Sensorimotor Integration in Monogenic Parkinson-dystonia Syndromes

NCT ID: NCT05713721

Last Updated: 2023-06-23

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 120 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2023-01-01
• Study Completion Date: 2024-12-31

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.

Conditions

Parkinson; Dystonia; DYT3; DYT5; PINK1 Gene Deletion; Dystonia, Familial

Study Design

• Observational Model Type: OTHER
• Study Time Perspective: PROSPECTIVE

Study Groups

SMC DYT/PARK-TAF1

Symptomatic mutation carriers (SMC) of the TAF1 gene, which is associated with X-linked Dystonia-Parkinsonism, will be examined.

Transcranial magnetic stimulation (TMS)

Intervention Type: DEVICE

TMS over the left primary motor cortex will be performed. To investigate sensorimotor integration, an electrical stimulus on the right index finger will precede the TMS pulse.

Video-based clinical examination

Intervention Type: OTHER

A standardized neurological examination will be performed and video taped. The videos will be rated by movement disorder specialists, wo are blinded for the symptom and mutation status of the participants.

24 hours drug withdrawal of dopaminergic medication

Intervention Type: OTHER

Examinations will be done under chronic dopaminergic treatment and after a 24 hours dopaminergic drug withdrawal.

Evaluation of deep brain stimulation

Intervention Type: OTHER

Examinations will be done before and after implantation of deep brain stimulation (clinically optimal stimulation vs. switched off stimulation)

AMC DYT/PARK-TAF1

Asymptomatic mutation carriers (AMC) of the TAF1 gene will be examined.

Transcranial magnetic stimulation (TMS)

Intervention Type: DEVICE

TMS over the left primary motor cortex will be performed. To investigate sensorimotor integration, an electrical stimulus on the right index finger will precede the TMS pulse.

Video-based clinical examination

Intervention Type: OTHER

A standardized neurological examination will be performed and video taped. The videos will be rated by movement disorder specialists, wo are blinded for the symptom and mutation status of the participants.

SMC DYT/PARK-GCH1

Symptomatic mutation carriers (SMC) of the GCH1 gene, which is associated with dopa-responsive Dystonia, will be examined.

Transcranial magnetic stimulation (TMS)

Intervention Type: DEVICE

TMS over the left primary motor cortex will be performed. To investigate sensorimotor integration, an electrical stimulus on the right index finger will precede the TMS pulse.

Video-based clinical examination

Intervention Type: OTHER

A standardized neurological examination will be performed and video taped. The videos will be rated by movement disorder specialists, wo are blinded for the symptom and mutation status of the participants.

24 hours drug withdrawal of dopaminergic medication

Intervention Type: OTHER

Examinations will be done under chronic dopaminergic treatment and after a 24 hours dopaminergic drug withdrawal.

AMC DYT/PARK-GCH1

Asymptomatic mutation carriers (AMC) of the GCH1 gene will be examined.

Transcranial magnetic stimulation (TMS)

Intervention Type: DEVICE

TMS over the left primary motor cortex will be performed. To investigate sensorimotor integration, an electrical stimulus on the right index finger will precede the TMS pulse.

Video-based clinical examination

Intervention Type: OTHER

A standardized neurological examination will be performed and video taped. The videos will be rated by movement disorder specialists, wo are blinded for the symptom and mutation status of the participants.

SMC PARK-Parkin/PARK-PINK1

Symptomatic mutation carriers (SMC) of the Parkin or PINK1 genes, which is associated with Parkinsonism, will be examined.

Transcranial magnetic stimulation (TMS)

Intervention Type: DEVICE

TMS over the left primary motor cortex will be performed. To investigate sensorimotor integration, an electrical stimulus on the right index finger will precede the TMS pulse.

Video-based clinical examination

Intervention Type: OTHER

A standardized neurological examination will be performed and video taped. The videos will be rated by movement disorder specialists, wo are blinded for the symptom and mutation status of the participants.

24 hours drug withdrawal of dopaminergic medication

Intervention Type: OTHER

Examinations will be done under chronic dopaminergic treatment and after a 24 hours dopaminergic drug withdrawal.

AMC PARK-Parkin/PARK-PINK1

Asymptomatic mutation carriers (SMC) of the Parkin or PINK1 genes will be examined.

Transcranial magnetic stimulation (TMS)

Intervention Type: DEVICE

TMS over the left primary motor cortex will be performed. To investigate sensorimotor integration, an electrical stimulus on the right index finger will precede the TMS pulse.

Video-based clinical examination

Intervention Type: OTHER

A standardized neurological examination will be performed and video taped. The videos will be rated by movement disorder specialists, wo are blinded for the symptom and mutation status of the participants.

Control group

A healthy control group will be examined.

Transcranial magnetic stimulation (TMS)

Intervention Type: DEVICE

TMS over the left primary motor cortex will be performed. To investigate sensorimotor integration, an electrical stimulus on the right index finger will precede the TMS pulse.

Video-based clinical examination

Intervention Type: OTHER

A standardized neurological examination will be performed and video taped. The videos will be rated by movement disorder specialists, wo are blinded for the symptom and mutation status of the participants.

Interventions

Transcranial magnetic stimulation (TMS)

TMS over the left primary motor cortex will be performed. To investigate sensorimotor integration, an electrical stimulus on the right index finger will precede the TMS pulse.

Intervention Type: DEVICE

Video-based clinical examination

A standardized neurological examination will be performed and video taped. The videos will be rated by movement disorder specialists, wo are blinded for the symptom and mutation status of the participants.

Intervention Type: OTHER

24 hours drug withdrawal of dopaminergic medication

Examinations will be done under chronic dopaminergic treatment and after a 24 hours dopaminergic drug withdrawal.

Intervention Type: OTHER

Evaluation of deep brain stimulation

Examinations will be done before and after implantation of deep brain stimulation (clinically optimal stimulation vs. switched off stimulation)

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Pathogenic Parkin, PINK1, GCH1, or TAF1 gene variant
• Age >18 years
• Informed consent

• No movement disorder
• Age >18 years
• Informed consent
• No medication with influences on the central nervous system

Exclusion Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Michael J. Fox Foundation for Parkinson's Research

OTHER

Sponsor Role: collaborator

University Hospital Schleswig-Holstein

OTHER

Sponsor Role: lead

Responsible Party

Anne Weißbach

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Anne Weissbach, MD

Role: PRINCIPAL_INVESTIGATOR

Institute of Systems Motor Science

Locations

Institute of Systems Motor Science Lübeck

Lübeck, Schleswig-Holstein, Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Anne Weissbach, MD

Role: CONTACT

anne.weissbach@neuro.uni-luebeck.de

+49 451 3101 8219

Feline Hamami, M. Sc.

Role: CONTACT

feline.hamami@neuro.uni-luebeck.de

+49 451 3101 8218

Facility Contacts

Anne Weissbach, MD

Role: primary

anne.weissbach@neuro.uni-luebeck.de

+49 451 3101 8219

Other Identifiers

MJFF-022062

Identifier Type: -

Identifier Source: org_study_id