Imaging Blood Brain Imaging Dysfunction in Parkinson's Disease

December 29, 2020 updated by: Ottawa Hospital Research Institute
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.

Study Overview

Status

Completed

Conditions

Detailed Description

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.

Study Type

Observational

Enrollment (Actual)

17

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Ottawa, Ontario, Canada, K1Y1J7
        • The Ottawa Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • ADULT
  • OLDER_ADULT
  • CHILD

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Patients having movement disorders undergoing deep brain stimulation (DBS) of the internal segment of the globus pallidus for treatment of motor symptoms refractory to medical therapy at the Ottawa Hospital, Civic Campus, will be recruited to participate in this pilot study. The cohort will include 10 PD patients and 10 control subjects. The PD subjects will have received a diagnosis of PD using established clinical criteria following clinical assessment at the Movement Disorders Clinic of The Ottawa Hospital. The 10 control subjects will consist of those undergoing DBS and assessed in the same clinic with a clinical diagnosis of either essential tremor or cervical dystonia.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Parkinson's disease group
  • 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
  • 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?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Degree of contrast enhancement
Time Frame: one year
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
Time Frame: one year
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ottawa Hospital Research Institute

Investigators

  • Principal Investigator: Thanh B Nguyen, MD, FRCP, The Ottawa Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

November 1, 2015

Primary Completion (ACTUAL)

September 8, 2020

Study Completion (ACTUAL)

September 8, 2020

Study Registration Dates

First Submitted

November 3, 2015

First Submitted That Met QC Criteria

November 12, 2015

First Posted (ESTIMATE)

November 16, 2015

Study Record Updates

Last Update Posted (ACTUAL)

December 31, 2020

Last Update Submitted That Met QC Criteria

December 29, 2020

Last Verified

December 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20150770-01H

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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