Imaging Neuromelanin and Iron in Dystonia/Parkinsonism

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Imaging Neuromelanin and Iron in Dystonia/Parkinsonism

Conditions
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Sporadic Dystonia, Dystonia, Familial, Parkinson Disease, Juvenile, Neurodegeneration With Brain Iron Accumulation 5, Mitochondrial Diseases

Intervention / Treatment
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* 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:


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sporadic Dystonia<br>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<br>* 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<br>Behavioral: Burke-Fahn-Marsden Dystonia Rating scale<br>* internationally standardized examination/quantification of dystonia<br>Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III<br>* most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society<br>Behavioral: Beck Depression Inventory<br>* internationally standardized examination to quantify traits of anxiety and depression<br>Behavioral: MoCA: Montreal Cognitive Assessment:<br>* internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism<br>|
| Familial Dystonia<br>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<br>* 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<br>Behavioral: Burke-Fahn-Marsden Dystonia Rating scale<br>* internationally standardized examination/quantification of dystonia<br>Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III<br>* most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society<br>Behavioral: Beck Depression Inventory<br>* internationally standardized examination to quantify traits of anxiety and depression<br>Behavioral: MoCA: Montreal Cognitive Assessment:<br>* internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism<br>|
| Parkinson´s disease, juvenile<br>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<br>* 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<br>Behavioral: Burke-Fahn-Marsden Dystonia Rating scale<br>* internationally standardized examination/quantification of dystonia<br>Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III<br>* most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society<br>Behavioral: Beck Depression Inventory<br>* internationally standardized examination to quantify traits of anxiety and depression<br>Behavioral: MoCA: Montreal Cognitive Assessment:<br>* internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism<br>|
| Neurodegeneration with brain iron acc.<br>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<br>* 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<br>Behavioral: Burke-Fahn-Marsden Dystonia Rating scale<br>* internationally standardized examination/quantification of dystonia<br>Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III<br>* most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society<br>Behavioral: Beck Depression Inventory<br>* internationally standardized examination to quantify traits of anxiety and depression<br>Behavioral: MoCA: Montreal Cognitive Assessment:<br>* internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism<br>|
| mitochondrial disease<br>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<br>* 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<br>Behavioral: Burke-Fahn-Marsden Dystonia Rating scale<br>* internationally standardized examination/quantification of dystonia<br>Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III<br>* most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society<br>Behavioral: Beck Depression Inventory<br>* internationally standardized examination to quantify traits of anxiety and depression<br>Behavioral: MoCA: Montreal Cognitive Assessment:<br>* internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism<br>|
| Healthy Controls<br>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<br>* 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<br>Behavioral: Burke-Fahn-Marsden Dystonia Rating scale<br>* internationally standardized examination/quantification of dystonia<br>Behavioral: MDS-United Parkinsons Disease Rating Scale, Part III<br>* most recent, internationally standardized examination/quantification of bradykinesia / rigidity according to the Movement Disorder Society<br>Behavioral: Beck Depression Inventory<br>* internationally standardized examination to quantify traits of anxiety and depression<br>Behavioral: MoCA: Montreal Cognitive Assessment:<br>* internationally standardized examination to quantify cognition, frequently used in studies of dystonia and parkinsonism<br>|

What is the study measuring?
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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 |