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Joint pattern analysis applied to PET DAT and VMAT2 imaging reveals new insights into Parkinson's disease induced presynaptic alterations.

ABSTRACT: Most neurodegenerative diseases are known to affect several aspects of brain function, including neurotransmitter systems, metabolic and functional connectivity. Diseases are generally characterized by common clinical characteristics across subjects, but there are also significant inter-subject variations. It is thus reasonable to expect that in terms of brain function, such clinical behaviors will be related to a general overall multi-system pattern of disease-induced alterations and additional brain system-specific abnormalities; these additional abnormalities would be indicative of a possible unique system response to disease or subject-specific propensity to a specific clinical progression. Based on the above considerations we introduce and validate the use of a joint pattern analysis approach, canonical correlation analysis and orthogonal signal correction, to analyze multi-tracer PET data to identify common (reflecting functional similarities) and unique (reflecting functional differences) information provided by each tracer/target. We apply the method to [¹¹C]-DTBZ (VMAT2 marker) and [¹¹C]-MP (DAT marker) data from 15 early Parkinson's disease (PD) subjects; the behavior of these two tracers/targets is well characterized providing robust reference information for the method's outcome. Highly significant common subject profiles were identified that decomposed the characteristic dopaminergic changes into three distinct orthogonal spatial patterns: 1) disease-induced asymmetry between the less and more affected dorsal striatum; 2) disease-induced gradient with caudate and ventral striatum being relatively spared compared to putamen; 3) progressive loss in the less affected striatum, which correlated significantly with disease duration (p?

SUBMITTER: Fu JF

PROVIDER: S-EPMC6517523 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Joint pattern analysis applied to PET DAT and VMAT2 imaging reveals new insights into Parkinson's disease induced presynaptic alterations.

Fu Jessie Fanglu JF Klyuzhin Ivan I McKenzie Jessamyn J Neilson Nicole N Shahinfard Elham E Dinelle Katie K McKeown Martin J MJ Stoessl A Jon AJ Sossi Vesna V

NeuroImage. Clinical 20190508

Most neurodegenerative diseases are known to affect several aspects of brain function, including neurotransmitter systems, metabolic and functional connectivity. Diseases are generally characterized by common clinical characteristics across subjects, but there are also significant inter-subject variations. It is thus reasonable to expect that in terms of brain function, such clinical behaviors will be related to a general overall multi-system pattern of disease-induced alterations and additional ...[more]

PMID: 31091502

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Project description:Background: Brain development and maturation in adolescence is a complex process with active changes of metabolic and neurotransmission pathways. Positron emission tomography (PET) is a useful imaging modality for tracking metabolic and functional changes in adolescent brain. In this study, changes of glucose metabolism, expression of vesicular monoamine transporter 2 and dopamine transporter during adolescent brain development in rats were investigated with PET/CT. Methods: A longitudinal PET/CT study of age-dependent changes of VMAT2, DAT and glucose metabolism in adolescent brain was conducted in a group of Wistar rats (n = 6) post sequential intravenous injection of 18F-PF-(+)-DTBZ, 11C-CFT, and 18F-FDG, respectively. PET acquisition was performed at 2, 4, 9, and 12 months of age. Radiotracer uptake in different brain regions, including the striatum, cerebellum, and hippocampus, were quantified and recorded as Standardized uptake value (SUV) and striatal specific uptake ratio (SUVR: SUV in brain regions/SUV in cerebellum). Results: Variable uptake of 18F-PF-(+)-DTBZ and 11C-CFT were detected, with highest level uptake in the striatum and accumbens. There was significant age-dependent increase of 18F-PF-(+)-DTBZ and 11C-CFT uptake in the striatum from 2 months of age (SUV: 1.36 ± 0.22, 1.37 ± 0.39, respectively), to 4 months (SUV: 2.22 ± 0.29, 2.04 ± 0.33), 9 months (1.98 ± 0.34, 2.09 ± 0.18), 12 months (SUV: 1.93 ± 0.19, 2.00 ± 0.17) of age, SUV of 18F-FDG also increased from 2 months of age to older ages (SUV in the striatum: 3.71 ± 0.78 at 2 month, 5.28 ± 0.81, 5.14 ± 0.73, 4.94 ± 0.50 at 4, 9, 12 month, respectively). Conclusion: Age-dependent increases of striatal of 18F-FDG, 18F-PF-(+)-DTBZ, and 11C-CFT uptake were detected in rats from 2 to 4 month of age, demonstrating striatal development presents over the first 4 months of age. Four months of age can be considered a safe threshold to launch brain disease studies for exclusion of confusion of continuing tissue development. These findings support further investigation of age-dependent changes in expression of DAT, VMAT2, and glucose metabolism for their potential use as a new imaging biomarker for study of brain development and functional maturation.

Project description:BackgroundDopamine transporter (DAT) PET provides higher resolution than DAT SPECT and opportunity for integrated imaging with MRI. The radioligand [18F]FE-PE2I is highly selective for the DAT, and PET measurements with this radioligand have good reliability and repeatability in patients with non-advanced Parkinson's disease.ObjectivesTo validate [18F]FE-PE2I PET as measurement tool of longitudinal DAT changes in patients with Parkinson's disease.MethodsThirty-seven subjects with Parkinson's disease (Hoehn and Yahr stage < 3) were included in a longitudinal PET study with [18F]FE-PE2I. DAT availability (BPND) in the caudate nucleus, putamen, sensorimotor striatum, and substantia nigra, was estimated with parametric imaging using Logan graphical analysis and cerebellum as reference region. For comparison with DAT-SPECT literature, sample size calculations for disease intervention studies were made.ResultsBaseline and follow-up PET data (interval: 2.3 ± 0.5 years) were available for 25 patients (9 females, 16 males). Median age was 64.7 years (range 46-76); symptom duration: 3 years (0.25-14); Hoehn and Yahr stage (H&Y): 1 (1-2). Annualized DAT decline and effect size were: -8.5 ± 6.6 % and 1.08 for caudate nucleus; -7.1 ± 6.1 % and 1.02 for putamen; -8.3 ± 8.5 % and 0.99 for sensorimotor striatum; -0.11 ± 9.3 % and 0.11 for substantia nigra. The estimated minimum sample size needed for a treatment trial using [18F]FE-PE2I PET as imaging marker is 2-3 times lower than is reported in literature on [123I]FP-CIT SPECT.ConclusionsLongitudinal [18F]FE-PE2I PET measurements in non-advanced PD demonstrate a striatal DAT decline consistent with previous SPECT and PET studies. No obvious changes of DAT availability were observed in the substantia nigra, indicating perhaps slower progression or compensatory changes. The effect sizes were numerically larger than reported in the literature for other DAT radioligands, suggesting that [18F]FE-PE2I might detect smaller DAT changes, and can be well used as progression marker in clinical trials.

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Joint pattern analysis applied to PET DAT and VMAT2 imaging reveals new insights into Parkinson's disease induced presynaptic alterations.

Publications

Joint pattern analysis applied to PET DAT and VMAT2 imaging reveals new insights into Parkinson's disease induced presynaptic alterations.

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