Neuronal Alterations in Secondary Thalamic Degeneration Due to Cerebral Infarction: A 11C-Flumazenil Positron Emission Tomography Study.

BACKGROUND: Studies using animal experiments have shown secondary neuronal degeneration in the thalamus after cerebral infarction. Neuroimaging studies in humans have revealed changes in imaging parameters in the thalamus, remote to the infarction. However, few studies have directly demonstrated neuronal changes in the thalamus in vivo. The purpose of this study was to determine whether secondary thalamic neuronal damage may manifest as a decrease in central benzodiazepine receptors in patients with cerebral infarction and internal carotid artery or middle cerebral artery disease. METHODS: We retrospectively analyzed the data of 140 patients with unilateral cerebral infarction ipsilateral to internal carotid artery or middle cerebral artery disease. All patients had quantitative measurements of 11C-flumazenil binding potential (FMZ-BP), cerebral blood flow, and cerebral metabolic rate of oxygen using positron emission tomography in the chronic stage. Region of interest analysis was performed using NeuroFlexer-an automated region of interest analysis software using NEUROSTAT. RESULTS: In the thalamus ipsilateral to the infarcts, the values of FMZ-BP, cerebral blood flow, and cerebral metabolic rate of oxygen were significantly lower than those in the contralateral thalamus. Significant correlations were found between the ipsilateral-to-contralateral ratio of FMZ-BP and the ipsilateral-to-contralateral ratio of cerebral blood flow or cerebral metabolic rate of oxygen in the thalamus. Patients with corona radiata infarcts and striatocapsular infarcts had significantly decreased ipsilateral-to-contralateral FMZ-BP ratio in the thalamus compared with those without. The ipsilateral-to-contralateral ratio of FMZ-BP in the thalamus was significantly correlated with the ipsilateral-to-contralateral cerebral metabolic rate of oxygen ratio in the frontal cortex and showed a significant negative correlation with the number of perseverative errors on the Wisconsin Card Sorting Test. CONCLUSIONS: Secondary thalamic neuronal damage may manifest as a decrease in central benzodiazepine receptors in patients with cerebral infarction and internal carotid artery or middle cerebral artery disease, which may be associated with frontal lobe dysfunction.

Misery Perfusion and Tau Deposition in Atherosclerotic Major Cerebral Artery Disease: A 18F-Florzolotau Positron Emission Tomography Study.

BACKGROUND: Studies using animal models have shown that cerebral hypoperfusion causes hyperphosphorylation of tau protein, leading to neuronal damage. However, the relationship between hypoperfusion and tau deposition in humans is unclear. Hence, we aimed to determine whether cerebral hypoperfusion leading to decreased blood flow relative to metabolic demand [increased oxygen extraction fraction (OEF), misery perfusion] is associated with increased tau deposition in patients with atherosclerotic internal carotid artery or middle cerebral artery disease. METHODS: We prospectively evaluated the distribution of tau aggregate deposition using positron emission tomography and 18F-florzolotau (PMPBB3 [1-fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol)]) in 8 patients with atherosclerotic disease of the internal carotid artery or middle cerebral artery. The standardized uptake value ratio of 18F-florzolotau at 100 to 110 minutes after injection was calculated using the cerebellar cortex as a reference region and was correlated with OEF obtained from 15O-gas positron emission tomography in the middle cerebral artery distributions. RESULTS: Significant decreases in cerebral blood flow and cerebral metabolic rate of oxygen and increases in OEF were found in the hemisphere ipsilateral to the arterial lesion. 18F-florzolotau standardized uptake value ratio in this region was also greater than that in the contralateral hemisphere. In the ipsilateral hemisphere, 18F-florzolotau standardized uptake value ratio positively correlated with OEF values. CONCLUSIONS: This pilot study with a small sample size suggests that increases in OEF-misery perfusion-may be associated with increased tau aggregates deposition in atherosclerotic internal carotid artery or middle cerebral artery disease.

Visit-to-Visit Blood PressureVariations and Hemodynamic Deterioration in Atherosclerotic Major Cerebral ArteryDisease.

OBJECTIVE: Visit-to-visit variations in blood pressure (BP) in patients with atherosclerotic major cerebral artery disease could impair the function of cerebral collaterals, leading to hemodynamic deterioration at follow-up. However, few studies have investigated the relationship between visit-to-visit BP variability and changes in hemodynamic parameters at follow-up. MATERIALS AND METHODS: We evaluated 35 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery disease with no ischemic episodes during follow-up (mean: 35 ± 20 months); these patients had a three-time visit for positron emission tomography examinations with 15O-gas. Differences in the mean hemispheric values of hemodynamic parameters in the cortical territory of the diseased artery between the first and third examinations (changes at follow-up) were correlated with the coefficient of variation (CoV) in three systolic BP (SBP) values at the three examinations (BP variability during follow-up). RESULTS: CoV values were negatively correlated with changes in oxygen metabolism or cerebral blood flow/cerebral blood volume (CBF/CBV) ratio. In 17 patients with higher CoV values (> group median, 0.072), decreases in CBF, cerebral metabolic rate of oxygen, and CBF/CBV ratio were observed at follow-up; CBV decreased in 18 patients without elevated CoV. A higher CoV was associated with a lack of statin use. CONCLUSION: In patients with atherosclerotic major cerebral artery disease, high visit-to-visit SBP variations during follow-up may be associated with deterioration in cerebral hemodynamics and metabolism.

Selective neuronal damage and blood pressure in atherosclerotic major cerebral artery disease.

OBJECTIVE: In patients with atherosclerotic major cerebral artery disease, low blood pressure might impair cerebral perfusion, thereby exacerbate the risk of selective neuronal damage. The purpose of this retrospective study was to determine whether low blood pressure at follow-up is associated with increased selective neuronal damage. METHODS: We retrospectively analysed data from 76 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery disease with no ischaemic episodes on a follow-up of 6 months or more. All patients had measurements of the distribution of central benzodiazepine receptors twice using positron emission tomography and 11C-flumazenil. Using three-dimensional stereotactic surface projections, we quantified abnormal decreases in the benzodiazepine receptors of the cerebral cortex within the middle cerebral artery distribution and correlated these changes in the benzodiazepine receptors index with blood pressure values at follow-up examinations. RESULTS: The changes in the benzodiazepine receptor index during follow-up (mean 27±21 months) were negatively correlated with systolic blood pressure at follow-up. The relationship between changes in benzodiazepine receptor index and systolic blood pressure was different among patients with and without decreased cerebral blood flow at baseline (interaction, p<0.005). Larger increases in benzodiazepine receptor index (neuronal damage) were observed at lower systolic blood pressure levels in patients with decreased cerebral blood flow than in patients without such decreases. CONCLUSION: In patients without ischaemic stroke episodes at follow-up but with decreased cerebral blood flow due to arterial disease, low systolic blood pressure at follow-up may be associated with increased selective neuronal damage.

Synthesis and characterization of novel radiofluorinated probes for positron emission tomography imaging of monoamine oxidase B.

Monoamine oxidase B (MAO-B), predominantly expressed in glial cells, plays an important role in neurotransmitter regulation, and MAO-B activity relates to several neuronal diseases. Here, we aimed to develop a radiofluorinated MAO-B imaging probe based on the structure of a selective MAO-B inhibitor, MD-230254. We synthesized and evaluated a series of compounds in vitro and in vivo. A series of fluorinated analogs of MD-230254 were synthesized and evaluated for inhibitory potency and selectivity toward MAO-B. 5-[4-(2-[18 F]Fluorobenzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one (2-[18 F]FBPO) was synthesized from a corresponding tributylstannyl precursor and [18 F]CH3 COOF. Biodistribution after intravenous injection of 2-[18 F]FBPO was evaluated in male ddY mice with or without pretreatment by inhibitors. Among the compounds synthesized and evaluated, 2-FBPO showed high inhibitory potency and selectivity toward MAO-B comparable with MD-230254. 2-[18 F]FBPO was successfully synthesized by an electrophilic reaction with a high radiochemical purity of more than 99%. 2-[18 F]FBPO was efficiently taken up by the brain and showed rapid blood clearance, which provided a brain/blood radioactivity ratio of 3.7 at 90 minutes postinjection. The brain radioactivity was significantly decreased by pretreatment with an MAO-B selective inhibitor. The great potential of 2-[18 F]FBPO as an MAO-B imaging probe, applicable to a variety of diseases, is indicated.

Progressive Cortical Neuronal Damage and Chronic Hemodynamic Impairment in Atherosclerotic Major Cerebral Artery Disease.

BACKGROUND AND PURPOSE: Cross-sectional studies suggest that chronic hemodynamic impairment may cause selective cortical neuronal damage in patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease. The purpose of this longitudinal study was to determine whether the progression of cortical neuronal damage, evaluated as a decrease in central benzodiazepine receptors (BZRs), is associated with hemodynamic impairment at baseline or hemodynamic deterioration during follow-up. METHODS: We evaluated the distribution of BZRs twice using positron emission tomography and (11)C-flumazenil over time in 80 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease that had no ischemic episodes during follow-up. Using 3D stereotactic surface projections, we quantified abnormal decreases in the BZRs in the cerebral cortex within the middle cerebral artery distribution and correlated changes in the BZR index with the mean hemispheric values of hemodynamic parameters obtained from (15)O gas positron emission tomography. RESULTS: In the hemisphere affected by arterial disease, the BZR index in 40 patients (50%) was increased during follow-up (mean 26±20 months). In multivariable logistic regression analyses, increases in the BZR index were associated with the decreased cerebral blood flow at baseline and an increased oxygen extraction fraction during follow-up. Increases in the oxygen extraction fraction during follow-up were associated with a lack of statin use. CONCLUSIONS: In patients with atherosclerotic internal carotid artery or middle cerebral artery disease, the progression of cortical neuronal damage was associated with hemodynamic impairment at baseline and hemodynamic deterioration during follow-up. Statin use may be beneficial against hemodynamic deterioration and therefore neuroprotective.

Radiosynthesis of novel pitavastatin derivative ([18 F]PTV-F1) as a tracer for hepatic OATP using a one-pot synthetic procedure.

Pitavastatin is an antihyperlipidemic agent, a potent inhibitor of 3-hydroxymethyl-glutaryl-CoA reductase, which is selectively taken up into the liver mainly via hepatic organic anion transporting polypeptide 1B1 (OATP1B1). OATP1B1 can accept a variety of organic anions, and previous reports indicated that it is responsible for the hepatic clearance of several clinically used anionic drugs. Therefore, the pharmacokinetics and the hepatic distribution of pitavastatin provide an insight into the function of OATP1B1 in humans. For the development of the in vivo evaluation of OATP1B1 function by positron emission tomography imaging, we designed a novel [18 F]pitavastatin derivative ([18 F]PTV-F1), in which a [18 F]fluoroethoxy group is substituted for the [18 F]fluoro group of [18 F]pitavastatin, with the aim of convenient radiolabeling protocol and high radiochemical yield. In vitro studies suggested that transport activities of PTV-F1 mediated by OATP1B1 and OATP1B3 were very similar to those of pitavastatin and PTV-F1 was metabolically stable in human liver microsomes. In the radiosynthesis of [18 F]PTV-F1 from the tosylate precursor, nucleophilic fluorination and subsequent deprotection were performed using a one-pot procedure. [18 F]PTV-F1 was obtained with a radiochemical yield of 45% ± 3% (n = 3), and the operating time for the radiosynthesis of [18 F]PTV-F1 is very short (30 minutes) compared with [18 F]pitavastatin.

Misery perfusion, blood pressure control, and 5-year stroke risk in symptomatic major cerebral artery disease.

BACKGROUND AND PURPOSE: The benefit of strict blood pressure (BP) control in high-risk patients with symptomatic major cerebral artery disease and misery perfusion (MP) is controversial. Our purposes were (1) to determine whether MP is a predictor of a 5-year risk of subsequent stroke and (2) to investigate the relationships among BP during follow-up, MP, and the stroke risk. METHODS: We studied 130 nondisabled patients with symptomatic major cerebral artery disease. Baseline hemodynamic measurements were obtained from (15)O-gas positron emission tomography, and patients received medical treatment and they were followed for 5 years or until stroke recurrence or death. RESULTS: During 5 years, strokes occurred in 6 of 16 patients with MP and in 15 of 114 without MP (log-rank test; P<0.01). There were 4 (25%) ipsilateral ischemic strokes in patients with MP and 4 in those without MP (P<0.001). The risk of ipsilateral ischemic stroke declined markedly after 2 years, and there was only 1 ipsilateral ischemic stroke in a patient without MP. Normal systolic BP (<130 mm Hg) was associated with an increased risk of ipsilateral ischemic strokes in patients with impaired perfusion (including MP), whereas systolic BP outside the 130 to 149 mm Hg range was associated with an increased risk of all strokes in patients without MP. CONCLUSION: Patients with MP showed a high-5-year stroke recurrence, but a large part of the 5-year stroke risk disappeared after 2 years. Aggressive BP control may be hazardous in patients with impaired perfusion, including MP.

Increase in [18F]-Fluoroacetate Uptake in Patients With Chronic Hemodynamic Cerebral Ischemia.

BACKGROUND AND PURPOSE: [18F]-fluoroacetate ((18)F-FACE) can be used for evaluating glial cell metabolism. Experimental studies have shown an increase in (18)F-FACE uptake in rodent models of cerebral ischemia. The aim of this study was to determine whether (18)F-FACE uptake is increased in the noninfarcted cerebral cortex in patients with hemodynamic ischemia owing to atherosclerotic internal carotid artery or middle cerebral artery disease. METHODS: We evaluated 9 symptomatic patients with unilateral atherosclerotic internal carotid artery or middle cerebral artery disease and no cortical infarction using positron emission tomography with (18)F-FACE and (15)O-gases. (18)F-FACE uptake during 40 to 60 minutes after injection was compared with the cerebral blood flow, cerebral metabolic rate of oxygen, oxygen extraction fraction, and cerebral blood volume in the middle cerebral artery distributions. RESULTS: Significant decreases of cerebral blood flow and cerebral metabolic rate of oxygen and increases of oxygen extraction fraction and cerebral blood volume were found in the hemisphere ipsilateral to the arterial lesion, and (18)F-FACE uptake in this region was greater than that in the contralateral hemisphere. The relative (18)F-FACE uptake (ipsilateral/contralateral ratio) was negatively correlated with cerebral blood flow or cerebral metabolic rate of oxygen values and was positively correlated with oxygen extraction fraction values. Multivariate analysis showed that the ipsilateral/contralateral (18)F-FACE uptake ratio was independently correlated with the cerebral blood flow (or oxygen extraction fraction) and cerebral metabolic rate of oxygen values. CONCLUSIONS: In patients with atherosclerotic internal carotid artery or middle cerebral artery disease, (18)F-FACE uptake is increased in the noninfarcted cerebral cortex with chronic hemodynamic ischemia characterized by misery perfusion with decreased oxygen metabolism. Increased (18)F-FACE uptake may indicate the cortical regions that are at particular risk for ischemic damage.

Monitoring of gefitinib sensitivity with radioiodinated PHY based on EGFR expression.

Epidermal growth factor receptor (EGFR) is attractive target for tumor diagnosis and therapy, as it is specifically and abundantly expressed in tumor cells. EGFR-tyrosine kinase (TK) inhibitors such as gefitinib and erlotinib are widely used in the treatment of non-small cell lung cancer (NSCLC). In this study, we investigated whether radioiodinated 4-(3-iodo-phenoxy)-6,7-diethoxy-quinazoline (PHY), which is a candidate EGFR-TK imaging agent for single photon emission computed tomography (SPECT) is able to predict gefitinib sensitivity. We used four NSCLC cell lines-A549 (wild-type EGFR), H1650 (mutant EGFR; del E746_A750), H1975 (mutant EGFR; L858R, T790M) and H3255 (mutant EGFR; L858R)-and one epidermoid carcinoma cell line, A431 (wild-type EGFR). Cell proliferation assay and Western blotting revealed that A431 and H3255 with high EGFR expression showed high sensitivity to gefitinib. On the other hand, A549, H1650 and H1975 showed much lower sensitivity to gefitinib. The blocking study revealed that gefitinib decreased tumor uptake in (125)I-PHY in A431-bearing mice. Moreover, in vivo tumor uptake of (125)I-PHY was correlated with the IC50 of gefitinib for cell proliferation. In the present study, tumor uptake of (125)I-PHY was correlated with the gefitinib sensitivity and this uptake was based on expression levels of EGFR, but not on mutation status. Although the mutation status is the most important factor for predicting gefitinib sensitivity, the abundant expression of EGFR is essential for therapy with EGFR-TK inhibitors. Therefore, radioiodinated PHY is a potential imaging agent to predict gefitinib sensitivity based on EGFR expression levels though further modifications of the imaging agent is needed to accurately estimate the mutation status.

New objective simple evaluation methods of amyloid PET/CT using whole-brain histogram and Top20%-Map.

OBJECTIVE: This study aims to assess the utility of newly developed objective methods for the evaluation of intracranial abnormal amyloid deposition using PET/CT histogram without use of cortical ROI analyses. METHODS: Twenty-five healthy volunteers (HV) and 38 patients with diagnosed or suspected dementia who had undergone 18F-FPYBF-2 PET/CT were retrospectively included in this study. Out of them, 11C-PiB PET/CT had been also performed in 13 subjects. In addition to the conventional methods, namely visual judgment and quantitative analyses using composed standardized uptake value ratio (comSUVR), the PET images were also evaluated by the following new parameters: the skewness and the mode-to-mean ratio (MMR) obtained from the histogram of the brain parenchyma; Top20%-map highlights the areas with high tracer accumulation occupying 20% volume of the total brain parenchymal on the individual's CT images. We evaluated the utility of the new methods using histogram compared with the visual assessment and comSUVR. The results of these new methods between 18F-FPYBF-2 and 11C-PiB were also compared in 13 subjects. RESULTS: In visual analysis, 32, 9, and 22 subjects showed negative, border, and positive results, and composed SUVR in each group were 1.11 ± 0.06, 1.20 ± 0.13, and 1.48 ± 0.18 (p < 0.0001), respectively. Visually positive subjects showed significantly low skewness and high MMR (p < 0.0001), and the Top20%-Map showed the presence or absence of abnormal deposits clearly. In comparison between the two tracers, visual evaluation was all consistent, and the ComSUVR, the skewness, the MMR showed significant good correlation. The Top20%-Maps showed similar pattern. CONCLUSIONS: Our new methods using the histogram of the brain parenchymal accumulation are simple and suitable for clinical practice of amyloid PET, and Top20%-Map on the individual's brain CT can be of great help for the visual assessment.

Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with ¹8F-FAHA.

Epigenetic modifications mediated by histone deacetylases (HDACs) play important roles in the mechanisms of different neurologic diseases and HDAC inhibitors (HDACIs) have shown promise in therapy. However, pharmacodynamic profiles of many HDACIs in the brain remain largely unknown due to the lack of validated methods for noninvasive imaging of HDAC expression-activity. In this study, dynamic PET/CT imaging was performed in 4 rhesus macaques using [(18)F]FAHA, a novel HDAC substrate, and [(18)F]fluoroacetate, the major radio-metabolite of [(18)F]FAHA, and fused with corresponding MR images of the brain. Quantification of [(18)F]FAHA accumulation in the brain was performed using a customized dual-tracer pharmacokinetic model. Immunohistochemical analyses of brain tissue revealed the heterogeneity of expression of individual HDACs in different brain structures and cell types and confirmed that PET/CT/MRI with [(18)F]FAHA reflects the level of expression-activity of HDAC class IIa enzymes. Furthermore, PET/CT/MRI with [(18)F]FAHA enabled non-invasive, quantitative assessment of pharmacodynamics of HDAC inhibitor SAHA in the brain.

Impaired perfusion modifies the relationship between blood pressure and stroke risk in major cerebral artery disease.

OBJECTIVE: Blood pressure (BP) lowering may increase stroke risk in patients with symptomatic major cerebral artery disease and impaired perfusion. To investigate the relationships among BP, impaired perfusion and stroke risk. METHODS: We retrospectively analysed data from 130 non-disabled, medically treated patients with either symptomatic extracranial carotid occlusion or intracranial stenosis or occlusion of the carotid artery or middle cerebral arteries. All patients had baseline haemodynamic measurements with (15)O-gas positron emission tomography and were followed for 2 years or until stroke recurrence or death. RESULTS: There was a negative linear relationship between systolic BP (SBP) and risk of stroke in the territory of the diseased artery. The 2-year incidence of ischaemic stroke in the territory in patients with normal SBP (<130 mm Hg, 5/32 patients) was significantly higher than in patients with high SBP (2/98, p<0.005). Multivariate analysis revealed that normal SBP and impaired perfusion were independently associated with increased risk of stroke in the previously affected territory, while risk of stroke elsewhere was positively correlated with SBP. Overall, high total stroke risk was observed at lower BP in patients with impaired perfusion and at higher BPs in patients without (interaction, p<0.01). Overall, the relationship between SBP and total stroke recurrence was J-shaped. CONCLUSIONS: Impaired perfusion modified the relationship between blood pressure and stroke risk, although this study had limitations including the retrospective analysis, the potentially biased sample, the small number of critical events and the fact that BP was measured only as a snapshot in clinic.

Is misery perfusion still a predictor of stroke in symptomatic major cerebral artery disease?

Studies in the 1990s demonstrated that misery perfusion is a predictor of subsequent stroke in medically treated patients with symptomatic major cerebral artery disease. A recent randomized controlled trial demonstrated no benefit of bypass surgery for such patients. In this light, outcome in patients with misery perfusion has regained interest. The purpose of this study was to determine whether misery perfusion is still a predictor of subsequent stroke despite recent improvements in medical treatment for secondary prevention of stroke, and if so, whether the predictive value of misery perfusion has changed in recent years. We prospectively studied 165 non-disabled patients with symptomatic atherosclerotic internal carotid artery or middle cerebral artery occlusive diseases who underwent positron emission tomography from 1999 to 2008. Misery perfusion was defined as decreased cerebral blood flow, increased oxygen extraction fraction and decreased ratio of cerebral blood flow to blood volume in the hemisphere supplied by the diseased artery. All patients were followed up for 2 years until stroke recurrence or death. Bypass surgery was performed in 19 of 35 patients with and 16 of 130 patients without misery perfusion. The 2-year incidence of ipsilateral ischaemic stroke was six and four patients with and without misery perfusion, including two and one after surgery, respectively (P < 0.002). Total strokes occurred in nine patients with misery perfusion and 12 patients without (P < 0.01). The relative risk conferred by misery perfusion in whole sample was 6.3 (95% confidence interval 1.7-22.4, P < 0.005) for ipsilateral ischaemic stroke and 3.5 (95% confidence interval 1.4-8.9, P < 0.01) for all strokes, while the respective values in medically treated patients were 12.6 (95% confidence interval 2.7-57.8, P < 0.005) and 4.7 (95% confidence interval 1.3-16.3, P < 0.02). The all-stroke incidence in patients entering the study from 2004 to 2008 (4/72) was significantly lower than in those entering from 1999 to 2003 (17/93; P < 0.02), although the prevalence of misery perfusion or bypass surgery did not differ. Between these periods, patients without misery perfusion demonstrated a decrease in stroke rate (from 16.2% to 0%), but patients with misery perfusion did not (26.3 and 25.0%). In symptomatic major cerebral artery disease, misery perfusion remains a predictor of subsequent stroke, although the recurrence rate was lower than the previous study. In patients without misery perfusion, the risk of stroke was reduced over time. Thus, identification and stricter management of patients with misery perfusion are essential to further improve prognosis.

Characteristic Muscular FDG Uptake Patterns Related to the Transportation Means Used by Patients to Visit the Hospital.

ABSTRACT: It is well-known that physiological FDG uptake in the skeletal muscles is affected by serum insulin levels and the extent to which the muscles contract before the examination. Patients are instructed to refrain from strenuous exercise, talking too much, and taking meals at least 4 hours before the administration of the tracer. Even if the patient does not intend to exercise, muscular accumulation related to specific behaviors can still be visualized in the images. In this manuscript, we present FDG PET/CT images from 4 cases reflecting the mode of transportation used by the patients to visit the hospital.

Radiation dosimetry and pharmacokinetics of the tau PET tracer florzolotau (18F) in healthy Japanese subjects.

OBJECTIVE: Abnormal aggregation of tau in the brain is a major contributing factor in various neurodegenerative diseases. Florzolotau (18F) (florzolotau, APN-1607, PM-PBB3) has been shown to be a probe for tau fibrils in an animal model and patients with Alzheimer's disease and those with non-Alzheimer's disease tauopathies. The objective of this study is to evaluate the safety, pharmacokinetics, and radiation dose following a single intravenous administration of florzolotau in healthy Japanese subjects. METHODS: Three healthy male Japanese subjects aged between 20 and 64 were enrolled in this study. Subjects were determined to be eligible based on the screening assessments at the study site. Subjects received a single intravenous dose of 195.0 ± 0.5 MBq of florzolotau and underwent the whole-body PET scan 10 times in total to calculate absorbed doses to major organs/tissues and effective dose. Radioactivities in whole blood and urine were also measured for pharmacokinetic evaluation. Absorbed doses to major organs/tissues and effective dose were estimated using the medical internal radiation dose (MIRD) method. Vital signs, electrocardiography (ECG), and blood tests were done for safety evaluation. RESULTS: The intravenous injection of florzolotau was well tolerated. There were no adverse events or clinically detectable pharmacologic effects related to the tracer in any subjects. No significant changes in vital signs and ECG were observed. The highest mean initial uptake at 15 min after injection was in the liver (29.0 ± 4.0%ID), intestine (4.69 ± 1.65%ID), and brain (2.13 ± 0.18%ID). The highest absorbed dose was 508 µGy/MBq of the gallbladder wall, followed by the liver of 79.4 µGy/MBq, the pancreas of 42.5 µGy/MBq, and the upper large intestine of 34.2 µGy/MBq. The effective dose was calculated as 19.7 µSv/MBq according to the tissue weighting factor reported by ICRP-103. CONCLUSION: Florzolotau intravenous injection was well tolerated in healthy male Japanese subjects. The effective dose was determined as 3.61 mSv when 185 MBq florzolotau was given.

Selective neuronal damage and Wisconsin Card Sorting Test performance in atherosclerotic occlusive disease of the major cerebral artery.

BACKGROUND: In atherosclerotic internal carotid artery (ICA) or middle cerebral artery (MCA) disease, selective neuronal damage can be detected as a decrease in central benzodiazepine receptors (BZRs) in the normal-appearing cerebral cortex. This study aimed to determine whether a decrease in the BZRs in the non-infarcted cerebral cortex is associated with poor performance on the Wisconsin Card Sorting Test (WCST), which assesses executive functions. METHODS: The authors measured the BZRs using positron emission tomography and (11)C-flumazenil in 60 non-disabled patients with unilateral atherosclerotic ICA or MCA disease and no cortical infarction. Using three-dimensional stereotactic surface projections, the abnormally decreased BZR index (extent (%) of pixels with Z score >2 compared with controls × average Z score in those pixels) in the cerebral cortex of the anterior cerebral artery (ACA) or MCA territory was calculated and found to be correlated with the patient's score on the WCST. RESULTS: On the basis of the WCST results, 39 patients were considered abnormal (low categories achieved) for their age. The BZR index of the ACA territory in the hemisphere affected by arterial disease was significantly higher in abnormal patients than in normal patients. The BZR index of the MCA territory differed significantly between the two groups when patients with left arterial disease (n=28) were analysed separately. CONCLUSIONS: In atherosclerotic ICA or MCA disease, selective neuronal damage that is manifested as a decrease in BZRs in the non-infarcted cerebral cortex may contribute to the development of executive dysfunction.

A dual fluorinated and iodinated radiotracer for PET and SPECT imaging of ß-amyloid plaques in the brain.

We report a fluorinated and iodinated radiotracer as a probe for PET/SPECT to detect of ß-amyloid (Aß) plaques in the brain of patients with Alzheimer's disease (AD). We successfully designed and synthesized the fluorinated and iodinated aurone derivative (3) and its radiolabels ([(125)I]3 and [(18)F]3). In binding experiments in vitro, 3 showed high affinity for Aß aggregates (K(i)=6.81nM). In brain sections of AD model mice, 3 intensely stained Aß plaques. Furthermore, a specific plaque labeling signal was observed on the autoradiography of postmortem AD brain sections using [(125)I]3. In biodistribution experiments using normal mice, [(125)I]3 and [(18)F]3 displayed good uptake into and a rapid washout from the brain, properties highly desirable for Aß imaging agents. These results suggest that 3 may function as a PET/SPECT dual imaging agent for detecting Aß plaques in AD brains.

Physiologically decreased F-18 fluorodeoxyglucose uptake in the lower vertebrae associated with daily drinking habit in Japanese men with alcohol flushing reaction.

Alcohol flushing reaction (AFR) is known as one of the risks for esophageal squamous cell cancer, and scientists have been elucidating this issue. However, little attention has been given to relevant imaging features. This study aims to investigate whether physiological 18F-fluorodeoxyglucose (FDG) uptake patterns in vertebrae are associated with drinking habits or AFR. Japanese male patients who underwent FDG positron emission computed tomography for evaluation of their known or suspected malignancies or inflammatory diseases were asked about their drinking habits and AFR. Altogether, 192 patients, 139 every-day drinkers and 53 non-drinkers were evaluated. Comparing the FDG uptake between that in the thoracic region and that in the lumbar region, vertebral uptake was visually classified into four patterns: Ld, dominant in lumbar region; TL, almost equal in both regions; BL, slightly higher in thoracic region (borderline pattern); Td, dominant in thoracic region. The uptake patterns were evaluated according to drinking habit (every-day drinker or non-drinker), AFR (flusher or non-flusher), and the combination of these two factors (habit/reaction: every-day drinker/flusher, every-day drinker/non-flusher, non-drinker/flusher, or non-drinker/non-flusher). There were 95 flushers (51 every-day drinkers and 44 non-drinkers) and 97 non-flushers (88 every-day drinkers and 9 non-drinkers). Ld, TL, BL, and Td patterns were observed in 0, 109 (56.8%), 31 (16.1%), and 52 (27.1%) patients, respectively. Td and BL patterns were more frequently observed in every-day drinkers compared with non-drinkers (p = 0.0467). Though the uptake patterns did not differ between flushers and non-flushers (p = 0.116), the Td pattern was more frequently observed in every-day drinkers/flushers (51%) compared with every-day drinkers/non-flushers (20.5%), non-drinkers/flushers (13.6%), and non-drinkers/non-flushers (22.2%) (p = 0.0014). The Td pattern was observed in patients with various diseases, with higher frequency in esophageal cancer, head and neck cancer, and lung cancer compared with other diseases. In conclusion, drinking habits and AFR were related to the vertebral uptake pattern with decreased uptake in the lumbar region in Japanese male patients.