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Measurement of regional cerebral blood volume by emission tomography.

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Measurement of Regional Cerebral Blood
Volume by Emission Tomography
Robert L. Grubb, Jr, MD, Marcus E. Raichle, MD, Carol S. Higgins, BA, and John 0. Eichling, PhD
The technique of positron emission tomography was used to measure cerebral blood volume (CBV) in 10 normal
right-handed human volunteers following inhalation of trace quantities of cyclotron-produced, "C-labeled carbon
monoxide. In scans obtained 4 cm above the orbitomeatal line, CBV was 4.3 ml per 100 gm of tissue, whereas in
scans obtained 8 cm above the orbitomeatal line, CBV was significantly less (3.3 ml per 1 0 0 gm; p < 0.001). This
difference reflects the greater proportion of gray matter in the lower scan. Furthermore, the CBV was significantly
larger Cp < 0.001) in the left cerebral hemisphere in the tomographic scans obtained 4 cm above the orbitomeatal
line. These scans include the region of the superior surface of the temporal lobe (planum temporale), which is
thought to be larger in individuals with left cerebral dominance for speech. This observation is the first in vivo
demonstration of a structural correlate of a known functional difference in the cerebral hemispheres of man.
Grubb RL Jr, Raichle ME, HigRins CS, et al: Measurement of regional cerebral blood volume by emission
tomography. Ann Neurol 4:322-328, 1978
Present methods of studying brain hemodynamics
(i.e., blood flow and blood volume) in vivo have serious shortcomings, particularly when applied to studies in humans [ 2 , 171. The appearance of linear accelerators and cyclotrons in the medical environment, the parallel development of rapid chemical
techniques for incorporating their products (i.e.,
short-lived, positron-emitting radionuclides lSO,I3N,
I1C, ISF) into compounds [23], plus recent developments in imaging systems employing the concept of
positron emission tomography offer an opportunity
to circumvent most of these shortcomings.
Emission tomography is a nuclear medicine visualization technique that yields an image of the distribution of a previously administered radionuclide in
any desired transverse section of the body. Positron
emission tomography utilizes the unique properties
of the annihilation radiation generated when positrons are absorbed in matter. It is characterized by the
fact that an image reconstructed from the radioactive
counting data is a highly faithful representation of the
spatial distribution of a radionuclide in the chosen
section. The resulting data make it possible to calculate values for parameters of physiological and biochemical significance when used with appropriate
mathematical models. This approach is analogous to
quantitative tissue autoradiography with the added
advantage of allowing in vivo studies.
In this report we describe the basis for a low-risk,
quantitative, in vivo method of measuring cerebral
blood volume (CBV) regionally in the human brain.
Our method employs emission tomography to
monitor externally the spatial distribution in brain of
carboxyhemoglobin labeled with the short-lived
(20-minute half-life), cyclotron-produced, positronemitting radionuclide carbon 11. The data for our
report were obtained from I 0 normal human volunteers.
From the Department of Neurology and Neurological Surgery and
the Division of Radiation Sciences, The Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine,
St. Louis, MO.
Accepted for publication Mar 30, 1978.
Methods
Cerebral blood volume was measured in 10 right-handed
normal male volunteers. Informed consent for these studies was obtained in accordance with the regulations of the
Washington University School of Medicine Human Use
Committee.
Emission tomographic scans of the head were performed
following inhalation of "C-labeled carbon monoxide. A
positron emission tomograph developed in our laboratory
was used to quantitatively image the cross-sectional blood
volume. The basic principles, design, and performance
characteristics of the positron emission tomograph used in
this study have been previously described [ 3 , 7, 14-16,
2 11.
The subjects for this study were in a resting normocapnic
state. End-tidal carbon dioxide tension was monitored with
a capnograph. An estimate of arterial carbon dioxide tension (P+O,) was calculated by multiplying the end-tidal carbon dioxide tension by atmospheric pressure with a correction for water vapor pressure. Each subject was positioned
in the tomograph with the aid of a low-power laser beam of
light across the center plane of the tomograph.
By having the subject breathe approximately 10 to 15
Address reprint requests tO Dr Grubb,
of Neurology
and Neurological Surgery, Barnes Hospital Plaza, St. Louis, MO
631 10.
322 0364-5134/78/0004-0406S01.25 @ 1978 by Robert L. Grubb, Jr
mCi of high-specific-activity "C-labeled carbon monoxide
contained in 800 fil of helium and 1,000 nil of room air
from an Ambu bag, the blood was labeled with "Ccarboxyhemoglobin. Following inhalation of the gas, 6 to 7
minutes were allowed for the labeled blood to reach an
equilibrium state. Two emission tomographic scans were
then obtained sequentially 4 and 8 cm above the orbitomeatal (0-M) line. Data were collected for a period
long enough to ensure sufficient counts in the image for
an accurate image reconstruction (range, 370,000 to
1,000,000 counts; mean, 600,000 counts). This usually required 6 minutes for the first scan and 10 minutes for the
subsequent one. Scans of the brain were computer processed in order to calculate a mean value of the scan for
each region of interest.
During each emission scan, several blood samples were
drawn from a peripheral vein. These blood samples were
weighed and counted in a 7.5 x 7.5 cm thallium-activated
sodium iodide well detector to obtain the activity of the
labeled blood (counts per second per gram of blood). A
curve of the activity of "C-tagged carbon monoxide in the
blood, corrected for the physical decay of "C from the
beginning of the emission scan, was constructed as a function of time. The value for blood "C carbon monoxide
activity used in the calculation of CBV (see the equation)
was obtained from this curve by selecting the point in time
corresponding to the midpoint of the emission scan.
Calibration of the emission tomograph in order to determine the actual concentration of "C-labeled carbon
monoxide in brain from the emission scan (counts per second per cubic centimeter of tissue), was performed by iniaging an appropriately designed phantom. This phantom, a
cylinder 18 cm in diameter divided into five pie-shaped
chambers of equal size, was filled with varying concentrations of "C-labeled bicarbonate in saline (typically a
1:2:3:4:5ratio). T h e phantom was then scanned twice. Because of the short half-life of " C (approximately 20 minutes), we obtained ten concentrations of radioactivity
which bracketed the radioactivity concentration of "Clabeled carbon monoxide in the subject's scan. Weighted
aliquots were then taken from each phantom chamber and
counted in the same well detector used to count the blood
samples. Scans of the phantom were computer processed in
order to calculate a mean relative value of the scan for each
chamber. A regression equation was then obtained for
these data comparing the relative scan data and the directly
measured activity from the phantom. This equation was
used to determine the actual concentration of "C-labeled
carbon monoxide in the subject's scan.
Subject and phantom scan data from the emission tomograph were acquited to yield a spatial resolution of 15
mm full width at half maximum. Corrections for detector
nonuniformity, physical decay of the radionuclide, and attenuation were made, and images were reconstructed using
an Interdata Model 70 computer. T h e attenuation correction factors were computed using an experimentally determined value for the attenuation coefficient and the physical dimensions of the scanned object. Each data point is
where x is the
corrected for attenuation by the factor efiXx,
thickness of the object along the coincidence line a n d F is
the experimentally derived average linear attenuation
coefficient. The validity of this method has been previously
reported [ 1 5 ] . The scan reconstruction algorithm was a
convolution-based, filtered back projection that resulted in
a 100 x 100 array representing the 48 cm diameter field;
thus, each picture element size is 0.48 cm. Images were
displayed and regions of interest sclected o n a 256 X 240
imaging system with 64 gray levels.
Cerebral blood volume (milliliters per 100 g m of brain
tissue) was calculated by the equation:
CBV =
Cbr
Cb, * f *P h , ' P,
x 100
where Cbr is the concentration of "C-labeled carbon
monoxide (counts per second per cubic centimeter of tissue) in the brain determined by the emission tomographic
scan; Cbl is the concentration of "C-tagged carbon
monoxide (counts per second per gram of blood) in the
peripheral venous blood; f is the ratio of the mean cerebral
small vessel hematocrit to large vessel hematocrit; Pblis the
density of blood (gm per milliliter), and Pt is the density of
brain tissue (gm per milliliter). An average value of 0.85 for
the ratio of cerebral small vessel hematocrit to large vessel
hematocrit was used in these studies [5]. A value of 1.05
g m per milliliter was used for both the density of blood and
the density of brain tissue.
The significance of differences between values of CBV
obtained at 4 cm and 8 cm above the 0 - M line was tested
by t tests, and paired t tests were used to test the significance of differences in CBV values obtained in the left
and right cerebral hemispheres
Results
Figures 1 and 2 show horizontal sections of the brain
and "C carbon monoxide scans 4 and 8 cm, respectively, above the 0 - M line. The values of CBV and
estimated P k o Z are contained in Table 1. In scans
obtained 4 cm above the 0 - M line, an average CBV
value of 4.3 (k0.4 SD) ml per 100 gm of tissue was
found. At 8 cm above the 0 - M line the average value
was 3.3 (k0.5 SD). The differences in CBV value at
the two different levels scanned is significant ( p <
0.001). The mean estimated Paco2 in scans 4 cm
above the 0 - M line was 4 1 (25 SD);8 cm above the
0 - M line the mean estimated Paco, was 38 ( - t 2 SD).
The differences in Paco, were not significant.
At 4 cm above the 0 - M line the CBV in the left
cerebral hemisphere was 4.3 (k0.5 SD) ml per 100
gm of tissue while the CBV in the right cerebral
hemisphere was 4.1 ( k 0 . 4 SD) ml per 100 gm.These
left-right cerebral hemisphere differences in CBV 4
cm above the 0 - M line were significant ( p < 0.001).
CBV was slightly greater in the left than in the right
cerebral hemisphere 8 cm above the 0 - M line, but
these differences were not significant.
Figure 3 illustrates the typical area of a scan used to
calculate whole-brain CBV. Figure 4 shows the typical areas of a scan used t o compute CBV for the left
and right cerebral hemispheres.
Grubb et al: Cerebral Blood Volume in Humans 323
F i g 1 . (A) Horizontulsectiom of u huniun bruin. ( B , Emi.r.rivn
t oniopcrphi(.srun after inhulution lif C-labrhd 1.urho in
nionoxide. Brain slice and totnogruphic slice were both
obtcrined 4 cni ubove the orbitomeutulline. The “hot.spot” in
the posterior portion of the emission tomogruphir scavi vepre.sents
the superior .wgittcrl.rinu.r.
’‘
Fzg 2. (A)Horizontalsection of a human brain. ( B )EmiJsion
tomographicscan afrer inhalation of ’%labeled t arbon
nionoxide. Brain dice and tomographic slice were both obtained
8 cm about the orbitomru~dline.
324
Annals of Ncurology
Vol 4
No 4
October 1378
Table 1 . Cerebral Blood Volume und Estimated Arterial Carbon Dioxide Tension i n 10 Subjects
CBV, Whole Brain
Subject
(m11100 gm tissue)
A Scan 4 cm above 0 - M line
1
4.0
2
3
4
5
6
7
8
Mean
4.1
5.0
4.8
4.8
4.7
4.4
4.2
4.1
4.2
4.3
4.0
4.0
3.8
3.6
4.3 (20.4 SD)
(N = 15)
B Scan 8 cm above 0 - M line
8
3.1
2.9
9
3.1
3.1
10
4.0
3.8
Mean
3.3 (20.5 SD)
( N = 6)
CHV
CBV,Lcft Cerebral
Hemisphere
(m11100 gm tissue)
CBV,Right Cerebral
(mV100 gm tissue)
(mm kg)
4.2
4.3
5.0
4.8
4.9
4.6
4.6
4.3
3.9
4.0
4.8
4.7
4.4
4.5
4.3
4.0
3.8
4.0
4.4
4.0
3.7
3.5
i .4
4.1 (20.4 SD)
( N = 15)
37
36
40
41
48
48
40
41
35
41 ( 2 5 SD)
( N = 9)
3.1
2.6
3.0
2.9
3.6
3.1
3.1 (?0.3 SD)
( N = 6)
36
39
37
36
41
40
38 ( ? 2 SD)
( N 6)
4.2
4.3
4.6
4.2
3.9
3.6
3.2
4.3 ( 2 0 . 5 SD)
( N = 15)
3.1
2.8
3.0
3.0
3.9
3.6
3.2 (20.4 SD)
(N = 6)
Hemisphere
Estimated
Pace.
...
...
...
...
...
...
= cerebral blood volume.
Discussion
Our results demonstrate the feasibility of quantitatively measuring regional CBV in vivo using positron
emission tomography to image circulating "Clabeled carboxyhemoglobin. Because blood can be
easily labeled by inhalation of trace quantities of the
"C-labeled gas carbon monoxide, and quantitation
requires only sampling of peripheral venous blood,
this measurement is associated with minimal risk and
discomfort to the subject. Furthermore, we consider
the risk from exposure to ionizing radiation acceptable. For example, in a typical study in which the
subject inhales 10 to 15 mCi of "C-labeled carbon
monoxide, approximately 3 to 5 mCi actually labels
the blood, and the remainder is quickly ventilated.
Under these circumstances the blood receives approximately 50 mR per millicurie and the wholebody radiation dose is approximately 10 m R per millicurie.
In addition to its ease of administration and the low
radiation dose to the 'subject, our tracer, "C-labeled
carboxyhemoglobin, has the additional advantage of
selectively labeling red blood cells. The use of
labeled red cells to measure CBV circumvents the
potential problem of extravascular migration of the
tracer when damage has occurred to the blood-brain
barrier. This is always a potential problem that cannot
be anticipated when diseased tissue is studied. Data
based on studies employing a plasma tracer must, as
pointed out by others [2, 171, be viewed with caution
when damage to the blood-brain barrier is suspected.
The use of a red cell tracer-or, for that matter, a
plasma tracer-for measurement of CBV necessitates
knowledge of the local tissue hematocrit (see the
equation). As pointed out by others, this may differ
from the large vessel hematocrit. Thus, a correction
must be inserted in the calculation of CBV for this
discrepancy. In normal brain, the limited data currently available suggest a value of 0.85 for the ratio of
small vessel or tissue hematocrit to large vessel
hematocrit [51. Rosenblum [ 191 has cautioned that
the local tissue hematocrit may change in acute dis-
Grubb
et
al: Cerebral Blood Volume in Humans 325
Fig 3. Dortedlinesurroundr typicalarea of "C carbon monoxide
uitivity in emission tomographicscan used t o calculate wholebrain CBV.
Fig4. Dottedlinessurraundtypicalareasof "C carbon monoxide
aitivity in emission tomngraphicsi-anused to calculate CBV i n
left and right cerebral hemispheres.
eases of the brain such as ischemic infarction. Under
such circumstances, errors in the computation of
CBV couid be introduced by selection of an arbitrary
value. In the future it should be possible to characterize the local tissue hematocrit more thoroughly in
normal as well as diseased brain by sequential measurement of plasma and red cell volume in the same
patient by emission tomography. This could be accomplished by the use of "C carbon monoxidelabeled red blood cells followed by intravenous administration of "C-labeled methylalbumin [20].
The precise measurement of CBV has proved to
be difficult, and few studies in humans have been
done [ 5 , 8-1 1 , 131. Table 2 lists values of CBV
found in normal humans utilizing several different
merhods. With the exceprion of one srudy [ I I ] employing phosphorus 32-labeled red blood cells, all
these studies are in fairly close agreement.
Three observations in our data are worthy of note.
First, the average of CBV in normal humans was
higher in emission tomographic scans obtained 4 cm
above the 0 - M line compared with scans obtained 8
cm above this reference point. Although the mean
estimated PacoZ was slightly higher in the subjects
scanned 4 cm above the 0 - M line, this would not
account for the differences in CBV seen at the two
levels [ b ] .That different values of CBV were obtained at these two levels is not surprising, as different cross-sectional levels of the brain contain different ratios of gray to white matter. Gray matter is
known to have a higher capillary density [l] and a
higher resting cerebral blood flow [12]. As can be
seen in Figures 1 and 2, emission tomographic scans
obtained 4 cm above the 0 - M line contain a larger
amount of deeper gray structures compared to scans
8 cm above this point.
Second, in scans obtained 4 cm above the 0 - M
line, the CBV was found to be significantly greater in
the left cerebral hemisphere. This was, by history,
the dominant hemisphere in all the subjects studied.
Functional differences between the cerebral hemispheres of man have been noted for many years, but
until recently, structural differences between the
hemispheres have not been observed. However, in
326
Annals of Neurology
Vol 4
No 4
October 1078
Table 2 . Previously Determined Values
far CBV in Normal Humans
Average Value
of CBV
(mli 100
Method
g m tissue)
Positron emission tomographic scan
Radionuclide emission tomographic
scan [81
X-ray computed tomographic scan
3.3-4.3
2-4
3
[I31
X-ray fluorescence [ 5 ]
G a m m a camera mean transit time
(gYmTc)
[9, 101
Dye-dilution technique m e a n transit
time (3LPP-labeledR B C s ) [ 1 I ]
3.2
4.05
9
1968, Geschwind and Levitsky [4]found the superior
surface of the temporal lobe (planum temporale) to
be larger in the left hemisphere in 65% of brains examined at autopsy. This observation was extended by
Witelson and Pallie [22] in 1973 by their demonstration that this asymmetry is present in neonates as well
as adults. Our finding of an increase in CBV in this
area is further evidence of a structural asymmetry
underlying functional differences between the two
hemispheres. Our finding assumes special importance when it is realized that for the first time, such
differences can be determined safely in vivo. We recognize the need for additional work in this area. Of
particular interest would be the demonstration of an
increase in regional CBV in the right hemisphere in
patients known to have right cerebral dominance for
language.
Finally, our scans clearly reveal regional differences in "C activity, and hence CBV, within each
cerebral hemisphere, corresponding to anticipated
differences in CBV in gray and white matter structures. We are reluctant to quantitate these differences at this time because the emission tomograph
used in these studies has a minimum resolution of 1.5
cm3. We do not consider this resolution sufficient t o
allow quantitative independent determination of
CBV regionally in gray and white matter. Anticipated
advances in the design and resolution of emission
tomographs, however, should make such independent measurements available in the near future.
In summary, our studies demonstrate the feasihility of safely making quantitative in vivo measurements of regional CBV in humans. Such measurements should greatly facilitate studies designed
to understand cerebral hemodynamics in the normal
as well as diseased human central nervous system.
Furthermore, they should complement measurements of regional cerebral metabolism by emission tomography [ 181.
Supported by US Public Health Service Grants HL 1385 1 and
NSO 6833 (NINCDS) and by Teacher-Investigator Award NS
11059 from NINCDS (Dr Raichle).
The authors wish to thank the staff of the Washington University
School of Medicine cyclotron for their invaluable technical assistance in these experiments. We are grateful to Dr Michel M. TerPogossian for his generous support and helpful suggestions during
the course of this work.
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