Marios Politis

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.

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.

Staging of serotonergic dysfunction in Parkinson's Disease: An in vivo 11C-DASB PET study

Thirty Parkinsons disease (PD) patients were divided into three equal groups according to their disease duration while 10 normal healthy volunteers matched for age and sex served as a control group. Striatal and extrastriatal serotonergic function was studied with (11)C-DASB PET, a marker of serotonin transporter availability. (11)C-DASB binding was correlated with disease disability and exposure to dopaminergic therapy. We found significant (11)C-DASB binding reductions in striatal, brainstem, and cortical regions in PD but no correlations were evident between (11)C-DASB binding and UPDRS scores, Hoehn &Yahr staging, disease duration and level of exposure to dopaminergic therapy. Our results suggest that progressive non-linear serotonergic dysfunction occurs in PD but it does not determine levels of disability. Additionally, chronic exposure to dopaminergic therapy does not appear to influence SERT binding.

Depressive symptoms in PD correlate with higher 5-HTT binding in raphe and limbic structures

Background: Depression associated with Parkinson disease (PD) has a different symptom profile to endogenous depression. The etiology of depression in PD remains uncertain though abnormal serotonergic neurotransmission could play a role. Objective: To assess with PET serotonergic function via in vivo serotonin transporter (5-HTT) availability in antidepressant-naive patients with PD. Methods: Thirty-four patients with PD and 10 healthy matched control subjects had a clinical battery of tests including the patient-report Beck Depression Inventory–II (BDI-II), the clinician-report Hamilton Rating Scale for Depression (HRSD), and the structured clinical interview for DSM-IV Axis I Disorders (SCID-I). They underwent 11C-DASB PET, a selective in vivo marker of 5-HTT binding in humans. Results: BDI-II scores correlated with HRSD scores. Ten of 34 patients with PD (29.4%) had BDI-II and HRSD scores above the discriminative cutoff for PD depression though only half of these patients could be classed on SCID-I criteria as having an anxiety/mood disorder. Patients with PD with the highest scores for depression symptoms showed significantly raised 11C-DASB binding in amygdala, hypothalamus, caudal raphe nuclei, and posterior cingulate cortex compared to low score cases, while 11C-DASB binding values in other regions were similarly decreased in depressed and nondepressed patients with PD compared to healthy controls. Conclusion: Depressive symptoms in antidepressant-naive patients with PD correlate with relatively higher 5-HTT binding in raphe nuclei and limbic structures possibly reflecting lower extracellular serotonin levels. Our data are compatible with a key role of abnormal serotonergic neurotransmission contributing to the pathophysiology of PD depression and justify the use of agents acting on 5-HTT.

Long-term Clinical Outcome of Fetal Cell Transplantation for Parkinson Disease: Two Case Reports

IMPORTANCE Recent advances in stem cell technologies have rekindled an interest in the use of cell replacement strategies for patients with Parkinson disease. This study reports the very long-term clinical outcomes of fetal cell transplantation in 2 patients with Parkinson disease. Such long-term follow-up data can usefully inform on the potential efficacy of this approach, as well as the design of trials for its further evaluation. OBSERVATIONS Two patients received intrastriatal grafts of human fetal ventral mesencephalic tissue, rich in dopaminergic neuroblasts, as restorative treatment for their Parkinson disease. To evaluate the very long-term efficacy of the grafts, clinical assessments were performed 18 and 15 years posttransplantation. Motor improvements gained gradually over the first postoperative years were sustained up to 18 years posttransplantation, while both patients have discontinued, and remained free of any, pharmacological dopaminergic therapy. CONCLUSIONS AND RELEVANCE The results from these 2 cases indicate that dopaminergic cell transplantation can offer very long-term symptomatic relief in patients with Parkinson disease and provide proof-of-concept support for future clinical trials using fetal or stem cell therapies.

Microglial activation in regions related to cognitive function predicts disease onset in Huntington's Disease: A multimodal imaging study

Huntingtons disease (HD) is an inherited neurodegenerative disorder associated with motor, cognitive and psychiatric deficits. This study, using a multimodal imaging approach, aims to assess in vivo the functional and structural integrity of regions and regional networks linked with motor, cognitive and psychiatric function. Predicting disease onset in at risk individuals is problematic and thus we sought to investigate this by computing the 5‐year probability of HD onset (p5 HD) and relating it to imaging parameters. Using MRI, 11C‐PK11195 and 11C‐raclopride PET, we have investigated volumes, levels of microglial activation and D2/D3 receptor binding in CAG repeat‐matched groups of premanifest and symptomatic HD gene carriers. Findings were correlated with disease‐burden and UHDRS scores. Atrophy was detected in sensorimotor striatum (SMST), substantia nigra, orbitofrontal and anterior prefrontal cortex in the premanifest HD. D2/D3 receptor binding was reduced and microglial activation increased in SMST and associative striatum (AST), bed nucleus of the stria terminalis, the amygdala and the hypothalamus. In symptomatic HD cases this extended to involve atrophy in globus pallidus, limbic striatum, the red nuclei, anterior cingulate cortex, and insula. D2/D3 receptor binding was additionally reduced in substantia nigra, globus pallidus, limbic striatum, anterior cingulate cortex and insula, and microglial activation increased in globus pallidus, limbic striatum and anterior prefrontal cortex. In premanifest HD, increased levels of microglial activation in the AST and in the regional network associated with cognitive function correlated with p5 HD onset. These data suggest that pathologically activated microglia in AST and other areas related to cognitive function, maybe better predictors of clinical onset and stresses the importance of early cognitive assessment in HD. Hum Brain Mapp, 2011.

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson's disease patients.

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinsons disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.

Hypothalamic involvement in Huntington's disease: an in vivo PET study

Recent studies have shown alterations in metabolism, sleep and circadian rhythms as well as in several neuropeptides derived from the hypothalamic-pituitary axis in Huntingtons disease patients; however, the pathology underlying these abnormalities is not known. Our aim was to assess in vivo D(2) receptors loss/dysfunction and increases in microglial activation in the hypothalamus of symptomatic Huntingtons disease patients and premanifest Huntingtons disease gene carriers using PET with (11)C-raclopride (RAC), a specific D(2) receptor ligand and (11)C-(R)-PK11195 (PK), a marker of microglial activation. We have studied 9 symptomatic Huntingtons disease patients (age = 46.8 +/- 4.7 years; mean +/- SD) and 10 premanifest Huntingtons disease gene carriers (age = 41.9 +/- 8.2 years; mean +/- SD). RAC and PK findings for these subjects were compared with those of a group of normal controls (RAC, n = 9; PK, n = 10). In the symptomatic Huntingtons disease group, we found a significant decrease (P = 0.0012) in mean hypothalamic RAC binding potential (BP) and a significant increase in mean hypothalamic PK BP (P = 0.0008). Similarly, a significant decrease (P = 0.0143) in mean hypothalamic RAC BP and a significant increase in mean hypothalamic PK BP (P = 0.0057) were observed in the premanifest Huntingtons disease group. Hypothalamic RAC and PK BP values correlated with each other in combined Huntingtons disease groups (r = -0.6180, P = 0.0048) but not with striatal RAC and PK BP values. Our data demonstrate, for the first time, significant D(2) receptor loss and microglia activation in the hypothalamus of Huntingtons disease. These pathological changes occur very early in the course of the disease and may partly explain the development of commonly reported symptoms in Huntingtons disease including progressive weight loss, alterations in sexual behaviour and disturbances in the wake-sleep cycle.

Graft-Induced Dyskinesias in Parkinson's Disease: High Striatal Serotonin/Dopamine Transporter Ratio

Graft‐induced dyskinesias are a serious complication after neural transplantation in Parkinsons disease. One patient with Parkinsons disease, treated with fetal grafts 14 years ago and deep brain stimulation 6 years ago, showed marked improvement of motor symptoms but continued to suffer from OFF‐medication graft‐induced dyskinesias. The patient received a series of clinical and imaging assessments. Positron emission tomography and single‐photon emission computed tomography 14 years posttransplantation revealed an elevated serotonin/dopamine transporter ratio in the grafted striatum compatible with serotonergic hyperinnervation. Inhibition of serotonin neuron activity by systemic administration of a 5‐HT1A agonist suppressed graft‐induced dyskinesias. Our data provide further evidence that serotonergic neurons mediate graft‐induced dyskinesias in Parkinsons disease. Achieving a normal striatal serotonin/dopamine transporter ratio following transplantation of fetal tissue or stem cells should be necessary to avoid the development of graft‐induced dyskinesias.

Increased PK11195 PET binding in the cortex of patients with MS correlates with disability

Objective: Activated microglia are thought to play a major role in cortical gray matter (GM) demyelination in multiple sclerosis (MS). Our objective was to evaluate microglial activation in cortical GM of patients with MS in vivo and to explore its relationship to measures of disability. Methods: Using PET and optimized modeling and segmentation procedures, we investigated cortical 11C-PK11195 (PK11195) binding in patients with relapsing-remitting MS (RRMS), patients with secondary progressive MS (SPMS), and healthy controls. Disability was assessed with the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impact Scale (MSIS-29). Results: Patients with MS showed increased cortical GM PK11195 binding relative to controls, which was multifocal and highest in the postcentral, middle frontal, anterior orbital, fusiform, and parahippocampal gyri. Patients with SPMS also showed additional increases in precentral, superior parietal, lingual and anterior superior, medial and inferior temporal gyri. Total cortical GM PK11195 binding correlated with EDSS scores, with a stronger correlation for the subgroup of patients with SPMS. In patients with SPMS, PK11195 binding also correlated with MSIS-29 scores. No correlation with disability measures was seen for PK11195 binding in white matter. Higher EDSS scores correlated with higher levels of GM PK11195 binding in the postcentral gyrus for patients with RRMS and in precentral gyrus for those with SPMS. Conclusions: Microglial activation in cortical GM of patients with MS can be assessed in vivo. The distribution is not uniform and shows a relationship to clinical disability. We speculate that the increased PK11195 binding corresponds to enhanced microglial activation described in postmortem SPMS cortical GM.