Assessment of Hemodynamic Compromise Using Computed Tomography Perfusion in Combination with 123I-IMP Single-Photon Emission Computed Tomography without Acetazolamide Challenge Test.

OBJECTIVES: The acetazolamide challenge test in conjunction with 123I-IMP single-photon emission computed tomography (SPECT) is a known method of assessing cerebrovascular reserve capacity. In this study, we investigated whether CT perfusion in combination with resting state 123I-IMP SPECT could be used instead of the acetazolamide challenge test to evaluate hemodynamic compromise in patients with atherosclerotic occlusive disease. METHODS: Twenty consecutive patients with unilateral internal carotid artery or middle cerebral artery steno-occlusive disease were enrolled. 123I-IMP SPECT was performed with and without the acetazolamide challenge test, and with CT perfusion. Cerebral blood flow (CBF), cerebral blood volume, and mean transit time (MTT) obtained by CT perfusion were compared with CBF and cerebrovascular reactivity (CVR) obtained by 123I-IMP SPECT. RESULTS: The asymmetry ratio of MTT as measured by CT perfusion showed a strong correlation with the CVR to acetazolamide as measured by 123I-IMP SPECT (ρ = -.780, P <.001). Based on the CBF obtained through 123I-IMP SPECT and the MTT obtained through CT perfusion, hemodynamic compromise was detected with high sensitivity (1.000) and specificity (.929), and a cutoff value of 30% was found to be suitable for the asymmetry ratio of MTT. MTT prolongation was significantly improved after revascularization surgery in hemodynamic compromise (P = .028). CONCLUSION: MTT as measured by CT perfusion in combination with CBF as measured by resting state 123I-IMP SPECT may be useful for evaluating hemodynamic compromise as an alternative to the acetazolamide challenge test.

N-Isopropyl-p-iodoamphetamine hydrochloride Is predominantly metabolized by CYP2C19.

[(123)I]N-Isopropyl-p-iodoamphetamine hydrochloride ([(123)I]IMP) is clinically used to evaluate blood flow in the brain on single photon emission-computed tomography. This is a rare radiopharmaceutical that undergoes metabolism. The first step is reported to be [(123)I]p-iodoamphetamine formation. The drug-metabolizing enzyme(s) involved remain(s) unclear. This study examined the roles of human cytochrome P450 (P450) in the metabolism of nonradiolabeled IMP with the use of human liver microsomes (HLM) and recombinant human CYP1A1, -1A2, -1B1, -2A6, -2B6, -2C8, -2C9, -2C19, -2D6, -2E1, -3A4, and -3A5. Disappearance of IMP was examined because p-iodoamphetamine was not available. IMP (0.5 µM) time-dependently disappeared when HLM and NADPH-generating system were added to the reaction mixture. (S)-Mephenytoin (1 mM) inhibited the IMP disappearance by approximately 90%. The disappearance of IMP was predominantly catalyzed by recombinant CYP2C19, with K(m) and V(max) of 8.6 µM and 9.7 nmol · min(-1) · nmol P450(-1), respectively. IMP disappearance in CYP2C19-deficient HLM (CYP2C19*2/*2) was approximately 30% of that in the presence of HLM harboring wild-type CYP2C19, indicating that IMP is polymorphically metabolized by CYP2C19. High-performance liquid chromatography of the incubation mixture of IMP and CYP2C19 revealed an unidentified peak. As the area of the IMP peak decreased, the area of this unidentified peak increased in a time-dependent fashion. The peak was also detectable on incubation of IMP with HLM. Mass spectrometry revealed that the molecular weight of a compound in this unidentified peak was the same as that of p-iodoamphetamine. Thus, we demonstrated that IMP was predominantly metabolized by CYP2C19 to form p-iodoamphetamine.

The REICA method for quantification of cerebral blood flow is less affected by lung washout of [123I] IMP than the graph-plot method.

OBJECTIVE: The [Formula: see text]-Ray Evaluation with Iodoamphetamine for Cerebral blood flow Assessment (REICA) method is a new method for cerebral blood flow (CBF) quantification with SPECT and [123I] IMP, which does not require invasive arterial blood sampling, or the use of a regression formula. Moreover, it takes into consideration tracer retention, while the Graph-Plot (GP) method does not. This study aims to confirm the reliability of the REICA method in calculating CBF by accounting for pulmonary tracer retention artefact. METHODS: Data of 100 patients were retrospectively analyzed. Washout rate (WR) was defined as 1- (max count /min count) in the lungs. The bias due to WR was analyzed by dividing the data into high/low WR groups and a multiple regression analysis was also performed. RESULTS: The REICA method did not show significant bias according to the [Formula: see text] test ([Formula: see text]), while the GP method showed significant bias ([Formula: see text]). Both the REICA and GP methods showed significant correlation with autoradiography (ARG) method ([Formula: see text], [Formula: see text]) and WR ([Formula: see text], [Formula: see text]) when analyzed via multiple regression analysis with covariates of age and sex. CONCLUSIONS: The REICA method is a reliable method for CBF quantification, which is unaffected by tracer washout through the lungs unlike the GP method.

Assessment of SPECT-CT fusion images and semi-quantitative evaluation using SUV in 123I-IMP SPECT in patients with choroidal melanoma.

OBJECTIVES: The aim of this study was to assess the diagnostic ability of N-isopropyl-p-[I-123] iodoamphetamine (IMP) SPECT semi-quantitative evaluation based on the standardized uptake value (SUV) in patients with choroidal melanoma. The secondary aim was to investigate the 6-h IMP SPECT imaging in comparison with 24-h imaging. METHODS: Twenty-five patients (14 males and 11 females, mean age of 59.2-year-old) were analyzed in this retrospective study. Patients underwent 24-h IMP SPECT imaging with a gamma camera after intravenous injection of IMP. Twelve of 25 patients underwent 6-h SPECT imaging in addition to the 24-h imaging. All acquired SPECT images were fused with CT images using an image-analysis software. To assess the utility of semi-quantitative evaluation method, we introduced an image evaluation method using SUVmax comparing with conventional count-based uptake index (UI) evaluation of the lesion. Volumes-of-interest (VOIs) for SUVmax and regions-of-interest (ROIs) for UI were drawn referring to the SPECT-CT fusion image. Then the relationship between the 6- and 24-h images was examined both in SUV and UI evaluation. Furthermore, the relationship between the size category classification (SCC) by UICC/AJCC: 1-4 scales and each semi-quantitative value using SUVmax and UI was also assessed. RESULTS: SUVmax of the tumor was significantly higher than that of the normal side; 2.37 ± 0.88 and 1.77 ± 0.39 (P < 0.05) on 6-h image, 4.17 ± 1.73 and 2.04 ± 0.45 (P < 0.001) on 24-h image, respectively. UI of the tumor was also significantly higher than that of the normal side; 2.24 ± 0.67 and 1.53 ± 0.35 (P < 0.01) on 6-h image, 3.79 ± 1.24 and 1.67 ± 0.44 (P < 0.001) on 24-h image, respectively. There was a strong significant linear relationship in the evaluation with SUVmax between 6- and 24-h on the tumor side (R2 = 0.88, P < 0.0001), compared to that with Tumor-UI (R2 = 0.35, P < 0.05). In addition, SUVmax of the tumor clearly differentiated the SCC of the tumor category 4 from that of category 1, where SUVmax of the tumor for categories 1‒4 were 2.56 ± 0.59, 4.33 ± 1.92, 4.63 ± 1.45, and 5.73 ± 1.69, respectively (P < 0.05, for categories 1 and 4). CONCLUSIONS: The semi-quantitative evaluation by SUV of 123I-IMP SPECT images fused with CT images is useful for detecting choroidal melanoma. Moreover, 6-h imaging with SUV-based evaluation of 123I-IMP SPECT is promising compared to the conventional count-based UI evaluation method. Trial registration This study is registered in UMIN Clinical Trials Registry (UMIN-CTR) as UMIN study ID: UMIN000038174.

Serum protein binding displacement: theoretical analysis using a hypothetical radiopharmaceutical and experimental analysis with 123I-N-isopropyl-p-iodoamphetamine.

INTRODUCTION: The binding of radiopharmaceutical to serum proteins is thought to be an important factor that restricts its excretion and accumulation in tissue. We calculated the effect of inhibitors of serum protein binding using a hypothetical radiopharmaceutical. In vitro experiments and protein binding inhibitor-loaded monkey scintigraphy were then conducted using (123)I-N-isopropyl-p-iodoamphetamine (IMP) as the radiopharmaceutical. METHODS: Free fraction ratios of radiopharmaceutical were calculated with one radiopharmaceutical, two serum proteins and two specific inhibitors in the steady state at various serum protein concentrations. In vitro protein binding inhibition studies using human, rat and monkey sera were performed with site-selective displacers of specific binding sites: 400 microM 6-methoxy-2-naphthylacetic acid (6MNA; a major nabumeton metabolite) as a serum albumin Site II inhibitor and 400 microM erythromycin (ETC) as an alpha(1)-acid glycoprotein (AGP) site inhibitor. Scintigraphy with or without 6MNA loading of monkeys was performed. RESULTS: The theoretical findings roughly corresponded to the experimental results. Approximately 75% of IMP bound to serum albumin Site II and AGP in the species examined. The free fraction of IMP (25.0+/-0.6% for human, 22.8+/-0.4% for monkey, 23.7+/-0.3% for rat) increased with loading of specific protein binding inhibitors (6MNA: 28.0+/-0.3% for human, 24.5+/-0.7% for monkey, 24.3+/-0.2% for rat; ETC: 26.3+/-0.4% for human, 29.5+/-1.1% for monkey, 26.0+/-0.7% for rat) and was serum protein concentration dependant based on the results of calculations. Simultaneous administration of 6MNA and ETC produced a higher free fraction ratio of IMP (31.9+/-1.0% for human, 34.6+/-0.4% for monkey, 27.0+/-0.3% for rat) than summation of the single administrations of 6MNA and ETC (domino effect) in human, rat and monkey sera. Rapid cerebral accumulation was observed with 6MNA loading in monkey scintigraphy. CONCLUSIONS: 6MNA appears to change the pharmacokinetics and brain accumulation of IMP in monkeys. Further studies in human are required.

Frontotemporal Dementia Misdiagnosed for Post-Treatment Lyme Disease Syndrome or vice versa? A Treviso Dementia (TREDEM) Registry Case Report.

We describe the case of a 61-year-old woman diagnosed with Borreliosis at the age of 57. Subsequently, the patient developed depression, anxiety, and behavioral disturbances. A lumbar puncture excluded the condition of Neuroborreliosis. The diagnostic workup included: an MRI scan, a 18F-FDG PET, a 123I-ioflupane-SPECT, an amyloid-ß PET, a specific genetic analysis, and a neuropsychological evaluation. Based on our investigation, the patient was diagnosed with probable behavioral-frontotemporal dementia (bvFTD), whereas in the previous years, the patient had been considered firstly as a case of Post-Treatment-Lyme Disease and, secondly, a psychiatric patient. We believe that, in the present case, such initial symptoms of Borrelia infection may have superimposed on those of bvFTD rather than playing as a contributory cause.

Vestibular Function Impairment in Alzheimer's Disease.

BACKGROUND: Falls and fractures due to impaired balance in patients with Alzheimer's disease (AD) have an adverse effect on the clinical course of the disease. OBJECTIVE: To evaluate balance impairment in AD from the viewpoint of vestibular functional impairment. METHODS: The subjects were 12 patients with AD, 12 dementia-free elderly adults, and 12 younger adults. Vestibular function was assessed using a stepping test, caloric nystagmus, and a visual suppression (VS) test. RESULTS: The stepping test was abnormal in 9 of the 12 patients in the AD group. An abnormal stepping test was not associated with self-reported dizziness or tendency to fall. Significant VS abnormalities were present in the AD group. The suppression rate of VS was lower in AD patients with either a tendency to fall or constructional apraxia than in AD patients without either. The velocity of the rapid phase of caloric nystagmus before the VS test was similar in the AD group and the elderly control group. Significant abnormalities of both caloric nystagmus and VS were not present in either the elderly or the younger control groups. CONCLUSION: AD could involve impairments in the vestibular control of balance. The VS test is useful for assessing the tendency to fall in AD. Impairment of VS in AD might arise from cerebral vestibular cortex impairment rather than comorbid peripheral vestibular disorders.

Estimation of 123I-IMP arterial blood activity from dynamic planar imaging of the chest using a graph plot method for the quantification of regional cerebral blood flow.

PURPOSE: I-123-labeled N-isopropyl-p-iodoamphetamine ((123)I-IMP) is used for the measurement of regional cerebral blood flow (rCBF). A continuous or single arterial blood sampling (ABS) is necessary to estimate an integral of arterial input function (AIF) for the measurement of rCBF by using a microsphere model analysis. Therefore, a method of measuring rCBF without any blood sampling is desired. The aim of this study was to establish a method to estimate the AIF from the time-activity curve of the lungs after an injection of (123)I-IMP, using a regression analysis for the measurement of rCBF without any blood sampling. MATERIALS AND METHODS: Thirty-seven prospective studies in 10 consecutive patients were enrolled. A chest planar dynamic imaging for 3 min and continuous ABS for 5 min after a bolus injection of 167MBq (123)I-IMP were performed in all studies. Data from the chest imaging were analyzed in comparison with ABS data (AIF(5)) in the first 10 studies, and an equation for estimation yielding accurate AIF(5) from the total counts cleared from the lungs, during 5 min after injection of (123)I-IMP (TCL(5)), was derived. The validity of the proposed method was evaluated in the subsequent 27 studies. RESULTS: A good correlation was obtained between the AIF and TCL by regression analysis in the first 10 studies (r = 0.94, P < 0.001). An equation for the estimation of AIF by the regression analysis in the first 10 studies was defined as follows: estimated AIF = 2147 + 4.174 x TCL(5). In the subsequent 27 studies, a good linear correlation was obtained between the measured and the estimated AIF(5) by using the equation (r = 0.79, P < 0.001). CONCLUSION: AIF(5) can be accurately estimated from TCL(5). Therefore, estimated AIF(5) can be used for the measurement of rCBF instead of ABS data.

Remarkable increase in 14C-acetate uptake in an epilepsy model rat brain induced by lithium-pilocarpine.

The present study demonstrates changes in rat brain glial metabolism during the acute phase of epilepsy. Status epilepticus (SE) was induced using the lithium-pilocarpine model. Glial metabolism was measured with (14)C-acetate. Local cerebral blood flow and glucose metabolism were also measured using (14)C-N-isopropyl-p-iodoamphetamine (IMP) and (14)C-2-deoxyglucose (2DG), respectively. At the initiation of the seizure, (14)C-acetate uptake did not change significantly. However, a marked increase was observed 2 h after the pilocarpine injection in all brain regions studied. The increase of brain uptake was transient, and the maximum enhancement was seen at 2 h after the pilocarpine injection. The increase of (14)C-acetate uptake was almost to the same degree in all regions, whereas (14)C-IMP and (14)C-2DG uptakes showed a heterogeneous increase. In the case of (14)C-IMP, the highest increase was observed in the thalamus (280%), and a moderate increase (120 to 150%) was seen in the orbital cortex, cingulate cortex and pyriform cortex. (14)C-2DG uptake increased by 130 to 240% in most regions of the brain, however, an increase of only 40 and 20% was observed in the cerebellum and pons-medulla, respectively. These results demonstrated that glial energy metabolism was markedly enhanced during a prolonged seizure. To our knowledge, this study is the first observation showing large and widespread glial metabolic increases in the rat brain during status epilepticus.

Inhibitory effect of methyl ethyl ketone upon the enhancement of cerebral blood flow during status epilepticus induced by lithium-pilocarpine.

Significant increases in local cerebral blood flow during lithium-pilocarpine (Li-P) induced seizure have been reported. We recently found that both acetone and methyl ethyl ketone (MEK) showed anticonvulsive effects in status epilepticus induced by Li-P in rats. In this study, we examined whether MEK also suppressed the enhancement of local cerebral blood flow induced by Li-P with a simplified autoradiographic method using [(14)C]-para-iodo-N-isopropyl amphetamine ([(14)C]-IMP). Significant increases in local cerebral blood flow in the thalamus, hypothalamus, hippocampus and cerebellum were observed in Li-P induced status epilepticus rats. Pretreatment with MEK (8 mmol/kg) completely suppressed the enhancement of local cerebral blood flow to or below the control level in all regions.