Publications
280 results found
Reilmann R, Anderson KE, Feigin A, et al., 2024, Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study., Lancet Neurol, Vol: 23, Pages: 243-255
BACKGROUND: Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease. METHODS: LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21-55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were ass
Gonzalez-Robles C, Bartlett M, Burnell M, et al., 2024, Embedding patient input in outcome measures for long-term disease-modifying Parkinson disease trials, Movement Disorders, Vol: 39, Pages: 433-438, ISSN: 0885-3185
BACKGROUND: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. OBJECTIVES: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. METHODS: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. RESULTS: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. CONCLUSIONS: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Foltynie T, Gandhi S, Gonzalez-Robles C, et al., 2023, Towards a multi-arm multi-stage platform trial of disease modifying approaches in Parkinson's disease, BRAIN, Vol: 146, Pages: 2717-2722, ISSN: 0006-8950
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- Citations: 3
Roussakis A, Gennaro M, Gordon MF, et al., 2023, A PET-CT study on neuroinflammation in Huntington’s patients participating in a randomised trial with laquinimod, Brain Communications, Vol: 5, Pages: 1-10, ISSN: 2632-1297
Microglia activation, an indicator of central nervous system inflammation, is believed to contribute to the pathology of Huntington’s disease. Laquinimod is capable of regulating microglia. By targeting the translocator protein, 11C-PBR28 PET-CT imaging can be used to assess the state of regional gliosis in vivo and explore the effects of laquinimod treatment. This study relates to the LEGATO-HD, multi-centre, double-blinded, Phase 2 clinical trial with laquinimod (US National Registration: NCT02215616). Fifteen patients of the UK LEGATO-HD cohort (mean age: 45.2 ± 7.4 years; disease duration: 5.6 ± 3.0 years) were treated with laquinimod (0.5 mg, N = 4; 1.0 mg, N = 6) or placebo (N = 5) daily. All participants had one 11C-PBR28 PET-CT and one brain MRI scan before laquinimod (or placebo) and at the end of treatment (12 months apart). PET imaging data were quantified to produce 11C-PBR28 distribution volume ratios. These ratios were calculated for the caudate and putamen using the reference Logan plot with the corpus callosum as the reference region. Partial volume effect corrections (Müller–Gartner algorithm) were applied. Differences were sought in Unified Huntington’s Disease Rating Scale scores and regional distribution volume ratios between baseline and follow-up and between the two treatment groups (laquinimod versus placebo). No significant change in 11C-PBR28 distribution volume ratios was found post treatment in the caudate and putamen for both those treated with laquinimod (N = 10) and those treated with placebo (N = 5). Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the 11C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period.
Gonzalez-Robles C, Weil RS, van Wamelen D, et al., 2023, Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative, JOURNAL OF PARKINSONS DISEASE, Vol: 13, Pages: 1013-1035, ISSN: 1877-7171
Mohamed MA, Zeng Z, Gennaro M, et al., 2022, Astrogliosis in aging and Parkinson’s disease dementia: a new clinical study with 11C-BU99008 PET, Brain Communications, Vol: 4, ISSN: 2632-1297
The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites (I2BS) represent a possible target to map the distribution of reactive astrocytes. In this study, we use 11C-BU99008, an I2BS-specific PET radioligand, to image reactive astrocytes in vivo in healthy controls (HCs) andpatients with established Parkinson’s disease dementia (PDD).Eighteen HCs (age: 45−78 years) and six patients with PDD (age: 64−77 years) had one 11C-BU99008 PET-CT scan with arterial input function. All subjects underwent one 3T MRI brain scan to facilitate the analysis of the PET-CT data and to capture individual cerebral atrophy. Regional 11C-BU99008 volumes of distribution (VT) were calculated for each subject by two-tissue compartmental modelling.Positive correlations between 11C-BU99008 VT values and age were found for all tested regions across the brain within HCs (p<0.05); furthermore, multiple regression indicated that aging affects 11C-BU99008 VT values in a region-specific manner. Independent samples t-test indicated that there was no significant group difference in 11C-BU99008 VT values betweenPDD (n=6; mean age = 71.97±4.66 years) and older HCs (n=9; mean age = 71.90±5.51 years).Our dataset shows that astrogliosis is common with aging in a region-specific manner. However, in this set-up, 11C-BU99008 PET cannot differentiate patients with PDD from healthy controls of similar age.
Xing Y, Sapuan AH, Martin-Bastida A, et al., 2022, Neuromelanin-MRI to Quantify and Track Nigral Depigmentation in Parkinson's Disease: A Multicenter Longitudinal Study Using Template-Based Standardized Analysis, MOVEMENT DISORDERS, Vol: 37, Pages: 1028-1039, ISSN: 0885-3185
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- Citations: 9
Lee J-Y, Martin-Bastida A, Murueta-Goyena A, et al., 2022, Multimodal brain and retinal imaging of dopaminergic degeneration in Parkinson disease, NATURE REVIEWS NEUROLOGY, Vol: 18, Pages: 203-220, ISSN: 1759-4758
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- Citations: 28
Parkin B, Daws R, Das Neves I, et al., 2021, Dissociable effects of age and Parkinson's disease on instruction based learning, Brain Communications, Vol: 3, ISSN: 2632-1297
The cognitive deficits associated with Parkinson’s disease vary across individuals and change across time, with implications for prognosis and treatment. Key outstanding challenges are to define the distinct behavioural characteristics of this disorder and develop diagnostic paradigms that can assess these sensitively in individuals. In a previous study, we measured different aspects of attentional control in Parkinson’s disease using an established fMRI switching paradigm. We observed no deficits for the aspects of attention the task was designed to examine; instead those with Parkinson’s disease learnt the operational requirements of the task more slowly. We hypothesized that a subset of people with early-to-mid stage Parkinson’s might be impaired when encoding rules for performing new tasks. Here, we directly test this hypothesis and investigate whether deficits in instruction-based learning represent a characteristic of Parkinson’s Disease. Seventeen participants with Parkinson’s disease (8 male; mean age: 61.2 years), 18 older adults (8 male; mean age: 61.3 years) and 20 younger adults (10 males; mean age: 26.7 years) undertook a simple instruction-based learning paradigm in the MRI scanner. They sorted sequences of coloured shapes according to binary discrimination rules that were updated at two-minute intervals. Unlike common reinforcement learning tasks, the rules were unambiguous, being explicitly presented; consequently, there was no requirement to monitor feedback or estimate contingencies. Despite its simplicity, a third of the Parkinson’s group, but only one older adult, showed marked increases in errors, 4 SD greater than the worst performing young adult. The pattern of errors was consistent, reflecting a tendency to misbind discrimination rules. The misbinding behaviour was coupled with reduced frontal, parietal and anterior caudate activity when rules were being encoded, but not when attention was initially o
Hannaway N, Lao-Kaim NP, Martin-Bastida A, et al., 2021, Longitudinal changes in movement-related functional MRI activity in Parkinson's disease patients, PARKINSONISM & RELATED DISORDERS, Vol: 87, Pages: 61-69, ISSN: 1353-8020
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- Citations: 1
Tarkin JM, Corovic A, Wall C, et al., 2020, Positron emission tomography imaging in cardiovascular disease, HEART, Vol: 106, Pages: 1712-1718, ISSN: 1355-6037
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- Citations: 14
Zeng Z, Roussakis A-A, Lao-Kaim NP, et al., 2020, Astrocytes in Parkinson's disease: from preclinical assays to in vivo imaging and therapeutic probes, NEUROBIOLOGY OF AGING, Vol: 95, Pages: 264-270, ISSN: 0197-4580
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- Citations: 4
Porter E, Roussakis A-A, Lao-Kaim NP, et al., 2020, Multimodal dopamine transporter (DAT) imaging and magnetic resonance imaging (MRI) to characterise early Parkinson's disease, PARKINSONISM & RELATED DISORDERS, Vol: 79, Pages: 26-33, ISSN: 1353-8020
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- Citations: 9
Roussakis A-A, Zeng Z, Lao-Kaim NP, et al., 2020, Parkinson's disease laterality: a(11)C-PE2I PET imaging study, Journal of Neurology, Vol: 268, Pages: 582-589, ISSN: 0340-5354
Asymmetry of striatal dopaminergic deficits and motor symptoms is a typical characteristic of idiopathic Parkinson’s disease (PD). This study aims to characterise the trend of asymmetry in moderate-stage PD. We performed a 19-month longitudinal study in 27 patients with PET-CT imaging and appropriate clinical assessments. 11C-PE2I non-displaceable binding potential (BPND) was calculated bilaterally for the striatum at baseline and follow-up to estimate the in vivo density of striatal dopamine transporters (DAT). Changes in striatal 11C-PE2I BPND over time were more prominent in the ipsilateral as compared to contralateral side. Changes in MDS-UPDRS-III (motor component of the Movement Disorders Society Unified PD Rating Scale) were not different between the clinically most and least affected body sides. Our data support that the asymmetry in striatal dopaminergic degeneration becomes less prominent in moderate-stage PD. In contrast, during the above period, the asymmetry of motor symptoms was maintained between the clinically most and least affected body sides.
Roussakis AA, Gennaro M, Gordon MF, et al., 2020, A longitudinal PET study to assess the state of microglia activation in a Phase 2 study of Laquinimod as a treatment for Huntington's disease (LEGATO-HD), Movement-Disorder-Society (MDS) International Virtual Congress, Publisher: WILEY, Pages: S102-S102, ISSN: 0885-3185
Peters S, Gallo V, Vineis P, et al., 2020, Alcohol consumption and risk of Parkinson's disease: data from a large prospective European cohort, Movement Disorders, Vol: 35, Pages: 1258-1263, ISSN: 0885-3185
BackgroundParkinson's disease (PD) etiology is not well understood. Reported inverse associations with smoking and coffee consumption prompted the investigation of alcohol consumption as a risk factor, for which evidence is inconclusive.ObjectiveTo assess the associations between alcohol consumption and PD risk.MethodsWithin NeuroEPIC4PD, a prospective European population‐based cohort, 694 incident PD cases were ascertained from 209,998 PD‐free participants. Average alcohol consumption at different time points was self‐reported at recruitment. Cox regression hazard ratios were estimated for alcohol consumption and PD occurrence.ResultsNo associations between baseline or lifetime total alcohol consumption and PD risk were observed. Men with moderate lifetime consumption (5–29.9 g/day) were at ~50% higher risk compared with light consumption (0.1–4.9 g/day), but no linear exposure–response trend was observed. Analyses by beverage type also revealed no associations with PD.ConclusionOur data reinforce previous findings from prospective studies showing no association between alcohol consumption and PD risk. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Davies R, Babu-Narayan S, 2020, Deep learning in congenital heart disease imaging: hope but not haste, HEART, Vol: 106, Pages: 960-961, ISSN: 1355-6037
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- Citations: 3
Altmann DM, Douek DC, Boyton RJ, 2020, What policy makers need to know about COVID-19 protective immunity, The Lancet, Vol: 395, Pages: 1527-1529, ISSN: 0140-6736
Jenkins P, Roussakis A-A, De Simoni S, et al., 2020, Distinct dopaminergic abnormalities in traumatic brain injury and Parkinson’s disease, Journal of Neurology, Neurosurgery and Psychiatry, Vol: 91, Pages: 631-637, ISSN: 0022-3050
Objective: Traumatic brain injury (TBI) and REM behavioural disorder (RBD) are risk factors for Parkinson’s disease (PD). Dopaminergic abnormalities are often seen after TBI, but patients usually lack parkinsonian features. We test whether TBI, PD and RBD have distinct striatal dopamine abnormalities using dopamine transporter imaging. Methods: 123I-ioflupane SPECT scans were used in a cross-sectional study to measure dopamine transporter (DaT) levels in moderate/severe TBI, healthy controls, early PD and RBD patients. Caudate and putamen DaT, putamen-to-caudate ratios and left-right symmetry of DaT were compared.Results: 108 participants (43 TBI, 26 PD, 8 RBD, 31 controls) were assessed. Early PD patients scored significantly higher on the UPDRS motor subscale than other groups. TBI and PD patients had reduced DaT levels in the caudate (12.2% and 18.7% respectively) and putamen (9.0% and 42.6% respectively) compared to controls. RBD patients had reduced DaT levels in the putamen (12.8%) but not in the caudate compared to controls. PD and TBI patients showed distinct patterns of DaT reduction, with PD patients showing a lower putamen-to-caudate ratio. DaT asymmetry was greater in the PD group than other groups. Conclusions: The results show that early PD and TBI patients have distinct patterns of striatal dopamine abnormalities. Early PD and moderate/severe TBI patients showed similar reductions in caudate DaT binding, but PD patients showed a greater reduction in putamen DaT and a lower putamen-to-caudate ratio. The results suggest that parkinsonian motor signs are absent in these TBI patients because of relatively intact putaminal dopamine levels.
Roussakis A-A, Patel NH, Gennaro M, et al., 2020, The role of semi-quantification of 123I-FP-CIT SPECT scans in improving the quality of reporting, 6th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 973-973, ISSN: 1351-5101
Adilbekova B, Lin Y, Yengel E, et al., 2020, Liquid phase exfoliation of MoS<sub>2</sub> and WS<sub>2</sub> in aqueous ammonia and their application in highly efficient organic solar cells, JOURNAL OF MATERIALS CHEMISTRY C, Vol: 8, Pages: 5259-5264, ISSN: 2050-7526
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- Citations: 83
Li W, Lao-Kaim NP, Roussakis A-A, et al., 2020, Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson's disease, NeuroImage: Clinical, Vol: 28, Pages: 1-10, ISSN: 2213-1582
BackgroundResting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson’s disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time.ObjectivesTo examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally.MethodsWe assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using 11C-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 ± 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. 11C-PE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity.ResultsAt baseline, PD patients with greater dopaminergic deficits, as measured with 11C-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen.ConclusionsOur findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression.
van Eimeren T, Antonini A, Berg D, et al., 2019, Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: Proposal for a Neuroimaging Biomarker Utility System, ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING, Vol: 11, Pages: 301-309
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- Citations: 25
Roussakis A, Towey D, Gennaro M, et al., 2019, Parkinson’s disease dyskinesias possibly relate to greater dopamine transporter losses in the putamen over time, Journal of Neurology & Experimental Neuroscience, Vol: 5, Pages: S6-S11, ISSN: 2469-407X
The pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease is incompletely understood. This study was designed to investigate in Parkinson’s patients, whether time-related changes in striatal dopamine transporter availability are associated to the appearance of dyskinesias. 15 Parkinson’s patients had dopamine transporter-specific SPECT imaging with 123I-FP-CIT twice: at baseline (when they were drug naïve) and at follow-up (6.31±2.29 years from baseline), and were followed up clinically every six months. At the end of the study, patients were divided in two groups according to whether they had developed dyskinesias or not. Semi-quantification of 123I-FP-CIT data was performed using the occipital cortex as the reference region. Specific binding ratios were calculated for the putamen and the caudate. During the clinical follow-up, all Parkinson’s patients were treated pharmaceutically. 8 patients developed dyskinesias, while 7 remained nondyskinetic. At baseline, the two groups had similar 123I-FP-CIT specific binding ratio values for the putamen and the caudate (p>0.05). Also, between-group differences in age, disease duration, and Hoehn & Yahr scores were not statistically significant. Over-time, the putaminal 123I-FP-CIT specific binding ratio values in the dyskinetic group decreased significantly (p<0.01). The nondyskinetic patients had smaller reductions (p<0.05) during the same period of time. At follow-up, the dyskinetic patients had significantly higher Hoehn & Yahr scores (p<0.01) and were taking higher levodopa equivalent doses (p<0.001), as compared to the nondyskinetic patients. The development of Parkinson’s dyskinesias is related to a faster progression rate, as reflected by marked putaminal dopamine transporter decreases.
Piccini P, Pagano G, Politis M, 2019, Comparison of phosphodiesterase 10A and dopamine transporter levels as markers of disease burden in early Parkinson's disease, Movement Disorders, Vol: 34, Pages: 1505-1515, ISSN: 0885-3185
BackgroundRecent work has shown loss of phosphodiesterase 10A levels in middle‐stage and advanced treated patients with PD, which was associated with motor symptom severity.ObjectivesTo assess phosphodiesterase 10A levels in early PD and compare with loss of dopamine transporter as markers of disease burden.MethodsSeventy‐eight subjects were included in this study (17 early de novo, 15 early l‐dopa–treated, 24 moderate‐advanced l‐dopa–treated patients with PD, and 22 healthy controls). All participants underwent [11C]IMA107 PET, [11C]PE2I PET, and 3‐Tesla MRI scan.ResultsEarly de novo PD patients showed loss of [11C]IMA107 and of [11C]PE2I binding in caudate and putamen (P < 0.001); early l‐dopa–treated PD patients showed additional loss of [11C]IMA107 in the caudate (P < 0.001; annual decline 3.6%) and putamen (P < 0.001; annual decline 2.8%), but loss of [11C]PE2I only in the putamen (P < 0.001; annual decline 6.8%). Lower [11C]IMA107 correlated with lower [11C]PE2I in the caudate (rho = 0.51; P < 0.01) and putamen (rho = 0.53; P < 0.01). Longer disease duration correlated with lower [11C]IMA107 in the caudate (rho = –0.72; P < 0.001) and putamen (rho = –0.48; P < 0.01), and with lower [11C]PE2I only in the putamen (rho = –0.65; P < 0.001). Higher burden of motor symptoms correlated with lower [11C]IMA107 in the caudate (rho = –0.42; P < 0.05) and putamen (rho = –0.41; P < 0.05), and with lower [11C]PE2I only in the putamen (rho = –0.69; P < 0.001).ConclusionOur findings demonstrate loss of phosphodiesterase 10A levels very early in the course of PD and is associated with the gradual and progressive increase of motor symptoms. Phosphodiesterase 10A imaging shows similar potential with dopamine transporter imaging to follow disease progression.
Roussakis A, Lao-Kaim N, Piccini P, 2019, Brain imaging and impulse control disorders in Parkinson’s disease, Current Neurology and Neuroscience Reports, Vol: 19, ISSN: 1528-4042
Purpose of reviewParkinson’s disease (PD) has a wide spectrum of symptoms including the presence of psychiatric disease. At present, most treatment plans, comprised of dopaminergic drugs, are chronic and complex. Though dopaminergic agents are quite efficient in managing the motor aspects of the disease, chronic pharmacotherapy specifically with dopamine receptor agonists has been highly linked to the occurrence of Impulse Compulsive disorder (ICD), which can be problematic for individual patients.Recent findingsMuch of what is known today about PD-related ICD stems from brain imaging studies, however, evidence is not quite conclusive. Research in the field has been focused on identifying the underlying mechanisms of PD-related ICD and understanding the functions of the structures involved in the reward network. SummaryThis article presents an update of recent findings from key neuroimaging studies in PD-related ICD, discusses results from controversial studies, and identifies areas for future research in the field.
Schubert JJ, Veronese M, Bodini B, et al., 2019, Dynamic PET with 11C-and 18F-tracers for measuring cerebrospinal fluid alterations in multiple sclerosis, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 706-707, ISSN: 1352-4585
Parker RA, TRANSEURO consortium, Piccini P, 2019, Designing stem-cell-based dopamine cell replacement trials for Parkinson's disease, Nature Medicine, Vol: 25, Pages: 1045-1053, ISSN: 1078-8956
Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.
Martin Bastida A, Lao-Kaim N, Roussakis A, et al., 2019, Relationship between neuromelanin and dopamine terminals within the parkinson’s nigrostriatal system, Brain, Vol: 142, Pages: 2023-2036, ISSN: 1460-2156
Parkinson’s disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterising its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we utilised neuromelanin-sensitive magnetic resonance imaging and the highly specific dopamine transporter positron emission tomography radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson’s disease. Fifteen healthy controls also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal/ventral tiers and striatal nuclei into pre/post-commissural sub-regions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson’s disease subjects displayed reduced neuromelanin levels in the ventral (-30±28%) and dorsal tiers (-21±24%) as compared to the control group (F1,43 = 11.95, P = 0.001). Within the Parkinson’s disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier (F1,29 = 36.19, P < 0.001) and lower in the clinically-defined most affected side (F1,29 = 4.85, P = 0.036). Similarly, lower dopamine transporter density was observed in the ventral tier (F1,29 = 76.39, P < 0.001) and clinically-defined most affected side (F1,29 = 4.21, P = 0.049). Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-d
Pagano G, Wilson H, Yousaf T, et al., 2019, Comparison of PDE10A and DAT expression as markers of disease burden in early Parkinson's disease, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 532-532, ISSN: 1351-5101
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