Decreased dopamine D receptor binding in essential blepharospasm.

OBJECTIVES: The purpose of this study was to investigate whether dopamine D(2) receptor binding was altered in the striatum of essential blepharospasm patients. METHODS: Striatal dopamine D(2) receptor binding was measured with positron emission tomography and [(11)C]raclopride. We studied eight drug-naive patients with bilateral blepharospasm and eight age-matched normal controls. RESULTS: The uptake indices in the blepharospasm group were significantly reduced by 11.7% in the caudate (P < 0.005), 11.6% in the anterior putamen (P < 0.0001), and 10.3% in the posterior putamen (P < 0.005) relative to the control group. CONCLUSIONS: This study indicates decreased dopamine D(2) receptor binding in the entire striatal region of blepharospasm patients. The findings suggest that decreased dopamine D(2) receptor binding might be one of the predisposing factors that leads to the dysfunction of the motor circuit, resulting in the loss of broad inhibition of unwanted movements during an intended movement in blepharospasm patients.

Cortical hypometabolism and its recovery following nucleus basalis lesions in baboons: a PET study.

The cerebral metabolic rate for glucose was measured serially with positron emission tomography and [18F]fluorodeoxyglucose in five baboons with stereotactic electrocoagulation of the left nucleus basalis of Meynert (NbM). Four days after lesion, a significant metabolic depression was present in the ipsilateral cerebral cortex, most marked in the frontotemporal region, and which recovered progressively within 6-13 weeks. These data demonstrate that adaptive mechanisms efficiently compensate for the cortical metabolic effects of NbM-lesion-induced cholinergic deafferentation. Moreover, unilateral NbM lesions also induced a transient reduction in contralateral cortical metabolic rate, the mechanisms of which are discussed. Explanation of these effects of cholinergic deafferentation in the primate could further our understanding of the metabolic deficits observed in dementia of the Alzheimer's type.

Positron emission tomography in a patient with progressive multifocal leukoencephalopathy.

A 56-year-old man with chronic lymphocytic leukemia, progressive multifocal leukoencephalopathy, and a dense left homonymous hemianopia had 18F-fluorodeoxyglucose positron emission tomography. Cortical glucose metabolism was decreased in the right cerebral hemisphere and the left cerebellar hemisphere. To our knowledge, this is the first demonstration of cerebral and cerebellar hypometabolism due solely to white matter disease.

Carbon-11-labeled KF15372: a potential central nervous system adenosine A1 receptor ligand.

UNLABELLED: The carbon-11-labeled selective adenosine A1 antagonist KF15372 ([1-propyl-11C]8-dicyclopropylmethyl-1,3-dipropylxanthine) was elevated in vivo as a PET ligand for mapping CNS adenosine A1 receptors. METHODS: The regional brain distribution of [11C]KF15372 and the effects of adenosine antagonists on the distribution were determined in mice by tissue sampling. In rats, in which the retinal projection fibres to the superior colliculus had degenerated due to unilateral eye removal, the brain distribution of [11C]KF15372 was visualized by ex vivo autoradiography. RESULTS: The mouse brain uptake of [11C]KF15372 was 1.8% i.d./g at 5 min and then it gradually decreased. The uptake was high in the hippocampus, cerebral cortex, striatum and cerebellum, and was significantly reduced by A1 antagonists but not by A2 antagonists. The brain distribution of 11C assessed by the tissue sampling and autoradiography was compatible with that of the A1 receptors. Autoradiography clearly visualized unilaterally decreased A1 receptor binding in the superior colliculus. CONCLUSION: The results demonstrated that [11C]KF15372 is a selective and high-affinity adenosine A1 receptor ligand and is useful for detecting the degeneration of presynaptic neurons.

Partially deficient glutamate dehydrogenase activity and attenuated oscillatory potentials in patients with spinocerebellar degeneration.

Glutamate dehydrogenase (GDH, EC 1.4.1.2) catalyzes the synthesis and degradation of glutamate, an excitatory neurotransmitter in the retina. Recently, two forms of GDH, a soluble heat-stable form and a particulate heat-labile form, have been demonstrated to be deficient in some types of spinocerebellar degeneration (SCD). We measured these forms of GDH activity in leukocyte homogenate from patients with SCD (n = 22) and normal subjects (n = 20) who were examined ophthalmoscopically and electrophysiologically. Seven patients with SCD showed attenuated oscillatory potentials (OPs) on electroretinography. The heat-labile GDH activity in these seven patients (78 +/- 51 nmol/mg protein/h) was significantly lower than that of 15 patients with normal OPs (367 +/- 189) and the normal subjects (397 +/- 1720 (P less than 0.001). Our results indicated that patients with SCD could be separated into two groups electrophysiologically, one with normal OPs and one with attenuated OPs. Also indicated was that a deficiency of heat-labile GDH might affect some functions of neural elements in the retina that are responsible for the generation of OPs.

Visual temporal frequency characteristics determined by pseudorandom stimuli.

PURPOSE: To investigate whether a rapid and practical determination of the temporal frequency characteristic (TFC) of the visual system can be obtained by using the visually evoked potentials (VEPs) elicited by pseudorandom binary sequence (PRBS) stimulation. METHODS: VEPs were recorded from eight volunteers. For the conventional steady state VEPs (S-VEP), the eye was stimulated with five stimulus frequencies. To acquire the PRBS-VEPs, the eye was stimulated with a PRBS stimulus for 40 seconds. The TFC for the S-VEP was calculated from the root mean squared amplitude for each frequency using Fourier transform. For the PRBS stimulus, a cross-correlation function between PRBS (x[t]) and PRBS-VEP (y[t]) was calculated to obtain the TFC. RESULTS: The TFCs obtained by the PRBS and S-VEP methods were highly correlated (P < 0.05), and the TFC curves resembled those in the literature. Most important, the data necessary to determine the TFCs using the PRBS stimulus could be obtained in 4 minutes, whereas that for the S-VEP required 60 minutes for the two eyes. CONCLUSIONS: The high correlation between the TFCs obtained by the two methods indicated that the PRBS technique gives a good measure of the TFC of the human visual system. The significantly shorter time required for this method demonstrated that it is a practical method for determining the linear (and nonlinear) property of the visual system and that it may be useful in clinical applications.

Benzodiazepine receptor distribution and cerebral blood flow in early blindness--a PET study.

We studied benzodiazepine receptor (BZR) distribution, which is thought to be affected by neuronal density in the cerebral cortex, and CBF using [11C]flumazenil and [15O]water PET in early blind (EB) and in blindfold sighted control (SC) subjects. PET images were co-registered to the subject's MRI. Using SPM96, MRI images were normalized in the Talairach and Tournoux coordinate system, and accordingly MRI-registered PET images were spatially normalized. Statistical parametric maps were computed on a voxel-by-voxel basis, using the general linear model. CBF for EB was significantly larger in the Brodmann area 17 and 18, especially anterior area, than that for SC, while there was no significant difference in BZR distribution. Our BZR data suggest that the amount of neurons do not change due to early visual deprivation in the visual cortex, in spite of high CBF in visual cortex of EB subjects.

Ciliary and retinal changes in myotonic dystrophy.

We examined 15 patients with myotonic dystrophy by cycloscopy, ophthalmoscopy, and fluorescein angiography. In six cases, we found depigmentation in the relatively short ciliary processes, which may account for ocular hypotony in this disorder. Eight of the patients had retinal lesions, three with butterfly-shaped dystrophy, two with reticular dystrophy, and three with peripheral yellow flecks. These lesions were biomicroscopically at the level of the retinal pigment epithelium or in the deep retinal layer and did not substantially alter visual functions. Psychophysical and electrophysiologic test results were normal or only slightly affected. The butterfly-shaped and reticular dystrophies in myotonic dystrophy may be variant forms of patterned dystrophy of the retinal pigment epithelium. The peripheral yellow flecks in a stone-wall configuration noted in this disorder are particularly unique and, to our knowledge, have not been documented previously.

Unilateral eyeball enucleation differentially alters AMPA-, NMDA- and kainate glutamate receptor binding in the newborn rat brain.

The aim of the present work was to evaluate the neurochemical effects of early unilateral visual deprivation as a model of impaired visual maturation. For this purpose, binding to the different ionotropic glutamate receptor subtypes was quantified in vision-related and vision-unrelated brain structures of control and unilaterally deprived newborn rats. At post-natal (PN) day 10, male Sprague-Dawley rats underwent either unilateral eyeball enucleation (enucleation group, n = 12) or sham operation (control group, n = 12). In each group, brains were obtained either at post-natal day 20 (n = 6) or post-natal day 30 (n = 6) and processed for quantitative in vitro autoradiography selective for NMDA, kainate, and AMPA glutamate-binding sites, as well as for the presynaptic adenosine A1 receptor as a control of the deafferentation efficacy. In control animals, quantitative autoradiography revealed an increase in NMDA (e.g. +45% in superior colliculus) and kainate receptor binding (e.g. +55% in visual cortex, layer IV) from post-natal day 20 to post-natal day 30, associated with stable levels of AMPA receptor binding, in the vision-related structures. In the deafferented visual structures, monocular enucleation induced a marked decrease in A1 site density (e.g. -38 to -52%, in the superficial layer of superior colliculi, at PN day 20 and PN day 30, respectively) in parallel with a mild increase in both NMDA (e.g. +8 to 9%, in superior colliculi and visual cortex, layer IV at PN day 30, respectively) and AMPA (e.g. +16%, in layer IV of the visual cortex at PN day 30). Superimposed on marked bilateral decreases at PN day 30 in the enucleated rats, kainate receptor binding also revealed a slight but significant decrease (-5%) in the deafferented superior colliculus as compared to the non-deafferented side. The present findings (different time-courses of, and differential effects of deafferentation on, the NMDA, kainate and AMPA glutamate receptor subtypes throughout the visual brain structures) further support the involvement of these receptors in distinctive roles during maturation of the visual system.

Marked increase in [3H](R) alpha-methylhistamine binding in the superior colliculus of visually deprived rats after unilateral enucleation.

The binding of [3H](R)alpha-methylhistamine to histamine H3-receptors in visual structures of unilaterally enucleated rats was examined by quantitative autoradiography to clarify the involvement of histamine neurons in the visual system. [3H](R)alpha-Methylhistamine binding in the visually deprived superior colliculus, contralateral to the enucleated eye, was significantly increased 5, 15, 30 and 45 days after unilateral enucleation. Slight time-dependent increases in ligand binding were observed in the visual cortex, but the change was significant only 45 days after unilateral enucleation. Unilateral enucleation had no significant effect in the dorsal lateral geniculate nucleus at any time after enucleation. Continuous injection of (S)-alpha-fluoromethylhistidine, a specific inhibitor of L-histidine decarboxylase, attenuated the effect of unilateral enucleation in the superior colliculus. These results suggest that retinal deafferentation induced an increase in histamine H3-receptor binding sites, probably by selective adjustment of histamine neurons in response to unilateral enucleation.

[18F]setoperone: a new high-affinity ligand for positron emission tomography study of the serotonin-2 receptors in baboon brain in vivo.

The potential usefulness of 18F-labelled setoperone, a high-affinity antagonist of the serotonin-2 (S2) receptors, to study the S2 receptors in vivo with positron emission tomography (PET) was investigated in four baboons. In the control state, there was a rapid wash-out of intravenously injected tracer from the cerebellum, a structure essentially devoid of S2, receptors, and marked retention in both the cerebral cortex and the striatum (region/cerebellum ratios up to 3 and 3.5 after 60 min in cortex and striatum, respectively). The retention of radioligand in the cerebral cortex was abolished after pretreatment with spiperone or ketanserin at saturating doses. In striatum, however, radioligand retention was fully prevented by spiperone but only partly by ketanserin. These results demonstrate that [18F]setoperone was bound to the S2 receptors in the cerebral cortex, whereas the radioligand was bound to both the S2 and the dopamine D2 receptors in the striatum. The high cortex/cerebellum ratio achieved indicates that [18F]setoperone should be a useful radiotracer for PET studies of the S2 receptors.

Positron emission tomography in diagnosing brainstem vascular lesions that cause abnormal eye movements.

PURPOSE: To evaluate the efficacy of positron emission tomography (PET) in aiding in the diagnosis of brainstem infarctions that cause abnormal eye movements. METHOD: Cerebral glucose metabolism was examined by PET with 18F-fluorodeoxyglucose as a tracer in five normal control subjects and six patients with abnormal eye movements. The PET images were registered to and superimposed on magnetic resonance images (MRIs). RESULTS: All control subjects showed little asymmetry of glucose metabolism in the brainstem, whereas all six patients demonstrated areas of low glucose metabolism in the brainstem. Areas of low metabolism seen by PET were wider than they appeared to be by MRI; MRIs even appeared normal in some patients. Asymmetry index measurements at the level of the ischemic lesion ranged between 19% and 45%. CONCLUSIONS: Positron emission tomography detected metabolic abnormality in patients with brainstem lesions that caused abnormal eye movements. Superimposing PET images on MRIs accurately localized abnormally low metabolism in the brainstem. Combined imaging with PET and MRI can be used to diagnose ischemic lesions in the brainstem from functional (PET) and morphologic (MRI) viewpoints.

Nuclear magnetic resonance imaging of subretinal fluid.

We ascertained the relationship between the relaxation time of magnetic resonance imaging and the protein concentration of subretinal fluid, by examining rhegmatogenous and nonrhegmatogenous retinal detachments with a 0.15 tesla nuclear magnetic resonance system, and we calculated T1 and T2 relaxation times of subretinal fluid. The protein concentration of subretinal fluid obtained at the time of surgery was determined by a biochemical method. The subretinal fluid in a fresh rhegmatogenous retinal detachment had a low protein concentration and relaxation times equal to those of vitreous. Conversely, increased protein concentrations and shortened relaxation times were noted in subretinal fluid from long-standing rhegmatogenous retinal detachments. Subretinal fluid in a nonrhegmatogenous retinal detachment with a high concentration of protein showed much shorter relaxation times. The relaxation times and protein concentration of the subretinal fluid correlated closely. It may be possible to measure the protein concentration of subretinal fluid in vivo with nuclear magnetic resonance imaging.

Neuro-imaging and positron emission tomography of congenital homonymous hemianopsia.

Congenital homonymous hemianopsia is an uncommon asymptomatic visual field defect discovered typically in young adult life that is caused by a diverse group of insults to the retrochiasmal afferent visual system occurring prenatally, at birth, or during early childhood. We treated eight patients with congenital homonymous hemianopsia; seven with damage involving the optic radiations and one with an abnormality of the optic tract. We performed positron emission tomography using 18F-fluoro-2-deoxyglucose on two patients with dense homonymous hemianopsias, lesions of the contralateral optic radiations, and largely intact occipital cortex. These studies showed minimal abnormalities in resting visual cortex glucose metabolism of the affected visual cortex.

Positron emission tomography to study the effect of eye closure and optic nerve damage on human cerebral glucose metabolism.

We used 18F-2-fluoro-2-deoxyglucose and positron emission tomography to evaluate the effect of visual deprivation on brain glucose metabolism. In experiment 1, we compared local cerebral metabolic rates for glucose in seven normal volunteers studied with eyes closed to 11 age- and sex-matched normal volunteers studied with eyes open. Whole brain metabolism was similar in the two groups, and region/whole brain analysis of metabolic data showed that metabolism in the calcarine posterior cortex was decreased by 14% (P less than .05) with eye closure. Glucose metabolism in other regions was not different between the two groups. In experiment 2, we compared glucose metabolism in six patients with severe bilateral optic neuropathies to 12 age- and sex-matched normal controls. Whole brain glucose metabolism was unchanged in the optic neuropathy group compared to controls. However, statistically significant reductions in glucose metabolism in the optic neuropathy group were found in anterior calcarine cortex (17%), posterior calcarine cortex (27%), peristriate cortex (27%), and lateral occipital cortex (15%). The metabolic effects of damage to the pregeniculate visual system went well beyond those of simple eye closure.

Metabolic imaging in hemianopsia using positron emission tomography with 18F-deoxyfluoroglucose.

To evaluate the usefulness of metabolic mapping by positron emission tomography using 18F-deoxyfluoroglucose as a tracer in the diagnosis of hemianopsia, we examined eight patients who had had cerebrovascular accident, and four controls. Neuro-ophthalmologic examination disclosed hemianopsia in five and incomplete hemianopsia in three patients; computed tomography showed low-density areas in four patients; and nuclear magnetic resonance imaging demonstrated a prolonged T2 area in five patients. The cerebral metabolic rate for glucose without visual stimulation in the visual cortex was 7.4 +/- 1.0 mg/min/100 g of brain without interhemispheric asymmetry. Light stimulation increased cerebral metabolic rate for glucose in the visual cortex of the nonaffected hemisphere and decreased it in the affected hemisphere. Asymmetry in the metabolic rate in the posterior medial occipital cortex in complete hemianopsia was 22% 12% (P less than .01).

Evaluation of carbon-11 labeled KF15372 and its ethyl and methyl derivatives as a potential CNS adenosine A1 receptor ligand.

We prepared [11C]KF15372 ([1-propyl-11C]8-dicyclopropylmethyl-1,3-dipropylxanthine, refs 10, 13) as well as its 11C-ethyl and 11C-methyl derivatives ([11C]EPDX and [11C]MPDX), and examined the potential of the three compounds as PET ligands for CNS adenosine A1 receptors. The three compounds had high affinity for the A1 receptors in vitro in the following order; [11C]EPDX > [11C]KF15372 > [11C]MPDX. In mice, the highest initial brain uptake was found in [11C]MPDX followed by [11C]EPDX and [11C]KF15372, but the level of [11C]MPDX decreased faster than those of the other two compounds. The uptake of each compound was decreased by carrier KF15372, but not by an A2A antagonist, indicating the selective affinity for the A1 receptors. Autoradiography with [11C]MPDX ex vivo demonstrated decreased A1 receptor binding in the superior colliculus of rats deprived of retino-collicular fibers by contralateral eye enucleation. These results show that three compounds have potential as PET ligands for CNS adenosine A1 receptors.

Synthesis and evaluation of 5-HT3 receptor antagonist [11C]KF17643.

For imaging CNS 5-HT3 receptors by PET, a high affinity 5-HT3 receptor ligand, endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl 2-(n-propyloxy)-4-quinolinecarboxylate (KF17643), have been labeled with 11C. N-Methylation of the desmethyl compound with [11C]methyl iodide followed by HPLC separation produced [11C]KF17643 with the decay-corrected radiochemical yield of 19-28%, the specific activity of 7.5-49 GBq/mumol and the radiochemical purity of > 99% at 35-40 min from EOB. After i.v. injection of [11C]KF17643 into mice, it was taken by the brain at a high level and was stable for metabolism, but no sign for the 5-HT3 receptor selectivity was found in the brain tissues by the tissue sampling and autoradiography, probably because of large non-specific binding. The [11C]KF17643 was not suitable as a PET ligand for mapping the CNS 5-HT3 receptors.

Carbon-11-labeled KF21213: a highly selective ligand for mapping CNS adenosine A(2A) receptors with positron emission tomography.

In vivo assessment of the adenosine A(2A) receptors localized in the striatum with positron emission tomography (PET) may offers us a new diagnostic tool for neurological disorders. We evaluated the potential of [7-methyl-(11)C](E)-8-(2,3-dimethyl-4-methoxystyryl)-1, 3,7-trimethylxanthine ([(11)C]KF21213) as a PET ligand for mapping adenosine A(2A) receptors in the central nervous system. KF21213 showed a high affinity for the adenosine A(2A) receptors in vitro (Ki = 3.0 nM) and a very low affinity for the A(1) receptors (Ki > 10,000 nM). In mice, the striatal uptake of [(11)C]KF21213 increased for the first 15 min and then gradually decreased, whereas the uptake in the reference regions such as the cortex and cerebellum rapidly decreased. The uptake ratio of striatum to cortex and striatum to cerebellum increased to 8.6 and 10.5, respectively, at 60 min postinjection. The striatal uptake was significantly blocked by co-injection of carrier KF21213 or each of three other A(2A) antagonists, but not by co-injection of A(1) antagonist. The specific uptake was not detected in the cortex or in the cerebellum. Ex vivo autoradiography and PET clearly visualized adenosine A(2A) receptors in the rat striatum. [(11)C]KF21213 was the most selective tracer for mapping adenosine A(2A) in the central nervous system by PET among the tracers proposed to date.

Intraorbital ophthalmic artery aneurysm: case report.

A rare case is presented of a nonruptured aneurysm of the intraorbital ophthalmic artery in which successful resection of the aneurysm resulted in improvement of preoperative progressive signs caused by the mass effect of the aneurysm. The surgical management of this rare entity is discussed with special attention given to the collateral circulation of the ophthalmic artery from the external carotid artery.