Imaging Blood Brain Imaging Dysfunction in Parkinson's Disease

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the blood brain barrier in the striatum of patients that have other types of movement disorders compared to patients with Parkinson's Disease that are receiving similar treatment, to determine if a there is a disruption of the blood brain barrier in patients with Parkinson's Disease.

Detailed Description
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Parkinson's disease (PD) is the most common neurodegenerative movement disorder of aging. Its cause is unknown. Current evidence supports a stress-diathesis model of pathogenesis whereby some yet-to-be identified environmental trigger conspires with a permissive genetic background to initiate the disease process. Based on neuropathological observations in other neurodegenerative diseases, such as chronic traumatic encephalopathy where pathological protein aggregates form in close association with damaged blood vessels, investigators have hypothesized that the environmental trigger resides in the bloodstream. As a corollary of this hypothesis, investigators propose that the PD pathological process begins in the brain of affected individuals only after disruption of the blood brain barrier (BBB), thereby allowing access of the inciting agent to nigrostriatal axon terminals in the neostriatum. This forms the foundation for the investigators' hypothesis that the BBB in the neostriatum of PD patients is disrupted. Indeed, in a post-mortem study, investigators demonstrated histopathological evidence for significant striatal BBB disruption in sections of striatum from PD subjects relative to age-matched controls. Critics of this study indicate that post-mortem effects may result in artefactual disruption of the BBB, calling into question the validity and relevance of this potentially important finding to PD pathogenesis and progression. Therefore, investigators are performing this imaging study of live PD patients as a follow-up of their convincing post-mortem study to definitively establish whether BBB dysfunction is a feature of PD. The neostriatal BBB is dysfunctional in PD patients relative to controls and this can be demonstrated by significantly increased parenchymal enhancement on magnetic resonance imaging (MRI). The results of these studies could have important implications for the understanding of PD pathogenesis. There is emerging evidence that the key pathogenetic event in PD pathogenesis, aggregation of alpha-synuclein, begins within the axon terminals of neurons. The neurons most severely affected in PD reside in the substantia nigra and project to the neostriatum. Demonstrating disruption of the BBB in the PD striatum would render nigrostriatal axon terminals susceptible to a blood-borne disease trigger and allow researchers to generate hypotheses regarding the identity of this trigger. Immune/inflammatory candidates are particularly attractive in this regard. The results this study may also have therapeutic implications. For example, if alpha-synuclein disaggregating agents achieve therapeutic utility in the coming years, our studies may indicate that such agents may be capable of accessing nigrostriatal axon terminals without requiring pharmaceutical or mechanical disruption of the BBB.

Official Title
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Imaging Blood Brain Imaging Dysfunction in Parkinson's Disease

Conditions
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Parkinson's Disease, Movement Disorders

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease burden is dominated by motor symptoms such as rigidity, bradykinesia, akinesia, and tremor; Medications have been optimized by a movement disorder neurologist; Adequate social support to assist with preoperative recovery and problems during subsequent programming; No major mood disorder and any mood disorders are medically optimized; No major cognitive impairment; No underlying medical conditions that would preclude surgery; Adequate response to levodopa, as assessed by UPDRS-3 on and off levodopa. All participants has at least a 30% improvement; eGRF>30 Exclusion Criteria: Disease burden is not dominated by motor symptoms such as rigidity, bradykinesia, akinesia, and tremor; Medications have not bee optimized by a movement disorder neurologist; There is not adequate social support to assist with pre-operative recovery or problems during subsequent programming; Presence of major mood disorders or any mood disorders not medically optimized; Presence of major cognitive impairment; Presence of underlying medical conditions that would preclude surgery; Inadequate response to levodopa; eGFR<30
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Parkinson's disease group<br>patients diagnosed with Parkinson's disease by a movement disorder specialist from the deep brain stimulation program at The Ottawa Hospital, Civic Campus to undergo pre-operative MRI with contrast | |
| Control group<br>patients diagnosed with either essential tremor or cervical dystonia by a movement disorder specialist from the deep brain stimulation program at The Ottawa Hospital, Civic Campus to undergo pre-operative MRI with contrast | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Degree of contrast enhancement | Pre-contrast images will be used as mask images and will be digitally substracted from post-contrast images to obtain the difference images. From the difference images, two neuroradiologists blinded to the clinical status of the patient will assess the degree enhancement in the striatum (none,mild, moderate, marked). | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Permeability of blood brain barrier in the striatum | Quantitative assessment of the permeability of the blood brain barrier in the striatum will be assessed using dynamic contrast enhanced MRI. Specifically, the volume transfer constant (Ktrans) will be measured from the striatum in the control and patient groups. | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blood brain barrier, movement disorder, deep brain stimulation, essential tremor, cervical dystonia, magnetic resonance imaging, neostriatum