Striatal Dopamine Transporter Density Research Articles

Comparison between a dual-head and a brain-dedicated SPECT system in the measurement of the loss of dopamine transporters with [123I]FP-CIT

Dual-head SPECT systems are used by many clinical departments for [(123)I]FP-CIT SPECT imaging, while triple-head or brain-dedicated systems with better imaging performance are more commonly used by research institutions. There are limited data comparing the capability of the two types of system to measure dopamine transporter (DAT) loss in vivo. The aim of this study was to compare the ability of a dual-head and a brain-dedicated SPECT system to estimate the degree of DAT loss in different movement disorders with variable nigrostriatal impairment, with [(123)I]FP-CIT. Four patients with essential tremor, 24 with Parkinson's disease (PD), six with spinocerebellar ataxia type 2 and six controls were studied with [(123)I]FP-CIT. SPECT scans were performed on a dual-head (E.CAM-Siemens) and subsequently on a brain-dedicated system (Ceraspect-DSI). Striatal DAT outcome measures on the E.CAM and the Ceraspect were strongly correlated and the putamen-to-caudate ratios were almost identical. Although the measured values were lower by 52+/-25% in caudate and by 51+/-31% in putamen on the E.CAM (p<0.0001), the average striatal DAT decrease in each patient group compared with controls was similar for both systems. In PD patients, similar correlations (p<0.05) were found between motor UPDRS or Hoehn and Yahr stage and striatal DAT density. Despite underestimation of striatal DAT outcome measures, the E.CAM showed similar capability as the Ceraspect in measuring the degree of nigrostriatal dopaminergic deficit and assessing the correlation between DAT outcome measures and clinical variables of PD severity and stage.

MRI and SPECT of midbrain and striatal degeneration in fragile X-associated tremor/ataxia syndrome

Sirs: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inclusion disorder with an estimated prevalence among men > 50 years of age up to 1 in 3000 in the general population [16]. The neurologic phenotype of FXTAS is variable and includes intention tremor, ataxia, parkinsonism, and cognitive decline [7–10]. We report evidence from MRI and SPECT that the fragile X premutation determines a subcortical gray matter degeneration involving the midbrain and striatum associated with parkinsonian signs. We studied five men with FXTAS and documentation of the premutation by DNA testing whose genetic and clinical data are detailed in Table 1. In all patients prior MRI showed characteristic symmetric areas of signal changes in the peridentate, middle cerebellar peduncle and cerebral white matter and diffuse brain atrophy [2, 5]. MRI was obtained in patients 1, 2, 4 and 5 at 1.5 T with a protocol including 1 mm thick T1-weighted 3D gradient echo images and 5 mm thick T2-weighted spin-echo (SE) images for evaluation of hypointensities suggestive for possible iron deposits in the basal ganglia [6, 14]. Bulk and shape of the midbrain were evaluated subjectively [12] and midbrain anteroposterior diameter was measured in patients and in 12 healthy subjects [15]. Basal ganglia signals in T2-weighted SE images were visually assessed. Midbrain evaluation in case 4 was performed on hard copies of prior MRI. SPECT examinations were obtained in patients 1, 3–5. They were injected with 111–185 MBq of [123I]FP-CIT for evaluation of striatal dopamine transporter (DAT) density. Patient 3 was also injected with 160 MBq of [123I] idobenzamide (IBZM) for evaluation of striatal dopamine D2 receptors. SPECT examinations were evaluated visually [1]. MRI and SPECT findings are reported in Table 1. Atrophy of the midbrain with an AP diameter smaller than 17 mm [15] was observed in all patients. The superior profile of the midbrain was concave in two patients (Fig. 1) and linear in three. Symmetric hypointensity in the putamen and caudate in T2-weighted SE images was present in all four patients examined with the protocol. DATscan SPECT in patients 3, 4 and 5 showed an asymmetric decrease of the striatum tracer uptake which was mild in cases 4 and 5 and marked in case 3 (Fig. 1). IBZM SPECT in patient 3 revealed almost complete absence of striatal tracer uptake (Fig. 1) Parkinsonism is one of the most common other diagnoses given to FXTAS patients which also include tremor, ataxia, dementia or stroke [9] and fragile X premutation is found in 4 % of patients with diagnosis of probable multi-system atrophy cerebellar type (MSA-C) [10]. Neuropathological examination in FXTAS demonstrates, along with spongiosis of the white matter, nuclear eosinophilic inclusions in the neurons and astrocytes of the cortical and subcortical gray matter, including the substantia nigra and putamen, of possible pathogenetic role [7]. We found MRI evidence of midbrain and striatal neurodegeneration in five patients with FXTAS who showed extra-pyramidal signs. Three patients had vertical gaze palsy, namely a feature of midbrain involvement which is not observed in Parkinson disease (PD) and is characteristic of progressive supranuclear palsy (PSP). In particular, we measured atrophy of the midbrain in all five FXTAS patients that was accompanied by a concave or linear superior profile of the midbrain, instead of the convex profile observed in healthy subjects [12]. These features were emphasized as distinctive of PSP [12, 15]. It is noteworthy that also in LETTER TO THE EDITORS

Nigrostriatal involvement in ataxia with oculomotor apraxia type 1

Ataxia with oculomotor apraxia type 1 (AOA1) is a rare autosomal recessive neurodegenerative disease, recently associated with mutations in the aprataxin gene. Main features are early onset cerebellar ataxia, oculomotor apraxia and peripheral neuropathy. The presence of choreoathetosis or dystonia in some patients suggests basal ganglia involvement, but these structures appear preserved in a single case in which neuropathological examination was performed. To evaluate in vivo the nigrostriatal function we studied dopamine transporter (DAT) density with [(123)I] 2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FPCIT)-SPECT in four AOA1 patients and eight healthy volunteers. All patients showed ataxia and neuropathy; only one had chorea and none had dystonia. Comparing with controls, AOA1 patients showed a slight reduction of the average striatal DAT density, which was bilateral and uniform in caudate and putamen. Nigrostriatal impairment occurred even in the absence of extrapyramidal features. Our data suggest subclinical involvement of basal ganglia in AOA1.

A Preliminary Study of Dopamine Transporter Binding in Bipolar and Unipolar Depressed Patients and Healthy Controls

Objective: We examined striatal dopamine transporter (DAT) binding in bipolar and unipolar depressed patients and compared these values to those obtained from healthy control subjects using the selective DAT radioligand [^99mTc]TRODAT-1 and single photon emission computed tomography imaging. We hypothesized that DAT levels might be higher in bipolar versus unipolar patients. Methods: [^99mTc]TRODAT-1 scans were acquired from 5 bipolar and 10 unipolar patients and from 46 healthy controls. Distribution volume ratio (DVR) of [^99mTc]TRODAT-1 binding affinity was calculated for regions of interest in the striatum. Results: Bipolar patients had greater DVR values compared to controls in the right posterior putamen (p = 0.001) and in the left caudate region (p = 0.007). Bipolar patients had modestly lower DAT binding in all brain regions examined, and a significantly lower DVR in the right caudate region compared to unipolar patients (p = 0.05). Conclusion: These data suggest that striatal DAT density may be increased in bipolar and unipolar depressed patients compared to controls, and that bipolar and unipolar depressed patients may have a different pattern of striatal DAT binding.

Salt Appetite in Sodium-Depleted or Sodium-Replete Conditions: Possible Role of Opioid Receptors

Background/Aims: Acute sodium depletion by the combination of pharmacological natriuresis via furosemide administration and a sodium-deficient diet results in a strong induction of salt appetite in rats. Recent evidence suggests that acute furosemide decreases both dopamine uptake and striatal dopamine transporter density and increases enkephalin mRNA levels in the nucleus accumbens (Acb). Therefore, it has been hypothesized that the motivational/attentional circuit in the brain is activated in salt-appetitive rats. Methods: To determine which loci along the dopaminergic circuit are responsible for this behavior, 10–15 min before furosemide-treated adult male Sprague-Dawley rats were allowed 2-hour access to 2% salt solution (2-bottle choice), we pharmacologically blocked dopamine receptor subtype 1 (D1r) and subtype 2 (D2r) with SCH23390 or raclopride, respectively, and stimulated D1r with SKF81297 or D2r with quinpirole in the shell of the Acb (AcbSh). Furthermore, delta opioid receptors were blocked with naltrindole in the AcbSh or ventral tegmental area (VTA). Results: We found that microinjections (1 µg) of SCH23390, raclopride, SKF81297, quinpirole, or naltrindole into the AcbSh had no effect. However, infusion of naltrindole into the VTA attenuated salt intake, whereas [D-Ser²,Leu⁵,Thr⁶]-enkephalin had no effect. Additionally, in rats previously primed with furosemide to crave salt in a ‘need-free’ manner, salt intake was augmented in the VTA and reduced in the AcbSh after infusion of [D-Ser²,Leu⁵,Thr⁶]-enkephalin. Conclusion: These data provide evidence that mesolimbic opioid systems are involved in the facilitation of salt-appetitive behavior.

Parkinsonism and essential tremor in a family with pseudo‐dominant inheritance of PARK2: An FP‐CIT SPECT study

We report a family with 5 affected individuals manifesting either essential tremor (ET), Parkinsonism, or both, consistent with pseudo-dominant inheritance of PARK2. Two homozygotes presented postural and kinetic tremor several years before the onset of Parkinsonism. Postural and kinetic tremor mimicking ET was the only feature in 1 homozygous and 2 heterozygous carriers of the mutation. Striatal dopamine transporter density was reduced in accordance with phenotype and number of mutated alleles. In 3 homozygotes and 1 heterozygote, a 2-year follow-up single photon emission computed tomography suggested no progression of nigrostriatal deficit.

Neuropsychiatrie des Methylphenidat bei der Aufmerksamkeits-Defizit/Hyperaktivitäts-Störung (ADHS)

High prevalence and high co-morbidity rates with frequently aggravating psychosocial problems make the attention-deficit/hyperactivity disorder (ADHD) of children, adolescents and adults an important target for research and healthcare. Recent findings suggest a dopaminergic fronto-striatal information processing deficit in ADHD-patients (executive functions). This review summarizes and presents, in the context of recent studies (MRI, f-MRI, PET, SPECT, Mapping Genes) the neurobiochemical bases of the methylphenidate-therapy, clinically successfully applied since almost one half century by the ADHD. The increased striatal dopamine transporter density by the ADHD-methylphenidate-responder is reported as a scientifically sound and useful clinical working model.

Nicotine increases dopamine transporter function in rat striatum through a trafficking-independent mechanism

In previous in vivo voltammetry studies, acute nicotine administration increased striatal dopamine clearance. The current study aimed to determine whether nicotine also increases [ 3H]dopamine uptake across the time course of the previous voltammetry studies and whether dopamine transporter trafficking to the cell surface mediates the nicotine-induced augmentation of dopamine clearance in striatum. Rats were administered nicotine (0.32 mg/kg, s.c.); striatal synaptosomes were obtained 5, 10, 40 or 60 min later. Nicotine increased (25%) the V max of [ 3H]dopamine uptake at 10 and 40 min. To determine whether the increase in V max was due to an increase in dopamine transporter density, [ 3H]GBR 12935 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride) binding was performed using rat striatal membranes; no differences were found between nicotine and saline-control groups at 5, 10 or 40 min post-injection, indicating that nicotine did not increase striatal dopamine transporter density; however, [ 3H]GBR 12935 binding assays determine both cell surface and intracellular dopamine transporter. Changes in cellular dopamine transporter localization in striatum were determined using biotinylation and subfractionation approaches; no differences between nicotine and saline-control groups were observed at 10 and 40 min post-injection. These results suggest that the nicotine-induced increase in dopamine uptake and clearance in striatum may occur via a trafficking-independent mechanism.

Dopamine transporter density and behavioral response to methylphenidate in a hyperlocomotor rat model

Rats exposed prenatally to 5-bromo-2'-deoxyuridine (BrdU-rats) display hyperlocomotive activity, making them a possibly useful animal model for the study of attention deficit hyperactivity disorder (ADHD). Using this model, we investigated dopamine transporter (DAT) density and behavioral outcomes in BrdU-rats, some of which were also administered methylphenidate, a psychostimulant that is widely used for the treatment of ADHD. Pregnant rats were exposed to BrdU from gestational day 9 through 15. In male offspring, DAT densities in different regions of the striatum were quantified at three weeks of age. At seven weeks of age, locomotor, rearing and grooming behaviors were evaluated in an open-field setting, with or without methylphenidate treatment (1 mg/kg or 4 mg/kg). The results revealed no significant changes in striatal DAT densities in BrdU-rats compared with controls. Extreme hyperlocomotion of BrdU-rats was detected in the open-field environment, an effect that was exacerbated following treatment with the lower and higher dose of methylphenidate. Such increase in locomotor activity was observed only with the higher dose in control animals. In summary, degeneration of dopaminergic neurons in the terminal field was not detected in juvenile BrdU-rats, although adult animals displayed hyperactive behavior in a mildly stressful environment as well as hypersensitivity to a psychostimulant that facilitates dopaminergic neurotransmission.

Striatal dopamine transporter density in drug naive patients with attention-deficit/hyperactivity disorder

Dopamine transporters are the target of psychostimulants used for treatment of attention-deficit/hyperactivity disorder (ADHD). Therefore, the present study aimed to evaluate striatal dopamine transporter density in adult patients with ADHD. Twenty patients (11 female, nine male; mean age 35+/-7 years) and 20 control subjects (11 female, nine male, mean age 32 +/- 8 years) were examined with SPECT using the specific radiotracer 123I-FP-CIT. The ratio of striatal to cortical radioactivity concentration was used for semiquantitative evaluation of dopamine transporter binding potential (V3''). There was a significant influence of age (P < 0.001) and a trend towards an influence of gender (P = 0.053) on V3''. An ANCOVA with these covariates showed a slightly higher V3'' in the patients than in the control subjects (4.24 +/- 0.48 vs. 4.03 +/- 0.56; P = 0.02). This study provides further in-vivo evidence for an involvement of the dopamine transporter in ADHD. However, compared to previous studies, the increase of dopamine transporter density in the patient group is less pronounced here.

Dopamine in Striatum Linked To Action of SSRIs

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessDopamine in Striatum Linked To Action of SSRIsJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:17 Jun 2005https://doi.org/10.1176/pn.40.12.00400037The striatum, a large cluster of nerve cells tucked away within the depths of each hemisphere of the brain and heavily dependent on the neurotransmitter dopamine, is crucial for motion control, reward, and emotion. And new research suggests that the SSRI antidepressants may have some part to play with this region.Studies have suggested that depression might involve the striatum. For example, the concentration of dopamine and the density of striatal dopamine transporters were found to be abnormal in patients with major depressive disorder. Previous research has suggested that the actions of antidepressants are influenced by dopamine and by the interplay of serotonin and dopamine.John Dani, Ph.D., a professor of neuroscience at Baylor College of Medicine, and colleagues treated striatal slices from mouse brains with the SSRI antidepressant fluoxetine. They found that such treatment tricked transporters on striatal nerves that use dopamine as their neurotransmitter into ferrying serotonin instead of dopamine into striatal nerve terminals. Further, serotonin carried into these terminals was subsequently discharged along with dopamine. When the researchers injected mice with fluoxetine, it seemed to lead to the same serotonin “freeloader” phenomena in the striatum that fluoxetine treatment had produced in vitro. The researchers reported their findings in the April 7 Neuron.In an accompanying editorial, David Sulzer, Ph.D., an associate professor of psychiatry at Columbia University, and Robert Edwards, M.D., a professor of neurology at the University of California, San Francisco, said, “The evidence that antidepressants induce serotonin accumulation by dopamine neurons has now been significantly advanced.... [However,] it is not yet known if such serotonin release by dopamine neurons contributes to the therapeutic effect of these agents.”Dani and his coworkers think that it might. “We can conclude...that the extremely dense dopamine transporters in the striatum are able to transport serotonin into dopamine terminals when extracellular serotonin is elevated,” they said in their report. “Normally, this process may be of little significance because of its low efficiency and the low extracellular serotonin concentration. However, it may play a functional role when serotonin is elevated for prolonged times during treatment with SSRI-type antidepressants.”The study was funded by the National Alliance for Research on Schizophrenia and Depression and the National Institutes of Health.An abstract of “Corelease of Dopamine and Serotonin From Striatal Dopamine Terminals” is posted online at<www.neuron.org/content/article/abstract?uid=PIIS0896627305001261>.▪ ISSUES NewArchived

Carphology by Rajendra

Levodopa reduces the symptoms of Parkinson’s disease, but might it hasten neurodegeneration? A randomized placebo controlled trial evaluated 361 patients with early Parkinson’s disease who received varying amounts of carbidopa-levodopa...

The role of the striatal dopamine transporter in cognitive aging

We examined the relationship of age-related losses of striatal dopamine transporter (DAT) density to age-related deficits in episodic memory and executive functioning in a group of subjects ( n=12) ranging from 34 to 81 years of age. The radioligand [ 11C]β-CIT-FE was used to determine DAT binding in caudate and putamen. Results showed clear age-related losses of striatal DAT binding from early to late adulthood, and a marked deterioration in episodic memory (word and figure recall, face recognition) and executive functioning (visual working memory, verbal fluency) with advancing age. Most importantly, the age-related cognitive deficits were mediated by reductions in DAT binding, whereas DAT binding added systematic cognitive variance after controlling for age. Further, interindividual differences in DAT binding were related to performance in a test of crystallized intelligence (the Information subtest from the Wechsler Adult Intelligence Scale-Revised) that showed no reliable age variation. These results suggest that DAT binding is a powerful mediator of age-related cognitive changes as well as of cognitive functioning in general. The findings were discussed relative to the view that the frontostriatal network is critically involved in multiple cognitive functions.

P.6.078 Response to methylphenidate in adult ADHDpatients depends on striatal dopamine transporter density

P.6.078 Response to methylphenidate in adult ADHDpatients depends on striatal dopamine transporter density

Striatal dopamine transporter density in first episode schizophrenia assessed with IPT-SPECT

In an inbred line of Syrian hamsters attacks of sustained dystonic postures of the limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage). The severity of the dystonic syndrome in these mutant hamsters (gene symbol dtSZ) is age-dependent, with a peak at about 30–40 days of age. A scoring system for grading the type and severity of the dystonic attacks can be used to study the activity of drugs against dystonic movements with individual pre- and post-drug vehicle trials as control. The effects of drugs which alter dopaminergic or cholinergic functions in the brain were studied in selectively bred dystonic hamsters and age-matched non-dystonic controls. The dopamine precursor levodopa (injected together with carbidopa) and the dopamine receptor agonist apomorphine increased the severity of dystonia in hamsters when administered prior to the age of maximum severity of dystonia. A very similar effect was observed with the cholinomimetic pilocarpine. In contrast, the dopamine receptor antagonist haloperidol caused a marked overall reduction in dystonic movements. Anticholinergic drugs, i.e. trihexyphenidyl and biperden, increased the latency to onset of the dystonic attack, but did not reduce its severity. No differences were observed between dystonic and non-dystonic hamsters with respect to extent and duration of stereotypies induced by dopaminergic and cholinergic drugs or hypolocomotion and catalepsy produced by haloperidol. The data suggest that dopaminergic hyperactivity might be involved in the pathophysiology of dystonia in dtSZ mutant hamsters.

Imaging of dopamine transporters in rats using high-resolution pinhole single-photon emission tomography.

To date, the vast majority of investigations on the dopaminergic system in small animals have been in vitro studies. In comparison with in vitro studies, single-photon emission tomography (SPET) or positron emission tomography (PET) imaging of the dopaminergic system in small animals has the advantage of permitting repeated studies within the same group of animals. Dopamine transporter imaging is a valuable non-invasive tool with which to investigate the integrity of dopaminergic neurons. The purpose of this study was to investigate the feasibility of assessing dopamine transporter density semi-quantitatively in rats using a recently developed high-resolution pinhole SPET system. This system was built exclusively for imaging of small animals. In this unique single-pinhole system, the animal rotates instead of the collimated detector. The system has proven to have a high spatial resolution. We performed SPET imaging with [(123)I]FP-CIT to quantify striatal dopamine transporters in rat brain. In all seven studied control rats, symmetrical striatal binding to dopamine transporters was seen 2 h after injection of the radiotracer, with striatal-to-cerebellar binding ratios of approximately 3.5. In addition, test/retest variability of the striatal-to-cerebellar binding ratios was studied and found to be 14.5%. Finally, in unilaterally 6-hydroxydopamine-lesioned rats, striatal binding was only visible on the non-lesioned side. Quantitative analysis revealed that striatal-to-cerebellar SPET ratios were significantly lower on the lesioned (mean binding ratio 2.2 +/- 0.2) than on the non-lesioned (mean ratio 3.1 +/- 0.4) side. The preliminary results of this study indicate that semi-quantitative assessment of striatal dopamine transporter density using our recently developed high-resolution single-pinhole SPET system is feasible in living rat brain.

Protection of dopaminergic nigrostriatal afferents by GDNF delivered by microspheres in a rodent model of Parkinson's disease.

The use of glial cell line-derived neurotrophic factor (GDNF) appears to be a promising strategy to promote survival and function of the nigrostriatal dopaminergic pathway damaged in Parkinson's disease (PD). However, effective intracerebral administration is required for optimal therapeutic benefit and tools to evaluate such therapies must be developed. A rodent model of PD was therefore developed using striatal injection of 6-hydroxydopamine (6-OHDA) with simultaneous implantation of GDNF-delivering microspheres. The effects of GDNF released from microspheres were assessed by classical methods such as amphetamine-induced rotating behavior and tyrosine hydroxylase (TH) immunoreactivity, as well as by quantitative autoradiography using PE2I, a dopamine transporter (DAT) radiotracer, which is also suitable for SPET imaging in humans. 6-OHDA-lesioned animals that received microspheres without GDNF were used as controls. During the first 3 weeks after simultaneous lesion and implantation, the amphetamine-induced rotating behavior of GDNF-treated rats was improved compared to controls and an increase in TH expression (+26%) was measured in the striatum 6 weeks after lesion. In accordance with these results, an increase in striatal PE2I-labeled DAT density was obtained (+17%) after 3 and 6 weeks of treatment. In conclusion, this study demonstrates the neuroprotective action of GDNF delivered by microspheres and suggests that PE2I may be an appropriate radiotracer for use in SPET scintigraphy to follow up treatment of PD in humans.

Neither the density nor function of striatal dopamine transporters were influenced by chronic n-3 polyunsaturated fatty acid deficiency in rodents

We hypothesized that the chronic dietary deficiency of n-3 polyunsaturated fatty acids (n-3 PUFAs) might affect the density and/or function of dopamine transporters (DAT), which have a major role in regulating the synaptic level of dopamine. This hypothesis was tested by investigating DAT in the striatum using three complementary methods in control and deficient rats. The density of DAT was determined by quantitative autoradiography using [ 125I]PE2I, a specific ligand of this transporter. Functional investigations were performed (i) in vitro by measuring [ 3H]dopamine uptake on synaptosomes, and (ii) in vivo using intracerebral microdialysis. The results demonstrated that neither the density nor the function of DAT were influenced by n-3 PUFA deficiency in the striatum. This suggests lower sensitivity to n-3 PUFA deficiency in the striatum than that previously observed in the frontal cortex.

Normal IPT and IBZM SPECT in drug-naive and levodopa-treated idiopathic restless legs syndrome.

Fourteen drug-naive and 11 levodopa-treated patients with idiopathic restless legs syndrome (RLS), and 10 controls age-matched to each RLS group separately were examined with polysomnography (PSG), [(123)I]-(N)-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane ((123)I-IPT) SPECT, and [(123)I]-(S)-2-hydroxy-3-iodo-6-methoxy-[(1-ethyl-2-pyrrolidinyl)methyl] benzamide ((123)I-IBZM) SPECT. Drug-naive and levodopa-treated patients with RLS and controls showed similar striatal dopamine transporter and dopamine D(2)-receptor binding, the latter declining with age. The authors conclude that striatal dopamine transporter and receptor density is normal in drug-naive and levodopa-treated patients with RLS.

Early methylphenidate administration to young rats causes a persistent reduction in the density of striatal dopamine transporters

Early methylphenidate administration to young rats causes a persistent reduction in the density of striatal dopamine transporters