SensoMo-PD: Sensorimotor Integration in Monogenic Parkinson-dystonia Syndromes

Sponsor

University Hospital Schleswig-Holstein (Other)

Overall Status

Recruiting

CT.gov ID

NCT05713721

Collaborator

Michael J. Fox Foundation for Parkinson's Research (Other)

120

Enrollment

Location

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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, we want to look at how the brain works and how different areas of the brain communicate with each other. We 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, we 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 us, 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 our study, we will build up large groups of mutation carriers that have received an in-depth clinical and neurophysiological examination and can be investigated longitudinally in future studies.

Condition or Disease	Intervention/Treatment	Phase
Parkinson Dystonia DYT3 DYT5 PINK1 Gene Deletion Dystonia, Familial	Device: Transcranial magnetic stimulation (TMS) Other: Video-based clinical examination Other: 24 hours drug withdrawal of dopaminergic medication Other: Evaluation of deep brain stimulation

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, we 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, we will perform video-based clinical examination, 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 Design

Study Type:

Observational

Anticipated Enrollment :

120 participants

Observational Model:

Other

Time Perspective:

Prospective

Official Title:

SensoMo-PD: Sensorimotor Integration in Monogenic Parkinson-dystonia Syndromes

Actual Study Start Date :

Jan 1, 2023

Anticipated Primary Completion Date :

Jun 30, 2024

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
SMC DYT/PARK-TAF1 Symptomatic mutation carriers (SMC) of the TAF1 gene, which is associated with X-linked Dystonia-Parkinsonism, will be examined.	Device: 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. Other: 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. Other: 24 hours drug withdrawal of dopaminergic medication Examinations will be done under chronic dopaminergic treatment and after a 24 hours dopaminergic drug withdrawal. 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)
AMC DYT/PARK-TAF1 Asymptomatic mutation carriers (AMC) of the TAF1 gene will be examined.	Device: 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. Other: 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.
SMC DYT/PARK-GCH1 Symptomatic mutation carriers (SMC) of the GCH1 gene, which is associated with dopa-responsive Dystonia, will be examined.	Device: 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. Other: 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. Other: 24 hours drug withdrawal of dopaminergic medication 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.	Device: 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. Other: 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.
SMC PARK-Parkin/PARK-PINK1 Symptomatic mutation carriers (SMC) of the Parkin or PINK1 genes, which is associated with Parkinsonism, will be examined.	Device: 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. Other: 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. Other: 24 hours drug withdrawal of dopaminergic medication 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.	Device: 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. Other: 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.
Control group A healthy control group will be examined.	Device: 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. Other: 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.

Outcome Measures

Primary Outcome Measures

To compare 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)
To analyze 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
To investigate if clinical symptom severity correlates 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
To investigate 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)