Subclinical impairment of lung airways in patients with panic disorder.

Lung function was assessed in 17 panic patients and 20 healthy controls. Panic patients had abnormal values for some dynamic lung volumes, namely Peak Expiratory Flow Rate (PEFR), Expiratory Flow at 75% of Vital Capacity (FEF75) and Maximum Mid-Expiratory Flow Rate (MMEF). Such functional abnormalities might indicate subclinical obstruction of lung airways, possibly relevant to the mechanisms related to panic disorder (PD).

The feasibility of statistical parametric mapping for the analysis of positron emission tomography studies using 11C-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)-tropane in patients with movement disorders.

Movement disorders, including Parkinson's disease and parkinsonian syndromes, e.g. progressive supranuclear palsy, multiple system atrophy, and Lewy body dementia, may be difficult to differentiate among each other at an early stage, since they may share similar clinical features and response to dopaminergic drugs. As new tracers for imaging the dopamine transporters become available, the use of positron emission tomography (PET) for the differential diagnosis of movement disorders is gaining clinical relevance. Visual interpretation is generally used for PET image analysis. However, the use of some form of less subjective analysis is desirable in order to detect subtle changes that may be difficult to identify by visual interpretation and to achieve an operator independent analysis. To this end this study was aimed at assessing the feasibility of using statistical parametric mapping (SPM) for the clinical evaluation of single PET scans performed with 2-beta-carbomethoxy-3-beta-(4-fluorophenyl)-tropane ( C-beta-CIT-FE). Eleven healthy volunteers and five patients with movement disorders (Parkinson's disease, essential tremor, PSP and Lewy body dementia) were included in this study. Each subject underwent a PET study after i.v. injection of C-beta-CIT-FE. The PET images of C-beta-CIT-FE distribution acquired between 60 and 90 min were spatially fitted into the Talairach and Tournoux space. A template of normal C-beta-CIT-FE distribution was derived from studies in the 11 normal control subjects. Different patterns of reduction of the uptake of the tracer were detected in the basal ganglia of the five patients, in relation to each pathological condition. The patterns of distribution were all consistent with the severity and type of disease. The results of this study demonstrate the feasibility of differentiating among different states of dopaminergic impairment, due to Parkinson's disease and parkinsonian syndromes, by using PET scans with C-beta-CIT-FE and by using the SPM procedure for analysis of the data.

In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson's disease.

BACKGROUND: Reactive microgliosis, hallmark of neuroinflammation, may contribute to neuronal degeneration, as shown in several neurodegenerative diseases. We in vivo evaluated microglia activation in early dementia with Lewy bodies, still not reported, and compared with early Parkinson's disease, to assess possible differential pathological patterns. METHODS: We measured the [(11)C]-PK11195 binding potentials with Positron Emission Tomography, using a simplified reference tissue model, as marker of microglia activation, and cerebral spinal fluid protein carbonylation levels, as marker of oxidative stress. Six dementia with Lewy bodies and 6 Parkinson's disease patients within a year from the onset, and eleven healthy controls were included. Clinical diagnosis was confirmed at a 4-year follow-up. RESULTS: In dementia with Lewy bodies as well as in Parkinson's disease, we found significant (p < 0.001) [(11)C]-PK11195 binding potential increases in the substantia nigra and putamen. Patients with Lewy bodies dementia had extensive additional microglia activation in several associative cortices. This was evident also at a single subject level. Significant increase of Cerebral Spinal Fluid protein carbonylation was shown in both patients' groups. CONCLUSIONS: [(11)C]-PK11195 Positron Emission Tomography imaging revealed neuroinflammation in dementia with Lewy bodies and Parkinson's disease, mirroring, even at a single subject level, the common and the different topographical distribution of neuropathological changes, yet in the earliest stages of the disease process. Focusing on those events that characterize parkinsonisms and Parkinson's disease may be the key to further advancing the understanding of pathogenesis and to taking these mechanisms forward as a means of defining targets for neuroprotection.

Changes in brain glucose metabolism in subthalamic nucleus deep brain stimulation for advanced Parkinson's disease.

BACKGROUND: Despite its large clinical application, our understanding about the mechanisms of action of deep brain stimulation of the subthalamic nucleus is still limited. Aim of the present study was to explore cortical and subcortical metabolic modulations measured by Positron Emission Tomography associated with improved motor manifestations after deep brain stimulation in Parkinson disease, comparing the ON and OFF conditions. PATIENTS AND METHODS: Investigations were performed in the stimulator off- and on-conditions in 14 parkinsonian patients and results were compared with a group of matched healthy controls. The results were also used to correlate metabolic changes with the clinical effectiveness of the procedure. RESULTS: The comparisons using Statistical parametric mapping revealed a brain metabolic pattern typical of advanced Parkinson disease. The direct comparison in ON vs OFF condition showed mainly an increased metabolism in subthalamic regions, corresponding to the deep brain stimulation site. A positive correlation exists between neurostimulation clinical effectiveness and metabolic differences in ON and OFF state, including the primary sensorimotor, premotor and parietal cortices, anterior cingulate cortex. CONCLUSION: Deep brain stimulation seems to operate modulating the neuronal network rather than merely exciting or inhibiting basal ganglia nuclei. Correlations with Parkinson Disease cardinal features suggest that the improvement of specific motor signs associated with deep brain stimulation might be explained by the functional modulation, not only in the target region, but also in surrounding and remote connecting areas, resulting in clinically beneficial effects.

In vivo imaging of adenosine A2A receptors in rat and primate brain using [11C]SCH442416.

PURPOSE: The aim of this study was to evaluate the suitability of [11C]SCH442416 for the in vivo imaging of adenosine A2A receptors. METHODS: In rats and Macaca nemestrina, we evaluated the time course of the cerebral distribution of [11C]SCH442416. Furthermore, in rats we investigated the rate of metabolic degradation, the inhibitory effects of different drugs acting on adenosine or dopamine receptors and the modification induced by the intrastriatal administration of quinolinic acid (QA). RESULTS: The rate of metabolic degradation of [11C]SCH442416 in rats was slow; 60 min after tracer injection, more than 40% of total plasma activity was due to unmetabolised [11C]SCH442416. At the time of maximum uptake, radioactive metabolites represented only 6% of total extractable activity in the cerebellum and less than 1% in the striatum. In the striatum, the region with the highest expression of A2A receptors, the in vivo uptake of [11C]SCH442416 was significantly reduced only by drugs acting on A2A receptors or by QA, a neurotoxin that selectively reduces the number of intrastriatal GABAergic neurons. Position emission tomography (PET) studies in monkeys indicated that the tracer rapidly accumulates in brain, reaching maximum uptake between 5 and 10 min. Twenty minutes after the injection, radioactivity concentration in the striatum was two times that in the cerebellum. CONCLUSION: The specificity of binding, the rank order of regional distribution in the brain of rats and M. nemestrina, the good signal to noise ratios and the low amount of radioactive metabolites in brain and periphery indicate that [11C]SCH442416 is a promising tracer for the in vivo imaging of A2A adenosine receptors using PET.

Ventilatory responses to hypercapnia and hypoxia in elite breath-hold divers.

It was recently hypothesized that elite breath-hold divers may display blunted ventilatory responses to hypoxia and/or hypercapnia (Ferretti et al., J. Appl. Physiol. 70: 794-802, 1991). To test this hypothesis, the following measurements were made on three elite breath-hold divers (members of the same family), and on 9 healthy untrained control subjects (C): (1) Steady-state pulmonary ventilation (VE) at rest in the supine posture while breathing room air or normoxic CO2-enriched mixtures. (2) Breath-by-breath VE changes (delta VE), with respect to baseline conditions, after 4 breaths of 100% O2, under the following conditions: normoxia (PIO2 = 146 Torr) at rest (NR); normoxic exercise (60 watt on a bicycle ergometer) (NE); hypoxia (PIO2 = 77 Torr) at rest (HR); hypoxic exercise (HE). The results were as follows: (1) In hypercapnic experiments VE (normalized per unit of body surface area) was significantly lower in the divers than in C (4.32 +/- 0.04 [mean +/- SD]L.min-1.m-2 vs. 5.31 +/- 0.62 at FICO2 = 1.5%; 5.21 +/- 0.17 vs. 7.72 +/- 1.39 at FICO2 = 3%; 8.86 +/- 0.76 vs. 13.14 +/- 2.27 at FICO2 = 5%), as well as than in subjects described by previous authors as being characterized by 'low CO2 sensitivity'. (2) The 100% O2-breathing maneuvers did not induce significant delta VE both in NR and in HR, whereas peak delta VE were -6.73 +/- 1.38 L.min-1 (divers) vs. -5.24 +/- 3.10 (C) in NE, and -17.39 +/- 4.92 (divers) vs. -17.52 +/- 6.32 (C) in HE (no significant differences). It is concluded that the divers, compared to C, had a blunted ventilatory response to hypercapnia, but not to hypoxia. The former may represent an adaptive or genetically inherited phenomenon.

The status of dopamine nerve terminals in Parkinson's disease and essential tremor: a PET study with the tracer [11-C]FE-CIT.

Neuroimaging studies of the striatal dopamine transporter (DAT) are useful in the assessment of the dopaminergic system in Parkinson's disease (PD). We used positron emisson tomography (PET) and the tracer [11C]FE-CIT to measure DAT binding in the caudate nucleus and putamen of 31 patients with PD, 5 with essential tremor and 8 healthy control subjects. Of the patients with PD, 17 were drug naive, while the others were either on levodopa or dopamine agonist monotherapy. DAT binding was significantly reduced in the caudate nucleus and to a greater extent in the putamen of PD patients compared to both healthy controls and essential tremor individuals. No overlap was observed between putamen values in PD and normals. No differences were found between controls and essential tremor subjects. These data confirm that measurements of DAT binding can provide an accurate and highly sensitive measure of degeneration in the dopamine system in PD.

In vivo serotonin 5HT(2A) receptor binding and personality traits in healthy subjects: a positron emission tomography study.

Using positron emission tomography (PET) and [(11)C]raclopride, an association between striatal D(2) 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'-[(18)F]fluoroethyl)spiperone ([(18)F]FESP) to cortical 5HT(2) and striatal D(2) 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., Arch. Gen. Psychiatry 44: 573-588.) and underwent a PET scan with [(18)F]FESP. Harm avoidance showed a significant inverse correlation with [(18)F]FESP binding in the cerebral cortex, particularly in the frontal cortex (R(2) = -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 [(18)F]FESP binding values are associated with a high tendency to avoid danger, indicating involvement of the serotoninergic system and, in particular, 5HT(2A) 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.

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

Amantadine, is a non competitive NMDA receptors antagonist that has been proved beneficial in Parkinson's 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 [(11)C]raclopride binding to striatal D(2) dopamine receptors, in patients with moderate idiopathic Parkinson's 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 [(11)C-]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 D(2) 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 D(2) receptors in rats treated with amantadine or other non competitive NMDA antagonists and suggests that the neo-synthesis of D(2) receptors may represent a reinforcing mechanism of drug efficacy.

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).

Neuroimaging studies of striatal dopamine transporters (DAT) have shown that this measurement is a specific marker of dopaminergic degeneration in patients with Parkinson's 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 [(11)C]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.

Frontotemporal dementia: impact of P301L tau mutation on a healthy carrier.

Frontotemporal dementia (FTD) is the second commonest form of dementia after Alzheimer's disease, but its clinical and biological features are less well known. To uncover its earliest signs, we studied the main clinical, neuroimaging, and biochemical findings in an asymptomatic carrier from a three generation FTD family, bearing the P301L pathogenic mutation in the tau gene. Except for selective impairment on the Verbal Fluency Test for letters, all cognitive tests were normal. The brain computed tomography scan was normal, but the brain single photon emission computed tomography and statistical parametric mapping (SPECT-SPM) scan revealed bilateral frontal lobe hypoperfusion. Levels of total tau, 181P-tau, and Abeta1-42 in the cerebrospinal fluid were increased compared with control values. We conclude that detection of these distinctive abnormalities should improve early diagnostic accuracy for FTD and help distinguish it from Alzheimer's disease.