123 I- or 99m Tc-labeled radiotracers for measurement of CBF using SPECT have been developed in the last 20 years. N -isopropyl- p - 123 I-iodoamphetamine ( 123 I-IMP), 99m Tc-hexamethyl- propyleneamine-oxime ( 99m Tc-HMPAO), and 99m Tc-ethyl-cysteinate dimmer ( 99m Tc-ECD) have become available for CBF-SPECT imaging (Table 1 ). Functional neuroimagings using these tracers can be useful to evaluate the indications of surgical revascularization, the changes of hemodynamics after surgical revascularization, and the predictions of the clinical outcome [9– 13] . These radiotracers have a common character in the chemical microsphere which can be accumulated in the entire brain through the blood–brain barrier reflecting the distribution of regional CBF. However, different extraction and retention mechanisms in each tracer can result in differing distributions of tracers in the brain. 99m Tc-labeled CBF tracers generally underestimate true CBF due to the limited first-pass extraction fraction, and especially cannot accurately reflect further increase of CBF in the high flow range produced by the activation test. Out of these radiotracers, the distribution of 123 I-IMP in the brain can be linearly corresponding to the distribution of true CBF [14] (Fig. 2 ).
Technical advances have made it easy to quantify regional CBF using the 123 I-IMP SPECT and autoradiography (ARG) method based on a 2-compartment model [15] (Fig. 3 ). In this method, arterial input function is determined by one-point arterial blood sampling. Quantitative analysis of CBF-SPECT such as the IMP-ARG method can progress to making criteria for the stratification of hemodynamic cerebral ischemia. However, the IMP-ARG method is not yet widely adopted for pediatric patients because of its invasiveness, e.g., arterial blood sampling, which may make the patients cry and alter the result of the measurements. Therefore, semiquantitative ROI analysis using the dominant cerebellar hemisphere as the reference [10] , or statistical imaging analysis
173 Functional Neuroimagings “Overview”
Fig. 1 Severity of hemodynamic cerebral ischemia can be classified using lower limits of vascular and metabolic reserve which function as a compensatory system to preserve cerebral oxygen metabolism towards the reduction of CPP. CBF cerebral blood flow, CBV cerebral blood volume, CMRO 2 cerebral metabolic rate of oxygen, OEF oxygen extraction fraction, CPP cerebral perfusion pressure, Stage I main- tenance of CBF and decrease of vascular reserve, Stage II decrease of CBF with loss of vascular reserve and maintenance of CMRO 2 with increase of OEF (decrease of metabolic reserve) (misery perfusion)
II I
decrease
CPP increase
CBF
CBV
CMRO2
OEF
Stage
Autoregulation
Vascular reserve
Metabolic reserve
Metabolic compensation Vascular compensation
Table 1 Characteristics of CBF tracers for SPECT
Radiopharmaceuticals IMP HMPAO ECD
Labeled nuclide 123 I 99m Tc 99m Tc
Type of injection Labeled solution (LS) Labeling kit Labeling kit, LS
Injection amount 111~222 MBq 370~740 MBq 370~740 MBq
Stability (within 30 min) (over 30 min)
First-pass extraction
Back diffusion Little Much Moderate
Linearity to true CBF ∆
Wash-in to brain tissue Gradually continue Just after injection Just after injection Change of distribution Observed (redistribution) Rarely observed Rarely observed Influence of BBB disruptions Influenced Hyperfixation Hypofixation CBF quantification Microsphere model Patlak plot Patlak Plot
2-Compartment model Microsphere model
Balloon occlusion test estimated
Acetazolamide-activation
Emergency application Difficult Possible Possible
174 J. Nakagawara
Fig. 2 Underestimation of observed CBF by rCBF tracer is produced due to the limited first-pass extrac- tion fraction. The underestimation was estimated for four permeability-surface area product (PS) values, corresponding to four rCBF tracers of H 2 15 O, 123 I-IMP, 99m Tc-HMPAO, and 99m Tc-ECD, respectively, according to the Renkin-Crone’s equation (Renkin 1959; Crone 1963). PS values were obtained by Eichling et al. (1974) for H 2 15 O and by the Ehime group for other tracers (Murase et al. 1991) [14]
Microsphere model
a
b 2-compartment model BBB
BBB
Ca Cb
Ca Cb
K1
K2
K Cb(t) = KCa(t)dt
K = f •E t 0
Cb(t) = K1Ca(t)e-k2(t-t K1 = f •E, Vd = K1/
t 0
Fig. 3 Compartment models for the quantification of CBF using CBF tracer (chemical microsphere).
( a ) Microsphere model. ( b ) Two-compartment model. BBB blood–brain barrier, K ( K1 ) rate constant of tracer from blood to brain, k2 rate constant of tracer from brain to blood, Vd = K1/k2 distribution volume, f cerebral blood flow (CBF), Ca(t) arterial input function at time t , Cb(t) radioactivity in the brain at time t , E first-pass extraction ( E = 1 − ePS/f) (PS, permeability-surface area product)
175 Functional Neuroimagings “Overview”
such as 3-dimensional stereotactic surface projections (3D-SPP) [16] are accepted as an easy and less invasive method for pediatric patients.
Recently, both the dual-table ARG (DTARG) method [17] and segmental extraction estimation (SEE) analysis [18] have been developed. These methods could be clinically applied as newly standardized techniques to improve measurement accuracy and judgment accuracy for the stratification of hemodynamic cerebral ischemia.
Stratification of Hemodynamic Cerebral Ischemia Using IMP-ARG Method
Stratification of hemodynamic cerebral ischemia using the IMP-ARG method [15] could be established by both resting and acetazolamide-activated CBF quantification [19]
(Fig. 4 ). The stage of hemodynamic cerebral ischemia can be stratified, as follows: Stage 0:
vascular reserve [(acetazolamide-activated CBF-resting CBF)/resting CBF × 100%] is
IMP-ARG vascular reserve (%)
+50 +40 +30 +20 +10
0
−10
−20
−30 80
70
60
50
40
30
20
10
0
Acetazolamide-activated CBF (ml/100g/min)
Resting CBF (ml/100g/min) Normal mean 20%
0 10 20 30 34 40 50
42
Critical Level
0
I
II
Fig. 4 Stratification of hemodynamic cerebral ischemia using quantified resting and acetazolamide-activated CBF-SPECT (the slope of the oblique lin e corresponds to the vascular reserve). Stage 0 vascular reserve
>30%, Stage I vascular reserve reduced from 10 to 30%, or vascular reserve <10% and resting CBF >80%
of normal mean, Stage II vascular reserve <10% and resting CBF <80% of normal mean
176 J. Nakagawara preserved more than 30% (the oblique line slope corresponds to vascular reserve in Fig. 4 );
Stage I: vascular reserve is reduced from 10 to 30%, or vascular reserve is reduced less than 10% and resting CBF is preserved more than 80% of normal mean CBF; Stage II:
vascular reserve is reduced less than 10% and resting CBF is reduced less than 80% of normal mean CBF.
Figure 5 shows quantification of CBF-SPECT in a pediatric patient with moyamoya dis- ease before and after surgical revascularization. After the left STA-MCA bypass and EMS, preoperative Stage II ischemia in the left MCA territory was turned into postoperative Stage I ischemia.
A recent Japanese EC-IC Bypass Trial (JET Study) showed that the EC-IC Bypass was beneficial for stroke prevention in patients with Stage II hemodynamic cerebral ischemia [20] . Stage II hemodynamic cerebral ischemia defined by CBF-SPECT could be a surrogate marker of stroke recurrence.
Statistical Imaging Analysis Using 3-Dimensional Stereotactic Surface Projections (3D-SSP)
In statistical imaging analysis such as 3D-SSP [16] , axial images of CBF-SPECT from subjects are transformed to the frame of Talairach’s standard brain reference pixel by pixel, then the relative distribution of surface CBF from subjects is compared with the database from normal volunteers in which every pixel has both an average value and standard devia- tion (SD) normalized by specific brain territories. Differences between the subject’s data and the normal database in each pixel are converted to Z -score as a multiple of SD, then the cluster of pixels, which have significant difference of Z -score > 2, can be identified as the specific area with significant CBF reduction on the stereotactic surface projections (total eight directions). In group comparisons between pediatric patients and the normal database using 3D-SSP, a statistically significant decrease of resting CBF was observed in wide- spread cortical areas on the anterior circulation of the pediatric patients. In a comparison between resting and acetazolamide-activated CBF distribution with a Z -score map in the same patient as the case in Fig. 5 , the Z -score value in the cluster of pixels with a statistical difference on the resting Z -score map is augmented on the acetazolamide-activated Z -score map (Fig. 6 ). Therefore, the severity of hemodynamic cerebral ischemia can be classified by the combination of Z -score values estimated by resting and acetazolamide-activated Z -score maps (Table 2 ). Statistical imaging analysis using 3D-SSP can correspond to the stereotactic and qualitative analysis of CBF-SPECT.
Fig. 8 Assessment of hemodynamic cerebral ischemia using stereotactic extraction estimation (SEE) analysis for CBF-SPECT of a case in Fig. 5 . From upper to lower , brain surface images of standardized brain MRI, resting CBF, acetazolamide-activated CBF, cerebrovascular reserve, and stage of hemodynamic ischemia are indicated. From left to right , eight directions ( Rt Lat, Lt Lat, Sup, Inf, Ant, Post, Rt Med, Lt Med ) of brain surface images are demonstrated. On the left lateral direction, decrease of resting and acetazolamide-activated CBF, reduction of cerebrovascular reserve less than 10% and mixed Stage I and II ischemia were demonstrated within the left MCA territory. On the right lateral direction, no increase of acetazolamide-activated CBF, reduction of cerebrovascular reserve, and Stage I ischemia were observed in the frontal lobe within the left MCA territory
177 Functional Neuroimagings “Overview”
Fig. 5 Quantification of CBF-SPECT in a pediatric patient with moyamoya disease. ( Upper row ) resting CBF, ( lower row ) acetazolamide-activated CBF. A 7-year-old female, suffered from frequent TIA such as transient motor aphasia and bilateral hemiparesis. Initial EC-IC bypass surgery was scheduled for the left cerebral hemisphere based on severity of hemodynamic cerebral ischemia. Hemodynamic stage in the left MCA territory was estimated as Stage II based on the criterion of Fig. 4
Fig. 6 Comparison between resting and acetazolamide-activated CBF distribution with a Z -score map using 3D-SSP in the same patient as a case in Fig. 5 . From upper to lower , brain surface images of standardized brain (MRI), and 4 Z -score images normalized by global hemisphere (GLB), thalamus (TH), cerebellum (CBL), and pons (PNS). In a comparison between resting and acetazolamide-activated CBF distribution, a marked decrease of CBF in the left MCA territory and a mild decrease of CBF in the right frontal lobe were observed. On the other hand, in a comparison between resting and acetazolamide-activated Z -score maps, the Z -score value in the cluster of pixels with a statistical difference on the resting Z -score map is augmented on the acetazolamide-activated Z -score map
178 J. Nakagawara
Dual-Table ARG Method
Until now, stratification of hemodynamic cerebral ischemia has been defined using the IMP-ARG method; however, sufficient accuracy of vascular reserve using this method cannot yet be obtained. Especially, a measurement error can occur because of different arterial input functions associated with 2-day quantification of both resting and acetazolamide-activated CBF using the IMP-ARG method. On the other hand, the DTARG method [17] can provide same-day quantification of both resting and acetazolamide-activated CBF using a split dose
(resting)CBF CBF
(acetazolamide) CBF
Table 1 Table 2
Pixel value
Pixel value Pixel value
23
0 10 20 30 40 50 60
acetazolamide IMP
(min)
IMP
Fig. 7 Principle of dual-table ARG. In resting CBF quantification, a relationship between the pixel value of the first SPECT and resting CBF is calculated based on the two-compartment model to produce Table 1 , and then the first SPECT is transformed to the resting CBF map pixel by pixel using the table look-up method in the same manner as the IMP-ARG method [15] . On the other hand, in acetazolamide- activated CBF quantification, the pixel value of the second SPECT is influenced by the background radioactivity of the first tracer injection. Therefore, a relationship between the pixel value of the second SPECT and the acetazolamide-activated CBF is calculated to make up Table 2 which consists of both a resting table and an acetazolamide-activated table (dual-table). Table 2 starts from the pixel value calculated from the resting CBF map and then the second SPECT is transformed to the acetazolamide-activated CBF map pixel by pixel using the table look-up method
Table 2 Classifi cation of severity of hemodynamic cerebral ischemia by the combination of Z -score values estimated by resting and acetazolamide-activated Z -score map
Resting 3D-SSP Acetazolamide-activated 3D-SSP Normal Z (rest) < 2 Z (acetazolamide) < 2
Mild Z (rest) < 2 Z (acetazolamide) > Z (rest) + 2 Severe Z (rest) > 2 Z (acetazolamide) > Z (rest) + 2
179 Functional Neuroimagings “Overview”
of 123 I-IMP and common arterial input function (Fig. 7 ). Using the DTARG method, both resting and acetazolamide-activated CBF-SPECT can be serially quantified pixel by pixel to obtain high measurement accuracy on the vascular reserve.
Segmental Extraction Estimation
SEE analysis of hemodynamic cerebral ischemia has been developed to overcome the arbi- trary estimation due to ROI analysis for quantified CBF-SPECT [18] . In this analysis, resting and acetazolamide-activated CBF-SPECT are stereotactically and quantitatively converted to brain surface CBF. The conversions are performed pixel by pixel on the frame of Talairach’s standard brain reference which has been utilized in 3D-SSP analysis. Then, stereotactic estimations of cerebrovascular reserve and stereotactic stratification of hemodynamic cerebral ischemia (Stages 0–II) [19] can be completed pixel by pixel on the same frame (Fig. 8 ). SEE analysis for hemodynamic cerebral ischemia can correspond to the stereotactic and quantita- tive analysis of CBF-SPECT. As an advanced application of this analysis, the severity of hemodynamic cerebral ischemia can be estimated stereotactically using the identical template or segment on vascular territories for getting high judgment accuracy.