Autoregulation of cerebral blood flow to changes in arterial pressure in mild Alzheimer's disease

Studies in transgenic mice overexpressing amyloid precursor protein (APP) demonstrate impaired autoregulation of cerebral blood flow (CBF) to changes in arterial pressure and suggest that cerebrovascular dysfunction may be critically important in the development of pathological Alzheimer''s disease (AD). Given the relevance of such a finding for guiding hypertension treatment in the elderly, we assessed autoregulation in individuals with AD. Twenty persons aged 75±6 years with very mild or mild symptomatic AD (Clinical Dementia Rating 0.5 or 1.0) underwent ¹⁵O-positron emission tomography (PET) CBF measurements before and after mean arterial pressure (MAP) was lowered from 107±13 to 92±9 mm Hg with intravenous nicardipine; ¹¹C-PIB-PET imaging and magnetic resonance imaging (MRI) were also obtained. There were no significant differences in mean CBF before and after MAP reduction in the bilateral hemispheres (−0.9±5.2 mL per 100 g per minute, P=0.4, 95% confidence interval (CI)=−3.4 to 1.5), cortical borderzones (−1.9±5.0 mL per 100 g per minute, P=0.10, 95% CI=−4.3 to 0.4), regions of T2W-MRI-defined leukoaraiosis (−0.3±4.4 mL per 100 g per minute, P=0.85, 95% CI=−3.3 to 3.9), or regions of peak ¹¹C-PIB uptake (−2.5±7.7 mL per 100 g per minute, P=0.30, 95% CI=−7.7 to 2.7). The absence of significant change in CBF with a 10 to 15 mm Hg reduction in MAP within the normal autoregulatory range demonstrates that there is neither a generalized nor local defect of autoregulation in AD.     

Raised intracranial pressure and cerebral blood flow: 4. Intracranial pressure gradients and regional cerebral blood flow

Intracranial pressure was raised by expansion of a supratentorial subdural ballon in anaesthetized baboons. Pressures were measured at several sites, both supratentorial and infratentorial, and cerebral blood flow was measured in each cerebral hemisphere separately. Pressures recorded from the right and left lateral ventricles corresponded closely throughout. Highly significant correlations were also obtained between the pressures in the right and left subdural spaces and the mean intraventricular pressure. There was, thus, no evidence of intracompartmental pressure gradients within the supratentorial space. Pressure gradients did, however, develop between the supratentorial and infratentorial compartments in the majority of experiments, although the level of supratentorial pressure at which this occurred, varied. Despite the presence of a large mass lesion over the right cerebral hemisphere, no significant differences developed between levels of cerebral blood flow in the two hemispheres, although flow in the right hemisphere remained consistently slightly lower than that in the left after the ballon was inserted.     

Correlation between dominant EEG frequency, cerebral oxygen uptake and blood flow.

In 32 chronic patients the EEG in temporal and occipito-parietal bipolar leads was analyzed with a manual method giving a period frequency index. The cerebral oxygen uptake (CMRO2) was calculated from the arteriovenous oxygen difference between samples from the internal carotid artery and the jugular bulb respectively, and from measurement of cerebral blood flow with the 133Xenon clearance method. A strong correlation (r = 0.78, P less than 0.001) was found between the EEG frequency indices and the CMRO2 of the hemisphere from which the EEG was recorded. Significant correlations between the EEG indices and gray matter cerebral blood flow were also demonstrated, while the correlation between the EEG indices and the blood flow of the white matter was weak. No correlation at all was found between the EEG indices and the relative weight of the gray matter. We conclude that the EEG carries information about the metabolic activity of the brain tissue. The EEG frequency also correlates with the blood flow of the gray matter of the brain when tissue anoxia has not uncoupled the normal function--flow relationship prevailing in the brain.     

Regional differences in the cerebral blood flow velocity response to hypobaric hypoxia at high altitudes

Symptoms of acute mountain sickness (AMS) may appear above 2,500 m altitude, if the time allowed for acclimatization is insufficient. As the mechanisms underlying brain adaptation to the hypobaric hypoxic environment are not fully understood, a prospective study was performed investigating neurophysiological changes by means of near infrared spectroscopy, electroencephalograpy (EEG), and transcranial doppler sonography at 100, 3,440 and 5,050 m above sea level in the Khumbu Himal, Nepal. Fourteen of the 26 mountaineers reaching 5,050 m altitude developed symptoms of AMS between 3,440 and 5,050 m altitude (Lake-Louise Score ⩾3). Their EEG frontal beta activity and occipital alpha activity increased between 100 and 3,440 m altitude, i.e., before symptoms appeared. Cerebral blood flow velocity (CBFV) in the anterior and middle cerebral arteries (MCAs) increased in all mountaineers between 100 and 3,440 m altitude. During further ascent to 5,050 m altitude, mountaineers with AMS developed a further increase in CBFV in the MCA, whereas in all mountaineers CBFV decreased continuously with increasing altitude in the posterior cerebral arteries. These results indicate that hypobaric hypoxia causes different regional changes in CBFV despite similar electrophysiological changes.     

Correlation between regional cerebral blood flow and EEG frequency in the contralateral hemisphere in acute cerebral infarction.

The relationship between the rCBF and the electroencephalographic (EEG) frequency was investigated in the contralateral hemisphere of 22 patients with acute cerebral infarction. Reduced rCBF was observed in all patients studied. The degree of rCBF reduction was mild, moderate, or severe and ranged between 6 and 80% from the lowest age-matched normal values obtained in our laboratory. The frequency indices remained within normal limits (mean - 10.4 Hz) in 16 patients. Slower frequencies (mean - 6.3 Hz) were recorded in 6 patients. No correlation was found between the two parameters (P = 0.89). Both the EEG frequency and the rCBF are known to be closely related to the cerebral metabolic rate. The observed rCBF depression without concomitant changes in the EEG frequency raises the question of the role of globally-reduced cerebral metabolism as the cause of rCBF reduction in the noninfarcted hemisphere in stroke patients. Our findings constitute additional evidence that the contralateral hemisphere is involved in the haemodynamic changes occurring in acute cerebral infarction.     

Mechanisms underlying phase lag between systemic arterial blood pressure and cerebral blood flow velocity

To explore the mechanisms underlying the phase lag between oscillations in arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV), ABP and CBFV signals were recorded noninvasively from normal volunteers who lay quietly in a supine position. Mean ABP (MAP) and CBFV (MFV) were calculated beat-to-beat by means of integration. Cerebral vascular resistance (CVR) was calculated by dividing MAP with MFV. Frequency domain analysis of MAP, MFV and CVR signals revealed very-low frequency (VLF, 0.016-0.04 Hz), low-frequency (LF, 0.04-0.15 Hz), and high-frequency (HF, 0.15-0.4 Hz) components. The transfer phase of MAP-CVR coupling in the LF and HF range was frequency-dependent, which is equivalent to a time delay of 2 s. However, the transfer phase differed in the CVR-MFV coupling in that the phase was distributed around 180 degrees across the LF and HF ranges. Cross-correlation analysis revealed a positive relationship between MAP-CVR coupling, with MAP leading by 2 s, and a negative relationship between CVR-MFV coupling, with CVR leading by 0.3 s. We concluded that the phase lag between oscillations in ABP and CBFV was chiefly contributed to by the starting latency of cerebral autoregulation (i.e. cerebral vasomotion, revealed by MAP-CVR coupling). Moreover, the negative correlation of the CVR-MFV coupling could offer a different explanation for the physiologic significance of the phase lead of CBFV-ABP oscillations.     

Continuous comparison of cerebral blood flow velocity and volume on hypoxia.

Cerebral blood flow velocity (CBFV) in the basilar artery, monitored by Doppler sonography, and cerebral blood flow (CBF) in the parietal cortex, monitored by Laser Doppler flowmetry, were continuously recorded and compared during and after hypoxic loading with nitrogen (N2) or carbon dioxide (CO2). On severe hypoxic loading (10% O2) of N2, CBFV and CBF increased with an increase in blood pressure (BP). On the other hand, with 18% and 15% O2 with CO2, CBFV and CBF increased with BP. However, there was a difference between CBF and CBFV in the recovery stage. CBF continued to be elevated for a long time, while CBFV rapidly normalized after loading. With 10% O2 with CO2, CBFV, CBF and BP decreased at first, and then increased during loading. Also, the difference between CBF and CBFV in the recovery stage being more definite. Thus, on continuous measurement, CBFV shows similar changes to CBF in response to hypoxia. However, CBFV shows different changes from CBF in association with dilatation or constriction of cerebral vessels. Resistance index (RI) shows different changes and have a different significance from CBF and CBFV.     

Relation between middle cerebral artery blood flow velocity and stump pressure during carotid endarterectomy.

BACKGROUND AND PURPOSE: Many patient monitoring techniques have been used for detecting cerebral hypoperfusion during carotid endarterectomy. We compared middle cerebral artery blood flow velocities with carotid artery stump pressures to evaluate the indications for common carotid artery cross-clamp shunting and the probable hemodynamic causes of cerebrovascular complications. METHODS: Blood flow velocities were monitored with transcranial Doppler ultrasound and carotid stump pressures were measured at the time of common carotid artery cross-clamping during 97 carotid endarterectomy procedures. Stump pressures measured with the gauge zero reference at the common carotid artery level were correlated with the percentage change of velocities. RESULTS: Middle cerebral artery blood flow velocities usually decreased upon common carotid artery cross-clamping, depending on collateral availability and the autoregulation response. The best fit of the data was to an exponential function concave to the pressure axis, with velocity as a percentage of the pre-cross-clamp value reaching zero at 15 mm Hg stump pressure (r = 0.85 and p less than 0.001). CONCLUSIONS: There is a less critical margin of error with percentage middle cerebral artery blood flow velocity decreases than with stump pressure measurements. This relation establishes changes in middle cerebral artery blood flow velocities as a reliable parameter for judging the effects of carotid cross-clamping on cerebral blood flow and providing an excellent indicator as to the necessity for shunting.     

Relationship between psychiatric symptoms and regional cerebral blood flow in patients with mild Alzheimer's disease

Background: Behavioral and psychological symptoms of dementia (BPSD) are frequently observed in patients with dementia and often cause serious problems. However, the cause of BPSD has not yet been elucidated. Moreover, the precise evaluation of BPSD in mild dementia has not been studied in any great detail. In the present study, we investigated the relationship between psychiatric symptoms and regional cerebral blood flow (rCBF) in patients with mild Alzheimer's disease (AD). Methods: The present study included 47 patients (20 men and 27 women) who were diagnosed with mild AD. Mean patient age was 72.8 ± 8.2 years. Single photon emission computed tomography (SPECT) with ^99mTc‐ethyl cysteinate dimer (^99mTc‐ECD) was performed in all patients. The SPECT data were analyzed using a three‐dimensional stereotactic region of interest template, which evaluated CBF in 24 segments. Psychiatric symptoms were evaluated in patients using the Brief Psychiatric Rating Scale. Each psychiatric symptom was designated as ‘symptom present’ in cases in which the BPRS item score was more than 3. We compared 10 segments of rCBF in symptom‐present patients with those in symptom‐absent patients. Results: Motor retardation was the most common psychiatric symptom (36.2%), followed by depression (19.1%), anxiety (17.0%), emotional withdrawal (17.0%), and somatic concern (14.9%). Alzheimer's disease patients with motor retardation exhibited a tendency towards lower rCBF in seven segments (left callosomarginal, bilateral parietal, bilateral angular, and bilateral temporal). However, no specific tendency was observed in depression, anxiety, and somatic concern. Conclusions: In the present study, we observed a tendency for decreased brain perfusion in patients with motor retardation. Further studies are necessary to confirm that this trend contributes to the appearance of psychiatric symptoms in patients with mild AD.     

Cerebral blood flow velocities in the anterior cerebral arteries and basilar artery. II. Investigation in very low birth weight infants

We studied the values of the Pourcelot's index of resistance in the anterior cerebral artery (RI-ACA) and basilar artery (RI-BA) in very low birth weight infants weighing less than 1,500 g at birth. At the time of measurements, their postconceptional ages were 32, 34, 36, 38, 40 and 42 weeks. The mean value of RI-ACA (0.744 +/- 0.026, +/- SD) was significantly lower than that of RI-BA (0.766 +/- 0.026) (p less than 0.001), and they were higher than those in normal term infants. However, the mean value of RI-ACA and RI-BA, averaged from the measurements of postconceptional ages at 38, 40 and 42 weeks, showed no significant difference from those of normal term infants. In contrast, the mean value of RI ratio (= RI-ACA/RI-BA) in very low birth weight infants showed no significant difference from that of normal term infants.     

A common origin of the very low frequency heart rate and blood pressure variability--a new insight into an old debate

The purpose of this study was to assess the exact temporal and amplitude relationship between very low frequency heart rate variability waves and very low frequency blood pressure variability waves. We developed a computerized system based on a modified proportional-integral controller for the controlled increase of heart rate by isoproterenol. Heart rate and blood pressure were measured continuously in conscious tethered rats. Using time domain methods, we found that the very low frequency heart rate variability waves and the very low frequency blood pressure variability waves are irregular, while at the same time strikingly 1:1 synchronized with each other. In 78% of the cases, the phase between the peaks of the very low frequency heart rate variability waves and very low frequency blood pressure variability waves was negative (blood pressure leads). Their amplitudes were linearly related with a degree of hysteresis. As blood pressure went up, heart rate went down. Our results suggest with a high degree of probability that the very low frequency heart rate variability waves do not cause very low frequency blood pressure variability waves, and that these two signals are probably driven by the same autonomic nervous system controller/oscillator.     

Effect of carotid ligation on cerebral blood flow in baboons: 2. Response to hypoxia and haemorrhagic hypertension

Cerebral blood flow (CBF) measurements were carried out in two groups of anaesthetized normocapnic baboons. In the first group of five animals the effect of hypoxia on the CBF before and after ipsilateral carotid artery ligation was studied. The results showed that, although after ipsilateral carotid ligation there was little change in the CBF at normal PaO₂, at hypoxia there was only 20% rise in the CBF as compared with an 80% rise before the carotid ligation. In the second group of 10 animals, effects of haemorrhagic hypotension on the CBF after ipsilateral carotid artery ligation were estimated. The results indicated impairment of autoregulatory response of the cerebral circulation.     

Raised intracranial pressure and cerebral blood flow. 5. Effects of episodic intracranial pressure waves in primates.

The effects of episodic waves of intracranial pressure on cerebral blood flow were studied in primates. Six pressure waves each of 20 minutes' duration and ranging from 50 to 100 mmHg in magnitude were induced in baboons, at intervals of 30 minutes, in an attempt to simulate clinical plateau waves. With pressure waves up to 75 mmHg, cerebral blood flow remained at control levels despite falling cerebral perfusion pressures. Between the initial pressure waves a marked hyperaemia developed, with cerebral blood flow increasing by as much as 100%, and this appeared to be a means whereby adequate flow was maintained during pressure waves. Later pressure waves, up to 100 mmHg, eventually reduced blood flow below control levels, although moderately high flows were maintained during periods of very low perfusion pressure. Brain metabolism was affected by eht episodic pressure waves, although no consistent change was seen.     

Spectral analysis of arterial blood pressure and cerebral blood flow velocity during supine rest and orthostasis.

This study evaluates the effect of orthostasis on the low frequency (LF, 0.04 to 0.15 Hz) fluctuations in the blood flow velocity of the middle cerebral artery (MCAFV) in relation to its arterial blood pressure (ABP) equivalent to further define and quantify this relationship in cerebrovascular regulation. Spectral analysis was performed on 22 healthy subjects during supine rest and head-up tilt. The power in the LF range can be used to quantify the LF fluctuations, and four types of LF power data could be obtained for each individual: LF power of supine MCAFV, LF power of supine ABP, LF power of tilt MCAFV, and LF power of tilt ABP. By comparing LF power of MCAFV with LF power of ABP, two power ratios could be generated to describe the flow-pressure relationship during supine rest and head-up tilt, respectively, supine power ratio (LF power of supine MCAFV/ LF power of supine ABP) and tilt power ratio (LF power of tilt MCAFV/ LF power of tilt ABP). In addition, an index for dynamic autoregulation in response to orthostasis can be calculated from these two power ratios (tilt power ratio/supine power ratio). The authors found that this index was dependent on the extent of orthostatic MCAFV changes, and the dependency could be mathematically expressed (r = 0.61, P = .0001), suggesting its involvement in cerebrovascular regulation. Moreover, these data further support the previous observation that the LF fluctuations of MCAFV might result from modulation of its ABP equivalent, and the modulation effect could be quantified as the power ratio (LF power of MCAFV/ LF power of ABP). These observations could be an important step toward further insight into cerebrovascular regulation, which warrants more research in the future.     

易卒中型肾血管性高血压大鼠的脑血流自动调节下限与最低耐受压

目的　研究易卒中型肾血管性高血压大鼠 (RHRSP)的脑血流 (CBF)自动调节下限及其最低耐受压。　　方法　用氢清除法测定RHRSP和正常SD大鼠在不同低血压水平时 ,一侧顶枕交界区皮质和海马的局部CBF(rCBF) ;72小时后计算RHRSP和SD大鼠海马CA1 区神经细胞 (CA1 NC)线粒体的体密度 (Vv)、比表面 (δ)、平均体积 ( V)和数密度 (Nv) ,　　 结果　正常SD大鼠在平均动脉压 (MABP)为 1 0 67kPa、9 3 3kPa和 8kPa时 ,rCBF值无显著减少。在MABP为 1 0 67kPa时 ,RHRSP的rCBF值显著减少 ;超微结构观察发现CA1 NC无明显缺血改变 ,当MABP为 9 3 3kPa时 ,CA1 NC缺血明显 ;细胞形态分析发现 9 3 3kPa组与 1 0 67kPa组比较 ,前者线粒体的Vv和 V显著增大 ,δ和Nv显著减小。　　结论　RHRSP的CBF自动调节下限上移至 1 0 67kPa,并与其最低耐受压十分接近 ,表明RHRSP是一种研究高血压脑血管损害较理想的动物模型