Comparison of 18F- and 11C-labeled aryloxyanilide analogs to measure translocator protein in human brain using positron emission tomography.

PURPOSE: Translocator protein (TSPO) is a promising biomarker for neuroinflammation. We developed two new PET ligands, (18)F-PBR06 and (11)C-PBR28, to image TSPOs. Although our prior studies suggest that either of the two ligands could be used to quantify TSPOs in human brain, the studies were done in different sets of subjects. In this study, we directly compared (18)F-PBR06 and (11)C-PBR28 in eight human subjects to determine (1) whether either ligand provides more precise measurements of TSPOs and (2) whether the higher in vitro affinity of PBR06 compared to PBR28 led to higher in vivo binding of (18)F-PBR06 compared to (11)C-PBR28. METHODS: In vivo binding was calculated as total distribution volume (V(T)), using an unconstrained two-tissue compartment model. V(T) was corrected for plasma free fraction (f (P)) to measure ligand binding based on free ligand concentration in brain. RESULTS: Both ligands measured V(T) with similar precision, as evidenced by similarly good identifiability. However, V(T) for both radioligands increased with increasing lengths of data acquisition, consistent with the accumulation of radiometabolites in brain. Despite its higher lipophilicity and higher in vitro affinity, V(T)/f(P) of (18)F-PBR06 was similar to that of (11)C-PBR28. CONCLUSION: Both (18)F-PBR06 and (11)C-PBR28 are similar in terms of precision, sensitivity to accumulation of radiometabolites, and magnitude of in vivo binding. Thus, selection between the two radioligands will be primarily determined by the logistical impact of the different half-lives of the two radionuclides (110 vs 20 min).

PET measurement of the in vivo affinity of 11C-(R)-rolipram and the density of its target, phosphodiesterase-4, in the brains of conscious and anesthetized rats.

UNLABELLED: A variety of phosphodiesterases hydrolyze and terminate the effects of the intracellular second messenger 3',5'-cyclic adenosine monophosphate (cAMP). Phosphodiesterase subtype 4 (PDE4) is particularly abundant in the brain and has been imaged with (11)C-(R)-rolipram, a selective inhibitor of PDE4. We sought to measure in vivo both the binding site density (B(max)) and the radioligand affinity (1/K(D)) of (11)C-(R)-rolipram in the rat brain. We also studied 2 critical factors in small-animal PET scans: the influence of anesthesia and the difference in binding under in vivo and in vitro conditions. METHODS: In vivo, B(max) and K(D) were measured in PET saturation experiments by the administration of (11)C-(R)-rolipram and various doses of carrier (R)-rolipram in conscious and isoflurane-anesthetized rats. The metabolite-corrected arterial input function was measured in each scan. To image conscious rats, the head of the rat was fixed in a holder and the animals were trained to comply with this apparatus. Bound and free (R)-rolipram levels were calculated under transient equilibrium conditions (i.e., at the time of peak specific binding). RESULTS: The B(max) and K(D) of conscious rats were significantly greater than those of anesthetized rats, by 29% and 59%, respectively. In addition, the in vitro K(D) was 3-7 times greater than was the in vivo K(D), although the B(max) was similar in both conditions. CONCLUSION: The in vivo B(max) and K(D) of (R)-rolipram were successfully measured in both conscious and anesthetized rats. K(D) was affected to a greater extent than was B(max) by the 2 conditions. That is, K(D) was increased in the conscious rat, compared with in the anesthetized rat, and K(D) was increased in vitro, compared with in vivo. The current study shows that the rat, a readily available species for research, can be used to measure in vivo both affinity and density of radioligand targets, which can later be directly assessed with standard in vitro techniques.

Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo.

We sought to develop (11)C-labeled ligands for sensitive imaging of brain peripheral benzodiazepine receptors (PBR) in vivo. Two aryloxyanilides with high affinity for PBR were identified and synthesized, namely, N-acetyl- N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline ( 3, PBR01) and N-(2-methoxybenzyl)- N-(4-phenoxypyridin-3-yl)acetamide ( 10, PBR28). 3 was hydrolyzed to 4, which was esterified with [ (11)C]iodomethane to provide [ (11)C] 3. The O-desmethyl analogue of 10 was converted into [ (11)C] 10 with [ (11)C]iodomethane. [ (11)C] 3 and [ (11)C] 10 were each injected into monkey to assess their brain kinetics with positron emission tomography (PET). After administration of either radioligand there was moderately high brain uptake of radioactivity. Receptor blocking and displacement experiments showed that a high proportion of this radioactivity was bound specifically to PBR. In monkey and rat, 3 and 10 were rapidly metabolized by ester hydrolysis and N-debenzylation, respectively, each to a single polar radiometabolite. [ (11)C] 3 and [ (11)C] 10 are effective for imaging PBR in monkey brain. [ (11)C] 10 especially warrants further evaluation in human subjects.

Statistical parametric analysis of cerebral blood flow in vascular dementia with small-vessel disease using Tc-HMPAO SPECT.

BACKGROUND: Subcortical ischemic vascular dementia (SVD) caused by small-artery disease is a major cause of dementia. It still remains unclear, however, whether SVD may present with localized regional cerebral blood flow (rCBF) changes. We aimed to clarify the local rCBF changes associated with dementia in patients with early-stage SVD. METHODS: The subjects consisted of 15 patients with early-stage SVD [Mini Mental State Examination (MMSE) score: 20 +/- 3.5] without apparent brain atrophy (SVD group), 11 patients without dementia with white matter lesions (non-dementia-WML group) and 16 age-matched controls. All the subjects were right-handed and underwent brain perfusion single photon emission computed tomography (SPECT), magnetic resonance imaging and cognitive function testing. Statistical analysis of the differences in the SPECT rCBF was performed by SPM2. The degree of severity of the WMLs was evaluated based on the Scheltens rating scale. RESULTS: The results of SPM analysis revealed that the rCBF in the SVD group was significantly decreased in the pulvinar nuclei of the thalamus of both sides as compared with that in the controls, and in the left pulvinar nucleus as compared with that in the non-dementia-WML group. On the other hand, SPM analysis revealed no significant reduction in rCBF in the non-dementia-WML group as compared with that in the controls. The WMLs in the left parietal region were severer in the SVD group than in the non-dementia-WML group. CONCLUSIONS: In patients with early-stage SVD without apparent brain atrophy, significant rCBF reduction in the bilateral pulvinar nuclei as compared with that in normal controls, and in the left pulvinar nucleus as compared with that in patients without dementia with WMLs was found.

Radiation dosimetry and biodistribution in monkey and man of 11C-PBR28: a PET radioligand to image inflammation.

UNLABELLED: (11)C-PBR28 ([methyl-(11)C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine) is a recently developed radioligand to image peripheral benzodiazepine receptors (PBRs) in brain. The aim of this study was to estimate the human radiation doses of (11)C-PBR28 based on biodistribution data in monkeys and humans. In addition, we scanned 1 human subject who fortuitously behaved as if he lacked the PBR binding protein. METHODS: Whole-body PBR images were acquired after intravenous bolus administration of (11)C-PBR28 in 7 healthy humans (651 +/- 111 MBq) and 2 rhesus monkeys (370 +/- 59.9 MBq). One monkey was scanned after receptor blockade with PK 11195 (10.7 mg/kg intravenously). RESULTS: For typical subjects (subjects 1-6), the 3 organs with highest exposure were those with the high PBR densities (kidneys, spleen, and lungs), and the effective dose was 6.6 microSv/MBq. The unusual subject (subject 7) had 60%-90% less uptake in these 3 organs, resulting in 28% lower effective dose. The activity in the baseline monkey scans was greater than that in humans for organs with high PBR densities. For this reason, the human effective dose was overestimated by 60% with monkey biodistribution data. The monkey with receptor blockade had an overall distribution qualitatively similar to that of the unusual human subject (subject 7), with decreased exposure to lungs, kidney, and spleen. CONCLUSION: The effective dose of (11)C-PBR28 was modest and was similar to that of several other (11)C-radioligands. Lack of receptor binding in the unusual human subject and in the monkey with receptor blockade decreased exposure to organs with high PBR densities and enhanced uptake in excretory and metabolic pathways.

PET imaging with [11C]PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat.

Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia. We recently developed a promising positron emission tomography (PET) ligand, [11C]PBR28, with high affinity and excellent ratio of specific to nonspecific binding. We assessed the ability of [11C]PBR28 PET to localize PBRs in a rat permanent middle cerebral artery occlusion (MCAO) model of neuroinflammation. [11C]PBR28 was intravenously administered to rats at 4 and 7 days after permanent MCAO. In all experiments, arterial blood was sampled for compartmental modeling of regional distribution volumes, and rat brains were sampled after imaging for in vitro [3H]PK 11195 autoradiography and histological evaluation. [11C]PBR28 PET and [3H]PK 11195 autoradiography showed similar areas of increased PBRs, especially in the peri-ischemic core. Results from these in vivo and in vitro methods were strongly correlated. In this first study to demonstrate neuroinflammation in vivo with small animal PET, [11C]PBR28 had adequate sensitivity to localize and quantify the associated increase in PBRs.

PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements.

UNLABELLED: 18F-2beta-Carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (18F-FECNT), a PET radioligand for the dopamine transporter (DAT), generates a radiometabolite that enters the rat brain. The aims of this study were to characterize this radiometabolite and to determine whether a similar phenomenon occurs in human and nonhuman primate brains by examining the stability of the apparent distribution volume in DAT-rich (striatum) and DAT-poor (cerebellum) regions of the brain. METHODS: Two rats were infused with 18F-FECNT and sacrificed at 60 min. Extracts of brain and plasma were analyzed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometric (LC-MS) techniques. Two human participants and 3 rhesus monkeys were injected with 18F-FECNT and scanned kinetically, with serial arterial blood analysis. RESULTS: At 60 min after the injection of rats, 18F-FECNT accumulated to levels about 7 times higher in the striatum than in the cortex and cerebellum. The radiometabolite was distributed at equal concentrations in all brain regions. The LC-MS techniques identified N-dealkylated FECNT as a major metabolite in the rat brain, and reverse-phase HPLC detected an equivalent amount of radiometabolite eluting with the void volume. The radiometabolite likely was 18F-fluoroacetaldehyde, the product expected from the N-dealkylation of 18F-FECNT, or its oxidation product, 18F-fluoroacetic acid. The distribution volume in the cerebellum increased up to 1.7-fold in humans between 60 and 300 min after injection and 2.0 +/- 0.1-fold (mean +/- SD; n = 3) in nonhuman primates between 60 and 240 min after injection. CONCLUSION: An 18F-fluoroalkyl metabolite of 18F-FECNT originating in the periphery confounded the measurements of DAT in the rat brain with a reference tissue model. Its uniform distribution across brain regions suggests that it has negligible affinity for DAT (i.e., it is an inactive radiometabolite). Consistent with the rodent data, the apparent distribution volume in the cerebellum of both humans and nonhuman primates showed a continual increase at late times after injection, a result that may be attributed to entry of the radiometabolite into the brain. Thus, reference tissue modeling of 18F-FECNT will be prone to more errors than analysis with a measured arterial input function.

Diastolic blood pressure influences cerebrovascular reactivity measured by means of 123I-iodoamphetamine brain single photon emission computed tomography in medically treated patients with occlusive carotid or middle cerebral artery disease.

OBJECTIVE: Impaired cerebrovascular reactivity (CVR) to vasodilating agents is a predictor of the onset and prognosis of ischemic stroke. It is realized that the CVR improves or worsens when measured periodically during the clinical course in medically treated patients with occlusive cerebrovascular disease. In these patients, we investigated the possible relationship between the interval change in CVR and that in systemic blood pressure (BP). METHODS: Forty-two patients (14 females and 28 males, mean age +/- SD: 65.3 +/- 8.8 years) with severe stenosis or occlusion of the common carotid, internal carotid, or middle cerebral arteries repeatedly underwent single photon emission computed tomography (SPECT) studies using 123I-iodoamphetamine to measure cerebral blood flow (CBF) distribution and CVR at a more-than-6-month interval (mean +/- SD: 18.5 +/- 8.8 months). The CVR was separately estimated in cerebral hemispheres ipsilateral and contralateral to the most severe vascular lesion as the % increase in CBF after acetazolamide loading to CBF at rest. Systemic BP was measured four times at enrollment and the follow-up SPECT studies during resting and acetazolamide loading. Average BP at each SPECT study was an average of BP measurements during resting and acetazolamide loading. Interval changes in CVR were correlated with those in average systolic BP, average diastolic BP, and average mean arterial BP. RESULTS: The interval changes in CVR were significantly correlated with those in average diastolic BP in the ipsilateral hemisphere (y = 0.71x + 1.43, r2 = 0.11, p < 0.05) and in the contralateral hemisphere (y = 0.88x - 0.46, r2 = 0.16, p < 0.05) but not with those in average systolic BP or average mean arterial BP. CONCLUSIONS: In medically treated patients with steno-occlusive carotid artery or middle cerebral artery lesions, the interval change in CVR to acetazolamide by means of 123I-IMP SPECT was influenced by the diastolic BP at the SPECT studies. Monitoring diastolic BP is important to evaluate interval change in CVR.

Neural mechanism of residual inhibition of tinnitus in cochlear implant users.

Residual inhibition is a transient suppression of tinnitus after auditory stimulation has stopped. We used positron emission tomography to study brain regions underlying residual inhibition in three tinnitus patients with cochlear implants and six normal hearing controls. Regional cerebral blood flow was measured and compared under two conditions: with tinnitus and during the residual inhibition of tinnitus. The right anterior middle and superior temporal gyri (Brodmann areas 21 and 38) were activated during residual inhibition, while the right cerebellum was activated during tinnitus perception in the tinnitus patients. No significant activation was observed in the normal controls. Our results suggest that tinnitus and residual inhibition are related to cortical networks of auditory higher-order processing, memory and attention.

Hemodynamic influences of losartan on the brain in hypertensive patients.

The effects of angiotensin II receptor blockers on cerebral hemodynamics in humans have not been well elucidated. The present study evaluated the effects of losartan on cerebral hemodynamics in hypertensive patients using positron emission tomography. Ten patients with essential hypertension (mean age, 60.8 years) were examined. In each patient, regional cerebral blood flow was measured by [O-15] labeled water positron emission tomography before and after the oral administration of losartan for 8 to 23 weeks. In 8 patients, the baseline regional cerebral blood flow measurement was followed by 1,000 mg of acetazolamide challenge to measure the cerebral perfusion reserve. Systemic blood pressures before and after treatment were 153.8 +/- 10.8/96.0 +/- 6.5 mmHg (systolic mean +/- SD/diastolic mean +/- SD) and 133.4 +/- 11.2/83.6 +/- 6.5 mmHg, respectively; this difference was significant. The baseline global cerebral blood flow values before and after treatment were 38.4 +/- 6.9 ml/min/100 g and 38.2 +/- 8.2 ml/min/100 g, respectively; this difference was not significant. The results of the global cerebral blood flow response to the acetazolamide challenges were not statistically different before and after treatment. A regional analysis showed no statistical difference in regional cerebral blood flow or cerebral perfusion reserve throughout the brain before and after treatment. Losartan's effect on reducing the blood pressure did not affect either the baseline regional cerebral blood flow or the cerebral perfusion reserve in patients with mild to moderate hypertension. The inclusion of losartan in anti-hypertensive regimens could be advantageous for cerebral circulation in patients with essential hypertension.

Myocardial energy provision is preserved by increased utilization of glucose and ketone bodies in CD36 knockout mice.

AIMS: CD36 is an important transporter of long-chain fatty acids (LCFAs) in the myocardium. As we have reported previously, CD36-deficient patients demonstrate a marked reduction in myocardial uptake of (123)I-15-(p-iodophenyl)-(R, S)-methyl pentadecanoic acid (BMIPP), which is an analog of LCFAs, while myocardial (18)F-fluorodeoxy-glucose (FDG) uptake is increased. However, it has not been clarified whether energy provision is preserved in patients with CD36 deficiency. The aims of the current study were to investigate the myocardial uptake of glucose and alterations in myocardial metabolites in wild-type (WT) and CD36 knockout (KO) mice. METHODS AND RESULTS: High-resolution positron emission tomography (PET) demonstrated markedly enhanced glucose uptake in KO mouse hearts compared with those of WT mice in real-time. The myocardial protein expression of glucose transporter protein 1 (GLUT1) was significantly enhanced in KO mice compared to WT mice, whereas that of GLUT4 was not altered. While the myocardial expression of genes involved in fatty acid metabolism did not increase in KO mice, that of genes related to glucose utilization compensatorily increased in KO mice. The metabolomic analysis of cardiac tissues revealed that the myocardial concentrations of ATP and phosphocreatine were maintained, even in KO mice. The concentration of 3-hydroxybutyric acid and mRNA expression of hydroxybutyrate dehydrogenase in the heart were significantly higher in KO than in WT mice. CONCLUSION: These data suggest that high-energy phosphate might be preserved by the increased utilization of glucose and ketone bodies in CD36KO mouse hearts under conditions of deficient LCFA uptake.

Detection of misery perfusion with split-dose 123I-iodoamphetamine single-photon emission computed tomography in patients with carotid occlusive diseases.

BACKGROUND AND PURPOSE: Patients with carotid occlusive disease and stage 2 cerebral hemodynamic failure, characterized by an increased oxygen extraction fraction (OEF) as measured by positron emission tomography (PET) and otherwise known as misery perfusion, have a high risk of cerebral ischemia and subsequent stroke. In clinical practice, the detection of patients with misery perfusion through the use of widely available, noninvasive, and cost-effective modalities such as single-photon emission computed tomography (SPECT) is extremely important. METHODS: We evaluated the relationships between the regional hemodynamic status of cerebral circulation, measured with split-dose [123I] N-isopropyl-p-iodoamphetamine SPECT (123I-IMP SPECT) and an acetazolamide challenge, and hemodynamic parameters, including OEF measured with PET, in 27 patients with both unilateral and bilateral carotid occlusive diseases. RESULTS: A significant negative correlation was found between the SPECT-measured cerebrovascular reserve after acetazolamide administration and both the PET-measured OEF and cerebral blood volume. Neither the cerebrovascular reserve nor the cerebral blood flow index, when expressed as a SPECT-measured cerebrum-to-cerebellum ratio, was useful for detecting lesions with an elevated OEF. However, a combination of the cerebrovascular reserve and cerebral blood flow index showed high sensitivity, specificity, and positive predictive value for the detection of misery perfusion. CONCLUSIONS: Our study suggests that split-dose 123I-IMP SPECT with an acetazolamide challenge could be useful for screening patients with misery perfusion in carotid occlusive diseases.

Assessment of acetazolamide reactivity in cerebral blood flow using spectral analysis and technetium-99m hexamethylpropylene amine oxime.

Cerebral blood flow (CBF) can be quantified noninvasively using the brain perfusion index (BPI), determined from radionuclide angiographic data generated with technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO). Previously, the BPI has been calculated using graphical analysis (GA); however, the GA method is greatly affected by the first-pass extraction fraction and retention fraction, which are not only variable, but lower in cases with an increased CBF, such as after the administration of acetazolamide. Thus, GA-calculated BPI values (BPIG) may not reflect the absolute CBF. The objective of this study was to use the spectral analysis of radionuclide angiographic data collected using 99mTc-HMPAO to examine changes in the BPI after the administration of acetazolamide. We studied the CBF of both cerebral hemispheres in six healthy male volunteers; the BPI was measured at rest and after the intravenous administration of 1 g of acetazolamide. In all participants, an H215O positron emission tomography (PET) examination was also performed, and the spectral analysis-calculated BPI values (BPIS) and BPIG values were compared with the actual CBF measured using H215O PET (mCBFPET). The BPIS was 1.070 +/- 0.051 (mean +/- SD) at rest and 1.497 +/- 0.098 after acetazolamide; the corresponding BPIG values were 0.646 +/- 0.073 and 0.721 +/- 0.107. The BPIS values were significantly correlated with the mCBFPET values, whereas the BPIG values were not. According to the BPIS values, the increase in BPI after the intravenous administration of acetazolamide was 40.1 +/- 8.4%, as opposed to an increase of only 11.3 +/- 6.5% according to the BPIG values. These results suggest that the spectral analysis of 99mTc-HMPAO-generated data yields a more reliable BPI than GA for the quantification of CBF after acetazolamide administration.

Cerebral and cerebellar activation in power and precision grip movements: an H2 15O positron emission tomography study.

SUMMARY: Most human manual grip movements can be divided into power gripping and precision gripping, but central neural control during these tasks remains unclear. We investigated activation of the whole brain to analyze how simple hand movements are performed. The cerebral blood flow of seven healthy right-handed volunteers was measured by H2 15O positron emission tomography during right grip tasks without gripping a target object. Auditory-cued, repetitive power grips (i.e., fist making) and repetitive precision grips (i.e., opposition of the tip of the index finger and the tip of the thumb) were performed at 1.26 Hz. The areas activated during both tasks were the left primary sensorimotor cortex, caudal portion of the dorsal premotor, caudal portion of the supplementary motor area, cingulate motor area, and the right spinocerebellum and intermediate region of the cerebrocerebellum in comparison with the rest state. The analysis of power grip-precision grip tasks showed the activated peaks in the upper portion of the left sensorimotor area and right cerebellar vermis, but these areas were activated in both the tasks [(power grip-rest) and (precision grip-rest)] with uncorrected P < 0.001 as the statistical criterion. With P < 0.05 corrected as the statistical criterion, the results showed no significant activated peaks in regional cerebral blood flow. Our findings indicate no difference in brain activation between the acts of power grip and precision grip without a target object.

Statistical image analysis of cerebral blood flow in vascular dementia with small-vessel disease.

UNLABELLED: Small-vessel disease with dementia, which is the most frequent type of vascular dementia (VaD), often shows a cerebral blood flow (CBF) distribution with no obvious focal abnormalities and is therefore difficult to evaluate objectively. In this study, we combined CBF SPECT with 3-dimensional fractal analysis (3D-FA) to quantitatively assess the heterogeneity of CBF distribution and with 3-dimensional stereotactic surface projections (3D-SSP) to evaluate the distribution of CBF. We then evaluated the clinical validity of these techniques for the imaging diagnosis of VaD. METHODS: The subjects consisted of 17 patients who were diagnosed as having VaD due to small-vessel disease (VaD group) on the basis of a full clinical examination, including history, neuropsychologic tests, neurologic examination, and neuroimaging methods, and 20 healthy volunteers (control group). CBF SPECT was performed with (99m)Tc-hexamethylpropyleneamine oxime, and the reconstructed images were subjected to image processing by 3D-FA and 3D-SSP. Based on the results, the fractal dimension (FD) was compared between the VaD and control groups, and the distribution pattern of CBF was examined in the VaD group. RESULTS: The mean FD values in the VaD group and the control group were 1.093 +/- 0.153 and 0.853 +/- 0.062 (mean +/- SD), respectively. The mean FD value in the VaD group was significantly higher than that in the control group (P < 0.0001). 3D-SSP analysis in the VaD group showed that there were 2 abnormal patterns: One was globally reduced blood flow in the whole cerebral cortex, and the other was a reduction mainly confined to the frontal region. CONCLUSION: CBF SPECT images showed higher mean FD values in the VaD group than in the control group, suggesting a difference in the heterogeneity of CBF. Image processing with 3D-SSP successfully revealed that reduced cortical blood flow could be divided into 2 patterns. Because image analysis techniques, such as 3D-FA and 3D-SSP, allowed the simple and objective evaluation of CBF in patients with VaD, these methods seem to be useful for detailed examination of the blood flow pattern detected by CBF SPECT in patients with VaD.

Cortical processing of tactile language in a postlingually deaf-blind subject.

We compared neural activation detected by magnetoencephalography (MEG) during tactile presentation of words and non-words in a postlingually deaf-blind subject and six normal volunteers. The left postcentral gyrus, bilateral inferior frontal gyri, left posterior temporal lobe, right anterior temporal lobe, bilateral middle occipital gyri were activated when tactile words were presented to the right hand of the deaf-blind subject. This set of activated regions was not observed in the normal volunteers, although activation of several combinations of these regions was detected. Positron emission tomography confirmed the location of the MEG-activated areas in the deaf-blind subject. Our results demonstrated that the deaf-blind subject is heavily involved in interpreting tactile language by enhancing cortical activation of cognitive and semantic processing.

Quantification of the heterogeneity of cerebral blood flow in vascular dementia.

BACKGROUND: In vascular dementia (VaD), assessment of cerebral blood flow by single photon emission computed tomography (CBF SPECT) has been used to detect a patchy decrease of blood flow or a frontal reduction. In addition to reduced blood flow, the heterogeneous distribution of cerebral blood flow is often observed in VaD. However, no objective method to evaluate the heterogeneity has been established. In this study, we applied three-dimensional fractal analysis (3D-FA) to CBF SPECT images as a method for assessing the heterogeneity of the cerebral blood flow distribution in VaD. SUBJECTS AND METHODS: The subjects included 18 patients with a diagnosis of VaD (aged 69.7 +/- 8.3) based on neuropsychological testing and imaging findings and 18 age-matched controls (aged 66.9 +/- 10.3). CBF SPECT images were obtained with (99m)Tc-hexamethyl propyleneamine oxime. On the reconstructed images, we obtained a linear regression equation between the cut-off values (from 35 to 50 %) and the number of voxels with a radioactivity exceeding the cut-off value transformed into natural logarithms, and then calculated the fractal dimension from the slope of the regression line thus obtained. The Mini-Mental State Examination (MMSE) was used to evaluate cognitive function. RESULTS: The fractal dimensions were 1.084 +/- 0.153 and 0.853 +/- 0.062 (mean +/- SD) in the VaD and control groups, respectively. The fractal dimension was significantly greater in the VaD group than in the control group (p < 0.0001). A significant negative correlation was observed between the fractal dimension and the MMSE score in the VaD group (r = 0.871, p < 0.0001). CONCLUSIONS: Because the CBF SPECT images of VaD patients showed a higher fractal dimension, these images were quantitatively more heterogeneous than those of age-matched controls. In the VaD group, cognitive function was shown to decline as the fractal dimension increased and images became more heterogeneous.

Heterogeneity of cerebral blood flow in Alzheimer disease and vascular dementia.

BACKGROUND AND PURPOSE: Alzheimer disease (AD) and vascular dementia (VaD) are the two major diseases that cause dementia, and early diagnosis is important. Single photon emission CT (SPECT) of cerebral blood flow (CBF) is used for the early detection of dementia and as an auxiliary method for follow-up. AD shows reduced posterior blood flow and VaD manifests reduced anterior blood flow on CBF SPECT images. We examined the usefulness of 3D fractal analysis of CBF SPECT images to objectively quantify the heterogeneity of CBF in patients with AD and VaD. METHODS: Thirty-two patients with AD and 22 with VaD based on neuropsychologic tests and imaging findings, as well as 20 age-matched control subjects underwent technetium-99m hexamethyl propyleneamine oxime CBF SPECT. We then conducted statistical image processing by 3D fractal analysis on reconstructed data. Fractal dimension, an index of heterogeneity, was then calculated for the whole brain, as well as for the anterior and posterior regions of the brain. A higher fractal dimension indicates that the CBF SPECT image is uneven. The ratio of fractal dimension of the anterior region to fractal dimension of the posterior region (A/P ratio) was calculated. Heterogeneity of CBF was compared among the AD, VaD, and control groups. RESULTS: Fractal dimensions of the AD, VaD, and control groups were 1.072+/-0.179 (mean +/- SD), 1.005+/-0.156, and 0.806+/-0.06, respectively. A significant difference of fractal dimension was noted between the control group and the two types of dementia (P<.0001); however, no significant difference was noted between the AD and VaD groups. The A/P ratios of the AD and VaD groups were significantly different (0.952 and 1.163, respectively; P<.01). CONCLUSION: Analysis of CBF SPECT images quantitatively showed that the fractal dimension was significantly higher (indicating heterogeneity) in patients with AD and VaD when compared with age-matched control subjects. Comparison of the A/P ratio on CBF SPECT images between AD and VaD groups showed that the heterogeneity of CBF was posterior-dominant for AD and anterior-dominant for VaD. Thus, 3D fractal analysis enabled a simple and objective evaluation of the heterogeneity of CBF in patients with AD and VaD.

Clinical significance of cerebrovascular reserve in acetazolamide challenge -comparison with acetazolamide challenge H2O-PET and Gas-PET.

OBJECTIVE: The response of cerebral blood flow (CBF) to acetazolamide (ACZ) challenge is frequently determined in clinical settings to evaluate cerebrovascular reserve (CVR). A reduced CVR can indicate patients with occlusive cerebrovascular disease and compromised hemodynamics who may be at increased risk of cerebral ischemia. However, how precisely ACZ reflects cerebral hemodynamic impairment remains obscure. The present study aims to clarify the pathological significance of CVR in patients with occluded carotid arteries. METHODS: We recruited seventeen patients with occlusive lesions in the internal carotid artery (ICA) or middle cerebral artery (MCA). We assessed these patients in terms of resting cerebral blood flow (CBF) and the CVR response to ACZ challenge using H20 positron emission tomography (PET). In addition, we evaluated hemodynamic parameters including oxygen extraction fraction (OEF) using Gas-PET. RESULTS: We identified a significant negative correlation between the CVR and OEF or the cerebral blood volume (CBV)/CBF ratio, as a potential index of cerebral perfusion pressure. Although the CVR values were reduced in all regions with elevated OEF (Stage II), these values were highly variable regardless of the CBV/CBF ratios. The cut-off value of CVR alone could not detect Stage II, but when combined with resting CBF, misery perfusion accompanied by increased OEF was detected with high sensitivity (6/7) and specificity (61/62). CONCLUSION: CVR could be applied as an index reflecting both autoregulatory capacity and OEF. The present study also supported the notion that SPECT with ACZ challenge can be clinically applied to detect misery perfusion.

Cerebral hemodynamics and metabolism in adult moyamoya disease: comparison of angiographic collateral circulation.

PURPOSE: The extent of the hemodynamic and metabolic impairments in adult patients with moyamoya disease is still controversial. The aim of the present study was to evaluate the hemodynamic and metabolic status in relation to the development of basal moyamoya vessels (BMVs). METHODS: The cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral blood volume (CBV) were measured using PET in ten patients with ischemic adult moyamoya disease (mean age, 36.6 years) and six age-matched normal controls (mean age, 33.3 years). The cerebrovascular reserve (CVR) after acetazolamide (ACZ) loading was also estimated using iodine-123 N-isopropyl-p-iodo amphetamine single photon emission computed tomography (123I-IMP SPECT). RESULTS: Based on the angiographic findings, eleven cerebral hemispheres with well-developed BMV (extensive BMV hemispheres) and nine cerebral hemispheres with diminished BMV (diminished BMV hemispheres) were identified. The main routes of collateral circulation in extensive BMV hemispheres were BMVs and leptomeningeal anastomoses. On the other hand, in diminished BMV hemispheres, transdural anastomosis was predominant, and leptomeningeal anastomoses were less developed. In cortices distal to the occluded internal carotid artery, the extensive BMV hemispheres exhibited a significantly lower CBF, CMRO2, CBF/CBV, and CVR (p < 0.05) and a significantly higher CBV and OEF than in diminished BMV hemispheres and controls (p < 0.05). Except for the CBF in the white matter, the mean hemodynamic and metabolic parameters of the diminished BMV hemispheres were not significantly different from those of the controls. CONCLUSION: The extensive development of basal moyamoya vessels is a sign of severe hemodynamic impairment in adult patients with ischemic moyamoya disease. The results may not apply to adults with hemorrhagic onset.