Andrea Panzacchi

In vivo PET study of 5HT2A serotonin and D2 dopamine dysfunction in drug-naive obsessive-compulsive disorder

There are several lines of evidence, the majority indirect, suggesting that changes in serotonergic or dopaminergic neurotransmission may contribute to the pathogenesis of obsessive-compulsive disorder (OCD). We evaluated the co-occurrence of serotonergic and dopaminergic dysfunctions in OCD subjects, all drug-naive, with no co-morbidity and homogeneous for symptoms. Each subject underwent two positron emission tomography (PET) scans to measure in vivo both serotonin (5-HT(2A)) and dopamine (D(2)) receptor distribution. For this, we used [11C]MDL and [11C]Raclopride, highly selective antagonists of 5-HT(2A) and D(2) receptors, respectively. The comparison with a control group was carried out using both voxel-wise (SPM2) and regions of interest (ROI) approaches. There was a significant reduction of 5-HT(2A) receptor availability in frontal polar, dorsolateral, and medial frontal cortex, as well as in parietal and temporal associative cortex of OCD patients. We also found a significant correlation between 5-HT(2A) receptor availability in orbitofrontal and dorsolateral frontal cortex and clinical severity, suggesting a specific role for serotonin in determining the OCD symptoms. There was also a significant reduction of [11C]Raclopride uptake in the whole striatum, particularly in the ventral portion, possibly reflecting endogenous dopaminergic hyperactivity. The co-existence of serotonergic and dopaminergic dysfunction in the same homogeneous group of drug-naive OCD patients provides in vivo evidence for the complex molecular mechanisms of OCD, and represents the basis for further studies on the effect of therapeutic agents with specific modulatory effects on these neurotransmission systems.

In Vivo Serotonin 5HT2A Receptor Binding and Personality Traits in Healthy Subjects: A Positron Emission Tomography Study

Using positron emission tomography (PET) and [11C]raclopride, an association between striatal D2 dopamine receptors and emotional detachment has been recently reported. Several laboratory findings indicate a link between the serotoninergic system and harm avoidance. In this study we investigated, in a group of healthy volunteers, the relationship between the in vivo binding of 3-(2′-[18F]fluoroethyl)spiperone ([18F]FESP) to cortical 5HT2 and striatal D2 receptors and three personality dimensions, i.e., “novelty seeking,” “reward dependence,” and “harm avoidance.” Eleven healthy volunteers were evaluated by means of the Tridimensional personality Questionnaire (C. R. 11, Arch. Gen. Psychiatry 44: 573–588.) and underwent a PET scan with [18F]FESP. Harm avoidance showed a significant inverse correlation with [18F]FESP binding in the cerebral cortex, particularly in the frontal cortex (R2 = −0.709, P = 0.0145) and left parietal cortex (R = −0.629, P = 0.038) but not in the basal ganglia (r = −0.176, P = 0.651). Similar results were obtained using SPM at a P threshold of 0.05. No significant correlation was observed with novelty seeking or reward dependence. In the cerebral cortex, high values of [18F]FESP binding values are associated with a high tendency to avoid danger, indicating involvement of the serotoninergic system and, in particular, 5HT2A receptors, in this trait of personality. The results of this as well as of previous studies on personality dimensions indicate the existence of a relationship between behavioral and neurobiological factors. In addition these results support the concept that the variability of PET data may be explained by neurochemical differences related to the prevalence of specific personality traits.

GABAA receptor abnormalities in Prader–Willi syndrome assessed with positron emission tomography and [11C]flumazenil

Prader-Willi syndrome (PWS) is a multi-system disorder characterized clinically by abnormal mental and physical development. PWS patients have a deletion in an imprinted region on paternal chromosome 15 (15q11-13), maternal disomy for this segment, or rarely, a chromosomal imprinting center deletion that gives rise to suppression of the equivalent paternal genes. Within the affected segment of chromosome 15 are genes encoding the alpha(5), beta(3) and gamma(3) subunits of the gamma-aminobutyric acid type-A (GABA(A)) receptor. Therefore, altered neurobehavioral function could arise in PWS due directly to altered GABA(A) receptor composition and expression, or alternatively, from brain developmental and maturational effects of these or other genes in the imprinted region. The aim of the present study was to assess cerebral GABA(A) receptors in PWS with the use of positron emission tomography of the benzodiazepine binding site employing [11C]flumazenil ([11C]FMZ). A reduction in [11C]FMZ binding was found predominantly in the cingulate, frontal and temporal neocortices and insula in six adult PWS patients compared to nine normal subjects. A possible role for the deleted beta(3) subunit gene in PWS is supported in part by the wide cortical distribution of its mRNA expression and the effects of experimental knockouts on benzodiazepine binding described in prior studies. Altered GABA(A) receptor composition or number in these cortical regions may account for neurobehavioral abnormalities in PWS including mild mental retardation, poor impulse control, and impaired responses to somatic pain.

In Vivo Evidence for GABAA Receptor Changes in the Sensorimotor System in Primary Dystonia

Preclinical and clinical evidence suggests that impaired gamma‐aminobutyric (GABA) control, leading to disinhibition within the sensorimotor system, might play a role in dystonia. Aim of this study is the in vivo assessment of the GABAergic system in dystonia using positron emission tomography (PET) and 11C‐flumazenil, a selective GABAA receptor ligand.

New perspectives on neurochemical effects of amantadine in the brain of parkinsonian patients: a PET -[(11)C]raclopride study

Summary. Amantadine, is a non competitive NMDA receptors antagonist that has been proved beneficial in Parkinsons disease. However its mechanism of action at therapeutic doses is still under discussion. Aim of this study was to evaluate the effect of repeated administration of amantadine on striatal dopaminergic system by measuring [11C]raclopride binding to striatal D2 dopamine receptors, in patients with moderate idiopathic Parkinsons disease. Eight patients completed the study undergoing a PET scan, before and after 10–14 days treatment with Amantadine (200 mg/day). Patients were on treatment with L-DOPA, which was suspended 1 night before each PET scans, and free from dopaminergic agonists, anticholinergic and antidepressants. Amantadine treatment significantly increased [11C-]Raclopride binding (caudate: 10% p = 0.04; putamen 11% p = 0.01). A slight reduction (−7.3%, p = 0.062) of UPDRS total scores was also observed. The increased availability of striatal D2 receptors, is likely to be caused by drug induced modification of receptors expression. This hypothesis is consistent with previous experiments, indicating an increase in striatal D2 receptors in rats treated with amantadine or other non competitive NMDA antagonists and suggests that the neo-synthesis of D2 receptors may represent a reinforcing mechanism of drug efficacy.

A voxel-based PET study of dopamine transporters in Parkinson's disease: relevance of age at onset.

We used positron emission tomography (PET) and the dopamine transporter (DAT) ligand [(11)C]FECIT to measure loss of nigrostriatal dopaminergic neurons in early phase of early onset (EOPD) and late onset Parkinsons disease (LOPD). The analysis was carried out with both regions of interest and voxelwise method (SPM2), at group and single subject levels. Genetic analysis tested for the mutations occurring most frequently in Caucasian population. A significant, bilateral, asymmetric DAT reduction was observed in both EOPD and LOPD. Noteworthy, the side and severity of DAT binding reduction significantly correlated with the severity and asymmetry of motor clinical scores. The two EOPD patients carrying mutations in the PARK2 and PARK6 genes, respectively, displayed the lowest values, bilaterally. This work demonstrates that severity of nigrostriatal damage in early disease phase of sporadic PD is not dependent on age at onset. Genetically determined PD is associated with more severe and widespread dopaminergic impairment.

PET evidence of central GABAergic changes in stiff-person syndrome.

We measured expression of central nervous system GABA‐A receptors with 11C‐flumazenil (11C‐FMZ) and PET in two subjects with stiff person syndrome (SPS). We found reduced 11C‐FMZ binding potential (BP) in motor‐premotor cortex, and increased 11C‐FMZ BP in the cerebellar nuclei. This is the first in vivo PET evidence of central GABA‐A receptors dysfunction in SPS, possibly concurring to the motor symptoms.

[11C]-MP4A PET cholinergic measurements in amnestic mild cognitive impairment, probable Alzheimer's disease, and dementia with Lewy bodies: a Bayesian method and voxel-based analysis.

Non-invasive approaches for positron emission tomography (PET) parametric imaging of acetylcholinesterase (AChE) activity have been developed and applied to the investigation of dementia, mainly Alzheimers disease (AD), but also dementia with Lewy bodies (DLB), not including, however, patients in the early disease stage. The few cholinergic PET studies on mild cognitive impairment (MCI) did not provide clinical follow-up. One limitation of the methods used so far is the relatively low sensitivity in measuring subcortical or deep cortical structures, which might represent specific disease markers. Here we assessed AChE activity with [11C]-MP4A and PET by a maximum a posteriori Bayesian method (MAPB) based on a 2-tissue compartment-3-rate-constant reference region model. 30 subjects were included: 10 multi-domain amnestic MCI (aMCI) with a follow up of 2 years, 7 probable AD (pAD), 4 DLB subjects, and 9 healthy controls. Regions of interest and voxel-based statistical parametric mapping analyses revealed significant and widespread AChE reductions in several cortical regions and in the hippocampus in all pAD subjects and aMCI subjects who progressed to AD (converters). Noteworthy, hippocampal AChE activity correlated significantly with long-term verbal and non-verbal memory in both aMCI converters and pAD. The pattern was more heterogeneous in early DLB patients, with only 2 out of 4 cases showing a severe or intermediate reduction of AChE activity. The comparable AChE reductions in pAD and aMCI converters indicate the presence of a widespread impairment of the cholinergic system already in the MCI phase. A more variable degree of cholinergic dysfunction is present in early DLB.

Striatal dopaminergic denervation in early and late onset Parkinson's disease assessed by PET and the tracer [11C]FECIT: preliminary findings in one patient with autosomal recessive parkinsonism (Park2)

Abstract. Neuroimaging studies of striatal dopamine transporters (DAT) have shown that this measurement is a specific marker of dopaminergic degeneration in patients with Parkinsons disease. However, little data is available in subjects with early disease onset, particularly in those with autosomal recessive parkinsonism. We measured striatal DAT binding in 10 patients with early onset PD (onset <40 years) and in 10 with late onset PD (onset >50 years) using PET and the tracer [11C]FECIT. One early onset subject presented a mutation in the parkin gene consistent with autosomal recessive parkinsonism. Data were compared with those of 15 control subjects. We found a comparable decrement of striatal DAT binding in early and late onset PD. Loss was widespread and bilateral in the patient carrying the Park2 mutation, suggesting a different pattern of denervation in these individuals.

Data rebinning and reconstruction in 3D PET/CT oncological studies: a Monte Carlo evaluation

An accurate identification and interpretation of neoplastic lesions by PET is related to PET image quality, depending on several factors including data processing for image formation. Aim of this work was to assess the influence of data rebinning and reconstruction on lesion detectability and quantification for a high-resolution 3D PET/CT system, in order to optimize 3D PET/CT oncological protocols. Oncological 18F-FDG PET studies were Monte Carlo (MC) simulated, varying lesion size (LS), lesion-to-background ratio (LBR), statistics, and including or not attenuation and scatter effects. Single slice rebinned (SSR), Fourier rebinned (FORE) and fully 3D sinograms were considered. 2D/3D ordered subset expectation maximization (OSEM) reconstruction was applied. Human observers evaluated images in terms of clinical parameters characteristic of lesion detectability and quantification: lesion number, LS, and LBR. By comparison with the known activity map (input for MC simulations), identified lesions were classified as true and false positive (TP, FP), and % errors on LS and on LBR were calculated The results show that 2D rebinning allow more lesions to be identified than fully 3D, but SSR induces more FP than FORE. Quantitatively, smaller errors on LBR and on LS were found using FORE rebinning and fully 3D, respectively. Our findings suggest that FORE+2D OSEM is more suitable for lesion detectability and quantification, fully 3D OSEM is better for lesion spatial characterization