Sensorimotor Integration in Monogenic Parkinson-dystonia Syndromes

Recruiting

• Conditions: Parkinson; Dystonia, Familial; PINK1 Gene Deletion; DYT5; Dystonia; DYT3
• Interventions: Device: Transcranial magnetic stimulation (TMS); Other: Video-based clinical examination; Other: 24 hours drug withdrawal of dopaminergic medication; Other: Evaluation of deep brain stimulation

• Registration Number: NCT05713721
• Lead Sponsor: University Hospital Schleswig-Holstein

Brief Summary

Hereditary Parkinson and dystonia syndromes are rare, as are people who carry the predisposition for Parkinson or dystonia but do not have symptoms. It is particularly important to study these people because they are a good model for understanding the development of common non-hereditary Parkinson's and dystonia. To do this, the investigators want to look at how the brain works and how different areas of the brain communicate with each other. The investigators want to identify differences in brain regions connecting perception and action between mutation carriers that develop clinical symptoms and those who stay healthy in different subgroups of inherited Parkinson-dystonia syndromes. Mutation carriers with and without symptoms of three different inherited Parkinson-dystonia syndromes will be investigated at their homes with the help of a mobile examination unit. To detect even subtle signs, which the mutation carriers might not even be aware of, the investigators will use a detailed video-based and -documented movement examination and a non-invasive magnetic stimulation technique that investigates how a sensory, i.e., electrical stimulus can influence the motor response in a hand muscle. Our study will allow the investigators, on the one hand, to define specific markers that protect some mutation carriers from having clinical symptoms and, on the other hand, to identify neurophysiological characteristics that all mutation carriers share whether or not they have clinical symptoms. These are important information for a better understanding of the basis of these disorders and for the development of new treatment strategies, which can also be transferred to genetically-undefined Parkinson's and dystonia syndromes. Through this study, large groups of mutation carriers that have received an in-depth clinical and neurophysiological examination and can be investigated longitudinally in future studies will be build up.

Detailed Description

Monogenic Parkinson-dystonia syndromes are rare but very valuable model disorders for genetically undefined syndromes, as their genetic cause, i.e., pathogenic gene variants, have been identified. For certain subtypes, even the neuroanatomical basis was discovered. Despite the different genetic and anatomical characteristics, a strong clinical overlap was reported between PARK-Parkin/PARK-PINK1, DYT/PARK-GCH1, and DYT/PARK-TAF1.

Interestingly, previous research in these different Parkinson-dystonia syndromes suggests a distinct pattern of neurophysiological alterations within the primary motor and premotor-motor network for each syndrome. Even asymptomatic, heterozygous mutation carriers, show abnormalities within neurophysiological and in addition, functional, metabolic, and structural imaging studies.

In general, a better clinical and neurophysiological evaluation of asymptomatic compared to symptomatic mutation carriers and healthy controls across subgroups is warranted. However, the number of mutation carriers per subgroup is limited and some are unable to travel to Lübeck to participate in research. To increase the participant size, in addition to the examination in our neurophysiological laboratory, the investigators want to visit and investigate some mutation carriers in their home environment with a mobile examination unit. In this regard, the transcranial magnetic stimulation paradigm of short-latency afferent inhibition (SAI) is of great interest as it can reliably capture the effects of sensory input (median nerve stimulation) on motor output (MEP amplitude) without complex neuronavigation. Additionally, a video-based clinical examination will be performed, which will be rated offline in a blinded fashion by movement disorder specialists to correlate SAI with symptom severity.

Therefore, the proposed project will, for the first time, allow a direct comparison of sensorimotor integration deficits in correlation to clinical signs between three different monogenic Parkinson-dystonia syndromes. Furthermore, contrasting the findings between asymptomatic and symptomatic mutation carriers will help, on the one hand, to draw conclusions on potential protective markers, and on the other hand, to identify neurophysiological endophenotypes. Furthermore, successful completion of the project will generate clinically well-defined monogenic subgroups with particular sensorimotor abnormalities, who can serve as model disorders in further research projects that aim to characterize sensorimotor deficit in a cognitive framework and in a longitudinal fashion.

Study Timeline

• Study Start: 2023-01-01
• Study First Submitted: 2023-01-27
• Study First Submitted QC: 2023-01-27
• Study First Posted: 2023-02-06
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-21
• Last Update Posted: 2023-06-23
• Primary Completion: 2024-06-30
• Study Completion: 2024-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 120

Inclusion Criteria

Not provided

Exclusion Criteria

• Age <18 years
• Pregnancy
• Epilepsy
• Medication that reduces the seizure threshold

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
SMC DYT/PARK-TAF1	Transcranial magnetic stimulation (TMS)	Symptomatic mutation carriers (SMC) of the TAF1 gene, which is associated with X-linked Dystonia-Parkinsonism, will be examined.
SMC DYT/PARK-TAF1	Evaluation of deep brain stimulation	Symptomatic mutation carriers (SMC) of the TAF1 gene, which is associated with X-linked Dystonia-Parkinsonism, will be examined.
SMC DYT/PARK-GCH1	Transcranial magnetic stimulation (TMS)	Symptomatic mutation carriers (SMC) of the GCH1 gene, which is associated with dopa-responsive Dystonia, will be examined.
SMC PARK-Parkin/PARK-PINK1	Video-based clinical examination	Symptomatic mutation carriers (SMC) of the Parkin or PINK1 genes, which is associated with Parkinsonism, will be examined.
AMC PARK-Parkin/PARK-PINK1	Transcranial magnetic stimulation (TMS)	Asymptomatic mutation carriers (SMC) of the Parkin or PINK1 genes will be examined.
AMC DYT/PARK-TAF1	Video-based clinical examination	Asymptomatic mutation carriers (AMC) of the TAF1 gene will be examined.
AMC DYT/PARK-TAF1	Transcranial magnetic stimulation (TMS)	Asymptomatic mutation carriers (AMC) of the TAF1 gene will be examined.
SMC DYT/PARK-GCH1	Video-based clinical examination	Symptomatic mutation carriers (SMC) of the GCH1 gene, which is associated with dopa-responsive Dystonia, will be examined.
AMC DYT/PARK-GCH1	Transcranial magnetic stimulation (TMS)	Asymptomatic mutation carriers (AMC) of the GCH1 gene will be examined.
SMC PARK-Parkin/PARK-PINK1	24 hours drug withdrawal of dopaminergic medication	Symptomatic mutation carriers (SMC) of the Parkin or PINK1 genes, which is associated with Parkinsonism, will be examined.
SMC DYT/PARK-GCH1	24 hours drug withdrawal of dopaminergic medication	Symptomatic mutation carriers (SMC) of the GCH1 gene, which is associated with dopa-responsive Dystonia, will be examined.
AMC DYT/PARK-GCH1	Video-based clinical examination	Asymptomatic mutation carriers (AMC) of the GCH1 gene will be examined.
Control group	Video-based clinical examination	A healthy control group will be examined.
SMC DYT/PARK-TAF1	Video-based clinical examination	Symptomatic mutation carriers (SMC) of the TAF1 gene, which is associated with X-linked Dystonia-Parkinsonism, will be examined.
SMC DYT/PARK-TAF1	24 hours drug withdrawal of dopaminergic medication	Symptomatic mutation carriers (SMC) of the TAF1 gene, which is associated with X-linked Dystonia-Parkinsonism, will be examined.
SMC PARK-Parkin/PARK-PINK1	Transcranial magnetic stimulation (TMS)	Symptomatic mutation carriers (SMC) of the Parkin or PINK1 genes, which is associated with Parkinsonism, will be examined.
AMC PARK-Parkin/PARK-PINK1	Video-based clinical examination	Asymptomatic mutation carriers (SMC) of the Parkin or PINK1 genes will be examined.
Control group	Transcranial magnetic stimulation (TMS)	A healthy control group will be examined.

Primary Outcome Measures

Name	Time	Method
Define whether asymptomatic mutation carriers show abnormalities in sensorimotor integration and clinical signs of Parkinson and dystonia upon video examination.	One timepoint	Video based clinical examination
Correlate clinical symptom severity with changes in sensorimotor integration.	Two timepoints (patients) or one timepoint (asymptomatic mutation carriers and healthy control participants)	Transcranial magnetic stimulation (short-latency afferent inhibition) and Video based clinical examination
Contrast sensorimotor integration in patients with three different monogenic Parkinson-dystonia syndromes.	Two timepoints (if applicable): With chronic dopaminergic medication vs. 24h drug withdrawal OR before and after deep brain stimulation implantation	Transcranial magnetic stimulation (short-latency afferent inhibition)
Evaluate treatment effects on sensorimotor integration, e.g., for PARK-Parkin/PARK-PINK1 and DYT/PARK-GCH1 chronic dopaminergic medication and for DYT/PARK-TAF1 deep brain stimulation effects.	Two timepoints (if applicable): With chronic dopaminergic medication vs. 24h drug withdrawal OR before and after deep brain stimulation implantation	Transcranial magnetic stimulation (short-latency afferent inhibition)

Trial Locations

Locations (1)

Institute of Systems Motor Science Lübeck; 🇩🇪 Lübeck, Schleswig-Holstein, Germany