In vivo assessment of non-dopaminergic systems in Parkinson’s disease with Positron Emission Tomography

Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Non-dopaminergic neurotransmission is also impaired. Intraneuronal Lewy bodies, the pathological hallmark of PD, have been observed in serotoninergic, noradrenergic, and cholinergic neurons. Dysfunction of these systems could play a role in the occurrence of non-motor symptoms including fatigue. However, the extent of non-dopaminergic degeneration in PD, rates of its progression, and its contribution to the development of non-motor symptoms is unclear. First, I used 18F-dopa Positron Emission Tomography (PET), a marker of monoaminergic terminal function, to assess the involvement of dopaminergic, noradrenergic, and serotoninergic pathways in PD and in parkin-linked parkinsonism, a genetic form of PD. I found that parkin patients and PD patients have distinct patterns of monoaminergic involvement, with more widespread dysfunction in PD. In a second study, I used serial 18F-dopa PET to assess longitudinal changes in tracer uptake in brain monoaminergic structures over a 3-year period in a group of PD patients. I also assessed the relationship between striatal function decline and dysfunction in extra-striatal areas in the same patients. I found that the degeneration in extrastriatal monoaminergic structures in PD occurs independently from nigrostriatal degeneration and at a slower rate. Brain compensatory mechanisms disappear within the first years of disease. I then used 18F-dopa and 11C-DASB PET to investigate whether fatigue in PD is associated with dysfunction of dopaminergic/serotoninergic innervation. I found that PD patients with fatigue show severe loss of serotoninergic innervation in basal ganglia and limbic areas. Finally, I assessed the relationship between 18F-dopa uptake and measurements of serotonin transporter availability by 11C-DASB PET within brain serotoninergic structures and I provided evidence for the hypothesis that 18F-dopa PET can be used to evaluate the distribution and the function of serotoninergic systems in the brain of PD patients

Diagnosis and Treatment of Parkinson's Disease

Parkinson's disease is diagnosed by history and physical examination and there are no laboratory investigations available to aid the diagnosis of Parkinson's disease. Confirmation of diagnosis of Parkinson's disease thus remains a difficulty. This book brings forth an update of most recent developments made in terms of biomarkers and various imaging techniques with potential use for diagnosing Parkinson's disease. A detailed discussion about the differential diagnosis of Parkinson's disease also follows as Parkinson's disease may be difficult to differentiate from other mimicking conditions at times. As Parkinson's disease affects many systems of human body, a multimodality treatment of this condition is necessary to improve the quality of life of patients. This book provides detailed information on the currently available variety of treatments for Parkinson's disease including pharmacotherapy, physical therapy and surgical treatments of Parkinson's disease. Postoperative care of patients of Parkinson's disease has also been discussed in an organized manner in this text. Clinicians dealing with day to day problems caused by Parkinson's disease as well as other healthcare workers can use beneficial treatment outlines provided in this book

Rat Model of Pre-Motor Parkinson\u27s Disease: Behavioral and MRI Characterization.

Background: Parkinson\u27s disease (PD) is a chronic, progressive, neurodegenerative disorder with currently no known cure. PD has a significant impact on quality of life of the patients, as well as, the caregivers and family members. It is the second most common cause of chronic neurological disability in US and Europe. According to National Parkinson\u27s Foundation, there are almost 1 million patients in the Unites States and 50,000 to 60,000 new cases of PD are diagnosed each year. The total number of cases of PD is predicted to double by 2030. The annual cost associated with this disease is estimated to be $10.8 billion in the United States, including the cost of treatment and the cost of the disability. Although it is primarily thought of as a movement-disorder and is clinically diagnosed based on motor symptoms, non-motor symptoms such as cognitive and emotional deficits are thought to precede the clinical diagnosis by almost 20 years. By the time of clinical diagnosis, there is 80% loss in the dopamine content in the striatum and 50% degeneration of the substantia nigra dopamine cells. The research presented in this thesis was an attempt to develop an animal model of PD in its pre-motor stages. Such a model would allow us to develop pre-clinical markers for PD, and facilitate the development and testing of potential treatment strategies for the non-motor symptoms of the disorder. Specific Aims: There were five specific aims for this research: * The first specific aim dealt with development of a rat model of PD with slow, progressive onset of motor deficits, determination of timeline for future studies, and quantification the dopamine depletion in this model at a pre-motor stage. * The second and the third specific aims focused on testing for emotional (aversion) deficits and cognitive (executive functioning) deficits in this rat model at the 3 week timepoint determined during specific aim 1. * The fourth specific aim was to determine the brain network changes associated with the behavioral changes observed our rat model using resting state connectivity as a measure. * The fifth and the final specific aim was to test sodium butyrate, a drug from the histone deacetylase inhibitor family, as a potential treatment option for cognitive deficits in PD. Results: The 6-hydroxy dopamine based stepwise striatal lesion model of pre-motor PD, developed during this research, exhibits delayed onset of Parkinsonian gait like symptoms by week 4 after the lesions. At 3 weeks post lesion (3WKPD), the rats exhibit 27% reduction in striatal dopamine and 23%reduction in substantia nigra dopamine cells, with lack of any apparent motor deficits. The 3WKPD rats also exhibited changes in aversion. The fMRI study with the aversive scent pointed towards possible amygdala dysfunction sub-serving the aversion deficits. The executive function deficits tested using a rat analog of the Wisconsin card sorting test, divulged an extra-dimensional set shifting deficit in the 3WKPD rats similar to those reported in PD patients. The resting state connectivity study indicated significant changes in the 3WKPD rats compared to age matched controls. We observed increased overall connectivity of the motor cortex and increased CPu connectivity with prefrontal cortex, cingulate cortex, and hypothalamus in the 3WKPD rats compared to the controls. These observations parallel the observations in unmedicated early-stage PD patients. We also observed negative correlation between amygdala and prefrontal cortex as reported in humans. This negative correlation was lost in 3WKPD rats. Sodium butyrate treatment, tested in the cognitive deficit study, was able to ameliorate the extra-dimensional set shifting deficit observed in this model. This treatment also improved the attentional set formation. Conclusion: Taken together, our observations indicate that, the model of pre-motor stage PD developed during this research is a very high face validity rat model of late Braak stage 2 or early Braak stage 3 PD. Sodium butyrate was able to alleviate the cognitive deficits observed in our rat model. Hence, along with the prior reports of anti-depressant and neuroprotective effects of this drug, our results point towards a possible treatment strategy for the non-motor deficits of PD

Modulation of the 5-HT3 Receptor as a Novel Anti-Dyskinetic Target in Parkinson’s Disease

La L-3,4-dihydroxyphénylalanine (L-DOPA) est le traitement le plus efficace de la maladie de Parkinson. Cependant, avec une administration chronique de L-DOPA, les patients développent des complications motrices telles que les dyskinésies. Des études antérieures ont montré que le blocage des récepteurs type 3 de la sérotonine (5-HT3) réduit les niveaux de dopamine dans les ganglions de la base, suggérant qu'il pourrait atténuer la libération de dopamine qui caractérise l'état dyskinétique. Ici, nous avons étudié les effets de l’ondansétron, un antagoniste hautement sélectif du récepteur 5-HT3 à diminuer et à prévenir le développement des dyskinésies induites par L-DOPA chez le rat lésé a la 6-hydroxydopamine. Dans la première expérience, les rats sensibilisés avec L-DOPA pour induire des mouvements involontaires anormaux (AIMs), ont reçu L-DOPA en combinaison avec l'ondansétron ou un véhicule. Dans la seconde expérience, les doses efficaces d'ondansétron ont été administrées simultanément avec L-DOPA pendant 22 jours, et la sévérité des dyskinésies a été évaluée. Après 3 jours d’élimination, L-DOPA a été administré en aigu et la sévérité des dyskinésies évaluée. Nous avons trouvé que l'ondansétron 0,0001 mg/kg en combinaison avec L-DOPA, a significativement diminué la sévérité des dyskinésies par rapport à L-DOPA seul. Ondansétron 0,0001 mg/kg, administré en même temps que L-DOPA, a retardé le développement des dyskinésies. L'action anti-dyskinétique de l'ondansétron n'a pas compromis le bénéfice thérapeutique conféré par la L-DOPA. Ces résultats suggèrent que l'antagonisme des récepteurs 5-HT3 est une stratégie thérapeutique potentiellement nouvelle et efficace pour soulager la sévérité et prévenir le développement des dyskinésies.L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson’s disease However, with chronic administration of L-DOPA, patients develop motor complications such as dyskinesia. Previous studies have shown that 5-HT3 receptor blockade reduces dopamine levels within the basal ganglia, suggesting that it could mitigate the aberrant dopamine release that characterises the dyskinetic state. Here, we investigated the effects of the highly-selective 5-HT3 antagonist ondansetron at diminishing the expression of established, and preventing the development of L-DOPA-induced dyskinesia in the 6-hydroxydopamine-lesioned rat. In the first set of experiments, rats were primed with L-DOPA to induce abnormal involuntary movements (AIMs), after which L-DOPA was administered, in combination with ondansetron or vehicle. The effect of ondansetron on L-DOPA anti-parkinsonian action was subsequently determined by the cylinder test. In the second set of experiments, rats were administered effective doses of ondansetron, started concurrently with L-DOPA for 22 days, during which dyskinesia severity was monitored. After a 3-day washout period, an acute challenge of L-DOPA was administered and AIMs severity was assessed. We found that acute challenges of ondansetron 0.0001 mg/kg in combination with L-DOPA, significantly diminished the severity of AIMs compared to L-DOPA alone. Ondansetron 0.0001 mg/kg, when started concurrently with L-DOPA, attenuated the priming process leading to the development of dyskinesia. The anti-dyskinetic action of ondansetron did not compromise the therapeutic benefit conferred by L-DOPA. These results suggest that 5-HT3 receptor antagonism is a potentially new and effective therapeutic strategy to alleviate the severity, and prevent the development of dyskinesia

Molecular imaging in Parkinson's disease

The present work explores brain functional changes in drug-naïve Parkinson's disease (PD) patients by means of molecular imaging techniques. Thirty-one consecutive drug-naïve PD patients from the Neurological Clinic of the University of Flor-ence underwent clinical assessment, neuropsychological assessment, MRI, [123I]FP-CIT SPECT, [18F]FDG PET. First, [18F]FDG-PET was employed to identify in drug-naïve PD patients brain metabolic alteration uniquely related to disease process and not modulated by anti-parkinsonian therapeutic intervention. Second, [18F]FDG-PET and [123I]FP-CIT SPECT were employed together to explore the early functional changes in brain function related to dopaminergic depletion in the putamen and in the caudate nucleus

Clinical and PET Imaging Studies in Parkinson’s Disease Motor and Non-Motor Complications: Serotonergic and Dopamimergic Mechanisms and Applications in Treatment

The clinical course of Parkinson’s disease (PD) is complicated by the development of motor and non-motor complications. This thesis, using clinical motor and non-motor assessments and positron emission tomography (PET) imaging with 11C-raclopride, 11CDASB and 18F-DOPA, aims to explore in PD the role of: (1) postsynaptic dopamine D2 receptor dysfunction, (2) serotonergic dysfunction in the development of non-motor symptoms such as depression and body weight change, (3) striatal serotonergic neurons in levodopa- and graft -induced dyskinesias (LIDs and GIDs), and (4) the efficacy of treatment with continuous dopaminergic stimulation. The main findings are as follows: (1) D2 receptor dysfunction in the hypothalamus but not in the putamen was evident in PD, possibly accounting for the development of non-motor symptoms. (2) A staging of serotonergic dysfunction throughout the clinical course of PD has been demonstrated in this thesis and showed that serotonergic system is involved early on. (3) Higher serotonin transporter availability has been found in PD patients with elevated depressive symptoms and in PD patients with significant changes in their body weight. (4) Striatal serotonergic terminals are involved in peak-dose LIDs in PD, and administration of a high bolus dose of a 5-HT1A agonist was able to normalize extracellular dopamine levels and alleviate dyskinesias. (5) Excessive serotonergic innervation was found in two PD patients with GIDs who had experienced major recovery after striatal transplantation with fetal cells. GIDs were markedly attenuated by repeated administration of low doses of a 5-HT1A agonist, which dampens transmitter release from serotonergic neurons, indicating that serotonergic hyperinnervation was the likely cause of GIDs. (6) Continuous dopaminergic stimulation with levodopa intestinal gel induced good clinical response and stable and prolonged synaptic levels of striatal dopamine release. My observations provide fundamental insight for the role and interaction of serotonergic and dopaminergic systems in the pathophysiology of PD and have key implications for the management of motor and non-motor complications with drugs or cell therapies