Cerebral artery stenosis is an independent and important risk factor for ischemic stroke, and cerebral artery stenting is an important treatment for cerebral artery stenosis and is recommended as a non-pharmacological treatment for secondary prevention of stroke [1], and stenting after cerebral artery stenosis has been increasing in China in the last 5 years, and according to preliminary statistics more than 30,000 cases of cerebral artery stenting were performed in China in 2009. Currently in research and clinical work, the degree of stenosis of cerebral arteries is the main inclusion criteria and surgical indication for stenting [1,2,3]. However, the impairment of cerebral circulation function is not solely due to stenosis, and studies have shown that some cerebral arteries with severe stenosis have good cerebrovascular reserve (CVR) do not have a high incidence of stroke, whereas those with poor CVR can have cerebral ischemic events as high as 32.7%/year [4], and Yamamoto KK reported that patients with severe carotid stenosis had only Yamamoto KK reported that only 60% of patients with severe carotid stenosis had a reduced CVR, and also found that the risk of stroke was significantly increased in patients with impaired CVR compared to those with normal CVR [5]. Therefore, it is necessary to perform CVD detection and evaluation to screen out those patients with truly high-risk cerebral artery stenosis, especially those who are to undergo endovascular cerebral intervention. Shi Jin, Department of Neurology, Air Force General Hospital
Cerebrovascular reserve capacity refers to the ability of cerebral blood vessels to maintain normal and stable cerebral blood flow under physiological or pathological conditions through the regulation of vasodilation and contraction. When cerebral artery stenosis may cause cerebral hypoperfusion, cerebral blood vessels will ensure the stability of cerebral blood flow (CBF) through two compensatory responses, namely vasodilation and opening of collateral circulation. The brain tissue also maintains oxygen metabolism by increasing oxygen uptake, which is reflected by an increase in oxygen extraction fraction (OEF). The evaluation of CVR should also focus on cerebral metabolic reserve and collateral circulation compensation.
1. Detection and study of CVR
The cerebral resistance vessels are dilated to detect the maximum increase in CBF. Commonly used cerebral vasodilatation methods include: (1) breath-hold test, in which the subject holds his breath to increase the concentration of CO2 in the blood and cause cerebral vasodilation. ②C02 inhalation test, inhalation of C02 and O2 gas mixture to achieve the purpose of cerebral vasodilation. ③Acetazolamide test, acetazolamide can inhibit the carbonic anhydrase of red blood cells and can cross the blood-brain barrier, thus causing an increase in the concentration of C02 in brain tissue and blood, which causes cerebral resistance vasodilation in a highly selective manner. ④ Other methods include the fist-clenching method, dipyridamole and nitroglycerin vasodilation, which are not commonly used. It is generally considered that the breath-hold test is the easiest; inhalation of C02 can better dilate cerebral blood vessels, but there are more interfering factors and reliability is affected; acetazolamide is metabolized faster in vivo and does not affect cerebral oxygen consumption, and the effect of dilating cerebral blood vessels is stronger during the acetazolamide test [6], which is more reliable, but its effect is related to the dose, the time of cerebral blood flow measurement after drug administration, gender, age, and the subject’s individual physical condition and many other However, its effect is related to a variety of factors such as dose, time of cerebral blood flow measurement after administration, gender, age, and the subject’s individual physical condition.
There are four types of cerebrovascular reactivity to C02: Type A: CBF is normal before and after cerebrovascular dilation, suggesting good CVR; Type B: CBF is normal before dilation, but new areas of reduced perfusion appear after dilation, suggesting compensatory dilation of cerebrovascular vessels and poor CVR; Type C: CBF is reduced before dosing, and reduced more obviously after dosing, suggesting insufficient collateral circulation; Type D: local cerebral blood flow is reduced at rest, but improves after dosing, suggesting insufficient collateral circulation. Type D: local cerebral blood flow is reduced at rest and improves after drug administration, suggesting inadequate collateral circulation, but vascular reactivity is intact.
The main imaging methods commonly used to detect CVR are: positron emission tomography (PET), single photon emission tomography (SPECT), magnetic resonance techniques, xenon CT, perfusion CT, transcranial Doppler (TCD), laser Doppler flowmetry, and near-infrared spectral analysis. Most of these tests use mathematical models to calculate cerebral hemodynamic parameters such as CBF, cerebral blood volume (CBV), mean transit time (MTT), OEF, etc. PET can cover the whole brain, with a spatial resolution of 4-6 mm, high accuracy, and can detect the metabolic function of the brain, and is considered the best index for CBF and local oxygen uptake fraction detection [7], but due to the complexity of the equipment, high cost of the examination, and certain SPECT is a more commonly used method for semi-quantitative determination of perfusion parameters and can reflect the percentage decrease in local cerebral blood flow, but SPECT has a lower resolution and is also somewhat radioactive [8]. Magnetic resonance technology can detect ischemic lesions early, distinguish intracellular edema from extracellular edema, has high spatial resolution, is radiation-free, and can reflect the morphological structure of both brain tissue and blood vessels, so it is gradually gaining attention in clinical practice. Xenon CT is well defined for cerebral blood flow in the cortex, subcortex, and basal nucleus, and even very low cerebral blood flow can be measured, and the equipment is popular, but Xe-CT is a single-parameter imaging and can only calculate CBF, unlike PET, and cannot perform the observation of cerebral metabolic levels, in addition, changes in patient position can cause inaccurate results, and Xe is a radioactive gas, which has a certain impact on the subject and the environment [9], and is currently considered a promising means of detection. Perfusion CT can detect the CVR of anterior and posterior circulation with high image resolution and visualize the degree of compression, deformation and occlusion of the microvascular lumen in the ischemic area, and this test has been carried out in China, but some people believe that relying on the parameters measured by perfusion CT to assess the impaired CVR is unreliable [10], and artifacts can exist when the patient has dentures and cranial metal objects, and allergy may occur when the contrast agent is allergic.TCD is simple, noninvasive, Real-time and more reliable, it is the most widely used CVR detection method at home and abroad, but TCD cannot directly measure cerebral blood flow, and its accuracy is affected by various factors such as bone window, probe angle, and operator, and TCD cannot accurately detect the lower limit of cerebrovascular reserve function, so this technique still needs further improvement [11]. Some other testing methods are still being explored.
The hemodynamics of cerebral vascular stenosis can be divided into three phases by CVR assay: phase 0, normal hemodynamic state; phase 1, reflex vasodilation due to decreased perfusion pressure and insufficient collateral circulation, when blood volume increases and MTT is prolonged, but CBF and OEF remain unchanged; (3) phase 2, insufficient perfusion, decreased CBF and increased OEF.
Studies on CVR have been conducted for more than 20 years, and the importance of CVR detection for ischemic stroke is gradually recognized, but there are still some problems regarding the detection and study of CVR: (1) how many patients with cerebral artery stenosis have abnormal CVR, and how high the risk of ischemic stroke is in those with normal CVR in cerebral artery stenosis lacks information from large samples. (ii) There are many methods of CVR evaluation, and studies with CVR are often limited to a particular method, with few studies or small sample sizes of correlation between various methods, and even conflicting ones. ③There is not yet a rapid, safe, accurate, easy, and continuous means of monitoring changes in CVR. ④CVR evaluation is rarely used as a reference index before and after endovascular treatment of cerebral artery stenosis.
2. Evaluation of the collateral circulation
The collateral circulation of cerebral vessels is abundant, mainly including the collateral circulation between the intracranial and extracranial arteries and between the intracranial arteries.
The Willis loop is the most important of all the collateral circulation, because the presence of the Willis loop allows the anterior, posterior, left and right arteries of the brain to communicate, and some severe stenosis or even occlusion of the internal carotid artery or vertebral artery may be asymptomatic in clinical practice. However, not all people have complete Willis rings. In some people, the A1 segment of the anterior and posterior communicating arteries or the anterior cerebral artery may be missing or poorly developed and cannot play an effective role in communication, and in addition, the Willis rings cannot play a compensatory role in cerebral artery lesions after the Willis rings.
The most common collateral circulation between the intracranial and external arteries is the traffic between the superficial temporal artery, a branch of the external carotid artery, and the internal carotid artery through the ophthalmic artery, which often occurs when the ipsilateral internal carotid artery is occluded; the anastomosis between the soft meningeal arteries of the branches of the external carotid artery and the anterior, middle, and posterior cerebral arteries, and also the anastomosis of some other small arteries inside and outside the skull. They play a minor role under normal conditions, but may play a considerable role in cases of severe stenosis or occlusion of the internal carotid artery or vertebral artery.
Anastomoses between the uncinate branches of the anterior, middle, and posterior cerebral arteries, between the vertebral artery and the external carotid artery, and between the vertebral artery and other branches of the subclavian artery also play a compensatory role to varying degrees under different circumstances.
Some vascular variants also produce collateral compensations in specific cases, such as the immortal trigeminal artery, the auricular artery, and the subglottic artery, which can produce anastomoses of the anterior and posterior circulation.
When cerebral artery stenosis or occlusion causes decreased cerebral perfusion, the collateral branches can rapidly compensate. After cerebral artery stenosis or occlusion, the degree of collateral circulation compensation is closely related to CVR and prognosis. It has been reported that in patients with carotid artery occlusion, such as those with insufficient compensation or absence of anterior and posterior communicating arteries, CVR is significantly lower than those with intact collateral circulation, and prognosis is also significantly worse [12].
The collateral circulation of the cerebral arteries is complex and varies greatly among individuals, and morphological detection is currently performed mainly by imaging.DSA is the most effective method for evaluating collateral compensation after ischemic lesions of the cerebral arteries, but MRA with CTA is more advantageous for the integrity of the ring of Willis, and vascular ultrasound also plays a role. In determining the presence of anterior and posterior communicating arteries, TCD or DSA after compression of one side of the carotid artery will be better to detect if the patient’s condition allows.
The current evaluation of collateral circulation is still mainly limited to larger vessels, or the presence of large communicating arteries. When the vessel is acutely occluded, the collateral circulation is generally not yet sufficient for immediate and complete compensation. However, it is not clear whether the collateral circulation is originally capable of this, or whether there is a process of vasodilatation, whether there are still some new small vessels generated, how long this process takes, how much potential for different individuals to generate this collateral circulation, whether the CVR is variable after cerebral stenosis, and how long this change takes. etc. These deserve further study.
3. Detection and study of metabolic reserve power of the brain
When the CVR is damaged, the metabolic reserve comes into play to ensure the demand for oxygen and glucose and other nutrients in the brain tissue.
The evaluation of oxygen metabolism is mainly performed by PET on oxygen metabolism status, and there are few studies in this area in China. Studies have shown that when CBV increases with normal OEF in cerebral artery stenosis, it indicates that compensatory vascular dilation can still maintain oxygen supply to brain tissue without ischemic symptoms, and when cerebral blood flow decreases further OEF starts to increase, and in order to maintain normal metabolism and nerve cell function, OEF can increase from 30% to 80% in the basal state [13].Kenichiro Y through acetazolamide excitation trial investigated the correlation between metabolic reserve and vascular reserve after cerebral artery occlusion using PET assay and concluded that a significant increase in OEF, an indicator of metabolic reserve, begins at CBV/CBF ≥ 0.11 min in the cerebral hemisphere [14]. It has also been shown that a mild decrease in cerebral perfusion pressure can lead to an increase in OEF, that there is a negative linear relationship between cerebrovascular reserve capacity and OEF, that when OEF is elevated, cerebrovascular reserve capacity decreases, and that when OEF is normal at baseline, if OEF decreases after cerebral vasodilation predicts impaired hemodynamics in the cerebral hemispheres [15, 16]. In addition, blood oxygenation level dependent funtional MRI (BOLD-fMRI) is also used to detect the state of oxygen metabolism in brain tissue, based on the principle that mismatch between the degree of local oxygen consumption and blood flow alteration in brain tissue during neuronal activity causes changes in local magnetic properties [17].
Magnetic resonance spectroscopy (MR spectroscopy, MRS) is currently the only noninvasive analytical method that can study metabolic and biochemical alterations in brain tissue at the molecular level and can quantify the concentrations of molecules such as N-acetylaspartate, choline, creatine, and lactate in brain tissue [18], but the results of studies on the relationship between these indicators and CVD are still highly variable.
The detection of cerebral metabolic reserve capacity is still in the research stage, and some issues need further study, such as: whether impaired cerebral blood flow reserve capacity raises the evidence of stroke risk when OEF is normal; there is no specific index evaluation to evaluate impaired cerebral metabolic reserve.
Strengthening the study of CVR can provide a more in-depth understanding of ischemic cerebrovascular disease, but due to the different means of examination and the different stages of CVR, each evaluation parameter has its own advantages and disadvantages, and further research is needed to find easy and effective detection methods and criteria to apply in clinical practice.