Introduction

Energy in the brain is required for maintenance of membrane potentials, ionic transport, and the biosynthesis and transport of neurotransmitters and cellular elements. Energy for these functions is supplied via adenosine triphosphate (ATP) from metabolism of exogenous compounds with a high-energy content (primarily glucose) to simpler compounds with less energy content (lactate, CO₂, and H₂O). Since storage of substrates for energy metabolism in the brain is minimal, the brain is highly dependent on a continuous supply of oxygen and glucose from the blood for its functional and structural integrity. It is exquisitely sensitive to even brief disturbances in this supply.

Normal Values of CBF and CMR

Healthy young adults have an average whole-brain cerebral blood flow (CBF) of approximately 46 ml 100g⁻¹ min⁻¹, cerebral metabolic rate of oxygen (CMRO₂) of 3.0 ml 100g⁻¹ min⁻¹ (134 μmol 100g⁻¹ min⁻¹), and cerebral metabolic rate of glucose (CMRglc) of 25 μmol 100g⁻¹ min⁻¹.^1–4 The CMRO₂/CMRglc molar ratio of 5.4 is lower than the value of 6.0 expected for complete glucose oxidation due to the production of a small amount of lactate by glycolysis that occurs even with abundant oxygen supply.^1,3,5 CBF in gray matter (80 ml 100g⁻¹ min⁻¹) is approximately four times higher than in white matter (20 ml 100g⁻¹ min⁻¹).⁶ Under normal physiological conditions, regional CBF is closely matched to the resting regional metabolic rate of the tissue.^7,8 Thus CMRO₂ and CMRglc are also higher in gray matter than in white matter. Because of this relationship between regional flow and metabolism, the fraction of blood-borne glucose and oxygen extracted is relatively constant throughout the brain (Figure 1–1). The oxygen extraction fraction (OEF) is normally 30% to 40%, indicating that oxygen supply is two to three times greater than oxygen demand. The glucose extraction fraction (GEF) is normally about 10%.^8,9

Figure 1–1 Cerebral blood flow and metabolism in a 70-year-old female normal volunteer. Note that cerebral blood flow (top left), cerebral oxygen metabolism (top middle), and cerebral glucose metabolism (bottom right) all show higher values in cortical gray matter than in white matter, whereas oxygen extraction fraction (top right) and glucose extraction fraction (bottom left) are uniform.

(From Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular disease. Neuroimaging Clin N Am 2003;13:741–758; with permission.)

Many studies report that CBF declines from the third decade onward.^10–13 The change in metabolic rate for oxygen and glucose with age is less clear, with several studies showing a decrease ^{10,12,14–16} and others showing no change.^17–19 Studies that have corrected for brain atrophy show lesser or absent changes in CBF, CMRO₂, and CMRglc in the remaining tissue with increasing age.^15,20–22 Our own data corrected for brain atrophy from 23 normal subjects, ages 23 to 71 years, show no significant change in CBF or CMRO₂, but a significant decline in CMRglc of 4% to 5% per decade.

Control of CBF

Cerebral perfusion pressure (CPP) is equal to the difference between the arterial pressure driving blood into the brain and the venous backpressure. Venous backpressure is negligible unless there is elevated intracranial pressure (ICP) or obstruction of venous outflow. Thus, under most circumstances, regional CPP (rCPP) is equal to the regional mean arterial pressure (rMAP). The rMAP will be equal to the systemic MAP when there is no arterial obstruction, but may be substantially lower in the setting of acute or chronic arterial stenosis or occlusion.

Regional CBF (rCBF) is regulated by rCPP and the regional cerebrovascular resistance (rCVR):

Under conditions of constant rCPP, any changes in rCBF must occur as a result of changes in rCVR. CVR is affected by blood viscosity and vessel length but is primarily determined by vessel radius. Arterial resistance vessels (primarily arterioles) dilate and constrict in response to a variety of stimuli causing changes in rCVR that produce changes in rCBF.

When there is a primary reduction in the metabolic demand of brain cells, such as that caused by hypothermia or barbiturates, arterial resistance vessels constrict to produce a comparable decline in CBF and thus little or no change in OEF or GEF.^23–25 With normal physiological increases in neuronal activity, vessels dilate, producing an increase in regional CBF that is accompanied by an increase in regional CMRglc of similar magnitude, but with little or no increase in regional CMRO₂.^26–28 Acute changes in arterial pCO₂ cause proportional changes in CBF. The mechanism for the change in CBF is a change in CVR produced by vasodilation with increased pCO₂ and vasoconstriction with decreased pCO₂.²⁹ With prolonged hyperventilation, CBF returns toward normal values over a period of several hours.³⁰ The effects of changes in arterial pO₂ on the cerebral circulation show a threshold effect, different from the proportional changes seen with changes in pCO₂. CBF does not increase until arterial pO₂ is below about 30 to 50 mm Hg.^31,32 A significant reduction in hemoglobin saturation and hence in arterial oxygen content (CaO₂) does not occur until arterial pO₂ falls to about 50 to 60 mm Hg, indicating that it is primarily CaO₂ and not pO₂ that determines CBF.^31,33,34 Reductions in CaO₂ due to anemia cause vasodilation and compensatory increases in CBF, whereas the increase in CaO₂ with polycythemia is associated with a decrease in CBF.³⁴ Acute changes in CaO₂ produce less of an increase in CBF than do chronic changes.^35,36 Hematocrit is an important determinant of viscosity, and thus viscosity and CaO₂ often vary together. It is unlikely that viscosity is an important determinant of CBF under most circumstances, however. Increases in blood viscosity induce compensatory vasodilation to maintain cerebral oxygen delivery (CBF x CaO₂).^37–39 When pre-existing vasodilation impairs the ability of vessels to dilate further to changes in viscosity, this compensatory mechanism may be exhausted.⁴⁰ Thus increases in CBF brought about by hemodilution, if they are simply reciprocal responses to changes in arterial oxygen content, will not increase cerebral oxygen delivery and may even decrease it.⁴¹

In contrast to the relationship of CBF to oxygen supply and demand, the balance between glucose supply and demand has little effect on CBF. Severe reductions in blood glucose down to 1.1 to 2.2 mmol/L produced modest but significant increases in CBF of 12% to 23%.^42–46 This CBF response to severe hypoglycemia likely does not represent a compensatory mechanism to maintain glucose delivery to the brain since a blood glucose level of 2 mmol/L is well below the level at which brain dysfunction and counter-regulatory hormone response occur.⁴⁷ Furthermore, increases in CBF do not increase blood:brain glucose transport.^48,49

All of these responses of the cerebral vasculature occur at normal CPP. When CPP changes, a different set of cerebrovascular and brain metabolic responses occur.

Response of CBF to Changes in Cerebral Perfusion Pressure

Changes in CPP over a wide range have little effect on CBF.⁵⁰ When CPP decreases, vasodilation of the small arteries or arterioles reduces CVR. When CPP increases, vasoconstriction of the small arteries or arterioles increases CVR.^51,52 This compensatory mechanism is known as autoregulation.⁵⁰ In most studies, the limits of autoregulation in normal normotensive subjects are from approximately 70 to 150 mm Hg.^50,53 Strandgaard determined that the lower limit of autoregulation was 25 mm Hg below the resting BP in normotensive subjects.⁵⁴ A contrasting viewpoint has been offered by Schmidt et al., who proposed a new computer method for assessing the lower limit of autoregulation.⁵⁵ In this study, the lower limit in normotensive volunteers was only 85 mm Hg (11 mm Hg higher than that calculated from the conventional method) and at times was virtually identical to the baseline blood pressure. Within the limits of autoregulation, a 10% decrease in mean arterial pressure produces only a slight (2% to 7%) decrease in regional CBF.^56,57 When CPP is reduced below the lower limit of autoregulation, more marked reductions in CBF occur. When the cerebral blood vessels are already dilated in response to some other stimulus, they are less able to dilate in response to reduced CPP. Therefore, the autoregulatory response is attenuated or lost in the setting of pre-existing hypercapnia, anemia, or hypoxemia.^58,59

Chronic hypertension shifts both the lower and upper limits of autoregulation to higher levels. The average value of the lower limit of autoregulation in 13 poorly controlled hypertensive patients, ages 49 to 64, (113 ± 17 mm Hg) and 9 well-controlled hypertensives, ages 42 to 66, (96 ± 17 mm Hg) was elevated compared to 10 normotensive controls, ages 41 to 81 (73 ± 9 mm Hg).⁵⁴ For all three groups combined, the lower limit of autoregulation was 70% to 80% of the resting MAP (r = 0.80). In another study, the lower limit was 88% to 89% of resting MAP (r = 0.81) for 19 normotensive and hypertensive subjects.⁵⁵ Prolonged effective antihypertensive treatment may lead to a re-adaptation of autoregulation towards normal in some cases, but there are almost no data on this subject.⁵⁴ Because of this upward shift of the lower limit, acute reductions in MAP or CPP that would be safe in normotensive subjects may precipitate cerebral ischemia in patients with chronic hypertension.⁶⁰

These observations of the effect of changes in CPP on CBF were made by changing MAP or ICP over minutes, then measuring CBF at the new stable pressure. Recently, these responses have been termed “static cerebral autoregulation” to differentiate them from measurements of cerebral blood flow velocity with Doppler in response to more rapid and less marked fluctuations in MAP or ICP, termed “dynamic cerebral autoregulation.”⁶¹ The relationship between static and dynamic autoregulation is not clear. Abnormalities of dynamic cerebral autoregulation may be associated with normal or abnormal static autoregulation.^62,63

When CPP falls below the autoregulatory limit and the maximum compensatory vasodilatory capacity of the cerebral circulation has been exceeded, CBF will decline markedly with further reductions in CPP. A progressive increase in OEF occurs as CBF falls and oxygen metabolism is maintained (Figure 1–2).^64–66 OEF may increase by a factor of 2 or even more from its normal value of 30% to 40%.⁶⁵ When the increase in OEF is maximal and is no longer adequate to supply the energy needs of the brain, further reductions in CPP disrupt normal cellular metabolism, produce clinical evidence of brain dysfunction, and, if prolonged, will cause permanent damage.

Figure 1–2 Compensatory responses to reduced cerebral perfusion pressure (CPP). As CPP falls, cerebral blood flow (CBF) changes very little due to arteriolar dilation, which reduces cerebrovascular resistance. This vasodilation may be seen as an increase in cerebral blood volume (CBV), but this response is variable, ranging from a steady rise (of as much as 150%) to only a modest increase beginning at the point of autoregulatory failure. When vasodilatory capacity has been exhausted, cerebral autoregulation fails and CBF begins to decrease rapidly. A progressive increase in oxygen extraction (OEF) preserves cerebral oxygen metabolism (CMRO₂).

(Redrawn from Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular disease. Neuroimaging Clin N Am 2003;13:741–758; with permission.)

Cerebral blood volume (CBV) is the volume of circulating blood in cerebral vessels. CBV is composed of arterial, capillary, and venous segments. Veins account for some 80% to 85% of CBV, arteries 10% to 15%, and capillaries less than 5%.^67,68 Arteries are the most responsive to autoregulatory changes in CPP, veins respond less and capillaries even less.^69,70 During experimental reductions in CPP, it is often possible to measure an increase in CBV that is presumed to be due to autoregulatory vasodilation.^71–73 However, this increase in CBV to reduced CPP is not always evident (Figure 1–2),^66,74 and a decrease in CBV in response to severe reductions in CPP has even been observed.⁷⁵ Failure to demonstrate increased CBV in the setting of reduced CPP has been attributed to various possible mechanisms, including differential vasodilatory capacity of different vascular beds, passive collapse of vessels due to low intraluminal pressures, small vessel vasospasm, and re-setting of vascular tone in response to reduced metabolic demands.⁷⁶ The CBF/CBV ratio (or its reciprocal, the vascular mean vascular transit time, MTT) has been proposed to be a more sensitive indicator of reduced CPP than CBV alone.^66,77 Although it may be more sensitive, it is not reliable because it may decrease in conditions with low CBF and normal CPP, such as hypocapnia.^78,79

Hemodynamic Effect of Arterial Stenosis

Stenosis of the carotid artery produces no hemodynamic effect until a critical reduction of 60% to 70% in vessel lumen occurs. Even with this or greater degrees of stenosis, distal CPP is variable and may even remain normal with stenosis exceeding 90%.⁸⁰ This is because hemodynamic effect of carotid artery stenosis depends not only on the degree of stenosis but also on the adequacy of the collateral circulation. Vascular imaging techniques such as angiography or Doppler ultrasonography can identify the presence of these collateral vessels, but not necessarily the adequacy of the blood supply they provide.⁸¹

In patients with cerebrovascular disease, determining the hemodynamic effects of arterial stenosis or occlusion is of potential value in predicting the subsequent stroke risk or for choosing preventative therapy. Measurement of rCBF alone is inadequate for this purpose. Normal rCBF may be found when rCPP is reduced but rCBF is maintained by autoregulatory vasodilation of distal resistance vessels. Second, rCBF may be low when rCPP is normal, such as when the metabolic demands of the tissue are reduced by previous ischemic damage or by the destruction of afferent or efferent fibers by a remote lesion (Figure 1–3).⁶⁵

Figure 1–3 Primary metabolic depression in structurally normal brain overlying a subcortical infarct. Two months following a left subcortical infarct shown by CT (bottom right), PET shows reduced cerebral blood flow (top left) and oxygen metabolism (top right) with normal oxygen extraction (bottom left).

(From Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular disease. Neuroimaging Clin N Am 2003;13:741–758; with permission.)

Methods to Measure the Hemodynamic Effects of Large Artery Occlusive Disease

Three strategies are commonly used clinically to determine the local cerebral hemodynamic status. The first relies on measurement of rCBF at baseline and again after a vasodilatory stimulus, such as CO₂ inhalation, breath holding, acetazolamide administration, or physiological activity (e.g., hand movement). An impairment in the normal increase of rCBF or Doppler blood flow velocity in response to the vasodilatory stimulus is assumed to reflect existing autoregulatory vasodilation due to reduced rCPP. Responses to vasodilatory stimuli have been categorized into three grades of hemodynamic impairment: (1) reduced augmentation (relative to contralateral hemisphere or normal controls), (2) absent augmentation (same value as baseline), and (3) paradoxical reduction in regional blood flow compared with baseline measurement. This last category, also known as the “steal” phenomenon, can only be identified with quantitative CBF techniques.⁸²

The second strategy entails the quantitative measurement of regional CBV either alone or in combination with measurement of rCBF at rest to detect the presence of autoregulatory vasodilation. Increases in rCBV or the rCBV/rCBF ratio relative to the range observed in normal control subjects is assumed to indicate hemodynamic compromise.

The third strategy involves direct measurement of regional OEF as an indicator of a reduction in rCPP below the lower autoregulatory limit.

The pattern of arteriographic collateral circulation to the MCA distal to an occluded carotid artery does not consistently differentiate those patients with poor cerebral hemodynamics (Table 1–1).^74,81,83,84

Table 1–1 Arteriographic collateral patterns in Patients from St. Louis Carotid Occlusion Study.

Three-Stage Classification System of Cerebral Hemodynamics

Based on the known physiological responses of CBF, CBV, and OEF to reductions in CPP, we proposed a three-stage sequential classification system for the regional cerebral hemodynamic status in patients with cerebrovascular disease.⁸⁵ Stage 0 is normal with normal rCPP and normally matched regional CBF and CMRO₂, such that rOEF is normal, rCBV and rMTT are not elevated and the rCBF response to vasodilatory stimuli is normal. Stage I hemodynamic compromise represents reduced rCPP, but is still above the lower autoregulatory limit. It is manifested by autoregulatory vasodilation of arterioles to maintain rCBF matched to rCMRO₂. Consequently, rCBV and rMTT are increased and the rCBF response to vasodilatory stimuli is decreased, but rOEF remains normal. In Stage II hemodynamic failure, rCPP is below the lower autoregulatory limit. There is a decrease in CBF relative to rCMRO₂ with increased OEF (Figure 1–4). This stage has also been termed “misery perfusion” by Baron et al.^86,87 In all of these stages, rCMRO₂ is preserved at a level that reflects the underlying energy demands of the tissue, but may be lower than normal due to the effects of previous tissue damage or deafferentation (Figure 1–3).^65,88

Figure 1–4 Chronically elevated oxygen extraction fraction in a patient with carotid occlusion. In this 56-year-old man with left hemispheric transient attacks, PET show reduced cerebral blood flow (top left), symmetrical oxygen metabolism (top right) and increased oxygen extraction (bottom left) in the left hemisphere (left portion).

(From Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular disease. Neuroimaging Clin N Am 2003;13:741-758; with permission.)

Although the three-stage classification scheme is conceptually and practically useful, it is overly simplistic. First, as discussed above, increases in rCBV and rMTT are not reliable indices of reduced rCPP. Second, rCBF responses to different vasodilatory agents may be impaired or normal in the same patient.^89–91 A normal vasodilatory response may occur in the setting of increased rCBV.^92,93 Finally, according to the three-stage system, all patients with increased rOEF should have increased rCBV and poor response to vasoactive stimuli. However, this increase in rCBV is not always evident.⁷⁶

Correlation of Large Artery Cerebral Hemodynamics with Stroke Risk