Measurement of Cerebral Blood Flow

Measurement of
Cerebral Blood Flow
Presenter: Dr Kaushal Deep Singh
MCh Senior Resident
Department of Neurosurgery
Sher-i-Kashmir Institute of Medical Sciences,
Srinagar

CIRCLE OF WILLIS WITH ITS
COLLATERALS

CLINICAL MEASUREMENT OF
CEREBRAL BLOOD FLOW

HISTORICAL BACKGROUND
• Latter half of the 19th century – Fick did theoretical
groundwork.
• 1945 - Kety and Schmidt applied the Fick’s principle to
determine global CBF in conscious human subjects by
measuring the cerebral uptake of inhaled nitrous oxide,
(an inert and freely diffusible gas) through repeated
chemical analysis of arterial and jugular venous blood
sample.
• These CBF values, when combined with measurements
of cerebral arteriovenous differences in glucose and
oxygen concentration, permitted a crude determination of
some parameters of cerebral metabolism as well.

CLINICAL TECHNIQUES
CURRENTLY AVAILABLE
• The ideal clinical technique should be based on widely
available and relatively inexpensive technology, be non-
invasive, not require anesthesia, and permit accurate and
reproducible measurements with a high degree of spatial and
temporal resolution.
• Laser Doppler flowmetry, transcranial Doppler, and
electroencephalography (EEG) provide qualitative assessment
of CBF.
• Quantitative CBF measurement techniques can be divided into
two principal groups that use either a diffusible or non-diffusible
tracer and rely on entirely different mathematical models.

• The former group involves calculation of the uptake of
inert and highly diffusible tracers by the brain via some
modification of the Fick equation.
• Because these tracers are freely diffusible in the brain
parenchyma, the CBF values obtained reflect cerebral
perfusion.
• The remaining techniques are based on the central
volume theorem and require the construction of a time-
density curve after the injection of non-diffusible contrast
agents.
• Because these agents are confined to the vasculature,
the values obtained reflect intravascular flow rather than
perfusion.

CLINICAL TECHNIQUES
CURRENTLY AVAILABLE
1. Stable xenon–enhanced computed tomography
(Xe-CT)
2. Positron emission tomography (PET)
3. Single-photon emission computed tomography
(SPECT)
4. Intracarotid 133-Xenon studies
5. Computed Tomographic Perfusion (CTP) imaging
6. Magnetic Resonance Perfusion (MRP) imaging

• Stable xenon–enhanced computed tomography (Xe-CT)
comes closest to meeting IDEAL criteria for measurement
of CBF, but its availability is constrained by equipment
and gas requirements.
• Positron emission tomography (PET) has the benefit of
allowing both CBF and metabolic measurements but has
largely been confined to the research setting because of
the requirement for an in-house cyclotron.
• By comparison, the equipment and materials needed for
CBF measurement by single-photon emission computed
tomography (SPECT) and intracarotid 133-Xenon studies
are relatively accessible to clinicians, thus making these
the current modalities of choice in most centers.

CLINICAL MEASUREMENT OF
CEREBRAL BLOOD FLOW
• Computed tomographic perfusion (CTP) imaging has
emerged as a promising means of rapidly evaluating
cerebral perfusion in various clinical scenarios, although
the accuracy, reproducibility, and reliability of the
quantitative results are still in question.
• At the present time, MRI is not routinely used for
perfusion imaging because of the difficulty of obtaining
absolute quantification of perfusion parameters and
comparing relative MRI perfusion data between centers
as a result of the lack of standardization of MRI units.

INERT NON-DIFFUSIBLE
TRACER TECHNIQUES
• Two primary CT-based imaging techniques for the
quantitative evaluation of CBF: xenon-enhanced CT and
dynamic CTP imaging.

STABLE XENON-ENHANCED
COMPUTED TOMOGRAPHY
• Xenon-enhanced CT relies on the inert, freely diffusible,
and radio-dense properties of stable or nonradioactive
xenon (131Xe).
• 131Xe is gaseous at room temperature and is
administered with oxygen.
• With modern scanners, the test can be performed with a
gas mixture containing just 28% 131Xe.
• 131Xe diffuses into the circulation through the pulmonary
capillary bed and rapidly crosses the BBB into brain
tissue.

Enhancer 3000 gas delivery
system with patient monitor is
remotely controlled by the Xe
Normal CT scan machine

COMPUTED TOMOGRAPHY
• A series of dynamic images are obtained throughout the
brain over a 6-minute interval.
• Two baseline images at each slice location followed by
six additional images at each level during inhalation of
131Xe.
• CT scanner is able to measure even small amounts of
131Xe taken up by the brain inasmuch, as changes in the
parenchymal concentration of 131Xe are reflected by
proportional changes in attenuation.

COMPUTED TOMOGRAPHY
• Since the arterial 131Xe concentration can also be
indirectly determined from measurement of the end-
expiratory 131Xe concentration, CBF values can be
computed on a pixel-by-pixel basis by use of the
equilibrating (diffusible) indicator model.
• CBF for all values can then be displayed as a color-coded
flow map, and areas of interest can be drawn to outline
vascular territories.
• No other flow parameters can be obtained with xenon-
enhanced CT.

COMPUTED TOMOGRAPHY
ADVANTAGES
• Quick because it can be performed in the same sitting as
conventional diagnostic CT, and the time from completion
of the CT scan to obtaining clinically useful CBF
information is just 15 to 20 minutes.

COMPUTED TOMOGRAPHY
DISADVANTAGES
• Cause headaches, nausea, convulsions, respiratory
depression, and narcosis, but usually not until the
concentration in inhaled air approaches 80%, which is
much higher than the technique requires.
• Can induce cerebral vasodilation, which might be
dangerous in a patient with decreased intracranial
compliance, or might contribute to erroneous
measurements.
• No movement permitted between slice acquisitions.
• Pulmonary disease may be a limiting factor

Xenon-CT scans at different levels obtained by bedside mobile CT-scanner.
Conventional CT images to the left to demonstrate the areas. Following Xenon
delivery tissue enhancement of the Xenon wash-in enabled cerebral blood flow (CBF)
(ml/100 g/min) to be calculated and plotted as colored maps. Scale of CBF is ml/100
g/min and is given to the right. Twenty cortical ROIs are used for CBF calculation and
regional vascular territory is identified (anterior cerebral artery 1–2, 19–20, medial
cerebral artery 3–8, 13–18, posterior cerebral artery 9–10, 11–12).

Xe-CT CBF maps in a patient with Moyamoya disease. A , Baseline. B , After ACZ
administration. Baseline scan ( A ) shows reduced CBF in the bilateral ACA and
anterior watershed areas (areas 1, 2, 19, and 20, asterisk ). After ACZ, there is a
robust increase in the CBF, indicating a normal cerebral reserve in these
territories. There is reduced baseline flow with decreased augmentation of CBF
after ACZ, indicating poor cerebral reserve in the left posterior MCA and the left
posterior watershed territories (areas 13–15, arrows ).

COMPUTED TOMOGRAPHIC
PERFUSION IMAGING
• Basic principle - Standard iodinated contrast material is an
intravascular tracer, which allows the CT scanner to be a
detector of brain blood flow.
• Two imaging techniques have been developed – Slow-infusion
technique; and First Pass Technique.
• They differ distinctly in the volume of brain coverage and the
data obtained.
• The slow-infusion technique can provide high-resolution whole-
brain CT angiography and mapping of CBV but not mean
transit time or CBF.
• Voxel-by-voxel subtraction of the unenhanced attenuation
values from the enhanced attenuation values provides the
CBV map of the entire brain.

PERFUSION IMAGING
• In contrast, the first-pass technique allows quantitative
determination of CBV, mean transit time, and CBF, but in only
a limited region.
• There is a linear relationship between the concentration of the
contrast agent and the degree of attenuation.
• The attenuation data for each voxel in the scanned area and
the progressive changes in density in regions of interest
overlying a selected input artery and input vein are the data
required for the “deconvolution algorithm” to make contrast
agent time-concentration curves for each voxel.
• The software then generates color-coded parametric CBF,
CBV, and mean transit time maps.
• It has now become possible to combine both slow-infusion and
first-pass techniques in one sitting.

PERFUSION IMAGING
ADVANTAGES
• It does not require any special equipment, is fast, and barring
any contrast reactions, and is well tolerated.
• It requires only dedicated post-processing software.
DISADVANTAGES
• Even with a multidetector CT unit, CTP using the first-pass
technique differs from xenon-enhanced CT in not providing
whole-brain CBF coverage; in a typical protocol, only two 10-
mm cerebral CT slabs are examined.
• This is mainly because the kinetics of iodinated contrast
material is much quicker than that of stable xenon, and
because of the necessity of limiting radiation exposure to
acceptable levels.

NCCT (A) and CTP parametric maps, CBF (B), cerebral blood volume [CBV]
(C), and mean transit time [MTT] (D), demonstrate normal symmetric brain
perfusion. By convention, all color maps are coded red for higher values and
blue for lower values.

An 87-year-old woman presenting with acute dysarthria, left facial droop, and left-
sided weakness. On admission, NCCT and CTP were performed concurrently. A,
NCCT shows some microvascular ischemic changes posteriorly. B−D, CTP maps,
CBF (B), CBV (C), and MTT (D), demonstrate a large area of matched deficit on
CBF and MTT maps, indicative of core infarct in the right MCA territory.

CT perfusion maps in a 51-year-old patient presenting with right-sided hemiparesis who
was diagnosed with Moyamoya disease, demonstrating bilateral supraclinoid internal
carotid occlusion. A , Baseline. B , After ACZ administration. The baseline pre-ACZ P-CT (A)
demonstrates the typical pattern of Moyamoya disease with decreased CBF and increased
mean transit time (MTT) and time to peak (TTP) in the bilateral anterior and middle cerebral
distributions (arrows). After ACZ challenge (B), the CBF in the anterior circulation decreases
consistent with steal phenomenon (B, CBF, arrows). The CBF map demonstrates a normal
expected increase in the PCA territories. There is further prolongation of the MTT and TTP
in both ACA and MCA distributions (arrowheads, B), consistent with worsening of cerebral
hemodynamics after ACZ, and type III physiology. The patient successfully underwent left-
sided extracranial-intracranial (EC-IC) bypass surgery.

SINGLE-PHOTON EMISSION
COMPUTED TOMOGRAPHY
• SPECT determines the three-dimensional distribution of a
single gamma ray–emitting radiotracer in the body.
• Hence, SPECT machines are designed to detect single
gamma rays (photons) and determine their point of origin
from their trajectory.
• Most modern SPECT studies use the radioisotope
technetium 99m (99mTc) attached to a carrier that easily
crosses the BBB, is distributed in the brain in proportion
to regional CBF, and is temporarily retained there, thus
allowing detection of the radioisotope anytime within the
subsequent few hours.

COMPUTED TOMOGRAPHY
• The most commonly used SPECT brain blood flow tracer
is technetium 99m–hexamethylpropyleneamine oxime
(99mTc-HMPAO, also called 99mTc-exametazime, a lipid-
soluble macrocyclic amine.
• It is extracted on first pass by the brain, where it becomes
fixed for several hours by conversion to a hydrophilic
compound in the presence of intercellular glutathione.
• With 99mTc-HMPAO, CBF quantification is not
straightforward, and a semiquantitative approach is
generally used in which counts in a region of interest are
determined and compared with those in an analogous
region in the opposite, presumably normal hemisphere.

COMPUTED TOMOGRAPHY
• 133Xe-SPECT is ideally suited for quantitative CBF
determination with the inert gas clearance technique.
• The rapid clearance of 133Xe from the brain has the
advantage of allowing repeated studies within a short
interval but unfortunately requires dynamic
instrumentation, which has the significant disadvantage,
when combined with the low energy of the emitted
photons, of rendering poor spatial resolution of the
resulting images.
• Also to be considered are the same concerns about the
adverse effects of xenon inhalation that were mentioned
for xenon-enhanced CT.

COMPUTED TOMOGRAPHY
ADVANTAGES
• Necessary equipment and radiotracers are readily
available in the average nuclear medicine department.
• It is also relatively simple to use, and even with high-
resolution systems, it is considerably less expensive than
PET.
DISADVANTAGES
• When compared with equivalent CT or MRI studies, the
spatial resolution is inferior, although this can be partly
addressed by digital superimposition on the patient’s CT
and MRI data set.

Visual patterns of brain
perfusion on HMPAO-SPECT
scans. With normal perfusion,
HMPAO is distributed
symmetrically in both affected
and nonaffected hemispheres.
If the entire infarction zone
represents an area of focal
hyperactivity of the tracer (new
event, arrow), a high perfusion
pattern is reported.
A focal absence of perfusion may also be present in the same hemisphere in the area of an old infarction (arrow) and should be excluded
from the analysis by a comparison with CT scans. Mixed perfusion pattern is present when asymmetrical areas of increased and
decreased uptake of the tracer are seen within the involved region. Low perfusion pattern represents a focal area of HMPAO hypoactivity.
Absent perfusion pattern is present when no focal uptake of the tracer is noted in the involved region. Acutely normal and high perfusion
patterns predict minor stroke (CNS scores 11.5 to 9.1), mixed and low patterns predict moderate stroke (CNS scores 9.0 to 5.1), and
absent perfusion pattern is a predictor of severe stroke and death (CNS scores 5.0 to 0).

Brain SPECT Images of Healthy, PTSD, TBI and PTSD Co-morbid with TBI
Perfusion Patterns. Top row, underneath surface scans, threshold set at 55%,
looking at top 45% of brain perfusion. Bottom row, underneath active scans where
blue = 55%, looking at top 45% of brain perfusion, red = 85% and white 93%.
Healthy shows full even, symmetrical perfusion with most active area in cerebellum.
Classic PTSD shows increased anterior cingulate, basal ganglia and thalamus
perfusion. Classic TBI shows multiple areas of low perfusion seen on surface scans
(top row). TBI and PTSD show both.

CT (top) and 99mTc-HMPAO SPECT (bottom)
images from 16-y-old patient with traumatic
brain injury after traffic accident. (A) CT at time
of admission shows subarachnoid hemorrhage
with small contusional hemorrhagic foci in both
frontal lobes (orange arrowheads). Glasgow
score was 12. During hospitalization, patient’s
clinical status worsened, and Glasgow score
decreased to 6. No changes were seen on CT
scan. SPECT was subsequently performed and
shows absence of tracer uptake (cold areas) in
anteromedial aspect of both frontal lobes
corresponding to hemorrhagic lesions, in
addition to global hypoperfusion, more marked
in both frontal cortices (white arrows). (B) CT
and SPECT images obtained 1 mo later at time
of discharge after clinical recovery. Hypodense
images in both frontal lobes can be seen on CT
as consequence of hematoma’s resolution.
Corresponding cold areas persist on SPECT
image (orange arrowheads) but show
improvement in global cerebral perfusion,
particularly in both frontal lobes (white arrows).

SPECT-HMPAO CBF study. A right-handed female had the acute onset of right
hemiparesis and aphasia 5 hours previously. This study demonstrates
decreased levels of CBF in the left frontotemporal region, but when comparing
them to similar areas on the right, the ratio of counts suggests that the tissue is
still viable, and thrombolysis may be of benefit.

POSITRON EMISSION
TOMOGRAPHY
• PET involves the production of two- or three-dimensional
images of the distribution of inhaled or intravenously
administered tracer compounds that have been labeled with
radionuclides containing an excess of positrons.
• Because these tracers are taken up by and accumulate in the
brain, the radionuclide sspontaneously decay by positron
emission.
• The positrons travel up to a few millimeters through tissue
before eventually becoming annihilated by collision with an
electron, in the process simultaneously emitting two 511-keV
photons (gamma rays) traveling at 180 degrees to each other
that are registered by a ring array of external detectors.

POSITRON EMISSION
TOMOGRAPHY
• The detector electronics are designed in a manner to
recognize the close temporal coincidence of two detection
events as the result of one annihilation event.
• The trajectories of each pair of photon emissions can then be
used to calculate the point of origin of each annihilation event.
• The coincidence events are stored in arrays corresponding to
projections through the patient and reconstructed with
standard tomographic techniques to generate a map of
radioactivity as a function of location.
• The more intense the radioactivity, the greater the
concentration of radiotracer in an area of interest.

POSITRON EMISSION
TOMOGRAPHY
• PET can be used to study regional cerebral glucose utilization
through the use of intravenous fluorodeoxyglucose (18F-FDG).
• Active brain regions take up 18F-FDG as though it were
glucose.
• Once inside the cell, it is phosphorylated by hexokinase into
FDG-6-phosphate, which is not a substrate for glucose
transport and cannot be metabolized by phosphohexose
isomerase, the enzyme catalyzing the next step in glucose
metabolism.
• Thus, labeled FDG-6-phosphate becomes trapped within the
cell and contributes to a pattern of radioactivity that reflects
local glucose uptake and metabolism.

POSITRON EMISSION
TOMOGRAPHY
• Oxygen-15 (15O) can be inhaled for assessment of oxygen
metabolism.
• The most commonly used tracer for PET CBF imaging is
radiolabelled water (H2
15O) because it distributes freely in blood.
• This tracer has a very short half-life (≈2 minutes), so a bolus injection
provides a snapshot that can be repeated, if desired, every 12 to 15
minutes.
DISADVANTAGE
• Need for an expensive on-site cyclotron.
• Positron-emitting radionuclides are produced in these cyclotrons, and
because those in common use have a half-life ranging from mere
minutes to just under 2 hours, they must be produced in close
proximity to the PET scanner.

Normal metabolic (FDG) and perfusion ([15O]H2O) PET scans in a
neurologically normal individual. The red areas on the PET represent regions
with high activity of metabolism (FDG) and perfusion ([15O]H2O). Yellow
represents less activity. Green and blue denote progressively lower activity
levels. Black represents no measurable metabolic neuronal function.

T2 weighted MRI demonstrating multiple white matter and watershed bright lesions
in the frontal white matter and in the corona radiata, slightly more on the left.
Metabolic (FDG) PET imaging shows a severe left frontal gray matter deficit (middle
panel, arrowhead). There is hypoperfusion ([15O]H2O) of the right hemisphere most
marked in the right superior parietal lobe (right panel, arrowheads). This subject
recovered from a left hemiparesis, but is cognitively impaired.

Simultaneous quantification of cerebral blood flow ([15O]H2O-PET) and
gadolinium bolus Tmax (perfusion-weighted MRI) in a patient with acute
ischemic stroke. Deficits in the right medial cerebral artery territory were found
in this case in both modalities. A simultaneous imaging approach allows to
cross-evaluate and calibrate new MR techniques of CBF determination in acute
stroke against the gold standard [15O]H2O-PET

Example of perfusion images obtained with H215O PET (left) and ASL-MRI
(right) of a 65-year-old female patient with a unilateral left-sided ICA occlusion.

MAGNETIC RESONANCE IMAGING
AND SPECTROSCOPY
• Clinical MRI uses the magnetic properties of hydrogen and its
interaction with a large external magnetic field and radio waves
to produce highly detailed images of the human brain.
• Subatomic particles such as protons behave like a spinning
charge and induce microscopic loops of electric current.
• The nucleus of hydrogen contains a single proton and is
described as having a half-integer spin.
• As a result, it has a very small magnetic field, or magnetic
moment, that aligns itself either parallel or antiparallel to the
direction of a strong external magnetic field with a circular
oscillation of a certain frequency.

AND SPECTROSCOPY
• When electromagnetic energy in the form of a
radiofrequency pulse is delivered at this frequency, the
hydrogen atoms are excited by absorption of this energy,
which causes their magnetic moments to line up in the
same direction.
• When the external energy is turned off, the absorbed
energy is released, and the magnetic moments return to
their previous orientations.
• The energy released is the basis of the MRI signal and is
unique to the varying molecular structures and amount of
hydrogen in various brain regions.

AND SPECTROSCOPY
• Two approaches can be used for the measurement of
CBF with MRI.
• Akin to first-pass CTP imaging, the more established
approach involves administration of the paramagnetic
agent gadolinium and is variously referred to as dynamic
susceptibility contrast, first-pass, or bolus perfusion MRI.
• Of note, the contrast agent remains wholly intravascular
and only indirectly alters MRI signal intensity, thus
hindering absolute quantification of hemodynamic
parameters.

AND SPECTROSCOPY
• The other MRI approach for imaging CBF is called arterial
spin labeling and uses radiofrequency pulses to “tag”
arterial blood water molecules, thereby obviating the
need for exogenous contrast agent.
• Changes in the amplitude of the MRI signal can be used
to construct quantitative images of cerebral perfusion,
although there are still outstanding issues with absolute
quantification.
• Novel sequences, including the blood oxygen level–
dependent MRI and functional MRI combinations, may be
used to assess cerebral perfusion and blood flow.

AND SPECTROSCOPY
• Clinical magnetic resonance spectroscopy (MRS) is usually
based on the principle that protons resonate at different
frequencies in the same static magnetic field when located in
different chemical microenvironments.
• It can be performed with a variety of pulse sequences, the
simplest being the application of a 90-degree radiofrequency
pulse called free induction decay, which is then converted to a
spectrum by a Fourier transformation.
• The spectral chemical shift is measured in parts per million and
is a characteristic of the variation in resonance frequency.
• Its specific dependency on the chemical microenvironment of a
particular nucleus makes it resemble a “fingerprint” of the
analysed substance.

AND SPECTROSCOPY
• Both 1H-MRS and 31P-MRS are in clinical use, although
1H-MRS is more widely used.
• 1H-MRS allows the measurement of several brain
metabolites, including lactate, N-acetylaspartate, total
creatine, glutamine/glutamate, and choline, whereas 31P-
MRS can measure intracellular pH, as well as signals
from ATP and PCr.

AND SPECTROSCOPY
• MRI has the principal advantages of avoiding ionizing
radiation exposure and providing a high degree of
temporal and spatial resolution.
• The main limit on the wealth of diagnostic information that
can be obtained is the duration of the examination.
• However, it is susceptible to movement artifact and is
contraindicated in patients with ferromagnetic implants.

3.24 Arterial Spin Labeling (ASL)
perfusion-weighted MRI. Combined
ASL, (a) regional perfusion imaging
map showing the brain tissue
perfused by each intracranial artery.
The right medial and inferior frontal
lobes are supplied by the right ICA
(in red), whereas the parietal and
inferior temporal lobes are supplied
by the basilar artery (in blue). Some
areas in the ischemic right MCA
territory do not show perfusion by
any vascular territory (arrows). MR
angiography (b) shows right MCA
occlusion (arrow). Selective ASL of
the left ICA circulation (green box),
right ICA, and basilar arterial
circulations was performed in turn to
produce regional perfusion imaging
in (a). DSA confirms the posterior
cerebral artery pial collateral supply
to the right parietal lobe (arrows, c)

Measurement of Cerebral Blood Flow

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