Cerebrovascular Alterations Research Articles

Correlation of cerebrovascular disorder and anxiety: The Kecskemet study

In order to test the hypothesis that anxiety is a risk factor for cardiovascular disease, specifically stroke, we simultaneously measured anxiety and cerebral vascular alternation, using a computer-based system, "Cerberus." Sixty nine psychiatric patients (including an alcoholic subgroup) were selected as subjects for measurements conducted in Kecskemet, Hungary. The five-item short form of anxiety test (STAI) was administered twice during the same session. Between each test, brain pulse waves were recorded by rheoencephalogram (REG). A REG peak time above 180 milliseconds was considered a cerebrovascular alteration (modified after Jenkner). Data were sorted into two groups: low anxiety (N=10) and high anxiety (N=10). Significant differences were found between cardiovascular risk factors (p< 0.001), REG peak time (p<0.043), and heart rate (p< 0.045). Six subjects showed cerebrovascular alteration in the high anxiety group, and two in the low anxiety group. For the two anxiety groups, there were no significant differences in body mass index, cardiovascular sympathetic-parasympathetic balance, age and symptoms of transient ischemic attack. The correlation of REG and age was significantly different only for the alcoholic subgroup (Szalay et al, 2007). These data support the hypothesis that a correlation exists between cerebrovascular disorder and anxiety in the studied population.

Studies in Rheoencephalography (REG)

Abstract This article presents an overview of rheoencephalography (REG) – electrical impedance measurements of the brain – and summarizes past and ongoing research to develop medical applications of REG for neuro-critical care and for primary prevention of stroke and cardiovascular disease. The availability of advanced electronics and computation has opened up the potential for use of REG technology as a noninvasive, continuous and inexpensive brain monitor for military and civilian applications. The clinical background information presented here introduces physiological and clinical environments where REG has potential for use in research and clinical settings. REG studies over the past three decades have involved in vitro and in vivo groups (animal and human), including more than 1500 measurements and related electronic and computational results and practical applications. In vitro studies helped researchers understand the flow/volume relationship between Doppler ultrasound and electrical impedance signals and supported development of REG data processing methods. In animal studies, REG was used to monitor the lower limit of cerebral blood flow (CBF) autoregulation (AR) using a newly developed algorithm. These animal studies also confirmed correlations between REG and measurements of carotid flow (CF) and intracranial pressure (ICP). Human studies confirmed the applicability of REG for detecting cerebrovascular alteration, demonstrating the usefulness of REG in the field of stroke/cardio-vascular disease prevention. In these studies, REG was compared to known stroke risk factors and to results obtained using carotid ultrasound measurements. An intelligent REG system (Cerberus) has been developed for primary stroke prevention. In these studies, the biologically relevant variables of the REG signal were pulse amplitude (minimum – maximum distance) and duration of the anacrotic (rising) portion of the REG pulse wave. The principal limitation of REG for clinical application is the lack of pathological and physiological correlations. The studies presented here have initiated such inquiries, but many clinical questions about the pathophysiological background of REG remain unanswered. These results demonstrate that REG development is a multidisciplinary subject with relevance for medicine (vascular neurology and neurosurgery intensive care); electronic engineering; mathematics, and computer science (data processing). It is hoped that information presented in this article will provide assistance to those involved in REG research, particularly in development and clinical applications.

Cyclooxygenase 1–Derived Prostaglandin E 2 and EP1 Receptors Are Required for the Cerebrovascular Dysfunction Induced by Angiotensin II

Prostaglandin E(2) (PGE(2)) EP1 receptors (EP1Rs) may contribute to hypertension and related end-organ damage. Because of the key role of angiotensin II (Ang II) in hypertension, we investigated the role of EP1R in the cerebrovascular alterations induced by Ang II. Mice were equipped with a cranial window, and cerebral blood flow was monitored by laser-Doppler flowmetry. The attenuation in cerebral blood flow responses to whisker stimulation (-46+/-4%) and the endothelium-dependent vasodilator acetylcholine (-40+/-4%) induced by acute administration of Ang II (250 ng/kg per minute; IV for 30 to 40 minutes) were not observed after cyclooxygenase 1 or EP1R inhibition or in cyclooxygenase 1 or EP1-null mice. In contrast, cyclooxygenase 2 inhibition or genetic inactivation did not prevent the attenuation. Ang II-induced oxidative stress was not observed after cyclooxygenase 1 or EP1R inhibition or in EP1R-null mice. Prostaglandin E(2) reinstated the Ang II-induced cerebrovascular dysfunction and oxidative stress after cyclooxygenase 1 inhibition. Brain prostaglandin E(2) levels were not increased by Ang II but were attenuated by cyclooxygenase 1 and not cyclooxygenase 2 inhibition. The cerebrovascular dysfunction induced by 14-day administration of "slow-pressor" doses of Ang II (600 ng/kg per minute) was attenuated by neocortical application of SC51089. Cyclooxygenase 1 immunoreactivity was observed in microglia and EP1R in endothelial cells. We conclude that the cerebrovascular dysfunction induced by Ang II requires activation of EP1R by constitutive production of prostaglandin E(2) derived from cyclooxygenase 1. The findings provide the first evidence that EP1Rs are involved in the deleterious cerebrovascular effects of Ang II and suggest new therapeutic approaches to counteract them.

Detection of vascular alterations by in vivo magnetic resonance angiography and histology in APP/PS1 mouse model of Alzheimer’s disease

The brain of patients with Alzheimer's disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles. Vascular alterations such as amyloid angiopathy are also commonly reported in patients with AD and participate in mechanisms involved in disease onset and progression. Transgenic mouse models of AD have been engineered to evaluate the pathophysiology and new treatments of the disease. Our study evaluated vascular alterations in APP(SweLon)/PS1(M146L) mouse model of AD. Histological analysis and in vivo magnetic resonance angiography protocols based on time of flight (TOF) and contrast-enhanced (CE) angiography were applied to evaluate cerebrovascular alterations. Results Histological analysis showed that cerebrovascular amyloid deposition starts by the same time as extracellular amyloid plaques. However, unlike plaques deposition, severity of cerebrovascular alterations is stabilized in older animals. Alteration of the middle cerebral artery was detected in old APP(SweLon)/PS1(M146L) mice with respect to adult ones by evaluating the severity of vessel voids and the reduction of vessel length on TOF- and CE-angiograms. Age-related alterations in control PS1 mice were only detected as a reduced vessel length on CE-angiograms. These results show that macroscopic vascular abnormalities are part of the pathological alterations developed by APP(SweLon)/PS1(M146L) mouse models of AD.

Doppler indices of the middle cerebral artery in fetuses with cardiac defects theoretically associated with impaired cerebral oxygen delivery in utero: is there a brain‐sparing effect?

To assess changes in the Doppler flow profiles of the middle cerebral artery in fetuses with cardiac defects theoretically associated with impaired cerebral oxygen delivery in utero. Z-scores were calculated for pulsatility and resistance indices (PI and RI, respectively) of the middle cerebral artery (MCA) and the cerebroplacental ratio (CPR) between 19 and 41 weeks' gestation, and for head circumference at birth (HC), in 113 fetuses with the following isolated cardiac defects: transposition of the great arteries (TGA; n = 18), hypoplastic left heart (HLH; n = 46), severe aortic stenosis (n = 17), pulmonary atresia (n = 18) and tetralogy of Fallot (TOF; n = 14). Pregnancies with uteroplacental dysfunction (indicated by increased uterine and/or umbilical Doppler indices), growth restriction, extracardiac malformations, chromosomal anomalies as well as multiple pregnancies were excluded to avoid any additional hypoxemic effect as strictly as possible. The results were compared with 1378 normal controls. Fetuses with pulmonary atresia, severe aortic stenosis and TOF had no significant alterations of Doppler parameters or HC at birth. In fetuses with TGA, mean Z-scores of HC at birth were significantly smaller compared with controls (mean +/- SD, -0.73 +/- 1.25; P < 0.05), but there was no significant difference in the Doppler parameters. Fetuses with HLH had significantly lower MCA-PI (-0.57 +/- 0.74; P < 0.05), MCA-RI (-0.73 +/- 0.85; P < 0.05), CPR (-1.44 +/- 1.05; P < 0.05) and HC (-0.50 +/- 1.24; P < 0.05) Z-scores compared with controls. Fetuses with cardiac defects theoretically associated with markedly impaired cerebral oxygen delivery in utero (TGA and HLH) have smaller HCs at birth. However, only fetuses with HLH have cerebrovascular alterations that are detectable by evaluation of the Doppler indices MCA-PI, MCA-RI and CPR.

ENOS gene deletion restores blood‐brain barrier integrity and attenuates neurodegeneration in the thiamine‐deficient mouse brain

Wernicke's encephalopathy is a cerebral disorder caused by thiamine (vitamin B(1)) deficiency (TD). Neuropathologic consequences of TD include region-selective neuronal cell loss and blood-brain barrier (BBB) breakdown. Early increased expression of the endothelial isoform of nitric oxide synthase (eNOS) occurs selectively in vulnerable brain regions in TD. We hypothesize that region-selective eNOS induction in TD leads to altered expression of tight junction proteins and BBB breakdown. In order to address this issue, TD was induced in C57BL/6 wild-type (WT) and eNOS(-/-) mice by feeding a thiamine-deficient diet and treatment with the thiamine antagonist pyrithiamine. Pair-fed control mice were fed the same diet with additional thiamine. In medial thalamus of TD-WT mice (vulnerable area), increased heme oxygenase-1 and S-nitrosocysteine immunostaining was observed in vessel walls, compared to pair-fed control-WT mice. Concomitant increases in IgG extravasation, decreases in expression of the tight junction proteins occludin, zona occludens-1 and zona occludens-2, and up-regulation of matrix metalloproteinase-9 in endothelial cells were observed in the medial thalamus of TD-WT mice. eNOS gene deletion restored these BBB alterations, suggesting that eNOS-derived nitric oxide is a major factor leading to cerebrovascular alterations in TD. However, eNOS gene deletion only partially attenuated TD-related neuronal cell loss, suggesting the presence of mechanisms additional to BBB disruption in the pathogenesis of these changes.

Sepsis-Associated Delirium

In Brief Sepsis is, in 27% to 55% of cases, complicated by a deterioration of mental status, which is consistent with delirium as consciousness, awareness, cognition, and behavior are preferentially affected. Electroencephalogram and somatosensory-evoked potentials are often abnormal, plasma levels of S-100b protein or neuron-specific enolase increased, and magnetic resonance imaging may show leukoencephalopathy. Pathophysiological mechanisms include cerebrovascular alteration, blood-brain barrier breakdown, inflammatory and metabolic factors, notably tumor necrosis factor-α, inducible NO synthase, and abnormal blood glucose levels. These processes may induce brain damage, stress oxidative-related cellular dysfunction, or apoptosis. In septic patients, mortality is increased with severity of delirium, degree of electrophysiological abnormalities, and neuron-specific enolase or S-100b plasma levels. The daily evaluation of patients with sepsis should systematically include appropriate delirium scores and, if delirium is present, laboratory investigations may help assess the potential damage to the brain. There is no specific treatment for sepsis associated delirium. Patient management is mainly based on controlling infection, organ system failure, and metabolic homeostasis, while avoiding neurotoxic drugs. Future therapies may target neuroinflammation, blood-brain barrier dysfunction, brain cell oxidative stress, or apoptosis. Sepsis is a devastating disorder that results in organ dysfunction and ultimately patients may die with multiple organ failure. The brain is commonly affected in sepsis and delirium, the main clinical presentation, usually parallels the severity of the inflammatory response to sepsis. Physicians should systematically screen for brain dysfunction in patients with sepsis.

Remodelling of small cerebral arteries in human hypertension: structural and functional alterations

In the present issue of the journal, Rizzoni et al. [1] publish an interesting study reporting for the first time the structural as well as functional alterations of cerebral arterioles in human hypertension. By using the micromyographic technique applied to biopsies of cerebral tissue obtained during neurosurgery, the authors provide three findings. First, they show that the media-to-lumen ratio of cerebral arterioles is greater in hypertensive patients as compared with age-matched normotensive controls. Second, they provide evidence that cerebral cortical microvessel density is markedly reduced in patients with high blood pressure. Finally, Rizzoni et al. [1] document that the mechanical and microstructural properties of the cerebral arterioles, assessed via the strain–stress curves and the collagen microvessel wall content, respectively, are similar at normal and high levels of blood pressure. The authors conclude that the cerebral microcirculation undergoes profound structural modifications in the hypertensive state, without, however, concomitant alterations in arteriolar stiffness and in the fibrotic composition of the vessel wall. All of these structural alterations speak in favour of the so-called eutrophic vascular remodelling previously described in experimental animals [2]. The results of the present study offer new insights in the pathophysiology of hypertensive cerebral vascular disease. They also raise, however, several questions of both methodological and clinical relevance. Three of these questions will be discussed in the present editorial commentary, focusing in particular on what is the background knowledge for the present study, how do the new data fit with the well established pathophysiological picture of the cerebrovascular alterations provided by previous investigations and the study strengths and limitations.

Síndrome metabólico y envejecimiento: déficit cognitivo y alteraciones estructurales del sistema nervioso central

The metabolic syndrome is a cluster of vascular risk factors, including: hypertension, insulin resistance, low levels of high density lipoproteins, high levels of triglycerides and obesity. Nowadays the prevalence of the syndrome in the developmental societies increases and it is related to aging. To review the relation of metabolic syndrome to the cognitive impairment and cerebrovascular alterations during the aging. The syndrome involves higher risk of vascular pathologies and recently has been related to the pathological aging, including cognitive impairment and structural damage in the central nervous system. Specifically the studies about metabolic syndrome have described a profile of higher general cognitive impairment and higher risk of dementia, as well as concrete neuropsychological deficits probably related to white matter alterations. The independent effects of vascular risk factors in cognition have been studied before as well as their influences in structural integrity of the brain. Nowadays further research is necessary to know if the metabolic syndrome effects on cognition and brain are greater than the sum of the effect of his components. In the future the knowledge about the cognitive and structural damage due to the syndrome could be useful to design prevention programs and promote the healthy aging.

Plasma lipoprotein β-amyloid in subjects with Alzheimer's disease or mild cognitive impairment

Plasma amyloid beta-peptide (Abeta) can compromise the blood-brain barrier, contributing to cerebrovascular alterations and amyloid angiopathy in Alzheimer's disease (AD). The objectives of this study were to investigate the distribution of lipoprotein-bound plasma-Abeta isoforms. This involved a case-control study of subjects with AD or amnestic mild cognitive impairment (MCI) versus controls. Lipoprotein Abeta distribution was determined in fasted plasma. For assessment of chylomicron homeostasis in the postabsorptive state, subjects were bled 4 h after a low-fat meal. The main outcome measures were plasma lipoprotein Abeta isoform distribution and lipid homeostasis. We found the majority of plasma Abeta to be associated with triglyceride-rich lipoproteins (TRLs) encompassing chylomicrons, VLDL and IDL. For all lipoprotein groups, Abeta1-40 was the predominant isoform, accounting for approximately 50% of the total. Thereafter, equivalent amounts of the isoforms 1-42, 2-40, 1-38, 1-37 and 1-39 were found. Abeta1-37, Abeta1-38 and Abeta2-40 isoforms were significantly enriched within the TRL fraction of AD/MCI subjects and similar trends were observed for isoforms Abeta1-39, Abeta1-40 and Abeta1-42. Lipoprotein-Abeta was inversely associated with plasma total- and LDL cholesterol. AD/MCI subjects were not dyslipidaemic, however, there was evidence of accumulation of chylomicrons in the postabsorptive state. Our data show that Abeta was found to be associated with plasma lipoproteins, especially those enriched with triglyceride. We find that Abeta may be increased in normolipidaemic AD subjects, commensurate with possible disturbances in postprandial lipoprotein homeostasis.

Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein

Alterations in cerebrovascular regulation related to vascular oxidative stress have been implicated in the mechanisms of Alzheimer's disease (AD), but their role in the amyloid deposition and cognitive impairment associated with AD remains unclear. We used mice overexpressing the Swedish mutation of the amyloid precursor protein (Tg2576) as a model of AD to examine the role of reactive oxygen species produced by NADPH oxidase in the cerebrovascular alterations, amyloid deposition, and behavioral deficits observed in these mice. We found that 12- to 15-month-old Tg2576 mice lacking the catalytic subunit Nox2 of NADPH oxidase do not develop oxidative stress, cerebrovascular dysfunction, or behavioral deficits. These improvements occurred without reductions in brain amyloid-beta peptide (Abeta) levels or amyloid plaques. The findings unveil a previously unrecognized role of Nox2-derived radicals in the behavioral deficits of Tg2576 mice and provide a link between the neurovascular dysfunction and cognitive decline associated with amyloid pathology.

Differential age effects on cerebral blood flow and BOLD response to encoding: Associations with cognition and stroke risk

Changes in the cerebrovascular system due to age or disease can significantly alter the blood-oxygenation-level-dependent (BOLD) signal and complicate its interpretation. The simultaneous acquisition of arterial spin labeling (ASL) and BOLD data represents a useful technique to more fully characterize the neurovascular underpinnings of functional brain response to cognition. We conducted a functional magnetic resonance imaging (FMRI) study of episodic memory encoding to investigate whether age is related to cerebral blood flow (CBF) and BOLD response in the medial temporal lobe (MTL). Results demonstrated a significant reduction in resting-state CBF in older compared to young adults. Conversely, older adults showed significantly increased CBF but not BOLD response in the MTL during picture encoding relative to young adults. Correlations between CBF response and cognition were demonstrated whereas associations with BOLD were not observed. Stroke risk was associated with both CBF and BOLD response. Results suggest that aging effects on CBF and BOLD responses to encoding are dissociable and that cerebrovascular alterations contribute to findings of age-related differences.

Effects of Poststroke Losartan Versus Captopril Treatment on Myogenic and Endothelial Function in the Cerebrovasculature of SHRsp

We assessed the ability of poststroke captopril and losartan treatment to reverse myogenic and endothelial dysfunction in the middle cerebral arteries of Kyoto-Wistar stroke-prone spontaneously hypertensive rats (SHRsp) that developed intracerebral hemorrhagic stroke. SHRsp were sampled before and after stroke development and after up to 37 days of captopril (50 mg/kg per day) or losartan (35 mg/kg per day) treatment initiated after stroke. Pressure-dependent constriction to a 100-mm Hg pressure step, constriction to nitric oxide synthase inhibition (100 micromol/L N(omega)-nitro-l-arginine methyl ester), and endothelium-dependent vasodilation to bradykinin (1.6 micromol/L), 2-f-LIGRLO-NH(2) (1 micromol/L, a protease-activated receptor-2 agonist), and A23187 (2 micromol/L) were evaluated in middle cerebral arteries at 100 mm Hg with a pressure myograph. Middle cerebral arteries from SHRsp with stroke could not constrict to pressure or nitric oxide synthase inhibition, lacked the ability to vasodilate to bradykinin, and exhibited attenuated dilation and vasomotion in response to A23187. Vasodilation to 2-f-LIGRLO-NH(2) was unaltered. The aforementioned cerebrovascular alterations were reversed after 31 days of poststroke losartan but not of captopril treatment in the absence of an antihypertensive effect. Captopril treatment restored middle cerebral artery constriction to pressure, NOS inhibition, and bradykinin vasodilation temporarily after 7 to 18 days of treatment, after which function deteriorated to a level observed in SHRsp at stroke. Aspects of poststroke cerebrovascular dysfunction, which likely play an important role in altering and modulating cerebral blood flow autoregulation, can be reversed in SHRsp more effectively after stroke development by blocking angiotensin II type 1 receptors as opposed to lowering angiotensin II levels.

REG can be used to detect cerebrovascular alteration caused by alcoholism

Despite recent evidence of the beneficial effects of moderate alcohol consumption in arteriosclerosis prevention, the neurotoxic effects of alcohol abuse are well known. Our hypothesis was that uncontrolled alcohol consumption may cause cerebrovascular damage detectable by rheoencepholography (REG), a noninvasive bio-impedance technique for estimating cerebral blood flow. Test subjects were 48 alcoholic patients in Hungary; the control group consisted of 12 drug-addicted and depressed patients in Hungary and 13 healthy male subjects in the United States. Additional subgroups were formed according to smoking habits and average daily alcohol dose. REG was measured by a computer-based system, "Cerberus"; REG anacrotic time above 180 ms was considered pathological. ANOVA showed that daily alcohol consumption and smoking were significantly higher in alcoholics than in drug-addicted and depressed patients. Twelve alcoholics showed a pathological REG anacrotic time. Longer REG anacrotic time was correlated with higher daily alcohol consumption. In the alcoholic group, the steeper regression line of REG slope reflected the pathological impact of alcohol abuse. The healthy control sample showed a nearly identical slope for both REG and age. The correlation of increased REG anacrotic time and daily alcohol consumption supports the hypothesis that REG detects accelerated cerebrovascular aging (arteriosclerosis) in alcoholic subjects.

Cerebrovascular alteration in alcoholic patients

For most people who drink alcohol, the substance is viewed as a pleasant accompaniment to social activities. Moderate alcohol use (in general, two drinks per day for men and one drink per day for women and older people) is not harmful and protects against arteriosclerosis. However, uncontrolled alcohol consumption causes mental and somatic problems 1. Psychological and somatic variables were measured to establish possible correlations with cerebrovascular alterations due to alcoholism. Cerebrovascular alteration was estimated by rheoencepholography (REG) 2, a noninvasive bio-impedance technique acknowledged by the U.S. Food and Drug Administration as a tool for estimating cerebral blood flow 3. Jenkner 4 established the arteriosclerotic standard of REG. Our hypothesis was that uncontrolled alcohol consumption may cause cerebrovascular damage detectable by REG. The test subjects were 48 alcoholic patients in Hungary; the control group consisted of 12 drug-addicted and depressed patients in Hungary and 13 healthy male subjects in the United States. Subjects were subdivided into young and older subgroups (below and above 40 years). A REG anacrotic time above 180 ms was considered pathological. Four additional subgroups were formed according to smoking habits and average daily alcohol dose. Compared to alcoholic subjects, drug-addicted patients showed significantly shorter REG anacrotic time. Twelve alcoholics showed a pathological REG value. ANOVA showed that daily alcohol consumption and smoking were significantly higher in alcoholics than in drug patients or patients with depression. Factor analysis of variables showed gender differences. Three factors were found both for males (cumulative%= 64.86) and females (75.56): factor 1 - age and REG anacrotic time (males) and age with vegetative indexes (females); factor 2 - daily alcohol and cigarette consumption for both genders; factor 3 - REG and vegetative index (males). Longer REG anacrotic time was correlated with higher daily alcohol consumption (r = 0.683, p = 0.007) in a subgroup (n = 12). For all subjects, physiological cerebrovascular aging was expected to show an identical slope with age. However, in the Hungarian alcoholic group, the sharper REG slope: 36.68 vs. age: 0.56 (ratio: 64.39) reflected the pathological impact of alcohol abuse. The U.S. control sample showed a nearly identical slope for both REG (1.79) and age (3.45; ratio: 0.52). The correlation of increased REG and daily alcohol consumption supports the accelerated cerebrovascular aging (arteriosclerosis) of the alcoholic subjects. Further study will be performed to exclude greater Hungarian cardiovascular risk factors, which may influence the increased REG anacrotic time.

Use of rheoencephalography for primary stroke prevention

Stroke is the third leading cause of death worldwide and the most frequent cause of brain damage in adults. Screening for arteriosclerosis at an early stage of disease could detect high-risk individuals and populations before the onset of stroke. Doppler ultrasound, the traditional method to detect carotid disease, is expensive and difficult to administer on a large scale. The aim of this study was to test the applicability of a computerized screening system utilizing rheoencephalography (REG) to identify individuals at high-risk for stroke. REG estimates cerebrovascular alteration caused by arteriosclerosis, expressed as the elongated rise time of the REG pulse wave. Methodology was previously published 1, 2. Data were collected in a rural area (Hungary) using the computerized screening system to record risk factors for arteriosclerosis, including a history of transient ischemic attack. Carotid flow (CF) data measured by Doppler ultrasound were also collected for comparison. A cross-sectional survey was conducted for 546 people (REG, N=390; CF, N=252). Subjects' blood chemistry data and EKG were also assessed. In evaluating elasticity of brain arteries, the REG standard originally established by Jenkner was modified. A REG peak time of 180 ms or above (CF: mean velocity above 40 cm/sec) was considered a cerebrovascular alteration 3. REG and Doppler (CF) data: sclerotic brain arteries estimated by REG were 52.78% (m) and 55.8% (f). Pathologic CF was 29.41% (m) and 39.08% (f). The regression lines of age versus REG rise time and CF in male and female groups were similar, but the slope of REG was about ten times steeper than that of CF 1, 4. Brain vessel responses (CBF autoregulation) have been found to be size dependent. Previous results support the hypothesis that REG reflects CBF autoregulation (arteriolar functioning). Animal studies have shown that REG may reflect CBF autoregulation more accurately than Doppler. These results are consistent with REG literature indicating that an increase in REG rise time indicates decreased arteriolar elasticity. REG rise time may be the earliest sign of cerebrovascular sclerosis, indicating the presence of disease at an earlier stage than Doppler. The computerized system utilizing REG is simple to administer, non-invasive, cheap, and has potential as a tool for mass screenings of target populations.

NADPH oxidase-derived free radicals mediate neurovascular dysfunction in models of Alzheimer's disease

Overproduction of the amyloid (A) peptide is a key factor in the pathogenesis of Alzheimer's disease (AD), but the mechanisms of its pathogenic effects have not been defined. Patients with AD have cerebrovascular alterations attributable to the deleterious effects of A on cerebral blood vessels. Furthermore, mice overexpressing the amyloid precursor protein (APP) have marked alterations in the cerebrovasodilation produced by neural activity (functional hyperemia). Experimental evidence suggests that these cerebrovascular alterations are mediated by reactive oxygen species (ROS). However, the source of the ROS mediating the dysfunction has not been defined. NADPH oxidase has recently emerged as a major source of ROS at the vascular level. In this study we tested the hypothesis that NADPH-derived ROS mediate the vascular dysfunction produced by A.

Magnetic resonance imaging in experimental subarachnoid haemorrhage

We developed an MRI protocol to measure cerebrovascular diameter and blood flow velocity, and if we could detect cerebrovascular alterations after SAH and their impact on cerebral ischaemia. SAH was induced in 15 Wistar rats by means of the endovascular filament method; 6 other rats served as control. MRI measurements were performed on a 4.7T NMR spectrometer 1 and 48 hours after SAH and 9 days thereafter. Diffusion-weighted and T2-weighted images were acquired to detect cerebral ischaemia. The arterial spin labelling method was used to measure CBF. MR angiography was used to measure vessel diameter and blood flow velocity, from which the arterial blood flow was calculated. The ischemic lesion volume increased between 1 and 48 hours after SAH from 0.039 to 0.26 ml (P = 0.003). CBF decreased from 53.6 to 39.1 ml/100 g/min. The vessel diameter had narrowed, the blood flow velocity diminished as did the arterial blood flow in most vessels, but only the vasoconstriction in the right proximal ICA reached significance (0.49 mm to 0.43 mm, P = 0.016). Baseline values were restored at day 9. We showed that it is feasible to detect alterations of in-vivo vessel diameter and blood flow velocities and their consequences for brain damage after experimental SAH in the rat. The growth of the infarct volume between day 0 and 2 after SAH and the parallel vasoconstriction suggest that delayed cerebral ischaemia after SAH occurs in rats and that this may be caused by vasoconstriction.

Changes in the intracranial rheoencephalogram at lower limit of cerebral blood flow autoregulation

Cerebral blood flow (CBF) reactivity monitoring is an appropriate primary parameter to evaluate cerebral resuscitation due to a systemic or regional cerebral injury leading to possible irreversible brain injury. Use of the electrical impedance method to estimate CBF is rare, as the method's anatomical background is not well understood. Use of intracranial rheoencephalography (iREG) during hemorrhage and comparison of iREG to other CBF measurements have not been previously reported. Our hypothesis was that iREG would reflect early cerebrovascular alteration (CBF autoregulation). Studies comparing iREG, laser Doppler flowmetry and ultrasound were undertaken on anesthetized rats to define CBF changes during hemorrhage. Blood was removed at a rate required to achieve a mean arterial blood pressure (MABP) of 40 mm Hg over 15 min. Estimation of CBF was taken with intracranial, bipolar REG (REG I; n = 14), laser Doppler flowmetry (LDF; n = 3) and carotid flow by ultrasound (n = 11). Data were processed off-line. During the initial phase of hemorrhage, when MABP was close to 40 mm Hg, intracranial REG amplitude transiently increased (80.94%); LDF (77.92%) and carotid flow (52.04%) decreased and changed with systemic arterial pressure. Intracranial REG amplitude change suggests classical CBF autoregulation, demonstrating its close relationship to arteriolar changes. The studies indicate that iREG might reflect cerebrovascular responses more accurately than changes in local CBF measured by LDF and carotid flow. REG may indicate promise as a continuous, non-invasive life-sign monitoring tool with potential advantages over ultrasound, the CBF measurement technique normally applied in clinical practice. REG has particular advantages in non-hospital settings such as military and emergency medicine.

NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid β Peptide

Overproduction of the amyloid beta (Abeta) peptide is a key factor in the pathogenesis of Alzheimer's disease (AD), but the mechanisms of its pathogenic effects have not been defined. Patients with AD have cerebrovascular alterations attributable to the deleterious effects of Abeta on cerebral blood vessels. We report here that NADPH oxidase, the major source of free radicals in blood vessels, is responsible for the cerebrovascular dysregulation induced by Abeta. Thus, the free-radical production and the associated alterations in vasoregulation induced by Abeta are abrogated by the NADPH oxidase peptide inhibitor gp91ds-tat and are not observed in mice lacking the catalytic subunit of NADPH oxidase (gp91phox). Furthermore, oxidative stress and cerebrovascular dysfunction do not occur in transgenic mice overexpressing the amyloid precursor protein but lacking gp91phox. The mechanisms by which NADPH oxidase-derived radicals mediate the cerebrovascular dysfunction involve reduced bioavailability of nitric oxide. Thus, a gp91phox-containing NADPH oxidase is the critical link between Abeta and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD patients.