. We previously showed the ratio of myelin-associated glycoprotein to proteolipid protein 1 in post-mortem human brain tissue correlates with the degree of ante-mortem ischaemia. In age-matched post-mortem cohorts of Alzheimer's disease (n = 49), vascular dementia (n = 17) and control brains (n = 33) from the South West Dementia Brain Bank (Bristol), we have now examined the relationship between the ratio of myelin-associated glycoprotein to proteolipid protein 1 and several other proteins involved in regulating white matter vascularity and blood flow. Across the three cohorts, white matter perfusion, indicated by the ratio of myelin-associated glycoprotein to proteolipid protein 1, correlated positively with the concentration of the vasoconstrictor, endothelin 1 (P = 0.0005), and negatively with the concentration of the pro-angiogenic protein, vascular endothelial growth factor (P = 0.0015). The activity of angiotensin-converting enzyme, which catalyses production of the vasoconstrictor angiotensin II was not altered. In samples of frontal white matter from an independent (Oxford, UK) cohort of post-mortem brains (n = 74), we confirmed the significant correlations between the ratio of myelin-associated glycoprotein to proteolipid protein 1 and both endothelin 1 and vascular endothelial growth factor. We also assessed microvessel density in the Bristol (UK) samples, by measurement of factor VIII-related antigen, which we showed to correlate with immunohistochemical measurements of vessel density, and found factor VIII-related antigen levels to correlate with the level of vascular endothelial growth factor (P = 0.0487), suggesting that upregulation of vascular endothelial growth factor tends to increase vessel density in the white matter. We propose that downregulation of endothelin 1 and upregulation of vascular endothelial growth factor in the context of reduced ratio of myelin-associated glycoprotein to proteolipid protein 1 are likely to be protective physiological responses to reduced white matter perfusion. Further analysis of the Bristol cohort showed that endothelin 1 was reduced in the white matter in Alzheimer's disease (P < 0.05) compared with control subjects, but not in vascular dementia, in which endothelin 1 tended to be elevated, perhaps reflecting abnormal regulation of white matter perfusion in vascular dementia. Our findings demonstrate the potential of post-mortem measurement of myelin proteins and mediators of vascular function, to assess physiological and pathological processes involved in the regulation of cerebral perfusion in Alzheimer's disease and vascular dementia.

Influence of Posture on the Regulation of Cerebral Perfusion

Posture has a major influence on cerebral blood flow (CBF). Unlike head-up tilt (HUT), less is known about how CBF is regulated during head-down tilt (HDT). We hypothesized that CBF would be elevated during HDT and decreased during HUT. In 21 healthy young adults, while controlling for end-tidal Pco2, we combined concurrent measurements of middle cerebral artery velocity and posterior cerebral artery velocity (MCAv and PCAv, respectively), blood pressure (BP), and heart rate (HR). Measures were made at rest and, in a randomized order, during -90 degrees HDT and +900 HUT. Dynamic cerebral autoregulation was quantified using transfer function analysis. In a subgroup, volumetric blood flow recordings were obtained in the common carotid artery (CCA; N=11), internal and external carotid arteries (ICA; N=8 and ECA; N=6), and vertebral artery (VA; N=4). End-tidal Pco2, CCA, ICA, VA, MCAv(mean) and PCAv(mean) remained unchanged during -90 degrees HDT and +90 degrees HUT compared to supine. During -90 degrees HDT, mean BP (+22 mmHg) and cerebral vascular resistance (CVR) in both the MCA and PCA were elevated relative to supine, whereas HR remained unchanged. During +900 HUT, when compared to supine, HR increased (+18 bpm), and mean arterial pressure (MAP) total power and low frequency (LF) power in the MCA and PCA increased. In both the very low frequency (VLF) and LF ranges, coherence during +90 degrees HUT increased (P < 0.05 vs. supine) in both the MCA and PCA. In contrast, coherence was reduced during -90 degrees HDT. Despite marked changes in perfusion pressure with HUT or HDT, our findings indicate that cerebral perfusion is well maintained during acute severe changes in posture.

Interactions of PPARα and Acid Sensing Ion Channels on Cerebral Perfusion in Mice

Acid sensing ion channels (ASICs) are expressed in the brain and are made up of various proton sensitive channels which play critical roles in cellular physiology. Different genes have been shown to code for these channels. PPARα, a nuclear transcription factor that regulates many genes is also expressed in the brain and may have a regulatory role in the functions of ASICs. We have investigated the effects of interactions of PPARα and ASICs on the regulation of cerebral perfusion (CP) in mice. Anesthetized wild type (WT) or PPARα knockout (KO) mice received Amiloride (A), ENaC blocker, Benzamil (B), inhibitor of ENaC and Na+/Ca2+ exchange (NCX) blocker; Furosemide (F), inhibitor of Na‐K‐2Cl symporter, or Nigericin (N), ionophore and antiporter of H+ and K+(0.020, 0.35, 6.25, 0.025 mg/kg, respectively). Effects of the treatments were determined by Laser Doppler Scanner (Moor LDI 5152). CP was increased in the WT by 23, 38, or 26% and was attenuated in the KO to −6, 13, or 11% (A, p&lt;0.05), B increased CP in the WT to 24, 38, or 28% and was attenuated to −1, 17, 28% (p&gt;0.05) at 10, 30, or 60 min, respectively (n=3–5, ANOVA). Treatment with F or N reduced CP in the WT and the KO to similar extent. These data indicate that ASICs selectively sensitive to Amiloride and Benzamil are involved in maintaining basal brain perfusion and that PPARα gene is involved. The mechanism for such regulation needs further investigation.

Counterpoint: Sympathetic nerve activity does not influence cerebral blood flow

It is intuitively clear that the cerebral circulation cannot take part in general cardiovascular regulation. During states of shock, where the sympathetic nervous system is activated, leading to a decrease in the perfusion of kidneys and mesenteric vascular bed, the cerebral circulation is kept

Circadian periodicity in cerebral blood flow: Studies in normotensive and transgenic hypertensive rats

Cardiovascular parameters such as arterial blood pressure (ABP) and heart rate display pronounced circadian variation. In addition, evidence has been presented in favor of diurnal changes of perfusion in the heart, skin, kidney, and skeletal muscle. The present study was performed to detect whether there is a circadian periodicity in the regulation of cerebral perfusion. Normotensive Sprague Dawley rats (SDR, appr. 15 weeks old) and hypertensive (mREN2)27 transgenic rats (TGR, approximately 12 weeks old) were equipped in the abdominal aorta with a blood pressure sensor coupled to a telemetry system for continuous recording of systolic and diastolic ABP, heart rate, and locomotor activity. Five to twelve days later, a laser-Doppler flowmetry (LDF) probe was attached to the skull by means of a guiding device to measure changes of cerebral blood flow (CBF). After recovery from anesthesia, continuous measurements were taken for 3–5 days. The time series were analyzed with respect to the MESOR (midline estimating statistic of rhythm, i.e. the mean value of a given period), amplitude, and acrophase (i.e. the phase angle corresponding to the peak of a given period) of the 24 h period and subharmonics including 12 h, 8 h, 4.8 h and 4 h period length. All data are given as meanSD with the time indicated in 24 h format. The circadian rhythm was the most prominent one for each parameter throughout the experiments. In SDR the acrophases of systolic and diastolic ABP were at 04:12 h 42 min and 02:24 h 42 min, respectively. In the TGR the ABP signal showed its typical inverse pattern with the maximum of the ABP occurring during light on (acrophase of systolic ABP, 09:48 h 108 min; acrophase of diastolic ABP, 09:54 h 144 min), i.e. during the resting phase of the animals. The peak of the circadian periodicity in the LDF signal occurred around midnight in both, SDR (23:54 h 114 min) and TGR (00:48 h 78 min), i.e. during the subjective activity phase of the animals. The acrophase position of the LDF signal was consistently prior to that of the locomotor activity (SDR, 01:42 h 18 min; TGR, 1:18 h 66 min). The present data suggest the presence of a circadian periodicity in the regulation of cerebral perfusion. The generator of this periodicity is not yet known. The circadian rhythm in the LDF signal is independent from that of the ABP since it did not follow the inverse periodicity in TGR. It is probably also independent from locomotor activity since its peak occurred consistently prior to that of the locomotor activity. The presence of a circadian periodicity in the CBF may have implications for the occurrence of diurnal alterations of cerebrovascular events with a morning peak observed in humans.

Circadian periodicity of cerebral blood flow revealed by laser-Doppler flowmetry in awake rats: relation to blood pressure and activity

Cardiovascular parameters such as arterial blood pressure (ABP) and heart rate display pronounced circadian variation. The present study was performed to detect whether there is a circadian periodicity in the regulation of cerebral perfusion. Normotensive Sprague-Dawley rats (SDR, approximately 15 wk old) and hypertensive (mREN2)27 transgenic rats (TGR, approximately 12 wk old) were instrumented in the abdominal aorta with a blood pressure sensor coupled to a telemetry system for continuous recording of ABP, heart rate, and locomotor activity. After 5-12 days, a laser-Doppler flow (LDF) probe was attached to the skull by means of a guiding device to measure changes in brain cortical blood flow (CBF). After the animals recovered from anesthesia, measurements were taken for 3-4 days. The time series were analyzed with respect to the midline estimating statistic of rhythm (i.e., mean value of a periodic event after fit to a cosine function), amplitude, and acrophase (i.e., phase angle that corresponds to the peak of a given period) of the 24-h period. The LDF signal displayed a significant circadian rhythm, with the peak occurring at around midnight in SDR and TGR, despite inverse periodicity of ABP in TGR. This finding suggests independence of LDF periodicity from ABP regulation. Furthermore, the acrophase of the LDF was consistently found before the acrophase of the activity. From the present data, it is concluded that there is a circadian periodicity in the regulation of cerebral perfusion that is independent of circadian changes in ABP and probably is also independent of locomotor activity. The presence of a circadian periodicity in CBF may have implications for the occurrence of diurnal alterations in cerebrovascular events in humans.

Modulation of rat pial arteriolar responses to flow by glucose.

Pial arteriolar responses to flow contribute to regulation of cerebral perfusion and vary according to the transmural pressure to which the vessel is exposed. This study determined the effect of increased glucose concentration on the flow responses of pial arterioles at low and high levels of transmural pressure. Pial arterioles from Sprague-Dawley rats were mounted in a perfusion myograph. In some arterioles, the endothelium was removed by perfusion with air. Diameters were recorded at transmural pressures of 60 and 120 mmHg during superfusion with physiologic saline containing 5 mm D-glucose, 20 mm D-glucose, or 5 mm D-glucose and 15 mm L-glucose. Diameters during superfusion with saline containing 44 mm D-glucose were measured at an intraluminal pressure of 60 mmHg. Flow-diameter relationships (5-30 microl/min) were recorded during perfusion with the same solutions. Increasing D-glucose concentration caused constriction (P < 0.05) in endothelium-denuded but not in endothelium-intact arterioles. Addition of L-glucose caused constriction in endothelium-intact and -denuded vessels (P < 0.05 for both). At a D-glucose concentration of 5 mm and at low intraluminal pressure, flow elicits endothelium-dependent dilation such that shear stress remains constant. At a D-glucose concentration of 20 or 44 mm, after addition of L-glucose (15 mm), and at high intraluminal pressures, flow elicits constriction and shear stress is unregulated. High glucose concentrations elicit increased basal arteriolar smooth muscle tone that is counteracted by release of endothelium-derived relaxing factors. Endothelium-dependent relaxation to flow (shear stress) is inhibited at high glucose concentrations.

Interaction of carbon dioxide and sympathetic nervous system activity in the regulation of cerebral perfusion in humans.

Recent studies suggest that activation of the sympathetic nervous system either directly or indirectly influences cerebrovascular tone in humans even within the autoregulatory range. In 6 healthy subjects (aged 29+/-4 years), we used transcranial Doppler sonography to determine cerebral blood flow velocity during sympathetic activation elicited through head-up tilt (HUT) and sympathetic deactivation through ganglionic blockade. PaCO(2) was manipulated through hyperventilation and CO(2) breathing (5%). With subjects in the supine position and during HUT, mean arterial pressure was not influenced by PaCO(2). During ganglionic blockade, mean arterial pressure decreased markedly with hyperventilation (-13+/-1.9 mm Hg). Manipulation of sympathetic tone elicited only mild changes in cerebral blood flow (64+/-5.8 cm/s supine, 58+/-4.9 cm/s upright, and 66+/-6.2 cm/s during ganglionic blockade; P:=0.07 by ANOVA). The slope of the regression between PaCO(2) and mean velocity was 1.6+/-0.18 cm/(s. mm Hg) supine, 1.3+/-0.14 cm/(s. mm Hg) during HUT, and 2.3+/-0.36 cm/(s. mm Hg) during ganglionic blockade (P:<0.05). Spontaneous PaCO(2) and ventilatory response to hypercapnia were also modulated by the level of sympathetic activity. Changes in sympathetic tone have a limited effect on cerebral blood flow at normal PaCO(2) levels. However, the sympathetic nervous system seems to attenuate the CO(2)-induced increase in cerebral blood flow. This phenomenon may indicate a moderate direct effect of the sympathetic nervous system on the cerebral vasculature. Furthermore, sympathetic activation tends to increase ventilation and thus can indirectly increase cerebrovascular tone.

The effect of graded hypocapnia and hypercapnia on regional cerebral blood flow and cerebral vessel caliber in the rhesus monkey: study of cerebral hemodynamics following subarachnoid hemorrhage and traumatic internal carotid spasm.

Correlative cerebral blood flow (CBF) and vessel diameter studies were performed during graded Paco, change in control monkeys and in monkeys subjected to subarachnoid hemorrhage and internal carotid artery spasm. In the control series CBF increased linearly between Pa CO CO2 values of 30 mm Hg and 60 mm Hg. An increase in Pa CO CO2 from 40 mm Hg to 62 mm Hg produced a mean CBF increase of 74% while a reduction of Pa CO CO2 to 25 mm Hg resulted in a decrease of 40%. Cerebral gray matter was more responsive to Pa CO CO2 change than white matter. Caliber of the larger capacitance vessels did not provide an adequate index of the status of cerebral circulation. In the experimental series both SAH and traumatic internal carotid artery spasm caused a decreased hemodynamic responsiveness to Pa CO CO2 . However, when Pa CO CO2 was raised to 60 to 65 mm Hg, marked increases in cerebral perfusion occurred (breakthrough phenomenon). In general, a poor correlation between CBF and vessel diameter studies was found in the postinsult period. The studies indicated: (1) SAH caused an increase in cerebrovascular resistance and a decrease in CBF, (2) hemodynamic responses to Pa CO CO2 change, although diminished, were not abolished in the acute period after SAH, (3) hypercapnia (Pa CO CO2 &gt; 60 mm Hg) significantly increased cerebral perfusion whether or not vasospasm was alleviated, and (4) the small distal cerebral vessels were more reactive to Pa CO CO2 change and were more intimately associated with regulation of cerebral perfusion.