Pre- and post-synaptic dopamine imaging and its relation with frontostriatal cognitive function in Parkinson disease: PET studies with [11C]NNC 112 and [18F]FDOPA

Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-0135, USA.
Psychiatry Research (Impact Factor: 2.47). 08/2008; 163(2):171-82. DOI: 10.1016/j.pscychresns.2007.11.003
Source: PubMed


Frontostriatal cognitive dysfunction is common in Parkinson disease (PD), but the explanation for its heterogeneous expressions remains unclear. This study examined the dopamine system within the frontostriatal circuitry with positron emission tomography (PET) to investigate pre- and post-synaptic dopamine function in relation to the executive processes in PD. Fifteen non-demented PD patients and 14 healthy controls underwent [(18)F]FDOPA (for dopamine synthesis) and [(11)C]NNC 112 (for D(1) receptors) PET scans and cognitive testing. Parametric images of [(18)F]FDOPA uptake (K(i)) and [(11)C]NNC 112 binding potential (BP(ND)) were calculated using reference tissue models. Group differences in K(i) and BP(ND) were assessed with both volume of interest and statistical parametric mapping, and were correlated with cognitive tests. Measurement of [(18)F]FDOPA uptake in cerebral cortex was questionable because of higher K(i) values in white than adjacent gray matter. These paradoxical results were likely to be caused by violations of the reference tissue model assumption rendering interpretation of cortical [(18)F]FDOPA uptake in PD difficult. We found no regional differences in D(1) receptor density between controls and PD, and no overall differences in frontostriatal performance. Although D(1) receptor density did not relate to frontostriatal cognition, K(i) decreases in the putamen predicted performance on the Wisconsin Card Sorting Test in PD only. These results suggest that striatal dopamine denervation may contribute to some frontostriatal cognitive impairment in moderate stage PD.

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Available from: Vanessa Cropley, Oct 07, 2015
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    • "Studies employing Single Photon Emission Computed Tomography (SPECT) with the dopamine transporter-binding ligands (DaTSCAN) also suggest more severe striatal presynaptic dopaminergic deficiency in PDD compared to PD patients, especially in the caudate nuclei (O'Brien et al., 2004). In addition, there is also evidence suggesting an association between striatal 18 F-DOPA uptake and executive performance in PD patients (Bruck et al., 2001; Cheesman et al., 2005; Cropley et al., 2008). "
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    ABSTRACT: Cognitive impairment is a common non-motor feature of Parkinson’s disease (PD). The current study aimed to investigate resting state fMRI correlates of cognitive impairment in PD from a large-scale network perspective, and to assess the impact of dopamine deficiency on these networks. Thirty PD patients with resting state fMRI were included from the Parkinson’s Progression Marker Initiative (PPMI) database. Eighteen patients from this sample were also scanned with 123I-FP-CIT SPECT. A standardized neuropsychological battery was administered, evaluating verbal memory, visuospatial, and executive cognitive domains. Image preprocessing was performed using an SPM8-based workflow, obtaining time-series from 90 regions-of-interest (ROIs) defined from the AAL brain atlas. The Brain Connectivity Toolbox was used to extract nodal strength from all ROIs and modularity of the cognitive circuitry determined using the meta-analytical software Neurosynth. Brain-behavior covariance patterns between cognitive functions and nodal strength were estimated using Partial Least Squares. Extracted latent variable scores were correlated with performances in the three cognitive domains and striatal dopamine transporter binding ratios (SBR) using linear modeling. Finally, influence of nigrostriatal dopaminergic deficiency on modularity of the "cognitive network" was analyzed. Less severe executive impairment was associated with increased dorsal fronto-parietal cortical processing and inhibited subcortical and primary sensory involvement. This pattern was positively influenced by the relative preservation of nigrostriatal dopaminergic function. The pattern associated with better memory performance favored prefronto-limbic processing, and did not reveal associations with presynaptic striatal dopamine uptake. SBR ratios were negatively associated with modularity of the "cognitive network", suggesting integrative effects of the preserved nigrostriatal dopamine system on this circuitry.
    Frontiers in Systems Neuroscience 04/2014; 8(1):45. DOI:10.3389/fnsys.2014.00045
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    • "Here molecular imaging has linked these to altered dopaminergic and cholinergic function. For example, reduced [18F]DOPA uptake in the striatum has been correlated with impaired visual memory and verbal memory.128,129 Whilst this may reflect the impact of altered striatal dopaminergic function on cognition, there is also evidence for widespread reductions in cortical metabolism in PD.130 Furthermore, longitudinal imaging of PD patients has shown that PD patients initially without dementia who later developed dementia (PDD) showed decreases in metabolism over time in the occipital cortex, posterior cingulate cortex, and caudate nucleus, whereas PD patients not diagnosed with dementia at follow-up showed only mild reductions over time in the primary occipital cortex.131 "
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    ABSTRACT: Molecular imaging techniques have a number of advantages for research into the pathophysiology and treatment of central nervous system (CNS) disorders. Firstly, they provide a noninvasive means of characterizing physiological processes in the living brain, enabling molecular alterations to be linked to clinical changes. Secondly, the pathophysiological target in a given CNS disorder can be measured in animal models and in experimental human models in the same way, which enables translational research. Moreover, as molecular imaging facilitates the detection of functional change which precedes gross pathology, it is particularly useful for the early diagnosis and treatment of CNS disorders. This review considers the application of molecular imaging to CNS disorders focusing on its potential to inform the development and evaluation of treatments. We focus on schizophrenia, Parkinson's disease, depression, and dementia as major CNS disorders. We also review the potential of molecular imaging to guide new drug development for CNS disorders.
    09/2013; 15(3):315-28.
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    • "This is especially the case when reviewing the literature on dopamine replacement therapy in cognition. Study findings have been inconsistent across cognitive task demands and may be partly related to failure to control for disease severity and daily levodopa doses [9,10,11]. Nonetheless, mild cognitive impairment in PD is well accepted, and early cognitive impairment has demonstrated predictive validity for a later conversion to dementia as well as reductions in quality of life [7,12,13]. Clinically, the expected cognitive profile of patients with PD has been described as a ‘subcortical syndrome’ with greater impairment in executive and attentional functions and less impairment in memory, language, and visuospatial functions, presumably related to the involvement of the frontostriatal system [14]. "
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    ABSTRACT: The aim of this study was to identify mild cognitive deficits in Parkinson's disease (PD) prior to extensive neurodegeneration and to evaluate the extent to which dopamine depletion and other disease-related predictors can explain cognitive profiles. Neuropsychological performances of 40 nondemented early-stage PD patients and 42 healthy controls were compared across on or off dopaminergic medications. Stepwise regression evaluated cognitive predictors of early-stage PD and disease-related predictors of PD cognition (levodopa dose, disease duration, Unified Parkinson's Disease Rating Scale score, sleep, quality of life, and mood) across on and off states. Neuropsychological performance was lower in PD patients across cognitive domains with significant memory, naming, visuomotor, and complex attention/executive deficits, but with intact visuospatial, simple attention, and phonemic fluency functions. However, medication effects were absent except for simple attention. Regression analyses revealed age, working memory, and memory recall to be the best cognitive predictors of PD, while age, quality of life, disease duration, and anxiety predicted PD cognition in the off state. Nondemented early-stage PD patients presented with extensive mild cognitive deficits including prominent memory impairment. The profile was inconsistent with expected isolated frontostriatal dysfunction previously attributed to dopamine depletion and this highlights the need to further characterize extranigral sources of mild cognitive impairment in PD.
    05/2013; 3(1):168-78. DOI:10.1159/000351421
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