Francesco E. Pontieri

Magnetic resonance imaging markers of Parkinson's disease nigrostriatal signature

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, disease progression monitoring and long-term drug impact analysis. In this study, Parkinson-associated physiopathological modifications were characterized in six subcortical structures by simultaneously measuring quantitative magnetic resonance parameters sensitive to complementary tissue characteristics (i.e. volume atrophy, iron deposition and microstructural damage). Thirty patients with Parkinsons disease and 22 control subjects underwent 3-T magnetic resonance imaging with T₂*-weighted, whole-brain T₁-weighted and diffusion tensor imaging scans. The mean R₂* value, mean diffusivity and fractional anisotropy in the pallidum, putamen, caudate nucleus, thalamus, substantia nigra and red nucleus were compared between patients with Parkinsons disease and control subjects. Comparisons were also performed using voxel-based analysis of R₂*, mean diffusivity and fractional anisotropy maps to determine which subregion of the basal ganglia showed the greater difference for each parameter. Averages of each subregion were then used in a logistic regression analysis. Compared with control subjects, patients with Parkinsons disease displayed significantly higher R₂* values in the substantia nigra, lower fractional anisotropy values in the substantia nigra and thalamus, and higher mean diffusivity values in the thalamus. Voxel-based analyses confirmed these results and, in addition, showed a significant difference in the mean diffusivity in the striatum. The combination of three markers was sufficient to obtain a 95% global accuracy (area under the receiver operating characteristic curve) for discriminating patients with Parkinsons disease from controls. The markers comprising discriminating combinations were R₂* in the substantia nigra, fractional anisotropy in the substantia nigra and mean diffusivity in the putamen or caudate nucleus. Remarkably, the predictive markers involved the nigrostriatal structures that characterize Parkinsons physiopathology. Furthermore, highly discriminating combinations included markers from three different magnetic resonance parameters (R₂*, mean diffusivity and fractional anisotropy). These findings demonstrate that multimodal magnetic resonance imaging of subcortical grey matter structures is useful for the evaluation of Parkinsons disease and, possibly, of other subcortical pathologies.

Hippocampal abnormalities and memory deficits in Parkinson disease: A multimodal imaging study

Objectives: Investigating in a case-control study whether the performance scores of a group of patients with Parkinson disease (PD) without dementia on tests of declarative memory could be predicted by hippocampal volume reduction (as assessed by automatic segmentation of cerebral magnetic resonance [MR] images) or by the rate of microstructural alterations (as evaluated by diffusion tensor analysis of MR images). Method: Twenty-five individuals with PD and 25 matched healthy control subjects underwent a 3-T MRI protocol with whole-brain T1-weighted and diffusion tensor imaging and a neuropsychological assessment. Images were processed to obtain indices of macrostructural (volume) and microstructural (mean diffusivity [MD]) variation of bilateral hippocampi. Neuropsychological evaluation included tests of verbal memory (15-minute delayed recall of a 15-word list) and visuospatial memory (20-minute delayed reproduction of Rey complex figure). Results: MD in the hippocampi of patients with PD was significantly increased with respect to that of the group of control subjects. Moreover, patients with high hippocampal MD values obtained low memory scores. In contrast, no difference emerged between patients with PD and healthy control subjects for hippocampal size, and no relationship could be found between hippocampal volumes and memory scores. Conclusions: These data confirm that the declarative memory impairment in patients with PD without dementia may be predicted by the rate of microstructural alterations in the hippocampal formation as detected by diffusion tensor imaging analysis.

The recognition of facial emotion expressions in Parkinson's disease

A limited number of studies in Parkinsons Disease (PD) suggest a disturbance of recognition of facial emotion expressions. In particular, disgust recognition impairment has been reported in unmedicated and medicated PD patients. However, the results are rather inconclusive in the definition of the degree and the selectivity of emotion recognition impairment, and an associated impairment of almost all basic facial emotions in PD is also described. Few studies have investigated the relationship with neuropsychiatric and neuropsychological symptoms with mainly negative results. This inconsistency may be due to many different problems, such as emotion assessment, perception deficit, cognitive impairment, behavioral symptoms, illness severity and antiparkinsonian therapy. Here we review the clinical characteristics and neural structures involved in the recognition of specific facial emotion expressions, and the plausible role of dopamine transmission and dopamine replacement therapy in these processes. It is clear that future studies should be directed to clarify all these issues.

Behavioral sensitization to heroin by cannabinoid pretreatment in the rat

The behavioral consequences of acute heroin challenge (0.5 mg/kg, s.c.) were measured in rats previously submitted to repeated administration of increasing doses of the synthetic cannabinoid receptor agonist, R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN55212.2) (first day 2 mg/kg, second day 4 mg/kg, third day 8 mg/kg) or vehicle. Heroin administration to rats pretreated with vehicle produced catalepsy. The same dose of heroin in WIN55212.2-pretreated rats was followed by a marked increase of locomotor activity with stereotyped and non-stereotyped behaviors. These effects were blocked by the opioid receptor antagonist, naloxone. These findings indicate that pretreatment with WIN55212.2 produces cross-sensitization to heroin in the rat. These changes might reflect long-lasting changes of receptor population or transcriptional mechanisms in the mesolimbic system.

Dopamine transporter immunoreactivity in peripheral blood lymphocytes in Parkinson's disease

Summary. There is increasing interest in the identification of biological markers for the early diagnosis of Parkinsons disease (PD). Previous studies indicate changes of dopamine content, tyrosine hydroxylase immunoreactivity and dopamine receptors in peripheral blood lymphocytes (PBL) in PD. Here we demonstrate a reduction of dopamine transporter immunoreactivity in PBL in the early clinical stages of the disease. These findings contribute to our understanding of the peripheral dopamine system in PD.

Neuropharmacology and behavior in planarians: Translations to mammals

Planarians are the simplest animals to exhibit a body plan common to all vertebrates and many invertebrates, characterized by bilateral rather than radial symmetry, dorsal and ventral surfaces, and a rostrocaudal axis with a head and a tail, including specialized sense organs and an aggregate of nerve cells in the head. Neurons in planarian more closely resemble those of vertebrates than those of advanced invertebrates, exhibiting typical vertebrate features of multipolar shape, dendritic spines with synaptic boutons, a single axon, expression of vertebrate-like neural proteins, and relatively low spontaneously generated electrical activity. Here we report the most relevant contribution to the knowledge of the neuropharmacology of planarians, with particular reference to the behavioral consequences of the exposure to drugs acting on neural transmission. Neurochemical and histochemical data indicate the presence of several neurotransmitter-receptor systems in planarians. Moreover, a variety of experimental studies characterized specific behavioral patterns of these animals following the exposure to drugs acting on neural transmission. There is also evidence of the interactions between discrete neurotransmitter-receptor systems in modulating behavior in planarians. Finally, the model has proved efficacy for investigating the neurotoxicology of the dopamine neurons, and for the initial screening of the neuroprotective potential of drugs. In conclusion, these findings indicate that interactions between discrete neurotransmitter-receptor systems occur very early along phylogeny, although they may have evolved from very fundamental behaviors, such as motor activity in planarian, to more complex and integrated functions in vertebrates.

Metabolic mapping of the effects of intravenous methamphetamine administration in freely moving rats

The 2-[14C]deoxyglucose method was used to examine the effects of acute intravenous administration of methamphetamine (0.5–2.5 mg/kg) on rates of local cerebral glucose utilization in freely-moving rats. These effects were correlated with the effects of methamphetamine on locomotor activity assessed simultaneously in the same animals. Methamphetamine administration resulted in widespread dose-dependent increases in glucose utilization within structures of the extrapyramidal motor system. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, entopeduncular nucleus, subthalamic nucleus, and the lateral cerebellar cortex. In contrast, within the limbic system alterations in metabolic activity were smaller and more selective. Glucose utilization was increased in the nucleus accumbens at all doses tested, but alterations in glucose utilization in the ventral tegmental area, amygdala, and anterior cingulate were observed only at the highest doses of methamphetamine tested. Significant increases in rates of glucose metabolism were also found in the substantia nigra compacta and in the median and dorsal raphe nuclei. Dopamine and serotonin are depleted in these regions, as well as in the ventral tegmental area where glucose utilization was also increased, following chronic treatment with high doses of methamphetamine. These changes in glucose utilization may be indicative of disturbances in the biochemical processes involved in the neurotoxic effects of methamphetamine.

Opioid-dopamine interaction in planaria: a behavioral study.

The behavioral response of planaria to the exposure to selective opioid agonists was studied. The mu agonist [d-ala2, N-methyl-Phe4,Gly5-ol]enkephalin (DAMGO) and the 6 agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) failed to alter motor activity at all doses tested. Low doses of the selective kappa agonist (+/-)-trans-U-50-trans-3,4-dichloro-N-methyl-N[2-(1-pyrrodinyl)-cyclohexyl]benzene acetamide methasulphonate (U50, 488) and bremazocine-HCl increased motor activity leading to C-like position (CLP) and screw-like hyperkinesia (SLH). These changes were identical to those seen previously with the exposure to D2 or D1 dopamine receptor agonists, respectively. Higher doses of kappa agonists produced the enhancement of CLP and SLH together with robust snake-like movements (SLM). This latter response, that was typical of stimulation of kappa opioid receptors, was blocked by co-exposure to naloxone or the selective kappa antagonist Nor-binaltorphimine (Nor-BNI). Finally, co-exposure to sulpiride or SH-23390 respectively blocked the CLP or SLH response produced by U50,488 or bremazocine. Our data indicate the presence of kappa opioid receptors in planaria and suggest the functional interaction between the opioid and dopamine system in this simple animal model.

Psychosis associated to Parkinson's disease in the early stages: relevance of cognitive decline and depression

Objective To evaluate the prevalence of psychosis associated with Parkinsons disease (PSY-PD) in its early stages, its incidence over a 24 month follow-up period and the association with motor and non-motor clinical features. Methods PRIAMO is a 2 year longitudinal observational study that has enrolled patients with parkinsonism in 55 Italian centres. A cohort of 495 patients with early disease stage PD (baseline Hoehn and Yahr score ≤2, diseases duration (median) 3.4 years) were followed for 2 years. PSY-PD was evaluated by means of a clinician rated questionnaire and defined as the presence of at least one of the following symptoms occurring for at least 1 month: illusions, hallucinations, jealousy ideas and persecutory ideas. Patients with and without PSY-PD were compared on several clinical variables, encompassing motor and non-motor features. Results The prevalence of PSY-PD at baseline was 3%; the incidences at 12 and 24 months were 5.2% and 7.7%, respectively. Longer disease duration and prescription of dopamine agonists at baseline were associated with the development of PSY-PD over the 24 month period. At this follow-up time, worse disease severity, decline in cognitive performances, presence of depressive symptoms and anxiety were more frequently observed in PSY-PD. Conclusions Psychotic type symptoms may occur in the early stages of PD although less frequently than in later stages. Beyond dopaminergic treatment, there are disease related factors, such as disease severity and the occurrence of cognitive and depressive symptoms, which may underlie the onset of psychotic type symptoms from the earliest stages.

The Dopaminergic System in Peripheral Blood Lymphocytes: From Physiology to Pharmacology and Potential Applications to Neuropsychiatric Disorders

Besides its action on the nervous system, dopamine (DA) plays a role on neural-immune interactions. Here we review the current evidence on the dopaminergic system in human peripheral blood lymphocytes (PBL). PBL synthesize DA through the tyrosine-hydroxylase/DOPA-decarboxylase pathway, and express DA receptors and DA transporter (DAT) on their plasma membrane. Stimulation of DA receptors on PBL membrane contributes to modulate the development and initiation of immune responses under physiological conditions and in immune system pathologies such as autoimmunity or immunodeficiency. The characterization of DA system in PBL gave rise to a further line of research investigating the feasibility of PBL as a cellular model for studying DA derangement in neuropsychiatric disorders. Several reports showed changes of the expression of DAT and/or DA receptors in PBL from patients suffering from several neuropsychiatric disorders, in particular parkinsonian syndromes, schizophrenia and drug- or alcohol-abuse. Despite some methodological and theoretical limitations, these findings suggest that PBL may prove a cellular tool with which to identify the derangement of DA transmission in neuropsychiatric diseases, as well as to monitor the effects of pharmacological treatments.