Nicola Pavese

Amyloid, hypometabolism, and cognition in Alzheimer disease: An [11C]PIB and [18F]FDG PET study

Objective: To investigate the association between brain amyloid load in Alzheimer disease (AD) measured by [11C]PIB-PET, regional cerebral glucose metabolism (rCMRGlc) measured by [18F]FDG-PET, and cognition. Methods: Nineteen subjects with AD and 14 controls had [11C]PIB-PET and underwent a battery of psychometric tests. Twelve of those subjects with AD and eight controls had [18F]FDG-PET. Parametric images of [11C]PIB binding and rCMRGlc were interrogated with a region-of-interest atlas and statistical parametric mapping. [11C]PIB binding and rCMRGlc were correlated with scores on psychometric tests. Results: AD subjects showed twofold increases in mean [11C]PIB binding in cingulate, frontal, temporal, parietal, and occipital cortical areas. Higher cortical amyloid load correlated with lower scores on facial and word recognition tests. Two patients fulfilling the clinical criteria for AD had normal [11C]PIB at baseline. Over 20 months this remained normal in one but increased in the cingulate of the other. Mean levels of temporal and parietal rCMRGlc were reduced by 20% in AD and these correlated with mini mental scores, immediate recall, and recognition memory test for words. Higher [11C]PIB uptake correlated with lower rCMRGlc in temporal and parietal cortices. Conclusion: [11C]PIB-PET detected an increased amyloid plaque load in 89% of patients with clinically probable Alzheimer disease (AD). The high frontal amyloid load detected by [11C]PIB-PET in AD in the face of spared glucose metabolism is of interest and suggests that amyloid plaque formation may not be directly responsible for neuronal dysfunction in this disorder.

Dyskinesias following neural transplantation in Parkinson's disease

Severe dyskinesias during the off phases (periods of increased Parkinsons disease (PD) disability) have been observed following intrastriatal transplantation of human embryonic mesencephalic tissue. Here we retrospectively analyzed 14 patients who were followed for up to 11 years after grafting, and found that dyskinesias (abnormal involuntary movements and postures) increased during postoperative off phases, but were generally of mild to moderate severity. Dyskinesia severity was not related to the magnitude of graft-derived dopaminergic re-innervation, as judged by 18F-labeled 6-L-fluorodopa (FD) positron emission tomography (PET), indicating that off-phase dyskinesias probably did not result from excessive growth of grafted dopaminergic neurons.

Compulsive drug use linked to sensitized ventral striatal dopamine transmission.

A small group of Parkinsons disease (PD) patients compulsively use dopaminergic drugs despite causing harmful social, psychological, and physical effects and fulfil core Diagnostic and Statistical Manual (of Mental Disorders) Fourth Edition criteria for substance dependence (dopamine dysregulation syndrome [DDS]). We aimed to evaluate levodopa‐induced dopamine neurotransmission in the striatum of patients with DDS compared with PD control patients.

Clinical correlates of levodopa-induced dopamine release in Parkinson disease : A PET study

Objective: To evaluate the relationship between clinical improvement and in vivo synaptic dopamine (DA) release after a single oral dose of levodopa (LD) in patients with advanced Parkinson disease (PD). Methods: We studied 16 patients with advanced PD with [11C]raclopride (RAC) PET. Each patient had RAC PET twice: once when medication had been withdrawn and once after an LD challenge. On the day of the LD challenge scan, oral 250 mg LD/25 mg carbidopa was given before scanning. Unified Parkinsons Disease Rating Scale (UPDRS) motor scores were rated in an “off” state before LD and again at the end of PET. Results: All the patients were still in “on” state at the end of their LD challenge RAC PET scans. Following LD, mean caudate and putamen RAC binding potentials (BPs) were significantly lower vs baseline, consistent with increased synaptic DA. Individual LD-induced improvements in UPDRS score correlated significantly with reductions in putaminal BP. Additionally, large putaminal RAC BP changes were associated with higher dyskinesia scores. When motor UPDRS subitems were examined, improvements in rigidity and bradykinesia, but not in tremor or axial symptoms, correlated with putamen DA release. Conclusion: In advanced Parkinson disease, the improvement of rigidity and bradykinesia and the presence of dyskinesias after a single dose of oral levodopa are governed by the level of dopamine generated at striatal D2 receptors. In contrast, relief of parkinsonian tremor and axial symptoms is not related to striatal synaptic dopamine levels and presumably occurs via extrastriatal mechanisms.

Endogenous dopamine release after pharmacological challenges in Parkinson's disease

Using 11C‐raclopride positron emission tomography after methamphetamine challenge, we have evaluated regional brain changes in synaptic dopamine (DA) levels in six volunteers and six advanced Parkinsons disease (PD) patients. The pharmacological challenge induced significant release of endogenous DA in putamen not only in the normal subjects, as reflected by a 25.2% reduction in 11C‐raclopride binding potential as compared with placebo, but also in the PD patients (6.8%). In individual PD patients, we found a correlation between putamen DA release and DA storage, as measured by 18F‐dopa uptake. Localization of significant changes in 11C‐raclopride binding after methamphetamine at a voxel level with statistical parametric mapping identified striatal and prefrontal DA release in both cohorts. Statistical comparisons between normal subjects and PD confirmed significantly reduced DA release in striatal areas in PD, but normal levels of prefrontal DA release. In conclusion, significant endogenous DA release can still be induced by pharmacological challenges in the putamen of advanced PD patients, and this release correlates with residual DA storage capacity. Our data also show that the capacity to release normal DA levels in prefrontal areas after a pharmacological challenge is preserved in severe stages of the disease. Ann Neurol 2003

Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease

Objective: To investigate striatal adenosine A2A receptor availability in patients with Parkinson disease (PD) with and without levodopa-induced dyskinesias (LIDs). While providing effective relief from the motor symptoms of PD, chronic levodopa use is associated with development of LIDs. A2A receptors are expressed on the bodies of indirect pathway medium spiny striatal neurons and on dopamine terminals and play a role in modulating dopamine transmission. A2A antagonists have antiparkinsonian activity by boosting levodopa efficacy. We aimed to study A2A receptor availability in patients with PD with and without LIDs using PET and [11C]SCH442416, an A2A antagonist. Methods: Six patients with PD with and 6 without LIDs were studied withdrawn 12 hours from medication. Their PET findings were compared with 6 age-matched healthy controls. Using spectral analysis, [11C]SCH442416 regional volumes of distribution (VT) were computed for the caudate, putamen, and thalamus and binding potentials (BPND) reflecting the ratio of specific:nonspecific uptake were compared between groups. Results: A2A binding in the caudate and putamen of subjects with PD with LIDs was far higher (p = 0.026 and p = 0.036, respectively) than that of subjects with PD without LIDs, which lay within the control range. Thalamic A2A availability was similar for all 3 groups. Conclusion: Patients with PD with LIDs show increased A2A receptor availability in the striatum. This finding is compatible with altered adenosine transmission playing a role in LIDs and provides a rationale for a trial of A2A receptor agents in the treatment of these motor complications.

Combined pedunculopontine-subthalamic stimulation in Parkinson disease

Objective: To assess the effect of deep brain stimulation (DBS) in the pedunculopontine nucleus (PPN) and caudal zona incerta (cZi)—both separately and in combination—on motor symptoms and regional cerebral blood flow (rCBF) in patients with Parkinson disease (PD). Methods: Four patients with bilateral cZi and PPN DBS electrodes were rated with the Unified Parkinsons Disease Rating Scale motor subscale (UPDRS-III) when taking and withdrawn from medication. A block of 16 [15O]-H2O PET resting measurements of rCBF were performed in 4 different states with patients withdrawn from medication: 1) no stimulation, 2) cZi stimulation alone, 3) PPN stimulation alone, 4) combined PPN/cZi stimulation. Results: When patients were medicated, combined PPN/cZi stimulation produced a statistically significant improvement in UPDRS-III score compared to cZi stimulation alone. In the “off” medication state, the clinical effect of combined stimulation was not significantly different from that induced by cZi stimulation alone. Concomitant PPN/cZi stimulation had a cumulative effect on levels of rCBF, effectively combining subcortical and cortical changes induced by stimulation of either target in isolation. Conclusions: These findings suggest that concomitant low frequency stimulation of PPN and cZi regions induces additive brain activation changes and provides improved control of PD symptoms when medicated. Classification of evidence: This study provides Class IV evidence that concomitant low frequency stimulation of PPN and cZI improves motor symptoms in patients with PD on dopamine replacement. It provides Class III evidence that concomitant low frequency stimulation of PPN and cZi induces additive rCBF changes in motor areas of brain.

Cortical dopamine dysfunction in symptomatic and premanifest Huntington's disease gene carriers

We used (11)C-raclopride PET, a marker of D(2) dopamine receptor binding, and statistical parametric mapping (SPM) to localise cortical D(2) receptor dysfunction in individual Huntingtons disease (HD) gene carriers (16 symptomatic and 11 premanifest subjects) and assess its clinical significance. 62.5% of symptomatic HD patients and 54.5% of premanifest carriers showed cortical reductions in D(2) binding. The most frequent decreases in cortical binding in individual HD subjects were seen in temporal and frontal areas. Symptomatic HD subjects with decreased cortical D(2) binding had worse scores on neuropsychological tests assessing attention and executive functions than subjects without cortical dopamine dysfunction, notwithstanding comparable reduction in striatal D(2) binding and motor disability. Our results indicate that cortical dopaminergic dysfunction is common in both symptomatic and premanifest HD gene carriers. It is an early event in HD pathophysiology and could contribute to the impairment in neuropsychological performance in these patients.

A systematic comparison of kinetic modelling methods generating parametric maps for [(11)C]-(R)-PK11195

[(11)C]-(R)-PK11195 is presently the most widely used radiotracer for the monitoring of microglia activity in the central nervous system (CNS). Microglia, the resident immune cells of the brain, play a critical role in acute and chronic diseases of the central nervous system and in host defence against neoplasia. The purpose of this investigation was to evaluate the reliability and sensitivity of five kinetic modelling methods for the formation of parametric maps from dynamic [(11)C]-(R)-PK11195 studies. The methods we tested were the simplified reference tissue model (SRTM), basis pursuit, a simple target-to-reference ratio, the Logan plot and a wavelet based Logan plot. For the reliability assessment, the test-retest data consisted of four Alzheimers patients that were scanned twice at approximately a six-week interval. For the sensitivity assessment, comparison of [(11)C]-(R)-PK11195 binding in Huntingtons disease (HD) patients and normal subjects was performed using a group contrast to localize significant increases in mean pixel volume of distribution (VD) in HD. In all instances, a reference region kinetic extracted by a supervised clustering technique was used as input function. Reliability was assessed by use of the intra-class correlation coefficient (ICC) across a wide set of anatomical regions and it was found that the wavelet-based Logan plot, basis pursuit and SRTM gave the highest ICC values on average. The same methods produced the highest z-scores resulting from increases in mean striatal VD in HD patients compared with controls. The reference-to-target ratio and the Logan graphical approach were significantly less reliable and less sensitive.

Upregulation of dopamine D2 receptors in dopaminergic drug-naive patients with Parkin gene mutations.

Medicated patients with Parkinsonism and parkin gene mutations have been reported to show a significant decrease in striatal dopamine D2 receptors (D2R) in comparison to medicated idiopathic Parkinsons disease (IPD) patients with similar age and disease severity. The aim of this study was to verify whether the genetic defect per se is responsible for this decrease. We have studied with [11C]raclopride (RAC) positron emission tomography (PET) in a group of 14 sporadic patients with parkin‐linked Parkinsonism, 6 of whom had never received levodopa or dopamine agonists. The remaining 8 patients had been treated with levodopa for at least 5 years. Presynaptic striatal [18F]dopa storage was not significantly different between these two groups of patients. In untreated parkin‐positive patients, significant putaminal increases in RAC‐binding potential (BP) were found in comparison to an age‐matched healthy control group by using a classical region of interest approach and statistical parametric mapping. In contrast, levodopa‐treated parkin‐positive patients showed significant decreases in RAC‐BP in the caudate and putamen when compared to an age‐matched healthy control group. The RAC PET findings revealed that striatal D2R upregulation occurs in dopaminergic drug‐naive parkin‐positive patients, in a similar fashion to the upregulation reported in drug‐naive IPD. D2R downregulation observed in medicated parkin‐positive patients, therefore, is not caused primarily by the genetic defect itself. Parkin‐positive patients appear to have a greater susceptibility to the exposure to dopaminergic medication than IPD patients, which in turn might be an indirect effect of their genetic mutation.