Imaging Neuromelanin and Iron in Dystonia/Parkinsonism

To generate pilot data to investigate the potential to use in vivo iron- and neuromelanin-quantification as imaging tools for the diagnostic evaluation of movement disorders with predominant dystonia / parkinsonism. To this end we are planning to compare the MR imaging neuromelanin and iron-pattern and content in midbrain, striatum and further brain structures in clinically similar entities and respective, sex- and age-matched healthy controls.

Study Overview

• Status: Unknown
• Conditions: Mitochondrial Diseases; Dystonia, Familial; Sporadic Dystonia; Parkinson Disease, Juvenile; Neurodegeneration With Brain Iron Accumulation 5
• Intervention / Treatment: Diagnostic test: 3Tesla MRI; Behavioral: Burke-Fahn-Marsden Dystonia Rating scale; Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III; Behavioral: Beck Depression Inventory; Behavioral: MoCA: Montreal Cognitive Assessment:

Detailed Description

Iron- or Neuromelanin-sensitive MR-imaging has not been consistently applied to the study of syndromes presenting with predominant dystonia/parkinsonism yet. We are planning to study the following groups, as they can often be very difficult to be distinguished from PD and in particular young-onset PD, on clinical grounds only:

• Dopa-responsive dystonia (DRD) can present similar to young-onset PD, but carries a completely different prognosis, necessitating different treatment requirements due to fundamentally different underlying physiology.
• Sporadic and Inherited dystonias (i.e. due to TorsinA (DYT1) and other gene mutations) often present with dystonia, particularly affecting the leg, which is clinically indistinguishable from young-onset PD.
• Young-onset PD, i.e. PD presenting with motor symptoms before 45 years of age, caused by a familiar gene mutation (PARKIN, Pink, DJ-1, PLA2G6, FBX07, ATP13A2, VPS13C, RAB39B, Lubag), often presents with predominant dystonia, particularly with leg-onset.
• NBIAs present with dystonia/parkinsonism: while basal ganglia iron accumulation is a known hallmark feature of the condition [3], the characteristics of neuromelanin regulation are unknown.
• Mitochondrial disease presenting with dystonia / parkinsonism (such as for example Leigh syndrome due to mutations in the Surf-1 gene or mutations m.3243A>G or POLG) [4]
• Respective age- and sex-matched healthy controls This study is designed to produce pilot data on these disease entities. By potentially accelerating the diagnostic process and identification of disease entities, neurologists might be able to deliver more selective and dedicated treatment.

Furthermore, combining Neuromelanin- and iron-specific imaging will offer the possibility to study the condition- specific dynamics of iron homeostasis in these rare conditions.

• Study Type: Observational
• Enrollment (Anticipated): 80

Contacts and Locations

• Study Contact: Name: Sebastian R Schreglmann, MD; Phone Number: 0203448 8604; Email: skgtsrs@ucl.ac.uk
• Study Contact Backup: Name: Bhatia P Kailash, MD, DM, FRCP; Phone Number: 0203448 4252; Email: k.bhatia@ucl.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients from the National Hospital of Neurology, Queen Square, movement disorder outpatient clinic;

Description

Inclusion Criteria:

• clinical diagnosis of parkinsonism and/or dystonia due to
• dopa-responsive dystonia
• sporadic or inherited/genetic dystonia
• young-onset Parkinson's disease
• NBIA

• Mitochondrial disease

  • OR healthy controls
  • 18 to 60 years of age
  • able to give informed consent

Exclusion Criteria:

• Inability to tolerate 35min in an MRI machine
• Participated in a clinical drug trial up to 28 days before inclusion into the present study
• Contra-indications to 3T MRI on MRI safety grounds, such as presence of contra-indicated medical implants, as according to the established routine operating procedures for clinical MRI in the Lysholm Department of Neuroradiology at the National Hospital for Neurology and Neurosurgery.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Sporadic Dystonia; 3 Tesla MRI Burke-Fahn-Marsden Dystonia Rating scale MDS-United Parkinsons Disease Rating Scale, Part III Beck Depression Inventory MoCA: Montreal Cognitive Assessment	Diagnostic test: 3Tesla MRI; A previously validated multi-parameter mapping protocol sensitive to neuromelanin and iron content; Iron mapping and micro-bleed detection: QSM (quantitative susceptibility mapping), a fully flow-compensated, susceptibility-weighted gradient-echo sequence (5 minutes).; 1-mm isotropic anatomical MPRAGE (magnetization-prepared rapid gradient-echo); conventional FLAIR sequence; Behavioral: Burke-Fahn-Marsden Dystonia Rating scale; internationally standardized examination/quantification of dystonia; Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III; most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society; Behavioral: Beck Depression Inventory; internationally standardized examination to quantify traits of anxiety and depression; Behavioral: MoCA: Montreal Cognitive Assessment: internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism
Familial Dystonia; 3 Tesla MRI Burke-Fahn-Marsden Dystonia Rating scale MDS-United Parkinsons Disease Rating Scale, Part III Beck Depression Inventory MoCA: Montreal Cognitive Assessment	Diagnostic test: 3Tesla MRI; A previously validated multi-parameter mapping protocol sensitive to neuromelanin and iron content; Iron mapping and micro-bleed detection: QSM (quantitative susceptibility mapping), a fully flow-compensated, susceptibility-weighted gradient-echo sequence (5 minutes).; 1-mm isotropic anatomical MPRAGE (magnetization-prepared rapid gradient-echo); conventional FLAIR sequence; Behavioral: Burke-Fahn-Marsden Dystonia Rating scale; internationally standardized examination/quantification of dystonia; Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III; most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society; Behavioral: Beck Depression Inventory; internationally standardized examination to quantify traits of anxiety and depression; Behavioral: MoCA: Montreal Cognitive Assessment: internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism
Parkinson´s disease, juvenile; 3 Tesla MRI Burke-Fahn-Marsden Dystonia Rating scale MDS-United Parkinsons Disease Rating Scale, Part III Beck Depression Inventory MoCA: Montreal Cognitive Assessment	Diagnostic test: 3Tesla MRI; A previously validated multi-parameter mapping protocol sensitive to neuromelanin and iron content; Iron mapping and micro-bleed detection: QSM (quantitative susceptibility mapping), a fully flow-compensated, susceptibility-weighted gradient-echo sequence (5 minutes).; 1-mm isotropic anatomical MPRAGE (magnetization-prepared rapid gradient-echo); conventional FLAIR sequence; Behavioral: Burke-Fahn-Marsden Dystonia Rating scale; internationally standardized examination/quantification of dystonia; Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III; most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society; Behavioral: Beck Depression Inventory; internationally standardized examination to quantify traits of anxiety and depression; Behavioral: MoCA: Montreal Cognitive Assessment: internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism
Neurodegeneration with brain iron acc.; 3 Tesla MRI Burke-Fahn-Marsden Dystonia Rating scale MDS-United Parkinsons Disease Rating Scale, Part III Beck Depression Inventory MoCA: Montreal Cognitive Assessment	Diagnostic test: 3Tesla MRI; A previously validated multi-parameter mapping protocol sensitive to neuromelanin and iron content; Iron mapping and micro-bleed detection: QSM (quantitative susceptibility mapping), a fully flow-compensated, susceptibility-weighted gradient-echo sequence (5 minutes).; 1-mm isotropic anatomical MPRAGE (magnetization-prepared rapid gradient-echo); conventional FLAIR sequence; Behavioral: Burke-Fahn-Marsden Dystonia Rating scale; internationally standardized examination/quantification of dystonia; Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III; most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society; Behavioral: Beck Depression Inventory; internationally standardized examination to quantify traits of anxiety and depression; Behavioral: MoCA: Montreal Cognitive Assessment: internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism
mitochondrial disease; 3 Tesla MRI Burke-Fahn-Marsden Dystonia Rating scale MDS-United Parkinsons Disease Rating Scale, Part III Beck Depression Inventory MoCA: Montreal Cognitive Assessment	Diagnostic test: 3Tesla MRI; A previously validated multi-parameter mapping protocol sensitive to neuromelanin and iron content; Iron mapping and micro-bleed detection: QSM (quantitative susceptibility mapping), a fully flow-compensated, susceptibility-weighted gradient-echo sequence (5 minutes).; 1-mm isotropic anatomical MPRAGE (magnetization-prepared rapid gradient-echo); conventional FLAIR sequence; Behavioral: Burke-Fahn-Marsden Dystonia Rating scale; internationally standardized examination/quantification of dystonia; Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III; most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society; Behavioral: Beck Depression Inventory; internationally standardized examination to quantify traits of anxiety and depression; Behavioral: MoCA: Montreal Cognitive Assessment: internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism
Healthy Controls; 3 Tesla MRI Burke-Fahn-Marsden Dystonia Rating scale MDS-United Parkinsons Disease Rating Scale, Part III Beck Depression Inventory MoCA: Montreal Cognitive Assessment	Diagnostic test: 3Tesla MRI; A previously validated multi-parameter mapping protocol sensitive to neuromelanin and iron content; Iron mapping and micro-bleed detection: QSM (quantitative susceptibility mapping), a fully flow-compensated, susceptibility-weighted gradient-echo sequence (5 minutes).; 1-mm isotropic anatomical MPRAGE (magnetization-prepared rapid gradient-echo); conventional FLAIR sequence; Behavioral: Burke-Fahn-Marsden Dystonia Rating scale; internationally standardized examination/quantification of dystonia; Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III; most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society; Behavioral: Beck Depression Inventory; internationally standardized examination to quantify traits of anxiety and depression; Behavioral: MoCA: Montreal Cognitive Assessment: internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
neuromelanin content	absolute amount of neuromelanin in midbrain, striatum and other areas of the brain	up to 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
neuromelanin association	correlate neuromelanin quantification with demographic and clinical details	up to 8 weeks
iron association	correlate neuromelanin quantification with demographic and clinical details	up to 8 weeks
Iron content	absolute amount of iron in midbrain, striatum and other areas of the brain	up to 8 weeks

Collaborators and Investigators

• Sponsor: University College, London
• Investigators: Principal Investigator: Bhatia P Kailash, MD, DM, FRCP, UCL, Institute of Neurology, Sobell Department

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2018
• Primary Completion (Anticipated): July 1, 2021
• Study Completion (Anticipated): July 1, 2021

Study Registration Dates

• First Submitted: February 8, 2018
• First Submitted That Met QC Criteria: June 27, 2018
• First Posted (Actual): June 28, 2018

Study Record Updates

• Last Update Posted (Actual): June 28, 2018
• Last Update Submitted That Met QC Criteria: June 27, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Neuroaxonal Dystrophies; Mitochondrial Diseases; Parkinson Disease; Dystonia; Dystonic Disorders; Parkinsonian Disorders; Pantothenate Kinase-Associated Neurodegeneration; Nerve Degeneration
• Other Study ID Numbers: 18/0075; IRAS ID 243171 (Other Identifier: UCL R&D)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No