246 research outputs found

    Physiological and Biomechanical Analyses of Rigidity in Parkinson\u27s Disease

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    Diagnostic and prognostic aspects of clinical brain dopamine transporter imaging in parkinsonism

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    Idiopathic Parkinson’s disease (PD) is the most frequent cause of clinical parkinsonism. However, the diagnostic accuracy of PD is suboptimal. One biomarker that assists with the parkinsonism differential diagnostics is functional dopamine transporter (DAT) imaging. The accuracy of DAT single photon emission computed tomography (SPECT) imaging is high for detecting striatal dopamine deficiency associated with neurodegenerative parkinsonism. However, its limitations and associations with clinical characteristics are not yet fully understood, particularly in patients with clinical parkinsonism of uncertain origin. In this thesis, the retrospective studies investigated the associations between striatal dopamine deficiency and structural midbrain atrophy measurements and long-term survival in PD patients. As both visual and semi-quantitative analysis methods are broadly used for DAT SPECT scans, the concordance between these methods was investigated. The cross-sectional clinical and imaging study investigated which of the parkinsonian motor signs are associated with a higher likelihood of striatal DAT deficiency, and whether these signs are associated with DAT loss in certain striatal regions in patients with neurodegenerative parkinsonism. The results showed that there were no associations between the midbrain-to-pons ratios, suggestive of midbrain atrophy, and striatal dopamine deficiency in DP. Expert visual DAT image analyses and the semi-quantitative analyses did not match in 10% of cases; however, none of these patients had neurodegenerative parkinsonism according to the clinical follow-ups. The level of DAT deficiency was not associated with survival in PD. Finally, both upper extremity rigidity and hypomimia were independently associated with a higher likelihood of striatal dopamine deficiency. Hypomimia was specifically associated with caudate nucleus dopamine loss in patients with abnormal striatal DAT binding. The results indicate that midbrain-to-pons ratios cannot be used to estimate the level of striatal DAT deficiency in patients with PD. The scans that showed a discrepancy between the different analysis methods should likely be interpreted as normal. Dopamine deficiency levels cannot be used to predict patient survival in PD. Presence of upper extremity rigidity and hypomimia in clinical neurological examinations may be useful markers in the differential diagnosis of clinically uncertain parkinsonism and tremor as they point to striatal DAT deficiency

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

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    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

    Investigation of intraoperative accelerometer data recording for safer and improved target selection for deep brain stimulation

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    Background: Deep Brain Stimulation (DBS) is a well established surgical treatment for Parkinson’s Disease (PD) and Essential Tremor (ET). Electrical leads are surgically implanted in the deeply seated structures in the brain and chronically stimulated. The location of the lead with respect to the anatomy is very important for optimal treatment. Therefore, clinicians carefully plan the surgery, record electrophysiological signals from the region of interest and perform stimulation tests to identify the best location to permanently place the leads. Nevertheless, there are certain aspects of the surgery that can still be improved. Firstly, therapeutic effects of stimulation are estimated by visually evaluating changes in tremor or passively moving patient's limb to evaluate changes in rigidity. These methods are subjective and depend heavily on the experience of the evaluator. Secondly, a significant amount of patient data is collected before and during the surgery like various CT and MR images, surgical planning information, electrophysiological recordings and results of stimulation tests. These are not fully utilized at the time of choosing the position for lead placement as they are either not available or acquired on separate systems or in the form of paper notes only. Thirdly, studies have shown that the current target structures to implant the leads (Subthalamic Nucleus (STN) for PD and Ventral Intermediate Nucleus (VIM) for ET) may not be the only ones responsible for the therapeutic effects. The objective of this doctoral work is to develop new methods that help clinicians subdue the above limitations which could in the long term improve the DBS therapy. Method: After a thorough review of the existing literature, specifically customized solutions were designed for the shortcomings described above. A new method to quantitatively evaluate tremor during DBS surgery using acceleration sensor was developed. The method was then adapted to measure acceleration of passive movements and to evaluate changes in rigidity through it. Data from 30 DBS surgeries was collected by applying these methods in two clinical studies: one in Centre Hospitalier Universitaire, Clermont-Ferrand, France and another multi-center study in UniversitĂ€spital Basel and Inselspital Bern in Switzerland. To study the role of different anatomical structures in the therapeutic and adverse effects of stimulation, the data collected during the study was analysed using two methods. The first classical approach was to classify the data based on the anatomical structure in which the stimulating contact of the electrode was located. The second advanced approach was to use patient-specific Finite Element Method (FEM) simulations of the Electric Field (EF) to estimate the spatial distribution of stimulation in the structures surrounding the electrode. Such simulations of the adverse effect inducing stimulation current amplitudes are used to visualize the boundaries of safe stimulation and identify structures that could be responsible for these effects. In addition, the patient-specific simulations are also used to develop a new method called "Improvement Maps" to generate 2D and 3D visualization of intraoperative stimulation test results with the patient images and surgical planning. This visualization summarized the stimulation test results by dividing the explored area into multiple regions based on the improvement in symptoms as measured by the accelerometric methods. Results: The accelerometric method successfully measured changes in tremor and rigidity. Standard deviation, signal energy and spectral amplitude of dominant frequency correlated with changes in the symptoms. Symptom suppressing stimulation current amplitudes identified through quantitative methods were lower than those identified through the subjective methods. Comparison of anatomical targets using the accelerometric data showed that to suppress rigidity in PD patients, stimulation current needed was marginally higher for Fields of Forel (FF) and Zona Incerta (ZI) compared to STN. On the other hand, the adverse effect occurrence rate was significantly lower in ZI and FF, indicating them to be better targets compared to STN. Similarly, for ET patients, other thalamic nuclei like the Intermediolateral (InL) and Ventro-Oral (VO) as well as the Pre-Lemniscal Radiations (PLR) are as efficient in suppressing tremor as the VIM but have lower occurrence of adverse effects. Volumetric analysis of spatial distribution of stimulation agreed with these results suggesting that the structures other than the VIM could also play a role in therapeutic effects of stimulation. The visualization of the adverse effect simulations clearly show the structures which could be responsible for such effects e.g. stimulation in the internal capsula induced pyramidal effects. These findings concur with the published literature. With regard to the improvement maps, the clinicians found them intuitive and easy to use to identify the optimal position for lead placement. If the maps were available during the surgery, the clinicians' choice of lead placement would have been different. Conclusion: This doctoral work has shown that modern techniques like quantitative symptom evaluation and electric field simulations can suppress the existing drawbacks of the DBS surgery. Furthermore, these methods along with 3D visualization of data can simplify tasks for clinicians of optimizing lead placement. Better placement of the DBS lead can potentially reduce adverse effects and increase battery life of implanted pulse generator, resulting in better therapy for patients

    Functional mobility in Parkinson’s disease

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    Introduction: Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting 1% of the world population over the age of 60. The presence of a large and heterogeneous spectrum of motor and non-motor symptoms, some resistant to levodopa therapy, is usually a major source of disability that affects patients’ daily activities and social participation. Functional mobility (FM) is an outcome that merges the concepts of function with mobility, autonomy, and the accomplishment of daily tasks in different environments. Its use in PD studies is common. However, several aspects associated with its application in PD remain to be defined, hampering a wider use of the concept in clinical practice and the comparison of clinical study results. Aim: This thesis aimed to provide evidence on the appropriateness of the concept of FM in the PD field. A two-fold approach was used to this end: 1) To investigate the clinical and research applicability of the concept of FM in PD; 2) To identify the most suitable clinical and technological outcome measures for evaluating the response of PD patients’ FM to a therapeutic intervention. Methods: A narrative review using the framework of the International Classification of Functioning, Disability, and Health (ICF) was performed to explore the concept of FM when applied to PD. This first study aimed to provide a better understanding of the interaction between PD symptoms, FM, and patients’ daily activities and social participation. To identify and recommend the most suitable outcome measures to assess FM in PD, a systematic review was conducted using the CENTRAL, MEDLINE, Embase, and PEDro databases, from their inception to January 2019. During this review, we also explored the different definitions of FM present in the literature, proposing the one we believed should be established as the definition of FM in the PD field. We then conducted a focus group to explore PD patients' and health professionals’ perspectives on the proposed definition. Part of the scope of the focus group was also to investigate the impact of FM problems on patients’ daily living and the strategies used to deal with this. The study included four focus groups, two with patients (early and advanced disease stages), and two with health professionals (neurologists and physiotherapists). A second systematic review using the CENTRAL, MEDLINE, Embase, and PEDro databases, from their inception to September 2019, was performed to summarize and critically appraise the published evidence on PD spatiotemporal gait parameters. Finally, a pragmatic clinical study was conducted to identify the clinical and technological outcome measures that better predict changes in FM, when patients are submitted to a specialized multidisciplinary program for PD. Results: All the definitions found in an open search of the literature on the FM concept included three key aspects: gait, balance, and transfers. All participants in the focus group study were able to present a spontaneous definition of FM that matched the one used by the authors. All also agreed that FM reflects the difficulties of PD patients in daily life activities. Early-stage PD patients mentioned needing more time to complete their usual tasks, while advanced-stage PD patients considered FM limitations as the main limiting factor of daily activities, especially in medication “OFF” periods. Physiotherapists maintained that the management of PD FM limitations should be a joint work of the multidisciplinary team. For neurologists, FM may better express patients’ perception of their overall health status and may help to adopt a more patient-centered approach. Of the 95 studies included in the systematic review aiming to appraise the outcome measures that have been used to assess FM in PD patients, only one defined the concept of FM. The most frequent terms used as synonyms of FM were mobility, mobility in association with functional activities/performance, motor function, gait-related activity, or balance. In the literature, the Timed Up and Go (TUG) test was the most frequently reported tool used as a single instrument to assess FM in PD. The changes from baseline in the TUG Cognitive test, step length, and free-living step time asymmetry were identified as the best predictors of TUG changes. Conclusion: The information generated by the different studies included in this thesis revealed FM as a useful concept to be adopted in the PD field. FM was shown to be a meaningful outcome (for patients and health professionals), easy to measure, and able to provide more global and ecological information on patients’ daily living performances. Our results support the use of FM for PD assessment and free-living monitoring, as a way to better understand and address patients’ needs. The changes in the TUG Cognitive test, the supervised step length, and the free-living step time asymmetry seem the most suitable outcomes to measure an effect in FM. Future research should focus on determining the severity cut-off for FM changes, the minimal clinical important difference (MCID) for each of these outcome measures and resolve the current obstacles to the widespread use of technological assessments in PD clinical practice and research

    Late onset depression: Association with clinical and imaging indicators of prodromal Parkinson’s disease

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    The pathology of late onset depression (LOD) is unclear, with vascular and structural abnormalities reported through the use of magnetic resonance imaging (MRI). Parkinson’s disease (PD) can be preceded by LOD several years before overt motor symptoms. Use of the Dopamine Transporter Single Photo Emission Computerised Tomography (DAT SPECT) has been approved by the Food and Drugs Administration (FDA) for imaging pre synaptic dopaminergic dysfunction; aiding diagnosis in disorders such as PD. We investigated; a) presence of early clinical features associated with PD in patients with LOD (pLOD), b) dopaminergic functioning in pLOD, c) structural and vascular pathology associated with LOD. This thesis also compared visual and semi quantitative analysis (SQA) methods when rating DAT SPECTs. When compared with healthy controls (HC) (n=30) overall, pLOD (n=36) scored significantly higher on symptoms of apathy, REM sleep behaviour disorder (RBD), sleep symptoms associated with PD and autonomic and motor dysfunction. Seven pLOD were visually rated with abnormal uptake in comparison to one HC, also confirmed by the SQA which additionally found that overall, pLOD (n=29 with a DAT SPECT) had significantly lower binding in the caudate nuclei (CN). The pLOD with visually abnormal SPECTs had significantly lower clinical scores relating to olfactory dysfunction, cognition and autonomic dysfunction compared to pLOD with normal SPECTs. There were no significant group differences in structural or vascular pathology. There were significant correlations between age and left and right hippocampi (HIPP) and amygdala (AMY) and global white matter (WM) and grey matter (GM) volumes in pLOD (n=28 with an MRI). Overall, in controls (n=25), age and gender correlated with global WM. Severity of depression was not associated with regional volumes. An audit of the correct use of clinical indications for the DAT SPECT at an NHS trust confirmed correct use in all cases (n=74) and a comparison of visual and SQA methods when rating DAT SPECTS in clinical cases also confirmed very good agreement between methods
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