Vijay Dhawan

Parkinson's disease tremor-related metabolic network: Characterization, progression, and treatment effects

The circuit changes that mediate parkinsonian tremor, while likely differing from those underlying akinesia and rigidity, are not precisely known. In this study, to identify a specific metabolic brain network associated with this disease manifestation, we used FDG PET to scan nine tremor dominant Parkinsons disease (PD) patients at baseline and during ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS). Ordinal trends canonical variates analysis (OrT/CVA) was performed on the within-subject scan data to detect a significant spatial covariance pattern with consistent changes in subject expression during stimulation-mediated tremor suppression. The metabolic pattern was characterized by covarying increases in the activity of the cerebellum/dentate nucleus and primary motor cortex, and, to a less degree, the caudate/putamen. Vim stimulation resulted in consistent reductions in pattern expression (p<0.005, permutation test). In the absence of stimulation, pattern expression values (subject scores) correlated significantly (r=0.85, p<0.02) with concurrent accelerometric measurements of tremor amplitude. To validate this spatial covariance pattern as an objective network biomarker of PD tremor, we prospectively quantified its expression on an individual subject basis in independent PD populations. The resulting subject scores for this PD tremor-related pattern (PDTP) were found to exhibit: (1) excellent test-retest reproducibility (p<0.0001); (2) significant correlation with independent clinical ratings of tremor (r=0.54, p<0.001) but not akinesia-rigidity; and (3) significant elevations (p<0.02) in tremor dominant relative to atremulous PD patients. Following validation, we assessed the natural history of PDTP expression in early stage patients scanned longitudinally with FDG PET over a 4-year interval. Significant increases in PDTP expression (p<0.01) were evident in this cohort over time; rate of progression, however, was slower than for the PD-related akinesia/rigidity pattern (PDRP). We also determined whether PDTP expression is modulated by interventions specifically directed at parkinsonian tremor. While Vim DBS was associated with changes in PDTP (p<0.001) but not PDRP expression, subthalamic nucleus (STN) DBS reduced the activity of both networks (p<0.05). PDTP expression was suppressed more by Vim than by STN stimulation (p<0.05). These findings suggest that parkinsonian tremor is mediated by a distinct metabolic network involving primarily cerebello-thalamo-cortical pathways. Indeed, effective treatment of this symptom is associated with significant reduction in PDTP expression. Quantification of treatment-mediated changes in both PDTP and PDRP scores can provide an objective means of evaluating the differential effects of novel antiparkinsonian interventions on the different motor features of the disorder.

Radiosynthesis of [18F] N-3-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl) nortropane and the first human study with positron emission tomography☆

A procedure for the routine preparation of [18F]FP-CIT has been developed. Purification of the final product was achieved by preparative HPLC using phenethyl column without decomposition or epimerization. [18F] labeled-N-fluoropropyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane was prepared and PET imaging was performed on human subjects. A high uptake into striatal regions was observed. HPLC plasma analysis using [18F]FP-CIT indicated the presence of only one metabolite. By directly comparing the behavior of these three radiotracers ([18F]DOPA, [123I]FP-CIT, and [18F]FP-CIT) in the same subjects, we can enhance our understanding of the dopaminergic system as well as the relative potential of these techniques in a clinical research setting.

Combined FDOPA and 3OMFD PET Studies in Parkinson's Disease

This chapter presents the studies of 6-[ 18 F]fluoro-L-dopa (FDOPA)/positron emission tomography (PET) to determine the quantitative parameters that correlate closely with independent disease severity measures and discriminate reliably between patients with mild early disease, or with preclinical involvement, and normal control subjects. Five classical Parkinsons disease (PD) patients with mild or moderate clinical involvement and without dementia were studied with quantitative FDOPA and 3-O-MFD/PET. The control group consists of three normal volunteer subjects. All subjects fasted overnight prior to the PET scanning. All anti-Parkinsonian medications were discontinued at least 12 h before PET investigations. PET studies were performed using the SuperPETT 3000 tomograph. All subjects received 200 mg carbidopa 1.5 h before the study and 185–370 MBq of FDOPA was injected intravenously. The use of 3-O-MFD parameters in the FDOPA compartmental model allows one to simplify the model without making assumptions that are otherwise required. The results show that striatal dopadecarboxylation (DDC) activity estimated from a compartmental modeling approach is similar to the graphically derived unidirectional influx constant in discriminating normals from PD patients. In addition, unidirectional transport rate constant and various estimates of striatal DDC activity have similar correlations with disease severity. This suggests that with present PET methods, clinically relevant information can be obtained from a simple graphical approach rather than a more computationally demanding compartmental technique.UNLABELLED PET has been used to quantify striatal 6-[18F]fluoro-L-dopa (FDOPA) uptake as a measure of presynaptic dopaminergic function. It has been suggested that the estimation of dopa-decarboxylation (DDC) rate, kD3, using a compartmental approach to dynamic FDOPA/PET data, can provide a better objective marker of parkinsonism. This modeling process, however, requires many assumptions to estimate DDC activity with acceptable errors. METHODS We combined FDOPA 3-O-methyl-fluorodopa PET studies on three normal subjects and five Parkinsons disease patients. RESULTS The contradicted modeling assumptions are: (a) the rate constants across the blood-brain barrier, KD1 and kD2, for 3OMFD and FDOPA were in similar range (ratio approximately equal to 1) and thus not equal to assumed values of KM1/KD1 of 2.3 derived from rat studies and applied to human FDOPA studies and (b) the KD1/kD2 ratio for frontal cortex was not equal to that for the striatum (0.70 +/- 0.15 versus 1.07 +/- 0.3; p < 0.002). Discriminant analyses indicate that simple estimates like the striatum-to-occipital ratio, or the graphically derived unidirectional transport rate constant (KiFD) separate normals from Parkinsons disease patients at least as accurately as estimates of striatal DDC activity (kD3). CONCLUSION Measurements of striatal DDC activity with dynamic FDOPA/PET and compartmental modeling may be based on incorrect assumptions. Even though such complex models yield microparameters that may be applicable to certain clinical research demands, they may produce misleading results in other experimental settings.

Quantitative Brain PET. Comparison of 2D and 3D Acquisitions on the GE Advance Scanner.

PURPOSE: Recent developments in the design of positron emission tomography (PET) scanners have made three-dimensional (3D) data acquisition attractive because of significantly higher sensitivity compared to the conventional 2D mode (with lead/tungsten septa extended). However, the increased count rate in 3D mode comes at the cost of increased scatter, randoms, and dead time. Several schemes to correct for these effects have been proposed and validated in phantom studies. In this study, we evaluated the overall improvement afforded by 3D imaging in quantitative human brain PET studies carried out at our institution.METHODS: Subjects were studied using sequential/interleaved 2D and 3D data acquisition with a GE Advance scanner. We calculated regional and global cerebral glucose metabolism with [(18)F]flourodeoxyglucose (FDG) and estimated rate constants for striatal [(18)F]fluorodopa (FDOPA) uptake.RESULTS: FDG: Global mean glucose metabolic rates were in almost complete agreement (within 1%) between the two modes whereas the regional differences ranged from -7.7% to +9% for all cortical structures. However, for small regions (<2 cm(2)) like caudate nuclei, the maximum difference was 14.7%. FDOPA: A significant improvement in image quality was evident in 3D mode and there was complete agreement between the estimated parameters in the two scanning modes for the same noise equivalent counts: Striatal-to-occipital ratio (SOR) and striatal FDOPA uptake (K(i)(FD)) had mean differences of less than 2% and 5%, respectively.CONCLUSIONS: 3D FDG studies can be done with either half the injected dose or half the scan duration to a comparable 2D study. 3D PET imaging has distinct advantages over 2D in the quantitative fluorodopa studies.

Early Parkinson’s Disease: Longitudinal Changes in Brain Activity during Sequence Learning

Impairment of sequence learning is common in Parkinsons disease (PD), but the time course of this cognitive abnormality is not known. We assessed longitudinal changes in sequence learning performance and associated task-related cerebral blood flow in 13 early stage PD patients who underwent H(2)(15)O PET at baseline and again 2 years later. Ten healthy volunteer subjects served as controls. A trend toward decline in learning performance (p=0.08) was evident over the 2 years of follow-up. During this interval, significant declines in learning-related activation were detected in parietal and temporo-occipital association areas and in the right dorsolateral prefrontal cortex. Learning-related activation in these regions was normal at baseline, but declined to subnormal levels (p<0.01) at 2 years. Significant hippocampal activation (p<0.005) was present in the subjects with high learning performance over time. The findings are consistent with a decline in learning-related neural activity in cortical areas with prominent Lewy body formation.

Imaging cerebral function

The Scan Analysis and Visualization Processor (Scan/VP), a flexible, portable, Unix-based software package for visualizing and analyzing positron emission tomography (PET) images in a clinical-research setting, is described. PET systems are compared to computerized tomography (CT) and magnetic resonance imaging (MRI) systems. The imaging and software aspects of Scan/VP, and procedures devoted specifically to functional PET imaging, including mathematical modeling, image registration, regional thresholding, and derivation of regional covariation patterns, are discussed. Basic surface display, animation, and stereo techniques for visualizing variations in metabolic topology and underlying disease patterns are also discussed.<<ETX>>

Visualizing the evolution of abnormal metabolic networks in the brain using PET

By applying novel statistical methods and visualization techniques to PET data obtained from combined groups of patients and normals, we are able to illustrate topographic covariance profiles unique to neurodegenerative disorders such as Parkinsons Disease at various stages of progression. Each profile represents a neuroanatomical network of metabolically covarying regions. The expression of the profile in each patient is characterized by a subject score which can correlate with independent clinical disease severity measures. To visualize these profiles, a semi-automatic routine is used (3D) animation of the metabolic topography as it evolves from initial to final stages of the disease.

Synthesis of 6-[18F]fluorodopamine with a synthetic unit made up of primarily sterile disposable components and operated by a master slave manipulator

Abstract A synthetic procedure for the routine preparation of 6-[18F]fluorodopamine has been developed. The synthesis is based on electrophilic fluorination of a 6-mercurated dopamine precursor. Fluorodemercuration of the dopamine precursor using [18F]acetylhypofluorite and hydrolysis by a mixture of acetic anhydride and HI gave the desired radiopharmaceutical with a radiochemical yield of 13.7 ± 0.7% calculated at the end of synthesis based on five synthetic preparations (without decay correction) and also based on the amount of total [18F]F2 recovered from the target. Radiochemical purity as well as chemical purity were > 98%. In order to maintain good sterility and pyrogenicity, the synthetic unit is made up of mostly sterile disposable components that are readily available. The routine operations of the synthetic unit are carried out in a closed hot cell, using a Master Slave Manipulator arm. Since no manual handling of radioactivity is involved, the operation of the synthetic unit is radiation safe and the radiation exposure to the operator is minimized.

Radiosynthesis of [18F] N-(3-Fluoropropyl)-2-β-Carbomethoxy-3-β-(4-Bromophenyl) Nortropane and the regional brain uptake in non human primate using PET

Abstract A synthetic procedure for the preparation of [ 18 F]FPCBT, an imaging agent for the dopamine transporter (DAT), has been developed. The radiosynthesis was carried out in a two step procedure. Even though the yield was low, we were able to prepare 20 to 30mCi of the product, which was enough for two or three studies. The radiochemical purity was greater than 96%. The in vivo properties of this radiotracer were evaluated using baboon and it showed highest uptake in the striatum. The studies also revealed that the maximum uptake was reached within 7 to 10 minutes post injection. Plasma metabolite analysis indicated that there is only one metabolite and it is less lipophilic than the parent compound. [ 18 F]FPCBT displayed good brain uptake and its high target to non target ratio indicate that it is a potential candidate for DAT imaging.

A disposable synthetic unit for the preparation of 3-O-methyl-6-[18F]fluorodopa using a regioselective fluorodemercuration reaction

Abstract A regioselective synthetic procedure for the routine preparation of 3- O -methyl-6-[ 18 F]fluorodopa (3OMFD) has been developed. The synthetic procedure is based on electrophilic fluorination of the 6-mercurated 3OMFD precursor using fluorodemercuration reaction. Fluorination using [ 18 F]acetylhypofluorite (AcOF), hydrolysis and preparative HPLC purification, followed by solvent removal gave the desired radio-pharmaceutical with a radiochemical yield of 16.2 ± 2.1% at EOS based on 4 synthetic preparations. Radiochemical purity was >98% and the chemical purity was >97%. By using sterile disposable components, the required sterility and pyrogenicity are met. Since the synthesizer is operated in a closed hot cell using manipulator arm, radiation exposure to the operator is minimized. The authenticity of the 3OMFD was confirmed by 1 H-NMR, 19 F-NMR, HPLC and thin layer chromatography.