Positron emission tomography of monoaminergic vesicular binding in aging and Parkinson disease

Department of Radiology, Division of Nuclear Medicine, The University of Michigan Medical School, Ann Arbor, 48109-0028, USA.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 10/2006; 26(9):1198-212. DOI: 10.1038/sj.jcbfm.9600276
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The type-2 vesicular monoamine transporter (VMAT2) might serve as an objective biomarker of Parkinson disease (PD) severity. Thirty-one subjects with early-stage PD and 75 normal subjects underwent continuous intravenous infusion of (+)-[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography (PET) imaging to estimate the striatal VMAT2 binding site density with equilibrium tracer modeling. Parkinson disease patients were evaluated clinically in the practically defined 'off' state with the Unified Parkinson Disease Rating Scale (UPDRS), the Hoehn and Yahr Scale (HY), and the Schwab and England Activities of Daily Living Scale (SE). In normal subjects there was age-related decline in striatal DTBZ binding, approximating 0.5% per year. In PD subjects, specific DTBZ binding was reduced in the caudate nucleus (CD; -44%), anterior putamen (-68%), and posterior putamen (PP; -77%). The PP-to-CD ratio of binding was reduced significantly in PD subjects. Dihydrotetrabenazine binding was also reduced by approximately 50% in the PD substantia nigra. Striatal binding reductions correlated significantly with PD duration and SE scores, but not with HY stage or with UPDRS motor subscale (UPDRS(III)) scores. Striatal and midbrain DTBZ binding was asymmetric in PD subjects, with greatest reductions contralateral to the most clinically affected limbs. There was significant correlation between asymmetry of DTBZ binding and clinical asymmetry measured with the UPDRS(III). In HY stage 1 and 1.5 subjects (n=16), PP DTBZ binding contralateral to the clinically unaffected body side was reduced by 73%, indicating substantial preclinical nigrostriatal pathology in PD. We conclude that (+)-[(11)C]DTBZ-PET imaging displays many properties necessary of a PD biomarker.

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Available from: Satoshi Minoshima, May 24, 2014
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    • "Each subject was scanned with vesicular monoamine transporter (VMAT2) PET radioligand, as a marker of dopamine neuronal integrity. The selection of VMAT2 (now known as SLC18A2) as the present 'gold standard' dopamine marker is based on extensive animal data suggesting that levels of VMAT2 are more resistant to drug-compensatory regulation affecting other dopamine markers such as the dopamine transporter (Kilbourn et al., 1996; Wilson et al., 1996; Kemmerer et al., 2003), and is well established in the literature as a tool for measuring striatal dopamine neuron degeneration in Parkinson's disease (Frey et al., 1996; Bohnen et al., 2006; Martin et al., 2008; Stoessl, 2011). Subjects were also scanned with 11 C-FLB 457, which binds to D2 receptors. "
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    ABSTRACT: The ability to dynamically use various aspects of cognition is essential to daily function, and reliant on dopaminergic transmission in cortico-striatal circuitry. Our aim was to investigate both striatal and cortical dopaminergic changes in patients with Parkinson's disease with mild cognitive impairment, who represent a vulnerable group for the development of dementia. We hypothesized severe striatal dopamine denervation in the associative (i.e. cognitive) region and cortical D2 receptor abnormalities in the salience and executive networks in Parkinson's disease with mild cognitive impairment compared with cognitively normal patients with Parkinson's disease and healthy control subjects. We used positron emission tomography imaging with dopaminergic ligands (11)C-dihydrotetrabenazine, to investigate striatal dopamine neuron integrity in the associative subdivision and (11)C-FLB 457, to investigate cortical D2 receptor availability in patients with Parkinson's disease (55-80 years of age) with mild cognitive impairment (n = 11), cognitively normal patients with Parkinson's disease (n = 11) and age-matched healthy control subjects (n = 14). Subjects were administered a neuropsychological test battery to assess cognitive status and determine the relationship between dopaminergic changes and cognitive performance. We found that patients with mild cognitive impairment had severe striatal dopamine depletion in the associative (i.e. cognitive) subdivision as well as reduced D2 receptor availability in the bilateral insula, a key cognitive hub, compared to cognitively normal patients and healthy subjects after controlling for age, disease severity and daily dopaminergic medication intake. Associative striatal dopamine depletion was predictive of D2 receptor loss in the insula of patients with Parkinson's disease with mild cognitive impairment, demonstrating interrelated striatal and cortical changes. Insular D2 levels also predicted executive abilities in these patients as measured using a composite executive z-score obtained from neuropsychological testing. Furthermore we assessed cortical thickness to ensure that D2 receptor changes were not confounded by brain atrophy. There was no difference between groups in cortical thickness in the insula, or any other cortical region of interest. These findings suggest that striatal dopamine denervation combined with insular D2 receptor loss underlie mild cognitive impairment in Parkinson's disease and in particular decline in executive function. Furthermore, these findings suggest a crucial and direct role for dopaminergic modulation in the insula in facilitating cognitive function.
    Brain 12/2013; 137(2). DOI:10.1093/brain/awt337 · 9.20 Impact Factor
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    • "We found that neocortical and thalamic acetylcholinesterase activity in the PD group showed substantial overlap with normal range activity, as evidenced by the small absolute mean difference (B10% decrease) across all PD patients compared with the control group for both neocortical and thalamic [ 11 C]methyl- 4-piperidinyl propionate acetylcholinesterase activity. This is strikingly different from the typical complete group separation for nigrostriatal denervation levels (especially at the level of the posterior putamen) between PD and control groups (Bohnen et al, 2006a). Our approach of defining a patient subgroup with below normal range cholinergic activity is intended as a more effective strategy to investigate clinical phenotypic variations because of cholinergic denervation in PD. "
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    ABSTRACT: Parkinson's disease (PD) is a multisystem neurodegenerative disorder. Heterogeneous clinical features may reflect heterogeneous changes in different brain regions. In contrast to the pronounced nigrostriatal denervation characteristic of PD, cholinergic changes are less marked. We investigated cholinergic innervation activity in PD subjects relative to normal subjects. Nondemented PD subjects (n=101, age 65.3±7.2 years) and normal subjects (n=29, age 66.8±10.9 years) underwent clinical assessment and [(11)C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11)C]dihydrotetrabenazine monoaminergic positron emission tomography (PET) imaging. Cholinergic projection changes were heterogeneous for 65 out of 101 PD subjects who had neocortical and thalamic acetylcholinesterase activity within the normal range. The remainder had combined neocortical and thalamic (13/101), isolated neocortical (18/101), or isolated thalamic (5/101) acetylcholinesterase activity below the normal range. The low neocortical acetylcholinesterase activity subgroup had significantly lower global cognitive performance compared with the normal range subgroup (F=7.64, P=0.0069) with an independent effect for nigrostriatal denervation (F=7.60, P=0.0074). The low thalamic acetylcholinesterase activity subgroup did not differ from the normal thalamic acetylcholinesterase activity subgroup in cognitive performance or motor impairments except for a history of falls (P=0.0023). Cholinergic denervation is heterogeneous with reduced neocortical and/or thalamic acetylcholinesterase activity in 36% of nondemented PD subjects with corresponding clinical phenotypic variation. Results also show independent cognitive effects for both cholinergic and dopaminergic system changes in nondemented PD subjects.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 05/2012; 32(8):1609-17. DOI:10.1038/jcbfm.2012.60 · 5.41 Impact Factor
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    • "This infusion schedule produced a wide range of severity of unilateral stable hemi-parkinsonism while minimizing exposure of the contralateral hemisphere to MPTP [11]–[13]. [3H]WIN 35,428 was chosen to label DAT [14] and (+)-[3H] dihydrotetrabenazine (DTBZ) was used for VMAT2 [15], [16]. This experimental design permitted comparison of changes in DAT and VMAT2 binding sites in a full spectrum of nigrostriatal neuronal loss induced by MPTP. "
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    ABSTRACT: Radioligands for DAT and VMAT2 are widely used presynaptic markers for assessing dopamine (DA) nerve terminals in Parkinson disease (PD). Previous in vivo imaging and postmortem studies suggest that these transporter sites may be regulated as the numbers of nigrostriatal neurons change in pathologic conditions. To investigate this issue, we used in vitro quantitative autoradioradiography to measure striatal DAT and VMAT2 specific binding in postmortem brain from 14 monkeys after unilateral internal carotid artery infusion of 1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine (MPTP) with doses varying from 0 to 0.31 mg/kg. Quantitative estimates of the number of tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in substantia nigra (SN) were determined with unbiased stereology, and quantitative autoradiography was used to measure DAT and VMAT2 striatal specific binding. Striatal VMAT2 and DAT binding correlated with striatal DA (r(s) = 0.83, r(s) = 0.80, respectively, both with n = 14, p<0.001) but only with nigra TH-ir cells when nigral cell loss was 50% or less (r = 0.93, n = 8, p = 0.001 and r = 0.91, n = 8, p = 0.002 respectively). Reduction of VMAT2 and DAT striatal specific binding sites strongly correlated with each other (r = 0.93, n = 14, p<0.0005). These similar changes in DAT and VMAT2 binding sites in the striatal terminal fields of the surviving nigrostriatal neurons demonstrate that there is no differential regulation of these two sites at 2 months after MPTP infusion.
    PLoS ONE 02/2012; 7(2):e31439. DOI:10.1371/journal.pone.0031439 · 3.23 Impact Factor
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