Paola Piccini

Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient

Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinsons disease using [11C]-raclopride positron emission tomography to measure dopamine D2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.

Compulsive drug use linked to sensitized ventral striatal dopamine transmission.

A small group of Parkinsons disease (PD) patients compulsively use dopaminergic drugs despite causing harmful social, psychological, and physical effects and fulfil core Diagnostic and Statistical Manual (of Mental Disorders) Fourth Edition criteria for substance dependence (dopamine dysregulation syndrome [DDS]). We aimed to evaluate levodopa‐induced dopamine neurotransmission in the striatum of patients with DDS compared with PD control patients.

The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins.

Despite the major finding of a genetic defect being responsible for the Parkinsons disease (PD) phenotype in some kindreds with dominantly transmitted PD, the role of inheritance in the cause of the more widespread sporadic form of the disease is still unclear. Twin studies are a classic tool for assessing the influence of hereditary factors in diseases; however, the application of this approach to late‐onset illnesses, like PD, poses some problems because of the identification of subclinical cases. In the present longitudinal study we have used [18F]dopa and positron emission tomography to study dopaminergic function in twin pairs at baseline clinically discordant for PD. At baseline, the concordance for subclinical striatal dopaminergic dysfunction was found to be significantly higher in 18 monozygotic than in 16 dizygotic twin pairs (55% vs 18%, respectively). The asymptomatic monozygotic cotwins all showed progressive loss of dopaminergic function over 7 years and 4 developed clinical PD. None of the dizygotic twin pairs became clinically concordant. At follow‐up, the combined concordance levels for subclinical dopaminergic dysfunction and clinical PD were 75% in the 12 monozygotic and 22% in the 9 dizygotic twin pairs evaluated twice. Our findings suggest a substantial role for inheritance in sporadic PD. Ann Neurol 1999;45:577–582

Priorities in Parkinson's disease research

The loss of dopaminergic neurons in the substantia nigra pars compacta leads to the characteristic motor symptoms of Parkinsons disease: bradykinesia, rigidity and resting tremors. Although these symptoms can be improved using currently available dopamine replacement strategies, there is still a need to improve current strategies of treating these symptoms, together with a need to alleviate non-motor symptoms of the disease. Moreover, treatments that provide neuroprotection and/or disease-modifying effects remain an urgent unmet clinical need. This Review describes the most promising biological targets and therapeutic agents that are currently being assessed to address these treatment goals. Progress will rely on understanding genetic mutations or susceptibility factors that lead to Parkinsons disease, better translation between preclinical animal models and clinical research, and improving the design of future clinical trials.>

Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts

Intrastriatal transplantation of dopaminergic neurones aims to repair the selective loss of nigrostriatal projections and the consequent dysfunction of striatocortical circuitries in Parkinsons disease (PD). Here, we have studied the effects of bilateral human embryonic dopaminergic grafts on the movement‐related activation of frontal cortical areas in 4 PD patients using H215O positron emission tomography and a joystick movement task. At 6.5 months after transplantation, mean striatal dopamine storage capacity as measured by 18F‐dopa positron emission tomography was already significantly elevated in these patients. This was associated with a modest clinical improvement on the Unified Parkinsons Disease Rating Scale, whereas the impaired cortical activation was unchanged. At 18 months after surgery, there was further significant clinical improvement in the absence of any additional increase in striatal 18F‐dopa uptake. Rostral supplementary motor and dorsal prefrontal cortical activation during performance of joystick movements had significantly improved, however. Our data suggest that the function of the graft goes beyond that of a simple dopamine delivery system and that functional integration of the grafted neurones within the host brain is necessary to produce substantial clinical recovery in PD. Ann Neurol 2000;48:689–695

Serotonergic Neurons Mediate Dyskinesia Side Effects in Parkinson's Patients with Neural Transplants

Two patients with Parkinson’s disease, successfully treated with fetal tissue transplants more than a decade ago, developed troublesome involuntary movements, which could be treated with a serotonin receptor agonist. The Two Faces of Fetal Grafts Before stem cells, there were fetal grafts. Pioneering treatments performed in the 1990s in patients with Parkinson’s disease proved that the diseased brain could be repaired, at least for a while. Two of these patients received grafts, one in the putamen and the other in both the caudate and the putamen, of fetal midbrain tissue. For several years, the patients showed mild improvement but eventually were able to function well with no drugs. Recently, however, both have started to experience abnormal uncontrolled movements, which Politis and colleagues have determined are a result of an overabundance of serotonin-using neurons that developed from the graft. A serotonin agonist eliminates these dyskinesias. Brain imaging exposed what was happening in these patients’ brains. When imaged by positron emission tomography, radioactive tracers that tag dopaminergic neurons and that bind to the dopamine receptor showed that the dopamine neurons that decay during Parkinson’s disease were restored by the grafts. Another scan with an agent that binds to the serotonin transporter showed an abnormality; there seemed to be more serotonin neurons than usual. This presented a conundrum because dyskinesias in Parkinson’s disease are thought to be a result of dopamine, not serotonin, stimulation. The authors hypothesized that the explanation lies in the ability of the serotonin neurons to switch to a different neurotransmitter—to adopt dopamine as a so-called false transmitter, releasing it to cause dyskinesias. If this were the case, then desensitizing these serotonin neurons, and so inhibiting their activity, would reduce the dyskinesias. They tested this idea by giving the patients low doses of a serotonin receptor agonist called buspirone. Both patients responded by a sudden and almost complete resolution of the troublesome abnormal movements, suggesting that the excess serotonergic neurons had in fact been pumping out dopamine, causing the dyskinesias. The patients described here are only two of a larger number who received fetal neural tissue implants years ago. In some patients, the grafted cells survived, possibly as a result of stem cells within the graft, and were able to replace the function of the diseased dopamine cells, forming connections with the existing brain cells. Exploration of the long-term consequences of such replacement tissue, such as the atypical movements and their inhibition reported here, is important in that it will inform future treatments with grafts that consist of cells from other sources, such as bioengineered or stem cells. Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson’s disease. The mechanisms underlying these dyskinesias are not well understood, and it is not known whether they are the same as in the dyskinesias induced by l-dopa treatment. Using in vivo brain imaging, we show excessive serotonergic innervation in the grafted striatum of two patients with Parkinson’s disease, who had exhibited major motor recovery after transplantation with dopamine-rich fetal mesencephalic tissue but had later developed off-medication dyskinesias. The dyskinesias were markedly attenuated by systemic administration of a serotonin [5-hydroxytryptamine (5-HT)] receptor (5-HT1A) agonist, which dampens transmitter release from serotonergic neurons, indicating that the dyskinesias were caused by the serotonergic hyperinnervation. Our observations suggest strategies for avoiding and treating graft-induced dyskinesias that result from cell therapies for Parkinson’s disease with fetal tissue or stem cells.

Increased dopamine tone during meditation-induced change of consciousness

This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to be organized in open loops subserving executive control. In the striatum, dopamine modulates excitatory glutamatergic synapses of the projections from the frontal cortex to striatal neurons, which in turn project back to the frontal cortex via the pallidum and ventral thalamus. The present study was designed to investigate whether endogenous dopamine release increases during loss of executive control in meditation. Participants underwent two 11C-raclopride PET scans: one while attending to speech with eyes closed, and one during active meditation. The tracer competes with endogenous dopamine for access to dopamine D2 receptors predominantly found in the basal ganglia. During meditation, 11C-raclopride binding in ventral striatum decreased by 7.9%. This corresponds to a 65% increase in endogenous dopamine release. The reduced raclopride binding correlated significantly with a concomitant increase in EEG theta activity, a characteristic feature of meditation. All participants reported a decreased desire for action during meditation, along with heightened sensory imagery. The level of gratification and the depth of relaxation did not differ between the attention and meditation conditions. Here we show increased striatal dopamine release during meditation associated with the experience of reduced readiness for action. It is suggested that being in the conscious state of meditation causes a suppression of cortico-striatal glutamatergic transmission. To our knowledge this is the first time in vivo evidence has been provided for regulation of conscious states at a synaptic level.

Clinical and subclinical dopaminergic dysfunction in PARK6-linked parkinsonism: an 18F-dopa PET study.

PARK6, a locus for early‐onset recessive parkinsonism, has been causally implicated in nine unrelated families from four different countries. The gene is still unidentified and hence the importance of PARK6 as a cause of Parkinsons disease is unknown. To date, no pathology or functional imaging studies are available on PARK6‐linked parkinsonism. We have used 18F‐dopa positron emission tomography to study four patients who are homozygous and three asymptomatic relatives who are heterozygous for PARK6. The clinically affected PARK6 subjects had a similar 85% reduction in posterior dorsal putamen 18F‐dopa uptake to a group of idiopathic Parkinsons disease patients matched for clinical disease severity and duration but showed significantly greater involvement of head of caudate and anterior putamen. The group of asymptomatic PARK6 carriers showed a significant mean 20 to 30% reduction in caudate and putamen 18F‐dopa uptake in comparison with controls, individual values falling toward the bottom of the normal range. Our results indicate that PARK6 pathology results in a more uniform loss of striatal dopamine terminal function than Parkinsons disease. The subclinical loss of striatal dopamine storage capacity found in the PARK6 carriers implies that the unidentified gene on the short arm of chromosome 1 exhibits either haploinsufficency or a dominant negative effect.

Cognitive deficits and striato-frontal dopamine release in Parkinson's disease

Idiopathic Parkinsons disease (PD) is often accompanied by a pattern of executive deficits similar to those found in patients with frontal lobe lesions. We investigated whether such cognitive deficits are attributable to frontal lobe dysfunction as a direct consequence of impaired mesocortical dopaminergic transmission or an indirect consequence of impaired nigrostriatal dopaminergic function. For this purpose, changes in synaptic dopamine levels during task performance were monitored using a marker of dopamine D2-receptor availability (11)C-raclopride (RAC) PET. During RAC PET, seven patients with early symptomatic PD and seven age-matched healthy controls performed two types of behavioural task, a spatial working memory task (SWT) and a visuomotor control task (VMT). The SWT involves an executive process which is known to be impaired by both frontal lobe lesions and PD while the VMT is a control test for the visuomotor component of the SWT. Parametric images of RAC binding potential during performance of each task were generated, and compared between the tasks using voxel-based statistical parametric mapping as well as region of interest analysis. In controls, RAC binding was reduced in the dorsal caudate during performance of the SWT compared with the VMT, compatible with increased levels of endogenous dopamine release due to the executive process. In PD patients, this RAC binding reduction was not observed. In contrast, RAC binding in the anterior cingulate cortex within the medial prefrontal cortex was reduced by a comparable level during the SWT both in controls and PD patients. Statistical comparisons between controls and PD patients confirmed significantly attenuated dopamine release in the dorsal caudate in PD, but preserved levels of medial prefrontal dopamine release. Our data suggest that executive deficits in early patients with PD are associated with impaired nigrostriatal dopaminergic function resulting in abnormal processing in the cortico-basal ganglia circuit. In contrast, mesocortical dopaminergic transmission appears well preserved in early PD patients.

Cue-induced striatal dopamine release in Parkinson's disease-associated impulsive-compulsive behaviours

Impulsive-compulsive behaviours are a significant source of morbidity for patients with Parkinsons disease receiving dopaminergic therapy. The development of these behaviours may reflect sensitization of the neural response to non-drug rewards, similar to that proposed for sensitization to drug rewards in addiction. Here, by using (11)C-raclopride positron emission tomography imaging, we investigated the effects of reward-related cues and L-dopa challenge in patients with Parkinsons disease with and without impulsive-compulsive behaviours on striatal levels of synaptic dopamine. Eighteen patients (11 with and seven without impulsive-compulsive behaviours) underwent three (11)C-raclopride positron emission tomography scans. The impulsive-compulsive behaviours included hypersexuality, binge eating, punding, compulsive use of dopamine replacement therapy, compulsive buying and pathological gambling, with eight patients exhibiting more than one impulsive-compulsive behaviour. There were no significant differences in baseline dopamine D2 receptor availability between the Parkinsons disease groups. No differences were found when comparing the percentage change of raclopride binding potential between the two Parkinsons disease groups following L-dopa challenge with neutral cues. The group with Parkinsons disease with impulsive-compulsive behaviours had a greater reduction of ventral striatum (11)C-raclopride binding potential following reward-related cue exposure, relative to neutral cue exposure, following L-dopa challenge (16.3% compared with 5.8% in Parkinsons disease controls, P = 0.016). The heightened response of striatal reward circuitry to heterogeneous reward-related visual cues among a group of patients with different impulsive-compulsive behaviours is consistent with a global sensitization to appetitive behaviours with dopaminergic therapy in vulnerable individuals. Our findings are relevant for the broader debate on the relation between impulsive-compulsive behaviours and addictions and may have important implications with regards to advertisement legislation in an effort to prevent the onset of behavioural addictions.