The role of serotonergic and dopaminergic mechanisms and their interaction in Levodopa-induced dyskinesias

Long–term levodopa treatment in Parkinson’s disease (PD) is commonly associated with troublesome levodopa–induced dyskinesias (LIDs). Striatal serotonergic terminals amid the degenerating dopaminergic ones are proposed to play an important role in LIDs by taking up exogenous levodopa and releasing dopamine in an unregulated fashion. However, to date, the underlying mechanisms of LIDs are not fully understood. By using single photon emission computed tomography (SPECT) with 123I–Ioflupane and positron emission tomography (PET) with 11C–DASB and 11C–PE2I, the clinical studies conducted for this thesis aimed (a) to estimate the role of striatal dopamine transporter (DAT) availability in early PD as a prognostic marker for LIDs, (b) to explore whether striatal DAT availability changes over time are related to the appearance of LIDs, (c) to estimate the role of striatal serotonin-to-dopamine transporter (SERT–to–DAT) binding ratios to LIDs, and (d) to look for a relation between the changes in striatal SERT, DAT and SERT–to–DAT binding ratios over time and the appearance of LIDs. The main findings are as follows: (a) in early PD, striatal DAT availability alone does not predict the appearance of future LIDs, (b) at later stages, the occurrence of LIDs may be dependent on the magnitude of DAT decline in the putamen, (c) the SERT–to–DAT binding ratio in the putamen is increased in PD patients as compared to controls, and within PD, it is higher in patients with LIDs as compared to nondyskinetic patients, (d) as PD continues to progress, putaminal serotonergic terminals remain relatively unchanged in comparison to the dopaminergic ones and the aforementioned imbalance (as reflected by the binding ratio) increases over time. These findings provide fundamental insight in the pathophysiology of LIDs and have direct implications for further research towards novel therapeutics in PD dyskinesia.Open Acces

Parkinson's disease laterality: a 11C-PE2I PET imaging study

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

Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system.

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 characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET 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 control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, 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 [F(1,43) = 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 [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 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-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) [FP7-242003], from the Medical Research Council (MRC) [MR/P025870/1] and from Parkinson’s UK [J-1204]. Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC) and NIHR Imperial CRF at Imperial College healthcare NHS trust. The views expressed are those of the authors and not necessarily those of the funder, the NHS, the NIHR, or the Department of Health. This work was also supported financially by a PhD studentship awarded to N.P.L-K from Parkinson’s UK

Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson's disease.

BACKGROUND: Resting-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. OBJECTIVES: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. METHODS: We 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. RESULTS: At 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. CONCLUSIONS: Our 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

Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson’s disease

Background: Resting-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. Objectives: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. Methods: We 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. 11CPE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity. Results: At 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. Conclusions: Our 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

A PET-CT study on neuroinflammation in Huntington’s disease patients participating in a randomized trial with laquinimod

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

The holistic perspective of the INCISIVE project : artificial intelligence in screening mammography

Finding new ways to cost-effectively facilitate population screening and improve cancer diagnoses at an early stage supported by data-driven AI models provides unprecedented opportunities to reduce cancer related mortality. This work presents the INCISIVE project initiative towards enhancing AI solutions for health imaging by unifying, harmonizing, and securely sharing scattered cancer-related data to ensure large datasets which are critically needed to develop and evaluate trustworthy AI models. The adopted solutions of the INCISIVE project have been outlined in terms of data collection, harmonization, data sharing, and federated data storage in compliance with legal, ethical, and FAIR principles. Experiences and examples feature breast cancer data integration and mammography collection, indicating the current progress, challenges, and future directions

Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson's disease.

BACKGROUND: Resting-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. OBJECTIVES: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. METHODS: We 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. RESULTS: At 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. CONCLUSIONS: Our 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

Longitudinal changes in movement-related functional MRI activity in Parkinson's disease patients

INTRODUCTION: Functional brain imaging has shown alterations in the basal ganglia, cortex and cerebellum in Parkinson's disease patients. However, few functional imaging studies have tested how these changes evolve over time. Our study aimed to test the longitudinal progression of movement-related functional activity in Parkinson's disease patients. METHODS: At baseline, 48 Parkinson's disease patients and 16 healthy controls underwent structural and functional magnetic resonance imaging during a joystick motor task. Patients had repeated imaging after 18-months (n = 42) and 36-months (n = 32). T-tests compared functional responses between Parkinson's disease patients and controls, and linear mixed effects models examined longitudinal differences within Parkinson's disease. Correlations of motor-activity with bradykinesia, rigidity and tremor were undertaken. All contrasts used whole-brain analyses, thresholded at Z > 3.1 with a cluster-wise P < 0.05. RESULTS: Baseline activation was significantly greater in patients than controls across contralateral parietal and occipital regions, ipsilateral precentral gyrus and thalamus. Longitudinally, patients showed significant increases in cerebellar activity at successive visits following baseline. Task-related activity also increased in the contralateral motor, parietal and temporal areas at 36 months compared to baseline, however this was reduced when controlling for motor task performance. CONCLUSION: We have shown that there are changes over time in the blood-activation level dependent response of patients with Parkinson's disease undertaking a simple motor task. These changes are observed primarily in the ipsilateral cerebellum and may be compensatory in nature