The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform

Olle Lindvall - One of the best experts on this subject based on the ideXlab platform.

  • Treatment of Parkinson's disease using cell transplantation.
    Philosophical transactions of the Royal Society of London. Series B Biological sciences, 2015
    Co-Authors: Olle Lindvall
    Abstract:

    The clinical trials with intrastriatal transplantation of human fetal Mesencephalic Tissue, rich in dopaminergic neurons, in Parkinson's disease (PD) patients show that cell replacement can work and in some cases induce major, long-lasting improvement. However, owing to poor Tissue availability, this approach can only be applied in very few patients, and standardization is difficult, leading to wide variation in functional outcome. Stem cells and reprogrammed cells could potentially be used to produce dopaminergic neurons for transplantation. Importantly, dopaminergic neurons of the correct substantia nigra phenotype can now be generated from human embryonic stem cells in large numbers and standardized preparations, and will soon be ready for application in patients. Also, human induced pluripotent stem cell-derived dopaminergic neurons are being considered for clinical translation. Available data justify moving forward in a responsible way with these dopaminergic neurons, which should be tested, using optimal patient selection, cell preparation and transplantation procedures, in controlled clinical studies.

  • Cell Therapeutics in Parkinson’s Disease
    Neurotherapeutics, 2011
    Co-Authors: Olle Lindvall, Anders Björklund
    Abstract:

    The main pathology underlying motor symptoms in Parkinson’s disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal Mesencephalic Tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process long-term after implantation. Mechanisms underlying graft-induced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal Mesencephalic Tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.

  • Cell Therapeutics in Parkinson's Disease.
    Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2011
    Co-Authors: Olle Lindvall, Anders Björklund
    Abstract:

    The main pathology underlying motor symptoms in Parkinson’s disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal Mesencephalic Tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process long-term after implantation. Mechanisms underlying graft-induced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal Mesencephalic Tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.

  • serotonergic neurons mediate dyskinesia side effects in parkinson s patients with neural transplants
    Science Translational Medicine, 2010
    Co-Authors: Marios Politis, Olle Lindvall, Stig Rehncrona, Anders Björklund, David J. Brooks, Clare Loane, Niall Quinn, Paola Piccini
    Abstract:

    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.

  • Serotonergic Neurons Mediate Dyskinesia Side Effects in Parkinson’s Patients with Neural Transplants
    Science translational medicine, 2010
    Co-Authors: Marios Politis, Olle Lindvall, Stig Rehncrona, Anders Björklund, David J. Brooks, Clare Loane, Niall Quinn, Paola Piccini
    Abstract:

    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.

Patrik Brundin - One of the best experts on this subject based on the ideXlab platform.

  • 429 PUBLICATIONS 24,967 CITATIONS SEE PROFILE
    2016
    Co-Authors: Mia Emgård, Patrik Brundin, See Profile, Klas Blomgren
    Abstract:

    Both apoptosis and necrosis occur early after intracerebral grafting of ventral Mesencephalic Tissue: A role for protease activatio

  • Combining neuroprotective treatment of embryonic nigral donor Tissue with mild hypothermia of the graft recipient.
    Cell transplantation, 2005
    Co-Authors: Jenny Karlsson, Åsa Petersén, Gunilla Gidö, Tadeusz Wieloch, Patrik Brundin
    Abstract:

    Around 80-95% of the immature dopaminergic neurons die when embryonic ventral Mesencephalic Tissue is transplanted. Cell death occurs both during the preparation of donor Tissue and after graft implantation, but the effect of combining successful neuroprotective treatments before and after transplantation has not been extensively investigated. We therefore treated embryonic rat Mesencephalic Tissue with a combination of the lipid peroxidation inhibitor tirilazad mesylate (3 microM) and the caspase inhibitor Ac.YVAD.cmk (500 microM) and transplanted the Tissue into hemiparkinsonian rats kept hypothermic (32-33 degrees C) or normothermic (37 degrees C) during, and 90 min following, graft surgery. Suspension cell number did not differ between untreated or tirilazad/YVAD-treated preparations prior to transplantation. When graft survival was evaluated 6 weeks after implantation, both tirilazad/YVAD pretreatment and mild hypothermia increased the survival of transplanted dopaminergic neurons. Approximately 50-57% of the embryonic dopaminergic neurons survived the dissociation and grafting procedure in rats rendered hypothermic, but there was no significant additive effect on graft survival with a combined treatment. All groups of rats exhibited behavioral recovery in the amphetamine-induced rotation test. There was a significantly enhanced functional capacity of grafts placed in hypothermic as compared to normothermic rats. However, tirilazad/YVAD pretreated implants did not afford greater behavioral improvement than control-treated grafts. Our results suggest that neuroprotective treatments administered prior to and immediately after neural graft implantation may under certain conditions rescue, at least in part, the same subset of dopaminergic neurons. The study also emphasizes the importance of the immediate time after grafting for transplant survival, with relevance both for primary Mesencephalic implants and stem cell grafts.

  • Ultrastructural characterization of dissociated embryonic ventral Mesencephalic Tissue treated with neuroprotectants.
    Cell transplantation, 2003
    Co-Authors: Young Hwan Ahn, Mia Emgård, Patrik Brundin
    Abstract:

    Poor survival and differentiation of grafted dopamine neurons limits the application of clinical transplantation in Parkinson’s disease. The survival of grafted dopamine neurons is only improved by a factor of 2–3 by adding neuroprotectants during Tissue preparation. We used dye exclusion cell viability and electron microscopy to investigate the effects of the caspase inhibitor ac-YVAD-cmk and the lazaroid tirilazad mesylate on ultrastructural changes in dissociated embryonic Mesencephalic cells. In addition, we examined whether the neuroprotectants selectively counteracted specific signs of neurodegeneration. Cell viability decreased significantly over time in both control and treated cell suspensions, but the number of viable cells remaining was significantly higher in tirilazad mesylate-treated cell suspensions. In control samples, the proportion of cells with an ultrastructure consistent with healthy cells decreased from 70%, immediately after dissociation, to 30% after 8 h of incubation. Similar changes were also observed in cell suspensions treated with neuroprotectants. Thus, the neuroprotectants examined did not block the development of specific morphological signs of neurodegeneration. However, when also taking into account that dead cells lysed and disappeared from each cell suspension with time, we found that the total number of remaining viable cells with healthy nuclear chromatin or intact membrane integrity was significantly higher in the tirilazad mesylate-treated group. The results indicate that tirilazad mesylate protects only a small subpopulation of embryonic Mesencephalic cells from degeneration induced by mechanical trauma during Tissue dissection and dissociation.

  • bilateral caudate and putamen grafts of embryonic Mesencephalic Tissue treated with lazaroids in parkinson s disease
    Brain, 2000
    Co-Authors: Patrik Brundin, Hakan Widner, Per Odin, Oliver Pogarell, Peter Hagell, P Piccini, Anette Schrag, Andreas Kupsch, Lesley Crabb, Björn Gustavii
    Abstract:

    Five parkinsonian patients were transplanted bilaterally into the putamen and caudate nucleus with human embryonic Mesencephalic Tissue from between seven and nine donors. To increase graft survival, the lipid peroxidation inhibitor tirilazad mesylate was administered to the Tissue before implantation and intravenously to the patients for 3 days thereafter. During the second postoperative year, the mean daily L-dopa dose was reduced by 54% and the UPDRS (Unified Parkinson's Disease Rating Scale) motor score in 'off' phase was reduced by a mean of 40%. At 10-23 months after grafting, PET showed a mean 61% increase of 6-L-[(18)F]fluorodopa uptake in the putamen, and 24% increase in the caudate nucleus, compared with preoperative values. No obvious differences in the pattern of motor recovery were observed between these and other previously studied cases with putamen grafts alone. The amount of Mesencephalic Tissue implanted in each putamen and caudate nucleus was 42 and 50% lower, respectively, compared with previously transplanted patients from our centre. Despite this reduction in grafted Tissue, the magnitudes of symptomatic relief and graft survival were very similar. These findings suggest that tirilazad mesylate may improve survival of grafted dopamine neurons in patients, which is in agreement with observations in experimental animals.

  • Intrastriatal ventral Mesencephalic xenografts of porcine Tissue in rats: Immune responses and functional effects
    Cell transplantation, 2000
    Co-Authors: Lena C. Larsson, Patrik Brundin, Kimberly A. Czech, Hakan Widner
    Abstract:

    Transplantation of neural Tissue from other species has the potential to improve function in patients with neurodegenerative disorders. We investigated the functional effects of embryonic porcine dopaminergic neurons transplanted in a rat model of Parkinson's disease and the immune responses to the grafts in immunosuppressed and nonimmunosuppressed hosts. Twenty-three rats with unilateral 6-hydroxydopamine lesions received dissociated, 27-day-old embryonic porcine ventral Mesencephalic Tissue in the right striatum. Eighteen rats received cyclosporine (10 mg/kg, IP, daily) during the whole period of 14 weeks, in combination with prednisolone (20 mg/kg, IP, daily) the first 4 days. Five rats served as nonimmunosuppressed controls. All rats were tested for amphetamine-induced rotational behavior at 3-week intervals. Two immunosuppressed rats were excluded due to severe side effects of the treatment. Functional recovery was seen in 9 of 16 immunosuppressed rats at 12 weeks. Six animals remained functionally recovered at 14 weeks and contained an average of 5750+/-1450 (SEM) dopaminergic neurons. Between 9 and 14 weeks, three immunosuppressed rats rejected their grafts, based on rotation scores and immunohistochemical demonstration of cell infiltrates. One additional immunosuppressed rat showed evidence of ongoing rejection at 14 weeks. The striata in animals with ongoing or recent rejection contained large numbers of CD4- and CD8-positive lymphocytes, NK cells, macrophages, and microglia cells, whereas scar Tissue was found in rats with grafts rejected at earlier time points (n = 11). Embryonic porcine ventral Mesencephalic Tissue matures in the adult rat striatum, reinnervates the host brain, and restores behavioral defects. Immunosuppressive treatment was necessary for long-term graft survival and functional recovery, but did not sufficiently protect from rejection mechanisms. Porcine neural Tissue is an interesting alternative to embryonic human Tissue for intracerebral transplantation in neurodegenerative diseases. However, to achieve stable graft survival in discordant xenogeneic combinations, an appropriate immunosuppressive treatment or donor Tissue modifications are needed.

P. Brundin - One of the best experts on this subject based on the ideXlab platform.

  • Both apoptosis and necrosis occur early after intracerebral grafting of ventral Mesencephalic Tissue: a role for protease activation.
    Journal of neurochemistry, 2003
    Co-Authors: Mia Emgård, P. Brundin, Jenny Karlsson, Ulrika Hallin, Ben A. Bahr, Klas Blomgren
    Abstract:

    Neural transplantation is an experimental treatment for Parkinson's disease. Widespread clinical application of the grafting technique is hampered by a relatively poor survival (around 10%) of implanted embryonic dopamine neurones. Earlier animal studies have indicated that a large proportion of the grafted cells die during graft Tissue preparation and within the first few days after intracerebral implantation. The present study was designed to reveal the prevalence of cell death in rat intrastriatal grafts at 90 min, 1, 3, 6 and 42 days after implantation. We examined apoptotic cell death using semi-thin and paraffin sections stained with methylene blue and an antibody against activated caspase 3, respectively. We identified abundant apoptotic cell death up to 3 days after transplantation. In addition, we studied calpain activation using an antibody specific for calpain-cleaved fodrin. We report a peak in calpain activity 90 min after grafting. Surprisingly, we did not observe any significant difference in the number of dopaminergic neurones over time. The present results imply that grafted cells may be victims of either an early necrotic or a later apoptotic cell death and that there is substantial cell death as early as 90 min after implantation.

  • Characterisation of cell damage and death in embryonic Mesencephalic Tissue: a study on ultrastructure, vital stains and protease activity.
    Neuroscience, 2002
    Co-Authors: M Emgård, Klas Blomgren, P. Brundin
    Abstract:

    Dissociated embryonic ventral Mesencephalic Tissue is a source of dopaminergic neurones in both cell culture and neural transplantation studies. Around 90% of grafted dopaminergic neurones die within 1 week after transplantation. Little is known about when the cell death is triggered and what forms of cell death predominate. Using electron microscopy, we characterised ultrastructural changes in dissected embryonic day 14 rat Mesencephalic Tissue before and after Tissue dissociation. In addition, cell viability was evaluated using Trypan Blue and Hoechst/Ethidium Homodimer. Several cells exhibited leaky outer membranes (permitting entry of vital stains) and ultrastructural degeneration already immediately after the mesencephalon was dissected, and before it was mechanically disrupted. After 2 h at room temperature, 90% of the remaining cells had intact outer membranes. However, when estimating cells lost acutely in the Tissue dissociation, in addition to cells exhibiting condensed chromatin and organellar changes, we suggest that only around 14% of the cells initially dissected in the Mesencephalic Tissue pieces remained healthy after 2 h. There was a peak in calpain activity (specific cleavage of fodrin) immediately following Tissue dissociation, and it subsided during the next few hours. Caspase-3 activity was initially low, but increased almost 20-fold 4 h after Tissue disruption. Interestingly, extensive degradation of caspase-3 occurred already directly after dissection and was at least partly calpain-dependent. Our data suggest that, in addition to cells undergoing primary necrosis, some cells undergo apoptotic or related changes soon after Tissue harvesting, and eventually undergo a secondary necrosis. In summary, embryonic Mesencephalic cells exhibit multiple degenerative changes very early on in the neural transplant/Tissue culture preparation protocol.

  • Sequential bilateral transplantation in Parkinson's
    1999
    Co-Authors: Peter Hagell, Hakan Widner, Stig Rehncrona, J C Rothwell, P. Brundin, Richard G. Brown, A Schrag, Paola Piccini, Marjan Jahanshahi, Per Odin
    Abstract:

    Summary Five parkinsonian patients who had received implants of human embryonic Mesencephalic Tissue unilaterally in the striatum 10‐56 months earlier were grafted with Tissue from four to eight donors into the putamen (four patients) or the putamen plus the caudate nucleus (one patient) on the other side, and were followed for 18‐24 months. After 12‐18 months, PET showed a mean 85% increase in 6-L-[ 18 F]fluorodopa uptake in the putamen with the second graft, whereas there was no significant further change in the previously transplanted putamen. Two patients exhibited marked additional improvements after their second graft: ‘on‐off’ fluctuations virtually

  • The lazaroid U-83836E improves the survival of rat embryonic Mesencephalic Tissue stored at 4°C and subsequently used for cultures or intracerebral transplantation
    Brain research bulletin, 1996
    Co-Authors: Eva Maria Grasbon-frodl, Naoyuki Nakao, P. Brundin
    Abstract:

    Abstract We assessed the effects of addition of the lazaroid U-83836E to a preservation medium on the survival of rat dopamine neurons stored before culturing or intracerebral transplantation. Embryonic ventral Mesencephalic Tissue was preserved at 4°C for 8 days with or without the addition of 0.3 μM of U-83836E to a chemically defined “hibernation” medium. Freshly dissected Mesencephalic Tissue was used in control groups. For culture experiments, the Mesencephalic Tissue was dissociated and grown in serum-containing medium. Following 24–48 h in vitro, the number of dopamine neurons in cultures derived from Tissue hibernated without the lazaroid was 40% of fresh control, compared with 67% of control in cultures prepared from Tissue stored in the presence of U-83836E. When Mesencephalic Tissue was transplanted to the dopamine-depleted striatum of hemiparkinsonian rats following 8 days storage at 4°C in a medium without U-83836E, the mean number of surviving dopamine neurons in the grafts was significantly reduced to 40% of control. In contrast, grafts of Tissue which had been hibernated in U-83836E-containing medium contained as many dopamine neurons as transplants of freshly dissected Tissue. High yields of surviving grafted dopamine neurons were correlated to a significantly faster onset of functional recovery of amphetamine-induced motor asymmetry. We conclude that the storage period for rat Mesencephalic Tissue can be prolonged up to 8 days when using lazaroid-supplemented hibernation medium. As lazaroids have undergone clinical safety testing, the application of lazaroids for Tissue storage in clinical transplantation trials can be envisaged.

  • immune reactions following systemic immunization prior or subsequent to intrastriatal transplantation of allogeneic Mesencephalic Tissue in adult rats
    Neuroscience, 1995
    Co-Authors: Weiming Duan, Hakan Widner, Eva M Frodl, P. Brundin
    Abstract:

    We have previously found that dissociated Mesencephalic Tissue, which differs from the host at both major histocompatibility complex and non-major histocompatibility complex gene loci, can survive stereotaxic transplantation to the striatum of adult rats. We have now studied the outcome of intrastriatal neural allografts in rats that were systemically immunized by an orthotopic skin allograft either prior or subsequent to intracerebral implantation surgery. Dissociated Mesencephalic Tissue from Lewis rat embryos was stereotaxically injected into the dopamine-depleted striatum of hemi-parkinsonian Sprague-Dawley rats. One group was immunized by an orthotopic allogeneic skin graft of the same genetic origin as the neural graft, six weeks before the neural transplantation (the pre-immunized group). Another group was post-immunized by an orthotopic skin allograft, six weeks after the neural transplantation (the post-immunized group). A control group of rats was not challenged by a skin allograft. Marked behavioural recovery was observed in six of seven rats in the control group, in six of eight rats in the post-immunized group, and in none of the pre-immunized rats. Tyrosine hydroxylase-immunopositive cells were found in rats from the two behaviourally compensated groups, but not in the pre-immunized group. The immune responses were evaluated by OX-18 (monoclonal antibody against major histocompatibility complex class I antigen), OX-6 (major histocompatibility complex class II antigen), OX-42 (microglia and macrophages), glial fibrillary acidic protein (astrocytes), OX-8 (cytotoxic T-lymphocytes) and W3/25 (helper T-lymphocytes) immunocytochemistry. All the neural allografts in the pre-immunized group were rejected, leaving scars only. There were more intense immune responses to the allografts in the post-immunized group than the control group, in terms of immunocytochemically higher expression of major histocompatibility complex class I and II antigens and more intense cellular reactions consisting of macrophages, activated microglia and astrocytes, in addition to CD8- and CD4-positive lymphocytes. In summary, the results show the following: (i) systemic pre-immunization leads to complete rejection of intrastriatal neural allografts, implying that the status of the host immune system before transplantation determines the outcome for intrastriatal neural allografts; (ii) established intrastriatal neural allografts can survive for at least six weeks after systemic immunization, in spite of increased host immune responses in and around the allografts; (iii) there are no marked immune reactions against intrastriatal neural allografts 13 weeks after implantation in rats which have not been systemically immunized by a skin allograft; (iv) pre-immunized rats may provide a very useful animal model to investigate the role of inflammatory lymphokines in immune rejection and to test alternative immunosuppressive drugs.

Paola Piccini - One of the best experts on this subject based on the ideXlab platform.

  • serotonergic neurons mediate dyskinesia side effects in parkinson s patients with neural transplants
    Science Translational Medicine, 2010
    Co-Authors: Marios Politis, Olle Lindvall, Stig Rehncrona, Anders Björklund, David J. Brooks, Clare Loane, Niall Quinn, Paola Piccini
    Abstract:

    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.

  • Serotonergic Neurons Mediate Dyskinesia Side Effects in Parkinson’s Patients with Neural Transplants
    Science translational medicine, 2010
    Co-Authors: Marios Politis, Olle Lindvall, Stig Rehncrona, Anders Björklund, David J. Brooks, Clare Loane, Niall Quinn, Paola Piccini
    Abstract:

    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.

  • Brain imaging after neural transplantation.
    Progress in brain research, 2010
    Co-Authors: Marios Politis, Paola Piccini
    Abstract:

    Abstract Functional imaging has provided objective evidence that human fetal ventral Mesencephalic Tissue implanted in the striatum of Parkinson’s disease patients can survive, grow, release dopamine, normalize brain metabolism, and restore striatal–cortical connections. Open-label clinical trials have shown robust clinical improvement in several PD patients but these results were not replicated in two double-blind sham-surgery controlled clinical trials. Graft-induced dyskinesias are serious adverse effects and a major roadblock for the further development of cell therapies, and functional imaging can help investigate the mechanisms underlying their cause. Functional imaging can also aid future trials by improving patient selection, assessing restoration of brain connectivity, and monitor inflammatory processes. Although functional imaging cannot currently be used as a primary endpoint in clinical transplantation trials, it can provide additional valuable information alongside clinical observations.

  • Sequential bilateral transplantation in Parkinson's
    1999
    Co-Authors: Peter Hagell, Hakan Widner, Stig Rehncrona, J C Rothwell, P. Brundin, Richard G. Brown, A Schrag, Paola Piccini, Marjan Jahanshahi, Per Odin
    Abstract:

    Summary Five parkinsonian patients who had received implants of human embryonic Mesencephalic Tissue unilaterally in the striatum 10‐56 months earlier were grafted with Tissue from four to eight donors into the putamen (four patients) or the putamen plus the caudate nucleus (one patient) on the other side, and were followed for 18‐24 months. After 12‐18 months, PET showed a mean 85% increase in 6-L-[ 18 F]fluorodopa uptake in the putamen with the second graft, whereas there was no significant further change in the previously transplanted putamen. Two patients exhibited marked additional improvements after their second graft: ‘on‐off’ fluctuations virtually

Marios Politis - One of the best experts on this subject based on the ideXlab platform.

  • Dyskinesias in Parkinson's disease: views from positron emission tomography studies.
    European journal of neurology, 2014
    Co-Authors: Flavia Niccolini, Clare Loane, Marios Politis
    Abstract:

    Levodopa-induced dyskinesias (LIDs) and graft-induced dyskinesias (GIDs) are serious and common complications of Parkinson's disease (PD) management following chronic treatment with levodopa or intrastriatal transplantation with dopamine-rich foetal ventral Mesencephalic Tissue, respectively. Positron emission tomography (PET) molecular imaging provides a powerful in vivo tool that has been employed over the past 20 years for the elucidation of mechanisms underlying the development of LIDs and GIDs in PD patients. PET used together with radioligands tagging molecular targets has allowed the functional investigation of several systems in the brain including the dopaminergic, serotonergic, glutamatergic, opioid, endocannabinoid, noradrenergic and cholinergic systems. In this article the role of PET imaging in unveiling pathophysiological mechanisms underlying the development of LIDs and GIDs in PD patients is reviewed.

  • serotonergic neurons mediate dyskinesia side effects in parkinson s patients with neural transplants
    Science Translational Medicine, 2010
    Co-Authors: Marios Politis, Olle Lindvall, Stig Rehncrona, Anders Björklund, David J. Brooks, Clare Loane, Niall Quinn, Paola Piccini
    Abstract:

    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.

  • Serotonergic Neurons Mediate Dyskinesia Side Effects in Parkinson’s Patients with Neural Transplants
    Science translational medicine, 2010
    Co-Authors: Marios Politis, Olle Lindvall, Stig Rehncrona, Anders Björklund, David J. Brooks, Clare Loane, Niall Quinn, Paola Piccini
    Abstract:

    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.

  • Brain imaging after neural transplantation.
    Progress in brain research, 2010
    Co-Authors: Marios Politis, Paola Piccini
    Abstract:

    Abstract Functional imaging has provided objective evidence that human fetal ventral Mesencephalic Tissue implanted in the striatum of Parkinson’s disease patients can survive, grow, release dopamine, normalize brain metabolism, and restore striatal–cortical connections. Open-label clinical trials have shown robust clinical improvement in several PD patients but these results were not replicated in two double-blind sham-surgery controlled clinical trials. Graft-induced dyskinesias are serious adverse effects and a major roadblock for the further development of cell therapies, and functional imaging can help investigate the mechanisms underlying their cause. Functional imaging can also aid future trials by improving patient selection, assessing restoration of brain connectivity, and monitor inflammatory processes. Although functional imaging cannot currently be used as a primary endpoint in clinical transplantation trials, it can provide additional valuable information alongside clinical observations.