Mario Matarrese

Different neural systems for the recognition of animals and man-made tools

Using positron emission tomography, we mapped brain activity in normal volunteers during the recognition of visual stimuli representing living (animals) and nonliving (artefacts) entities. The subjects had to decide whether pairs of visual stimuli were different representations of the same object, or different objects. Animal recognition was associated with activations in the inferior temporo-occipital areas, bilaterally, whereas artefact recognition engaged a predominantly left hemispheric network, involving the left dorsolateral frontal cortex. These findings, which concur with clinical observations in neurological patients, provide in vivo evidence for a fractionation of the neural substrates of semantic knowledge in man.

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.

Glucose metabolism and serotonin receptors in the frontotemporal lobe degeneration

In patients with the frontal variant of frontotemporal lobar degeneration (fv‐FTLD), behavioral abnormalities may vary from apathy with motor slowness (apathetic form) to disinhibition with agitation (disinhibited form). These clinical presentations may be related to specific regional cerebral dysfunction and to deficit in the serotoninergic system. We studied cerebral glucose uptake using 18F‐fluorodeoxyglucose and positron emission tomography in 18 patients fulfilling clinical criteria for fv‐FTLD and showing, respectively, an apathetic or disinhibited behavioral syndrome. In eight of these patients, we also evaluated the 5‐hydroxytryptamine‐2A receptor cerebral receptor distribution with [11C]MDL and positron emission tomography. We found a reduction of frontal glucose metabolism in the whole group of fv‐FTLD patients. Apathetic syndrome was associated with a prevalent dorsolateral and frontal medial hypometabolism, whereas the disinhibited syndrome demonstrated a selective hypometabolism in interconnected limbic structures (the cingulate cortex, hippocampus/amygdala, and accumbens nucleus). The in vivo measurements of [11C]MDL indicated a significant reduction of 5‐hydroxytryptamine‐2A receptors in orbitofrontal, frontal medial, and cingulate cortices. These 18F‐fluorodeoxyglucose positron emission tomography changes can be considered as specific functional markers of the different behavioral presentations in fv‐FTLD. The serotoninergic system dysfunction provides a rationale for therapeutic trials with selective serotonin reuptake inhibitors. Ann Neurol 2005;57:216–225

Basal ganglia and language: phonology modulates dopaminergic release

Basal ganglia have been implicated in syntactic and phonological processes, but direct evidence has been scarce. Here, we used [11C]raclopride and positron emission tomography to measure modulations of the dopaminergic system induced by phonological or syntactic processing. Two significant effects were found. First, the level of accuracy in phonological processing significantly correlated with tracer binding potential in the left caudate nucleus. Second, the speed in phonological processing significantly correlated with tracer binding potential in the left putamen. Thus, a more accurate and fast phonological processing was associated with a reduced dopamine requirement in the left striatum. These findings show that the striatal dopaminergic system plays an essential role in grammatical processes that form the core of human language.

Biodistribution of Tc-99m methoxy-isobutyl-isonitrile (MIBI) in humans

Hexakis (methoxyisobutilisonitrile) technetium(I), 99mTc-MIBI, has been proposed for myocardial perfusion studies. We have evaluated the biodistribution of this new agent in normal volunteers at rest and after stress. The biodistribution of 99mTc-MIBI is characterized by rapid blood clearance and a consequently early myocardial uptake. The initial intense hepatic activity is cleared into the gallbladder at 1 h after injection, and the best target to non target ratio is observed at 60–90 min after injection. Absorbed radiation dose calculations show that the thyroid is the critical target organ (230 mRad/mCi at rest), presumably because of 99mTc-pertechnetate generated in vivo. Our results indicate that 99mTc-MIBI is a promising tracer for myocardial perfusion imaging.

Evaluation of three quinoline-carboxamide derivatives as potential radioligands for the in vivo pet imaging of neurodegeneration.

The peripheral-type benzodiazepine receptors (PBRs) are only minimally expressed in normal brain parenchyma, where they are primarily localized in glial cells. Their basal expression rises in different neurodegenerative disorders, due to the presence of infiltrating inflammatory cells and activated microglia. [11C]PK11195, a selective PBR antagonist, has been used for the in vivo PET monitoring of neurodegeneration in clinical observations. We recently developed and labeled with carbon-11 three new carboxamide derivatives: [11C]VC193M, [11C]VC195 and [11C]VC198M. Aim of this study was to evaluate these ligands for the in vivo measuring of PBRs expression in neurodegenerations and compare their kinetic behavior with that of the reference tracer [11C]PK11195. Radioligands were evaluated in a preclinical model of Huntingtons disease consisting in the monolateral striatal injection of quinolinic acid (QA). Activated microglia and astrocytic gliosis was present only within the affected striatum. A concomitant increase in radioactivity accumulation was observed for all the tracers examined (P<0.01). Among the new compounds, [11C]VC195 showed higher levels of lesioned/unlesioned striatum ratios (3.28+/-0.44), in comparison with [11C]VC193M and [11C]VC198M (2.69+/-0.53 and 1.52+/-0.36, respectively), but slightly inferior to that observed for [11C]PK11195 (3.76+/-1.41).In conclusion, the results of the study indicate that [11C]VC195 is a promising candidate for in vivo PET monitoring of neurodegenerative processes but its in vivo behavior overlap that of [11C]PK11195.

Differentiation of clinically non-functioning pituitary adenomas from meningiomas and craniopharyngiomas by positron emission tomography with [18F]fluoro-ethyl-spiperone

The differential diagnosis among various types of non-functioning sellar and parasellar tumours is sometimes difficult using currently available methods of morphological imaging. The aim of this study was to define whether assessment of the uptake of [18F]fluoro-ethyl-spiperone (FESP) with positron emission tomography (PET) could be helpful for the differential diagnosis of pituitary adenomas and other parasellar lesions, and for establishing the appropriate therapeutic approach. The population examined comprised 16 patients with the diagnosis of primary tumour of the sellar/parasellar region who were waiting to undergo surgical treatment. The results demonstrated that PET with [18F]FESP is a very specific method for differentiating adenomas from craniopharyngiomas and meningiomas. The visual interpretation of images allows such differentiation at approximately 70 min after tracer injection. Semiquantitative analysis of the dynamic PET data confirmed the results of visual interpretation, demonstrating that the uptake of [18F]FESP was consistently (i.e. throughout the series) at least two- to threefold higher in non-functioning adenomas than in other parasellar tumours as early as 70 min after tracer injection, and that it increased still further thereafter. It is concluded that PET with [18F]FESP might be of clinical value in those cases in which the differential diagnosis among various histological types of sellar tumour is uncertain with conventional methods.

Automated production of copper radioisotopes and preparation of high specific activity [64Cu]Cu-ATSM for PET studies

(60)Cu and (64)Cu are useful radioisotopes for positron emission tomography (PET) radiopharmaceuticals and may be used for the preparation of promising agents for diagnosis and radiotherapy. In this study, the production and purification of (60/64)Cu starting from (60/64)Ni using a new automated system, namely Alceo, is described. A dynamic process for electrodeposition and dissolution of (60/64)Ni/(60/64)Cu was developed. Preliminary production yields of (60)Cu and (64)Cu were 400 and 300mCi, respectively. (64)Cu was used to radiolabel the hypoxia detection tracer ATSM with a specific activity of 2.2+/-1.3Ci/micromol.

PET and SPET Molecular Imaging: Focus on Serotonin System

Emission tomography techniques and, in particular, positron emission tomography (PET) enable the in vivo study of several physiological and neurochemical variables in human subjects using methods originally developed for quantitative autoradiography. In particular, PET allows one to evaluate in human subjects: (a) the effect of specific neurochemical challenges on regional brain function at rest or under activation; (b) the activity of neurotransmitters and the regional expression of specific molecular targets during pathology including their modulation by drug treatment; (c) the kinetics of drug disposition and activity directly in the target organ. This is of primary interest in the field of biological psychiatry and in psychoactive drugs development, where it is particularly difficult to reproduce human diseases using animal models in view of the peculiarity of this field and the large heterogeneity of each psychiatric illness also inside the same clinical definition. The aim of this paper is to review the principal strategies and the main results of the use of PET or single photon emission tomography (SPET) molecular imaging for the in vivo study of serotonin receptors and the main results obtained from their application in the study of major depression.

Preparation of [11C] radioligands with high specific radioactivity on a commercial PET tracer synthesizer

High specific radioactivity is required for receptor studies with PET. Hereby we wish to report our experience using Nuclear Interface PET Tracer Synthesizer for preparation of Carbon-11 radioligands and modules modifications, which allowed to achieve high specific radioactivity.