ro-16-0154 and Brain-Diseases

Nuclear medicine techniques have been powerful tools in neurology since their introduction. Computed tomography, magnetic resonance imaging and newer techniques, i.e. MR spectroscopy and angiography, sonography, Doppler sonography and EEG mapping with squid elements have overtaken most earlier nuclear medicine techniques for neurological diagnosis. Positron emission tomography is the gold standard for in vivo research in neurophysiology and pathology. The introduction of SPECT and the development of such tracers as 99mTc-HMPAO (99mTc-d,l-hexamethylpropylenaminoxim) and, more recently, 123I-iomazenil and 123I-IBZM (123I-3-iodo-6-methoxybenzamide) allowed closer examination of the perfusion of the brain and neuroreceptor density mapping in more than the few institutions that can afford PET and the production of special tracers marked with a positron emitting nucleus. Nuclear medicine's future will be based on neuroreceptor density mapping, as further tracers will become commercially available and no other technique can probably show such low concentrations of the receptors. Probably MR techniques will be used for brain's perfusion measurement in future. For examination of a limited cerebral region xenon-enhanced CT is an alternative to perfusion measurements with HMPAO, or a very interesting supplement. Of the old techniques in nuclear medicine, examination of the liquor dynamics is still feasible and well supplemented by SPECT.

Topics: Benzamides; Brain Diseases; Flumazenil; Humans; Iodine Radioisotopes; Organotechnetium Compounds; Oximes; Pyrrolidines; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

Iomazenil (IMZ) is a partial inverse agonist of central-type benzodiazepine receptors (BZR) which binds specifically to BZR with high affinity. The safety and clinical effectiveness of 123I-IMZ SPECT in the diagnosis of brain diseases were evaluated in 655 patients with various brain diseases, such as epilepsy, cerebrovascular diseases, degenerative diseases and mental disorders relating to BZR. This was a Phase 3 study conducted as a multicenter trial at 52 collaborating institutions. There was no significant adverse reactions in the clinical symptoms or abnormal laboratory test values. The investigators judged 123I-IMZ SPECT to be effective in 95% of 638 analyzed cases. The injected dose did not correlate with the image quality or the clinical effectiveness of 123I-IMZ SPECT, suggesting that these items depend largely on the characteristics of the apparatus used, the disease or pathology of the patients, rather than the dose. We conclude that 123I-IMZ imaging is safe and provides effective information based on BZR binding which is useful in the diagnosis of various brain diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brain; Brain Diseases; Flumazenil; GABA-A Receptor Agonists; Humans; Iodine Radioisotopes; Japan; Middle Aged; Predictive Value of Tests; Tomography, Emission-Computed, Single-Photon

A phase 2 study of 123I-Iomazenil (IMZ) was performed to evaluate its clinical usefulness in SPECT imaging of central-type benzodiazepine receptors (BZR). A total of 246 patients with various central nervous system disorders [82 with epilepsy, 94 with cerebrovascular disease (CVD), 47 with degenerative disorders, 14 with mental disorders relating to BZR and 9 with other diseases] were intravenously injected with 111-222 MBq of IMZ. Early and late images were obtained 15 min and 180 min after injection as the mid-scan time, respectively. In comparison with regional cerebral blood flow (rCBF) images, the uptake of IMZ in the late images, which reflect the regional distribution of BZR, was relatively preserved compared to the uptake of CBF tracers in most of the patients with CVD. In the area of hyperperfusion in the subacute phase of cerebral infarction, however, the defects of IMZ uptake were accompanied by increased uptake of the CBF tracers. On the other hand, late IMZ uptake in most of the patients with the other diseases was decreased more significantly than the uptake of the CBF tracers, suggesting that cortical neuronal damage is more prominent than rCBF in these diseases compared to the vascular perfusional state. No adverse reactions were recognized relating to the IMZ administration. These results suggest that IMZ may provide us with valuable information for assessing pathophysiological state in the brain, which are difficult to achieve with other imaging modalities.

Topics: Adult; Brain Diseases; Female; Flumazenil; Humans; Iodine Radioisotopes; Male; Mental Disorders; Middle Aged; Receptors, GABA-A; Tomography, Emission-Computed, Single-Photon

A phase 2 clinical study of 123I-iomazenil (IMZ) was performed to evaluate its clinical usefulness as central-type benzodiazepine receptor imaging agent in 81 cases with epilepsy, 82 cases with cerebrovascular diseases (CVD), 35 cases with degenerative disorders and 14 cases with mental disorders. In epilepsy, IMZ SPECT images for detection of epileptic foci showed relatively high specificity compared with EEG recording in not only interictal but also ictal state, in spite of the fact that IMZ SPECT images was performed during interictally. It was surmised that IMZ SPECT provides valuable clinical information for detection of epileptic foci which are hard to be diagnosed by EEG. The frequency of abnormal findings by IMZ late images was higher than that by interictal blood flow images and comparable to that by ictal blood flow images. In patients with CVD, different observations were obtained between IMZ late images and blood flow images; for example, in regions of hemodynamic cerebral ischemia, postischemic reperfusion and other pathological perfusion, IMZ late images seemed to reflect the degree of cortical neuronal loss. In patients with degenerative disorders, the binding potential (calculated by a simple quantitative method for IMZ) and other parameters correlated with the dementia score. While the number of examined cases with mental disorders was limited, the frequency of abnormal findings with IMZ imaging was higher than that with morphological imaging.

Topics: Adult; Brain Diseases; Female; Flumazenil; Humans; Iodine Radioisotopes; Male; Mental Disorders; Middle Aged; Receptors, GABA-A; Tomography, Emission-Computed, Single-Photon

Retrograde leptomeningeal venous drainage (RLVD) of a dural arteriovenous fistula (dAVF) is associated with neurological morbidity and unfavorable outcomes. However, the direct damage to cortical neurons by dAVF with RLVD has not been elucidated. 123I-iomazenil (123I-IMZ) SPECT can reveal cerebral blood flow and cortical neuronal damage in early and late images, respectively. This study aimed to assess the cerebral venous congestive encephalopathy caused by dAVF using 123I-IMZ SPECT.. Based on the pre- and posttreatment MRI findings, patients were divided into three groups: a normal group, an edema group, and an infarction group. Radioactive counts in the early and late images of 123I-IMZ SPECT were investigated using the affected-to-contralateral side asymmetry ratio (ACR).. None of the patients in the normal group showed any symptoms related to venous congestion. In contrast, all the patients in the edema and infarction groups developed neurological symptoms. The ACR in early images in the edema group was significantly lower than that in the normal group and significantly higher than that in the infarction group. The ACR in the late images of the infarction group was significantly lower than those of the normal and edema groups. After treatment, the neurological signs disappeared in the edema group, but only partial improvement was observed in the infarction group. The ACR in early images significantly improved after treatment in the edema group, but the ACR in late images did not change in any groups.. 123I-IMZ SPECT is useful for evaluating hemodynamic disturbances and neuronal damage in dAVFs. The reduction in early images was correlated with the severity of venous congestive encephalopathy, and the significant reduction in late images is a reliable indicator of irreversible venous infarction caused by RLVD.

Topics: Brain Diseases; Central Nervous System Vascular Malformations; Hemodynamics; Humans; Hyperemia; Infarction; Tomography, Emission-Computed, Single-Photon

Clinical and experimental studies on focal cortical dysplasia (FCD) were carried out.. For the experimental study, an experimental FCD model of rats was developed. Twenty Wistar rats at 0-2 days after birth were used for the study. Kainic acid (KA) solution was injected stereotaxically into medial and lateral sites of the sensori-motor cortex. Bipolar electrodes were inserted in five rats. Their behavior and electroencephalogram (EEG) were recorded using a digital-video-EEG monitoring system. After observation periods of 1, 2, and 6 months, rats were perfused for pathological study. FCD was observed adjacent to the site of KA injection in all rats more than 1 month after the injection.. EEG recording demonstrated focal spike discharges in and around the site of injection. However, clinical seizure was not observed. Pathological studies showed decrease in GABA-A receptors and increase in GABA-B receptors not only in the lesion but also in perilesional areas. Fifteen surgical cases of FCD with intractable epilepsy were subjected to the clinical study. Neuro-imaging studies including high-resolution magnetic resonance imaging and single-photon emission computed tomography were performed. Conventional EEG studies demonstrated focal EEG abnormalities with epileptic phenomena. At surgery, intraoperative electrocorticography (ECoG) was performed to localize epileptic foci under neuroleptoanalgesia. Thirteen patients showed epileptiform discharges on preresection ECoG. All foci in non-eloquent areas were resected. Pathological studies including immunohistochemical staining were performed, and the characteristics of the FCD in relation to EEG findings were analyzed. Patients in whom total lesionectomy with complete focus resection was performed had favorable postoperative courses. Nine patients (64.3%) have been seizure-free with reduced medication, and significant improvement was achieved in two patients (14.3%). Electrophysiological examination revealed epileptogenecity not only in the lesions but also in perilesional areas. The immunohistochemical studies showed a decrease in GABA-A receptors and an increase in GABA-B receptors in both the lesions and perilesional areas, but N-methyl-D: -aspartate receptors were almost negative in both areas. Glutamate R1 was decreased in both areas, but glutamate R2 was increased in both areas. These findings support the results of a electrophysiological study.. In conclusion, not only the epileptic property of experimental focal cortical dysplasia but also perilesional epileptogenesis was demonstrated. These findings supported the results of surgery for patients with focal cortical dysplasia. In cases of FCD, total removal of the lesion and resection of the perilesional epileptic focus are needed for a good outcome.

Topics: Adolescent; Animals; Animals, Newborn; Autoradiography; Behavior, Animal; Brain Diseases; Brain Mapping; Cerebral Cortex; Child; Electroencephalography; Epilepsy; Female; Flumazenil; gamma-Aminobutyric Acid; Humans; Immunohistochemistry; Iodine Radioisotopes; Kainic Acid; Male; Nervous System Malformations; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

We investigated the characteristics of 123I-Iomazenil (IMZ) SPECT images in 12 adults (six males and six females, with a mean age of 56.1 years). The washout rate of 123I-IMZ from the brain was estimated from two SPECTs done 15 min and 3 hr after injection. Although the washout was relatively slow, the rates differed in each intracerebral region, suggesting that the distribution of 123I-IMZ was gradually changing. Furthermore, assuming 123I-IMZ kinetics in the brain for the three-compartment, two-parameter model, the transition rate constant (K1) from the blood to the brain and the binding potentials (BP) of benzodiazepine to the receptor were calculated. The BP and K1 values were compared with 123I-IMZ SPECT counts and CBF values by 123I-IMP. The BP values correlated more closely with the counts on the delayed SPECT than those on the early SPECT. It was confirmed that delayed SPECT images reflect better the distribution of the benzodiazepine receptor than early images do. On the other hand, the K1 values correlated highly with CBF obtained by 123I-IMP, and this finding suggested that super-early SPECT images might be remarkably influenced by the distribution of CBF.

Topics: Adult; Brain; Brain Diseases; Cerebrovascular Circulation; Female; Flumazenil; Humans; Iodine Radioisotopes; Male; Middle Aged; Models, Biological; Radiopharmaceuticals; Receptors, GABA-A; Tomography, Emission-Computed, Single-Photon

The purpose of this study is to evaluate the central benzodiazepine (BZP) receptor binding of iomazenil (IMZ) by pharmacokinetic analysis and to establish a methodology for the diagnosis of CNS disorders with abnormalities in BZP receptor binding.. BZP receptor binding of IMZ was analyzed kinetically using plasma concentration-time profiles and dynamic single photon emission computed tomography (SPECT) data obtained after the intravenous administration of IMZ to patients with neuropsychiatric disease. The analysis was based on a 3-compartmental model including the processes of both blood-brain barrier (BBB) transport and BZP receptor binding.. Hydrolized metabolite of IMZ was detected in plasma, indicating the need for separation by HPLC. The BBB influx clearance and the receptor binding potential of IMZ in the medial temporal region was reduced in the epileptic patient.. Our findings suggest the possibility of detecting the epileptic focus by using our method.

Topics: Blood-Brain Barrier; Brain; Brain Diseases; Flumazenil; Humans; Injections, Intravenous; Iodine Radioisotopes; Receptors, GABA-A; Tomography, Emission-Computed, Single-Photon