VMAT2 Density Research Articles

Clinical and Preclinical Neuroimaging Changes in Spinocerebellar Ataxia Type 12: A Study of Three Chinese Pedigrees

Background: Spinocerebellar ataxia type 12 (SCA12) is a rare SCA subtype with unclear clinical and imaging features. Also, the radiological changes in prodromal and early stages remain unknown. Methods: Ten symptomatic and two pre­symptomatic cases from three Chinese pedigrees received clinical assessments and imaging studies including routine magnetic resonance imaging (MRI), diffusion kurtosis imaging (DKI), and positron emission tomography (PET) using ¹⁸F-flurodeoxyglucose (FDG) to investigate glucose metabolism in brain and ¹⁸F-vesicle monoamine transporter 2 (VMAT2) to inspect the integrity of the dopaminergic neuron. Seventy-two healthy individuals were recruited as controls in the quantitative FDG-PET analysis. Imaging parameters were compared between symptomatic and presymptomatic cases with different disease durations. Results: Patients displayed prominent action tremor, moderate ataxia, and subtle parkinsonism with poor levodopa-response. MRI showed extensive but heterogeneous cerebral atrophy, which was most evident in the frontoparietal lobes. Cerebellar atrophy was apparent in later stages. DKI detected impaired fibers in the cerebellar peduncles. In both symptomatic and pre­symptomatic cases, PET-CT showed an earlier FDG decline than atrophic changes in multiple regions, and the frontoparietal lobes were the earliest and most severe. However, the VMAT2 density were normal in the putamen and caudate nucleus of most cases (7/8). Conclusions: We first found that hypometabolism in the cerebral cortex, but not cerebellum, is an early and prominent change in SCA12. The integrity of presynaptic dopaminergic neurons remains largely spared during the whole disease process.

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

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 < 0.01 for DTBZ, p < 0.05 for MP). These common spatial patterns reproduce all known aspects of these two targets/tracers. In addition, orthogonality of the patterns may indicate different mechanisms underlying disease initiation or progression. Information unique to each tracer revealed a residual striatal asymmetry when targeting VMAT2, consistent with the notion that VMAT2 density is highly related to terminal degeneration; and a residual DAT disease-induced gradient in the striatum with relative DAT preservation in the substantia nigra. This finding may be indicative either of a possible DAT specific early disease compensation and/or related to disease origin.These results demonstrate the applicability and relevance of the joint pattern analysis approach to datasets obtained with two PET tracers; this data driven method, while recapitulating known aspects of the PD-induced tracer/target behaviour, was found to be statistically more robust and provided additional information on (i) correlated behaviors of the two systems, identified as orthogonal patterns, possibly reflecting different disease-induced alterations and (ii) system specific effects of disease. It is thus expected that this approach will be very well suited to the analysis of multi-tracer and/or multi-modality data and to relating the outcomes to different aspects of disease.

PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer’s disease and Lewy body disorders

BackgroundBiomarkers based on the underlying pathology of Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson’s disease (PD) using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 (florbenazine), a marker for vesicular monamine type 2 transporters (VMAT2).MethodsPatients with DLB and AD, Parkinson’s disease (PD) and healthy controls (HC) were recruited for this study. On separate days, subjects received intravenous injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 density were assessed quantitatively and by binary clinical interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathology (AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding) and correlated with measures of cognition and parkinsonism.Results11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group (n = 21) compared to the PD/HC groups (n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006). VMAT2 density was significantly lower in the PD/DLB group (n = 16) compared to the AD/ HC group (n = 15; 1.83 vs. 2.97; p < 0.0001). Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding (r = 0.73; p = 0.011).ConclusionsThe results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathology. In addition, VMAT density correlated significantly with cognitive impairment in DLB patients (ClinicalTrials.gov identifier: NCT00857506, registered March 5, 2009).

ChemInform Abstract: Vesicular Monoamine Transporters: Structure‐Function, Pharmacology, and Medicinal Chemistry

AbstractReview: 168 refs.

Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry.

Vesicular monoamine transporters (VMAT) are responsible for the uptake of cytosolic monoamines into synaptic vesicles in monoaminergic neurons. Two closely related VMATs with distinct pharmacological properties and tissue distributions have been characterized. VMAT1 is preferentially expressed in neuroendocrine cells and VMAT2 is primarily expressed in the CNS. The neurotoxicity and addictive properties of various psychostimulants have been attributed, at least partly, to their interference with VMAT2 functions. The quantitative assessment of the VMAT2 density by PET scanning has been clinically useful for early diagnosis and monitoring of the progression of Parkinson's and Alzheimer's diseases and drug addiction. The classical VMAT2 inhibitor, tetrabenazine, has long been used for the treatment of chorea associated with Huntington's disease in the United Kingdom, Canada, and Australia, and recently approved in the United States. The VMAT2 imaging may also be useful for exploiting the onset of diabetes mellitus, as VMAT2 is also expressed in the β-cells of the pancreas. VMAT1 gene SLC18A1 is a locus with strong evidence of linkage with schizophrenia and, thus, the polymorphic forms of the VMAT1 gene may confer susceptibility to schizophrenia. This review summarizes the current understanding of the structure-function relationships of VMAT2, and the role of VMAT2 on addiction and psychostimulant-induced neurotoxicity, and the therapeutic and diagnostic applications of specific VMAT2 ligands. The evidence for the linkage of VMAT1 gene with schizophrenia and bipolar disorder I is also discussed.

The utility of [ 11C] dihydrotetrabenazine positron emission tomography scanning in assessing β-cell performance after sleeve gastrectomy and duodenal-jejunal bypass

The aim of this study was to evaluate the effect of sleeve gastrectomy (SG) and duodenal-jejunal bypass (DJB) on glucose homeostasis and to evaluate the utility of positron emission tomography (PET) scanning for assessing beta-cell mass. Goto-Kakizaki rats were divided into 4 groups: control, sham, SG, or DJB. Oral glucose tolerance, insulin, and glucagon-like peptide-1 (GLP-1) were measured before and after surgery. Before and 90 days after treatment, [(11)C] DTBZ micro PET scanning was performed. The control and sham animals gained more weight compared with SG and DJB animals (P < or = .05). Compared with control animals, the glucose area under the curve was lower in DJB animals 30 and 45 days after operations (P < or = .05). At killing, GLP-1 levels were greater in the DJB group compared with sham and SG (P < or = .05), whereas insulin levels were greater in both DJB and SG compared with sham (P < or = .05). With PET scanning, the 90-day posttreatment mean vesicular monoamine transporter type 2 binding index was greatest in the DJB animals (2.45) compared with SG (1.17), both of which were greater than baseline control animals (0.81). In type 2 diabetic rodents, DJB leads to improved glucose homeostasis and an increase in VMAT2 density as measured by PET scanning.

Reduced platelet vesicular monoamine transporter density in Tourette's syndrome pediatric male patients

The vesicular monoamine transporter (VMAT2) plays a major role in the synaptic accumulation and quantal release of monoamines. In this study, we assessed high affinity [ 3H]dihydrotetrabenazine binding to platelet VMAT2, in a group of untreated male Tourette's syndrome (TS) patients (age: 8–17.5 years, n = 9) and in a group of age- and sex-matched healthy controls (age: 9–16 years, n = 16). Significantly decreased platelet VMAT2 density ( B max) (− 23%, p = 0.016) was observed in the TS patients. The affinity ( K d) of the ligand to platelet VMAT2 was similar in both groups. If the lower platelet VMAT2 density also occurred in the brain, it may have serve as an adaptive mechanism geared to decrease dopamine storage in the presynaptic neurons and thereby to attenuate the dopaminergic overactivity and ameliorate the movement disorder.

Elevated platelet vesicular monoamine transporter 2 in former heroin addicts maintained on methadone

The brain vesicular monoamine transporter (VMAT2) is essential for neuronal monoamine storage and regulation of monoaminergic neurotransmission. We demonstrated previously a high degree of similarity between the pharmacodynamic characteristics of platelet and brain VMAT2. Opioids induce increase of dopamine release in limbic structures. In the present study we assessed the VMAT2 pharmacodynamic characteristics using high affinity [(3)H]dihydrotetrabenazine (TBZOH) binding to platelets of former male heroin addicts maintained on methadone (n = 12) compared to age-matched healthy controls (n = 13). A significant increase (19%, p < 0.05) in platelet VMAT2 density (Bmax) was observed in the methadone treated patients compared to controls. There was no significant difference in the affinity of [(3)H]TBZOH to its platelet binding site. The increased VMAT2 density may reflect a compensatory attempt to prevent vesicular depletion due to chronic methadone exposure.

Platelet vesicular monoamine transporter density in untreated patients diagnosed with social phobia

The vesicular monoamine transporter (VMAT2) is important in the storage and release of monoamines. Platelet VMAT2 was characterized using high-affinity [ 3H]dihydrotetrabenazine ([ 3H]TBZOH) binding in untreated social phobia (SP) patients ( n = 20) compared with sex- and age-matched healthy controls ( n = 15). No significant differences in VMAT2 density ( B max) and affinity constants ( K d) were observed.

Decreased platelet vesicular monoamine transporter density in habitual smokers

The brain vesicular monoamine transporter (VMAT2) is part of the re-uptake mechanism which regulates monoaminergic neurotransmission. We demonstrated previously a high degree of similarity between the pharmacodynamic characteristics of platelet and brain VMAT2. Nicotine induced increase of dopamine and serotonin neurotransmission in limbic structures may alter the expression of VMAT2 in brains of smokers. In this study we measured the VMAT2 pharmacodynamic characteristics using high-affinity [ 3H]dihydrotetrabenazine (TBZOH) binding to platelets of smokers ( n=15) compared to sex and age matched healthy nonsmokers controls ( n=14). A significant decrease (17%, P=0.02) in VMAT2 density ( B max) was observed in platelets of smokers compared to nonsmokers. There was no significant difference in the affinity of [ 3H]TBZOH to its platelet binding site and the VMAT2 density did not correlate with the heaviness of smoking. The decreased density of the VMAT2 in the platelets of smokers may reflect nicotine induced desensitization of VMAT2, a phenomenon that may be relevant to the addictive properties of nicotine.

Decreased platelet vesicular monoamine transporter density in children and adolescents with attention deficit/hyperactivity disorder

The aim of the present study was to assess vesicular monoamine transporter (VMAT2) density in attention deficit/hyperactivity disorder (ADHD), a disorder involving monoaminergic dysregulation. It was hypothesized that the hypoactivity of monoaminergic neurotransmission related to ADHD could be associated with an under-expression of VMAT2. We assessed high affinity [ 3H]dihydrotetrabenazine [TBZOH] binding to platelet VMAT2 in untreated male ADHD children and adolescents ( n=11) as compared to age-matched controls ( n=14), as well as the correlation between VMAT2 density and the severity of ADHD symptoms as measured by the clinician-administered DSM-IV ADHD Scale (DAS) and the parent-administered Abbreviated Conners' Rating Scale (ACPRS). The [ 3H]TBZOH binding capacity (Bmax) was significantly lower (17%) in the ADHD group as compared to the controls. There was no difference between the two groups in the affinity ( K d value) of [ 3H]TBZOH to its binding site. An inverse correlation was found between the ADHD symptom scales and the Bmax values. It remains unclear whether the under-expression of platelet VMAT2 in ADHD children is reflective of a parallel change in the brain, and whether it is primary or an epiphenomenon of ADHD.

Elevated platelet vesicular monoamine transporter density in untreated patients diagnosed with major depression

The intraneuronal uptake of monoamines into brain synaptic vesicles is mediated by the vesicular monoamine transporter (VMAT2). This transporter plays a major role in monoamine storage and quantal release. Recently we demonstrated a high degree of similarity between the pharmacodynamic characteristics of platelet and brain VMAT2. In the present study we measured the VMAT2 density, using [ 3H]dihydrotetrabenazine ([ 3H]TBZOH) as a ligand, in platelets of untreated patients diagnosed with major depressive disorder (MDD) ( n=10; three with recurrent depression and seven with first episode depression) compared to sex- and age-matched healthy control subjects ( n=23). A significant elevation in the VMAT2 density ( B max) was observed in the platelets of untreated MDD patients (+24%) compared to healthy control subjects. No significant change was found in the affinity constant ( K d). The increased platelet VMAT2 density may reflect depression-related enhancement of the capacity to accumulate monoamines in the vesicles in the presence of lower monoamine turnover.

Increased platelet vesicular monoamine transporter density in adult schizophrenia patients

Vesicular monoamine transporter (VMAT2) plays a major role in the synaptic accumulation and release of monoamines. In the present study, we assessed high affinity [ 3H]dihydrotetrabenazine binding to platelet VMAT2 in a group of treated ( n=9) and untreated ( n=4) patients with schizophrenia and age- and sex-matched controls. Significantly elevated platelet VMAT2 density ( B max) (53%, P<0.0001) was observed in the mixed population of schizophrenia patients. The affinity of the ligand ( K d) to platelet VMAT2 was similar in both groups. The increased platelet VMAT2 density may indicate a schizophrenia-related hyperactivity of the monoaminergic system or an adaptive response to chronic drug treatment.

Cholinergic vesicular transporters in progressive supranuclear palsy.

To determine the status of cholinergic and monoaminergic vesicular transporter binding sites in progressive supranuclear palsy (PSP). The authors determined autoradiographically the regional expression of acetylcholine vesicular transporter (VAChT) and monoamine vesicular transporter type 2 (VMAT2) binding sites in postmortem basal ganglia samples from subjects with PSP. Comparison neurochemical measures included choline acetyltransferase (ChAT) enzyme activity and benzodiazepine (BZ) binding sites. VAChT expressions and ChAT activities in caudate nucleus and putamen were markedly decreased in PSP, whereas BZ binding was unaffected, consistent with selective losses of striatal cholinergic interneurons. VMAT2 density was reduced significantly in the caudate nucleus, putamen, and substantia nigra pars compacta, consistent with degeneration of dopaminergic nigrostriatal projection neurons in PSP. In the globus pallidus, BZ receptor binding sites were reduced, whereas VMAT2 and VAChT binding sites were unchanged, indicating losses of intrinsic pallidal neurons and synapses. These results confirm selective and marked degenerations of basal ganglia cholinergic and dopaminergic terminals in PSP. Striatal VAChT reduction may provide a unique neurochemical imaging marker for distinction of PSP from other types of basal ganglia neurodegeneration.

Acute interactions between l-DOPA and the neurotoxic effects of 1-methyl-4-phenylpyridinium or 6-hydroxydopamine in mice

We have compared the effects of an i.p. pretreatment with l-DOPA (200 mg/kg) associated with benserazide (25 mg/kg) on neurotoxic effects of either 6-hydroxydopamine (6-OHDA) (50 μg, 10 μl per mouse) or 1-methyl-4-phenylpyridinium (MPP +) (17.5 μg, 10 μl per mouse). The striatal dopamine (DA) content, the vesicular monoamine transporter (VMAT2) density, as well as the hypothalamic norepinephrine (NE) content were measured 8 days after treatments. The l-DOPA–benserazide pretreatment worsened by 65% the 6-OHDA-induced depletion in striatal DA. On the contrary, it reduced by 42% the MPP +-induced depletion in striatal DA and by 54% the MPP +-induced decrease in VMAT2 density. It was noticed that the l-DOPA–benserazide pretreatment did not modify the marked decrease in hypothalamic NE content induced by 6-OHDA.

Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging.

We present development and human application of a method for determining the regional cerebral density of the type 2 vesicular monoamine transporter (VMAT2) using positron emission tomography (PET) and [11C]dihydrotetrabenazine (DTBZ). Previous animal studies indicate striatal VMAT2 density is linearly related to the integrity of substantia nigra dopamine neurons and is not subject to drug- or lesion-compensatory regulation. In the present studies, kinetic compartmental modeling was employed to estimate blood-brain [11C]DTBZ transport (K1) and VMAT2 binding site density (tissue-to-plasma DTBZ distribution volume, DV) from the cerebral and plasma DTBZ time courses after intravenous tracer injection. In controls, we found reductions of putamen DTBZ DVwith advancing age, corresponding to losses of 0.77% per year in specific VMAT2 binding. Parkinson's disease (PD) patients had reduction in specific DTBZ DV in the putamen (-61%) and in the caudate nucleus (-43%). There was no overlap of lowest specific putamen DTBZ DV between individual elderly controls and PD patients. The present results indicate the suitability of [11C]DTBZ PET for objective quantification of nigrostriatal integrity, including evaluation of PD progression and its possible therapeutic modification.

Kinetic evaluation of [11C]dihydrotetrabenazine by dynamic PET: measurement of vesicular monoamine transporter.

(+)-alpha-[11C]Dihydrotetrabenazine (DTBZ) binds to the vesicular monoamine transporter (VMAT2) located in presynaptic vesicles. The purpose of this work was to evaluate various model configurations for analysis of [11C]DTBZ with the aim of providing the optimal measure of monoamine vesicular transporter density obtainable from a single dynamic PET study. PET studies on seven young normal volunteer subjects, ages 20-35, were performed following i.v. injection of 666 +/- 37 MBq (18 +/- 1 mCi) of (+)-alpha-[11C]DTBZ. Dynamic acquisition consisted of a 15-frame sequence over 1 h. Analysis methods included both creation of pixel-by-pixel functional images of transport (K1) and binding (DVtot) and nonlinear least-squares analysis of volume-of-interest data. Pixel-by-pixel calculations were performed for both two-compartment weighted integral calculations and slope-intercept estimations from Logan plots. Nonlinear least-squares analysis was performed applying model configurations with both two-compartments, estimating K1 and DVtot and three compartments, estimating K1-k4. For the more complex configuration, we examined the stability of various binding-related parameters including k3 (konBmax'), k3/k4 (Bmax'/Kd), DVsp[(K1/k2)(k3/k4)], and DVtot [K1/k2(1 + k3/k4)]. The three-compartment model provided significantly improved goodness-of-fit compared to the two-compartment model, yet did not increase the uncertainty in the estimate of the DVtot. Without constraining parameters in the three-compartment model fits, DVtot was found to provide a more stable estimate of binding density than either k3, k3/k4, or DVsp. The two-compartment least-squares analysis yielded approximately 10% underestimations of the total distribution. However, this bias was found to be very consistent from region to region as well as across subjects as indicated by the correlation between two- and three-compartment DVtot estimates of 0.997. We conclude that (+)-alpha-[11C]DTBZ and PET can provide excellent measures of VMAT2 density in the human brain.