[<Superscript>123</Superscript>I] ADAM brainstem binding correlates with the loudness dependence of auditory evoked potentials

The in vivo assessment of brain serotonergic function might be of clinical relevance in neuropsychiatry. The loudness dependence of auditory evoked potentials (LD) has been proposed as an indirect indicator of cortical serotonergic activity, whereas single photon emission computed tomography (SPECT) and [¹²³I]ADAM allow the selective assessment of brain serotonin transporters (SERT). The aim of this study was to investigate LD and SERT availability as independent variables of the brain serotonergic system in healthy volunteers. Fifteen (six male, nine female) subjects received both neurophysiological and imaging investigations. Evoked potentials were recorded following the application of acoustic stimuli with increasing intensities; the LD was analyzed using dipole source analysis. SPECT was performed four hours after injection of 137 ± 11.4 MBq [¹²³I]ADAM. As a measure of SERT availability specific ADAM brainstem binding was used. LD correlated significantly with SERT availability (Pearson’s correlations: rho = −0.57, p < 0.05). The correlations remained significant after controlling for the effects of age or gender (partial correlations: rho = −0.60, p < 0.05) but were pronounced in the female group (rho = −0.83, p < 0.01). Associations between LD and SERT availability contribute to the understanding of the central serotonergic system and further validate the use of neurophysiological approaches as indirect measures of neurochemical brain activity.     

Differential passage of [<Superscript>14</Superscript>C]sucrose and [<Superscript>3</Superscript>H]inulin across rat blood-brain barrier after cerebral ischemia

The biophysical nature of blood-brain barrier (BBB) opening after ischemic or hemorrhagic stroke or traumatic brain injury is unresolved. Ultrastructural (electron micrograph) investigations of experimental BBB injury commonly indicate the abnormal presence of vesicles or tubular structures in cerebrovascular endothelial cells, suggesting the likelihood of convective, fluid-phase transport of blood substances into brain. We measured transfer constants (K(i)s) for the simultaneous passage of two intravenously delivered tracers ([14C]sucrose, mol wt=342; [3H]inulin approximately 5,000) across the intact BBB in the rat, and 24 h after global cerebral ischemia (16-20 min duration) or 24, 48 or 72 h after focal ischemia (2 h duration). In both ischemia models, the upward increment in K(i) (DeltaK(i)) for sucrose, indicating the extra injury-related tracer flux into brain, significantly exceeded that for inulin, as might be expected with faster diffusion of the smaller molecule through injury pores or channels. This inequality of DeltaK(i)s did not suggest a major role for convective, fluid-phase transport by endothelial vesicular or tubular structures and a predominance of diffusional transport was indicated.     

5-HT<Subscript>1A</Subscript> gene promoter polymorphism and [<Superscript>18</Superscript>F]MPPF binding potential in healthy subjects: a PET study

Background  

Previous Positron Emission Tomography (PET) studies of 5-HT_1A receptors have shown an influence of several genetic factors, including the triallelic serotonin transporter gene-linked polymorphic region on the binding potential (BP_ND) of these receptors. The aim of our study was to investigate the relationship between a 5-HT_1A promoter polymorphism and the binding potential of another selective 5-HT_1A receptor antagonist, [¹⁸F]MPPF, in healthy subjects.     

Fluoride Alteration of [<Superscript>3</Superscript>H]Glucose Uptake in Wistar Rat Brain and Peripheral Tissues

The present study was designed to investigate the role of postnatal fluoride intake on [3H]glucose uptake and transport in rat brain and peripheral tissues. Sodium fluoride (NaF) in a concentration of 10 or 50 ppm was added to the drinking water of adult Wistar rats. The control group received distilled water. After 4 weeks, respective plasma fluoride levels were 0.0541 ± 0.0135 μg/ml (control), 0.0596 ± 0.0202 μg/ml (10 ppm), and 0.0823 ± 0.0199 μg/ml (50 ppm). Although plasma glucose levels were not altered in any group, the plasma insulin level in the fluoride (50 ppm) group was elevated (0.72 ± 0.13 μg/ml) versus the control group (0.48 ± 0.24 μg/ml) and fluoride (10 ppm) group. In rats receiving fluoride for 4 weeks at 10 ppm in drinking water, [3H]glucose uptake was unaltered in all tested parts of the brain. However, in rats receiving fluoride at 50 ppm, [3H]glucose uptake in cerebral cortex, hippocampus, and thalamus with hypothalamus was elevated, versus the saline group. Fluoride intake had a negligible effect on [3H]glucose uptake by peripheral tissues (liver, pancreas, stomach, small intestine, atrium, aorta, kidney, visceral tissue, lung, skin, oral mucosa, tongue, salivary gland, incisor, molars, and jawbone). In neither fluoride group was glucose transporter proteins 1 (GLUT 1) or 3 (GLUT 3) altered in frontal cortex and striatum versus control. On the assumption that increased glucose uptake (by neural tissue) reasonably reflects neuronal activity, it appears that fluoride damage to the brain results in a compensatory increase in glucose uptake and utilization without changes in GLUT 1 and GLUT 3 expression.     

[<Superscript>3</Superscript>H]GR113808 binding to serotonin 5-HT<Subscript>4</Subscript> receptors in the postmortem neocortex of Alzheimer disease: a clinicopathological study

Summary. Abnormalities in neural transmission of serotonin (5-HT) may play a role in both cognitive and neuropsychiatric features of Alzheimer disease (AD). We measured 5-HT₄ receptors in the postmortem frontal and temporal cortex of 34 AD subjects and 15 controls by radioligand binding with [³H]GR113808. Receptor binding data was then correlated with prospectively assessed cognitive (Mini-Mental State Examination, MMSE) and behavioral (Present Behavioural Examination, PBE) data. [³H]GR113808 binding affinity (K_D) and density (B_max) in AD were unchanged compared to controls in both cortical regions, and did not correlate with MMSE or PBE data. The binding parameters were also not related to disease duration, senile plaque and neurofibrillary tangle counts, and neuroleptic medication. We conclude that unlike other 5-HT receptors, 5-HT₄ receptor binding affinity and density do not seem to be affected in the frontal and temporal cortex in AD and may not have a direct role in the clinical features of the disease. Received October 10, 2002; accepted February 18, 2003 Published online April 22, 2003 Acknowledgments This work is supported by the National Medical Research Council of Singapore, the Department of Clinical Research, Singapore General Hospital, and the Wellcome Trust. We thank Dr. B. McDonald, Dr. J. Keene, and J. Carter for assistance with the collection and classification of data and postmortem samples. Authors' address: Dr. C. P. Chen, Neuroscience Research Laboratory, Block 6, Level 6, Room A5, Singapore General Hospital, Outram Road, Singapore 169608, e-mail: admin@neurochemalz.org     

Use of a single [<Superscript>123</Superscript>I]-FP-CIT SPECT to predict the severity of clinical symptoms of Parkinson disease

The aim of this study was to assess the ability of a single SPECT performed in the early stage of Parkinson’s disease (PD) to predict disease severity in 19 patients with early PD. [¹²³I]-FP-CIT striatal uptake was expressed as a ratio of specific:nonspecific uptake for defined brain areas. Clinical severity was determined by the UPDRS at baseline and 12–15 months following the SPECT procedure. [¹²³I]-FP-CIT uptake in the contralateral putamen and striatum was correlated with UPDRS score at baseline, with a more significant correlation after 1-year interval. [¹²³I]-FP-CIT uptake in all areas was correlated with bradykinesia and rigidity subscores only at follow up visit. Significant correlations were found between [¹²³I]-FP-CIT uptake in the contralateral striatum, putamen and caudate and the difference between motor scores of 1-year interval (ΔUPDRS). These results suggest that disease severity might be anticipated by a single SPECT at an early stage of the disease.     

[<Superscript>3</Superscript>H]-Flunitrazepam-labeled Benzodiazepine Binding Sites in the Hippocampal Formation in Autism: A Multiple Concentration Autoradiographic Study

Increasing evidence indicates that the GABAergic system in cerebellar and limbic structures is affected in autism. We extended our previous study that found reduced [³H]flunitrazepam-labeled benzodiazepine sites in the autistic hippocampus to determine whether this reduction was due to a decrease in binding site number (B _max) or altered affinity (K _d) to bind to the ligand. Quantitation of hippocampal lamina demonstrated a 20% reduction in B _max indicating a trend toward a decreased number of benzodiazepine binding sites in the autistic group but normal K _d values. A reduction in the number of hippocampal benzodiazepine binding sites suggests alterations in the modulation of GABA_A receptors in the presence of GABA in the autistic brain, possibly resulting in altered inhibitory functioning of hippocampal circuitry.     

Deep TMS of the insula using the H-coil modulates dopamine release: a crossover [<Superscript>11</Superscript>C] PHNO-PET pilot trial in healthy humans

Modulating the function of the insular cortex could be a novel therapeutic strategy to treat addiction to a variety of drugs of abuse as this region has been implicated in mediating drug reward and addictive processes. The recent advent of the H-coil has permitted the targeting of deeper brain structures which was not previously feasible. The goal of this study was to bilaterally target the insular region using the H-coil with repetitive Transcranial Magnetic Stimulation (rTMS) and subsequently measure changes in dopamine levels using Positron Emission Tomography (PET) with [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO). This was a within-subject, crossover, blinded and sham-controlled pilot study. Eight healthy, right-handed subjects, aged 19–45, participated in the investigation. All subjects underwent 3 PHNO-PET scans preceded by rTMS (sham, 1 Hz or 10 Hz), on 3 separate days. Low frequency rTMS (1 Hz), targeting the insular cortex, significantly decreased dopamine levels in the substantia nigra, sensorimotor striatum and associative striatum. Replicating this study in tobacco smokers or alcoholics would be a logical follow-up to assess whether H-coil stimulation of the bilateral insula can be employed as a treatment option for addiction. Trial registration: NCT02212405     

Comparison of the regional expression of nicotinic acetylcholine receptor α7 mRNA and [125I]-α-bungarotoxin binding in human postmortem brain

Neuronal nicotinic acetylcholine receptors are expressed in the human central nervous system. A specific subtype of this receptor family, the α7 nicotinic acetylcholine receptor, is thought to be the principal α-bungarotoxin (αBTX)-binding protein in mammalian brain. Although the expression of this receptor subtype has been characterized in rat, no study has specifically compared the expression of both the α7 gene and the localization of BTX binding sites in human brain. Expression of α7 mRNA and receptor protein in human postmortem brain tissue was examined by in situ hybridization and [¹²⁵I]-α-bungarotoxin autoradiography, respectively, with particular emphasis on regions associated with sensory processing. Regions with high levels of both α7 gene expression and [¹²⁵I]-αBTX binding include the nucleus reticularis of the thalamus, the lateral and medial geniculate bodies, the basilar pontine nucleus, the horizontal limb of the diagonal band of Broca, the nucleus basalis of Meynert, and the inferior olivary nucleus. High-to-moderate levels of α7 probe hybridization were also seen in the hippocampus and the cerebral cortex; however, there was a reduced or variable degree of [¹²⁵I]-αBTX binding in these regions compared with the level of probe hybridization. In most brain regions, [¹²⁵I]-αBTX binding was localized to neuronal cell bodies similar in morphology to those that exhibited α7 hybridization, suggesting that the high-affinity [¹²⁵I]-αBTX binding sites in the human brain are likely to be principally composed of α7 receptor subtypes. J. Comp. Neurol. 387:385–398, 1997. © 1997 Wiley-Liss, Inc.