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A J Stoessl

Publications and source records attributed to A J Stoessl.

At least 19 recordsLinked to original sources
PubMed2002

SCA-2 presenting as parkinsonism in an Alberta family: clinical, genetic, and PET findings.

The authors describe an Alberta family with levodopa-responsive parkinsonism without cerebellar abnormalities. Genetic testing showed expanded repeats for SCA-2; other mutations for parkinsonism were excluded. The expanded allele shows interruption of the CAG repeat with CAA. PET in two affected members showed reduced fluorodopa uptake in striatum and normal raclopride binding. Families with autosomal dominant, levodopa-responsive parkinsonism should be tested for the SCA-2 mutation.

Adult↗
PubMed2002

Bilateral human fetal striatal transplantation in Huntington's disease.

BACKGROUND: Transplanted striatal cells have been demonstrated to survive, grow, establish afferent and efferent connections, and improve behavioral signs in animal models of Huntington's disease (HD). OBJECTIVE: To evaluate feasibility and safety and to provide preliminary information regarding the efficacy of bilateral human fetal striatal transplantation in HD. METHODS: Seven symptomatic patients with genetically confirmed HD underwent bilateral stereotactic transplantation of two to eight fetal striata per side in two staged procedures. Tissue was dissected from the lateral half of the lateral ventricular eminence of donors 8 to 9 weeks postconception. Subjects received cyclosporine for 6 months. RESULTS: Three subjects developed subdural hemorrhages (SDHs) and two required surgical drainage. One subject died 18 months after surgery from probable cardiac arrhythmia secondary to severe atherosclerotic cardiac disease. Autopsy demonstrated clearly demarcated grafts of typical developing striatal morphology, with host-derived dopaminergic fibers extending into the grafts and no evidence of immune rejection. Other adverse events were generally mild and transient. Mean Unified HD Rating Scale (UHDRS) motor scores were 32.9 plus minus 6.2 at baseline and 29.7 plus minus 7.5 12 months after surgery (p = 0.24). Post-hoc analysis, excluding one subject who experienced cognitive and motor deterioration after the development of symptomatic bilateral SDHs, found that UHDRS motor scores were 33.8 plus minus 6.2 at baseline and 27.5 plus minus 5.2 at 12 months (p = 0.03). CONCLUSIONS: Transplantation of human fetal striatal cells is feasible and survival of transplanted cells was demonstrated. Patients with moderately advanced HD are at risk for SDH after transplantation surgery.

Adult↗
PubMed2002

Somatostatin modulates the behavioral effects of dopamine receptor activation in parkinsonian rats.

Somatostatin may play a role in several neuropsychiatric disorders, including Parkinson's disease. Although functional interactions between somatostatinergic and dopaminergic transmitter systems have been well documented, no study has been conducted in animals with experimental Parkinsonism to explore the effects of somatostatin on dopamine receptor-mediated behavior. In the present study, rats with unilateral 6-hydroxydopamine-induced destruction of the medial forebrain bundle were assessed following administration of the dopamine(1/2) receptor agonist apomorphine. Ipsilateral intrastriatal infusion of somatostatin produced a dose-related inhibition of apomorphine-induced rotations with maximal effect at a dose of 7.5 microg in 2 microl. This inhibitory effect of somatostatin was antagonized by the somatostatin antagonist cyclo-somatostatin (0.1 microg in 2 microl, intrastriatally). Neither somatostatin (up to 15 microg in 2 microl) nor cyclo-somatostatin on its own induced rotations; similarly, this dose of cyclo-somatostatin did not affect apomorphine-induced rotations. From these results we suggest that exogenous somatostatin, by directly acting on its specific receptors in the striatum, inhibits the effects of dopamine receptor activation in parkinsonian rats. We conclude that therapies based on modulation of somatostatin may be worth exploring in the management of Parkinson's disease and other disorders of the basal ganglia.

Animals↗
PubMed2002

Blockade of nigral and pallidal opioid receptors suppresses vacuous chewing movements in a rodent model of tardive dyskinesia.

Chronic neuroleptic treatment leads to the development of tardive dyskinesia in 20-30% of patients. While the pathogenesis of tardive dyskinesia remains elusive, altered opioid peptide function in striatal projection pathways of the basal ganglia has been implicated. Using a rodent model of vacuous chewing movements induced by chronic neuroleptic administration, we investigated regional involvement of opioid transmission in tardive dyskinesia. We examined the role of dynorphin in the direct striatonigral pathway by infusing nor-binaltorphimine, a selective kappa opioid receptor antagonist, into the substantia nigra pars reticulata. As well, infusions of naloxone (a non-specific opioid receptor antagonist), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP; a mu opioid receptor antagonist) or naltrindole (a delta opioid receptor antagonist) into the globus pallidus were used to establish the contribution of the striatopallidal pathway. Chronic fluphenazine treatment (25 mg/kg i.m. every 3 weeks for 18 weeks) resulted in a robust increase in vacuous chewing movements. Infusion of nor-binaltorphimine (5.0 nmol) into the substantia nigra pars reticulata significantly attenuated vacuous chewing movements. Infusion of naloxone (0.5 and 2.0 nmol) into the globus pallidus also significantly attenuated vacuous chewing. Infusion of naltrindole into the globus pallidus blocked vacuous chewing at all doses administered (0.5, 1.0, 2.0 nmol) while CTOP was only effective at the two higher doses. From these results we suggest that increases in dynorphin in the direct striatonigral pathway and enkephalin in the indirect striatopallidal pathway following chronic neuroleptic administration are both likely to contribute to tardive dyskinesia.

Animals↗
PubMed2002

Increase in dopamine turnover occurs early in Parkinson's disease: evidence from a new modeling approach to PET 18 F-fluorodopa data.

An increase in dopamine turnover has been hypothesized to occur early in Parkinson's disease (PD) as a compensatory mechanism for dopaminergic neuronal loss. A new approach to the determination of dopamine turnover was developed using 4-hour-long 18 F-fluorodopa (FD) positron emission tomography (PET) data. An effective dopamine turnover, an estimate of dopamine turnover, has been measured using its inverse, the effective dopamine distribution volume (EDV). This new method is based on a reversible tracer approach and determines the EDV using a graphical method. Six healthy subjects and 10 subjects with very early PD underwent a 4-hour-long FD scan. The EDV and the plasma uptake rate constant K(i), a marker of dopamine synthesis and storage, were compared according to their ability to separate the PD group from the healthy group. The EDV was the better discriminator (93.8% correct classification versus 81.3% for K(i)). Effective dopamine distribution volume decreased by 65% in the PD group relative to the healthy group, whereas the decrease in K(i) was 39%. These results show that changes in EDV are measurable with PET earlier than changes in the dopamine synthesis and storage rate, indicating that EDV is a sensitive marker for early PD and that a dopamine turnover increase likely serves as an early compensatory mechanism.

Aged↗
PubMed2001

Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease.

The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson's disease (PD). Little is known, however, about the mechanism underlying the placebo effect. Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography, we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo. Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system.

Aged↗
PubMed2001

Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease: PET evidence of increased dopamine turnover.

Motor fluctuations are a major disabling complication in the treatment of Parkinson's disease. To investigate whether such oscillations in mobility can be attributed to changes in the synaptic levels of dopamine, we studied prospectively patients in the early stages of Parkinson's disease with a follow-up after at least 3 years of levodopa treatment. At baseline, 3 positron emission tomography (PET) scans using [11C]raclopride before and after (1 hour and 4 hours) orally administered levodopa were performed on the same day for each patient. Patients who developed "wearing-off" fluctuations during the follow-up period had a different pattern of levodopa-induced changes in [11C]raclopride binding potential (BP) from that observed in patients who were still stable by the end of the follow-up. Thus, 1 hour post-levodopa the estimated increase in the synaptic level of dopamine was 3 times higher in fluctuators than in stable responders. By contrast, only stable responders maintained increased levels of synaptic dopamine in the PET scan performed after 4 hours. These results indicate that fluctuations in the synaptic concentration of dopamine precede clinically apparent "wearing-off" phenomena. The rapid increase in synaptic levels of dopamine observed in fluctuators suggests that increased dopamine turnover might play a relevant role in levodopa-related motor complications.

Brain↗
PubMed2001

Positron emission tomography of dopamine pathways in familial Parkinsonian syndromes.

Positron emission tomography (PET) scan is considered to be the most useful tool with which to assess the integrity of nigrostriatal function in the living brain. Recently, different genetic defects have been associated with a variety of familial parkinsonian syndromes, the clinical phenotypes of which have varying degrees of similarities to idiopathic parkinsonism (IP), (sporadic Parkinson's disease). This review summarizes: (1) the PET scan findings (fluorodopa uptake and raclopride binding) in both familial parkinsonian syndromes and IP; and (2) the similarities and differences of the clinical and PET features between familial parkinsonian syndromes and IP. This analysis demonstrates that more similarities than differences exist in PET scan findings in the different familial parkinsonian syndromes with the exception of pallido-ponto-nigral degeneration (PPND), that is perhaps best considered as multisystem degeneration. As a result of this analysis, we believe that while different genetic defects may underlie different mechanisms of nigrostriatal degeneration, the final pattern of nigrostriatal dysfunction is essentially similar to that of IP. 'Parkinson's disease', therefore, may not represent a single disease entity, but rather the final manifestation of different pathogenetic mechanisms-mediated by genetic or environmental factors, or an interaction of genetic and environmental factors.

Dopamine↗
PubMed2001

Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition.

The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors.

Antiparkinson Agents↗
PubMed2000

Dopamine transporter function assessed by antisense knockdown in the rat: protection from dopamine neurotoxicity.

The plasma membrane dopamine transporter is located on presynaptic nerve terminals and is responsible for the termination of dopaminergic neurotransmission via dopamine reuptake. The dopamine transporter may also contribute to the pathogenesis of Parkinson disease. Dopamine transporter expression correlates well with susceptibility to neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine (MPTP)-induced parkinsonism. Recent studies have implicated the dopamine transporter in the uptake of both this neurotoxin and its metabolite, MPP(+), as well as another experimental neurotoxin, 6-hydroxydopamine. In these studies we examined the role of the dopamine transporter in the neurotoxicity of both MPP(+) and 6-hydroxydopamine in the rat brain using in vivo administration of phosphorothioate antisense oligonucleotides targeting dopamine transporter mRNA. Infusion of dopamine transporter antisense (1 nmol/day, 7 days) into the left substantia nigra pars compacta resulted in reduced (3)H-WIN 35-428 binding in the left striatum and significant levodopa and amphetamine-induced contralateral rotations. Unilateral pretreatment with dopamine transporter antisense prior to bilateral intrastriatal infusion of either MPP(+) or 6-hydroxydopamine resulted in asymmetrical striatal (3)H-WIN 35-428 binding and dopamine content as well as significant apomorphine-induced ipsilateral rotations, suggesting neuroprotection of nigrostriatal neurons on the antisense-treated side. Thus, the dopamine transporter appears to play a critical role in determining susceptibility to the experimental neurotoxins MPP(+) and 6-hydroxydopamine. In light of this, the dopamine transporter may prove useful, both as a marker for susceptibility to Parkinson's disease and as a target for therapeutic intervention.

1-Methyl-4-phenylpyridinium↗
PubMed2000

Evidence for impaired presynaptic dopamine function in parkinsonian patients with motor fluctuations.

We used [18F]6-fluorodopa (FD) positron emission tomography (PET) to examine the severity of nigrostriatal dopaminergic dysfunction in 67 patients with Idiopathic Parkinsonism (IP), 52 with fluctuations and 15 with a stable response to levodopa. FD uptake (Ki) was reduced by 12% in the caudate (p = 0.08) and by 28% in the putamen (p = 0.0004) of patients with fluctuations compared to those with a stable response. However, there was considerable overlap of FD Ki values between the two groups. The fluctuators had a longer symptom duration (11.6 +/- 5.7 years) than the patients with a stable response to levodopa (4.3 +/- 2.4 years; p < 0.0001) and the age of onset of symptoms was earlier in the fluctuators (43.9 +/- 8.9 versus 54.1 +/- 10.4; p = 0.0004). Similar reductions in FD Ki in the fluctuators persisted following adjustment for these variables (7.5% in the caudate and 26% in the putamen; p = n.s. and 0.007, respectively). When smaller groups (n = 15 each) were matched for duration of symptoms, the reduction in caudate Ki in the fluctuators was only 1.9% (p = n.s.), but there was still a 24% reduction in putamen Ki (p = 0.05). These findings suggest that fluctuators and non-fluctuators may differ in the severity of their nigrostriatal damage and provide modest support for the hypothesis that fluctuations may in part reflect altered "buffering" capacity of dopaminergic nerve terminals. However, the considerable overlap between groups suggests that other factors such as altered postsynaptic mechanisms and/or increased turnover of dopamine may make a substantial contribution to the development of motor fluctuations.

Antiparkinson Agents↗
PubMed2000

Nigrostriatal dopamine system and motor lateralization.

The mechanism by which most people favor use of the right hand remains unknown. It has been proposed that asymmetries in the nigrostriatal dopamine system may be related to motor lateralization in humans. We explored this hypothesis in vivo by using [18F]fluorodopa positron emission tomography. Whereas the degree of right hand preference was found to correlate with left putamen dominance as assessed by asymmetry in fluorodopa uptake (K(i)), right caudate dominance was positively correlated with the level of performance during simultaneous bimanual movements in right-handed normal subjects. In addition, right-handed patients with Parkinson's disease with higher right than left caudate K(i) performed much better in bimanual movement tests than those in whom the K(i) value of the left caudate was higher than that of the right. These findings support the notion that the nigrostriatal dopaminergic system may play a role in motor lateralization, and suggest a functional model for bimanual movements. We propose that the skill for performing simultaneous bilateral hand movements in right-handed subjects might depend upon both the activation (through the dominant left putamen circuitry) of the left supplementary motor area (SMA), and the inhibition (through the right caudate circuitry) of motor programs stored in the right SMA.

Adult↗
PubMed2000

Effects of oligonucleotide antisense to dopamine D(1A) receptor messenger RNA in a rodent model of levodopa-induced dyskinesia.

Dyskinesias are abnormal involuntary movements which develop as a side-effect of long-term treatment with levodopa in patients with Parkinson's disease. The pathophysiology underlying these dyskinesias remains unclear, although, it has been suggested that heightened activity of dopamine D(1) receptor-bearing striatonigral neurons may play a key role. Chronic pulsatile levodopa administration to hemiparkinsonian rats results in sensitization of rotational responses to apomorphine. This sensitization is thought to be analogous to levodopa-induced dyskinesias in humans. In these studies, we further clarify the role of the dopamine D(1A) receptor in this rodent model of levodopa-induced dyskinesias using an in vivo oligonucleotide antisense approach. Hemiparkinsonian rats received twice daily injections of levodopa for three weeks followed by intrastriatal infusion of dopamine D(1A) receptor antisense (7nmol/day, three days), a scrambled missense control sequence, or saline. Those animals treated with antisense displayed significantly fewer apomorphine-induced rotations than saline- or missense-treated controls.By reducing dopamine D(1A) receptor expression, we were able to attenuate sensitization of the response to apomorphine resulting from chronic pulsatile levodopa treatment. Thus, the dopamine D(1A) receptor appears to play a significant role in levodopa-induced dyskinesias and warrants further examination. These findings may have important implications for the development of selective treatment strategies designed to alleviate parkinsonian symptoms, while minimizing motor complications.

Animals↗
PubMed2000

Dopamine D(1A) receptor function in a rodent model of tardive dyskinesia.

Tardive dyskinesia develops as a common complication of long-term neuroleptic use. The emergence of such dyskinesias may reflect a shift in the balance of dopamine D(1) and D(2) receptor-mediated activity, with a relative increase in activity in the D(1) receptor-regulated direct striatonigral pathway. In rats, chronic treatment with the antipsychotic fluphenazine triggers a syndrome of vacuous chewing movements, which are attenuated by dopamine D(1) receptor antagonists. A similar syndrome can be seen in drug-naive animals following acute administration of selective dopamine D(1) receptor agonists. However, not all dopamine D(1) receptor agonists elicit these mouth movements. Thus, some investigators have suggested the existence of novel subtypes of the dopamine D(1) receptor. In these studies, we sought to clarify the role of the dopamine D(1A) receptor in vacuous chewing movements induced both by the selective dopamine D(1) receptor agonist SKF 38393, as well as by chronic neuroleptic administration, using in vivo oligonucleotide antisense to dopamine D(1A) receptor messenger RNA. Intrastriatal antisense treatment significantly and selectively attenuated striatal dopamine D(1) receptor binding, accompanied by reductions in SKF 38393- and chronic fluphenazine-induced vacuous chewing movements. These findings suggest that the dopamine D(1A) receptor plays an important role in the expression of vacuous chewing movements in a rodent model of tardive dyskinesia and may contribute to the pathogenesis of the human disorder. This may have important implications for the treatment of tardive dyskinesia in humans.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Analysis of four dopaminergic tracers kinetics using two different tissue input function methods.

The integrity of the dopaminergic system can be studied using positron emission tomography. The presynaptic tracers [11C]-methylphenidate and [11C]dihydrotetrabenazine (DTBZ) are used to investigate the dopamine transporter availability, the dopamine vesicular transporter integrity; the postsynaptic tracers [11C]-raclopride and [11C]-Schering 23990 (SCH) are used to probe the D2 and D1 receptors. These are reversible tracers, where the binding potential (BP) = Bmax/Kd often is used to quantify the amount of their specific binding to the sites of interest. The simplified tissue input methods to calculate BP are attractive, since they do not require a blood input function. The suitability and performance of two such methods were evaluated: the Logan graphical tissue method, and the Lammertsma reference tissue method (RTM). The BP estimates obtained with the two methods were nearly identical in most cases, with similar reliability and reproducibility indicating that all four tracers satisfy the assumptions required by each method. The correlations among the fitted parameters obtained from the RTM were estimated and were found not to introduce noticeable bias in the RTM BP and R1 estimates. R1 showed low intersubject and intrasubject variability. The k2 estimate showed good reliability for SCH with cerebellar input function and DTBZ with occipital input function.

Adult↗
PubMed2000

In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease.

Clinical symptoms of Parkinson's disease (PD) do not manifest until dopamine (DA) neuronal loss reaches a symptomatic threshold. To explore the mechanisms of functional compensation that occur in presynaptic DA nerve terminals in PD, we compared striatal positron emission tomographic (PET) measurements by using [11C]dihydrotetrabenazine ([11C]DTBZ; labeling the vesicular monoamine transporter type 2), [11C]methylphenidate (labeling the plasma membrane DA transporter), and [18F]dopa (reflecting synthesis and storage of DA). Three consecutive PET scans were performed in three-dimensional mode by using each tracer on 35 patients and 16 age-matched, normal controls. PET measurements by the three tracers were compared between subgroups of earlier and later stages of PD, between drug-naive and drug-treated subgroups of PD, and between subregions of the parkinsonian striatum. The quantitative relationships of [18F]dopa and [11]DTBZ, and of [11C]methylphenidate and [11C]DTBZ, were compared between the PD and the normal control subjects. We found that [18F]dopa Ki was reduced less than the binding potential (Bmax/Kd) for [11C]DTBZ in the parkinsonian striatum, whereas the [11C]methylphenidate binding potential was reduced more than [11C]DTBZ binding potential. These observations suggest that the activity of aromatic L-amino acid decarboxylase is up-regulated, whereas the plasma membrane DA transporter is down-regulated in the striatum of patients with PD.

Aged↗