This study investigates magnetic resonance-guided focused ultrasound thalamotomy (MRgFUSth) for people with Parkinson's disease (PD) and tremor not responding to conventional standard doses of dopamine replacement therapy. The aim is to identify clinical and imaging biomarkers predictive of sustained tremor control up to 24 months after MRgFUSth treatment. Participants will undergo a suprathreshold levodopa test and ¹⁸F-DOPA PET imaging to evaluate dopaminergic and serotonergic involvement in tremor. All participants will receive MRgFUSth and be followed for 24 months with standardized clinical, cognitive, and quality-of-life assessments. The study seeks to improve understanding the possible mechanisms of tremor relapse and inform patient selection for MRgFUSth in PD.

Background

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, affecting approximately 2% of people over 65 years of age. The pathological hallmark of PD is the progressive degeneration of dopaminergic neurons in the substantia nigra, and the cardinal clinical features are bradykinesia, rigidity, and resting tremor.

Dopaminergic dysfunction within the striatum closely correlates with the severity of bradykinesia and rigidity. However, this relationship is less consistent for resting tremor, which likely reflects the involvement of additional neurotransmitter systems. While dopamine replacement therapy (DRT) is mostly effective for bradykinesia and rigidity, the effect on resting tremor is more variable.

Positron emission tomography (PET) findings indicate that tremor-dominant Parkinson's disease (TDPD), compared with the akinetic-rigid subtype, is characterized by relatively greater serotonergic than dopaminergic dysfunction. Previous studies have used the raphe nuclei and putamen as markers of serotonergic and dopaminergic terminal integrity, respectively. The interindividual relationship between serotonergic and dopaminergic terminal integrity can thus be expressed by the raphe/putamen specific binding ratio. Reduced integrity of the serotonergic system relative to dopaminergic integrity (low raphe/putamen ratio) has been associated with higher tremor amplitude and may partly account for the limited responsiveness of tremor to DRT compared with bradykinesia and rigidity.

Medical-refractory tremor is a clinical challenge and highlights the need for non-pharmacological treatment.

Magnetic resonance-guided focused ultrasound thalamotomy (MRgFUSth) is an incisionless treatment for both essential tremor and PD tremor. The procedure creates a focal lesion in the ventral intermediate (VIM) nucleus of the thalamus. MRgFUSth has been shown to effectively reduce PD tremor and to have a favorable safety profile. However, approximately 20% of treated patients experience tremor relapse within one to two years. The prevalence and causes of relapse are not well defined.

Hypothesis The investigators hypothesize that underlying differences in neurochemical and neuronal network integrity explain the variability in long-term response and relapse of tremor following MRgFUSth in PD.

Specifically, the expectation is that dopamine-resistant patients with lower raphe/putamen ratios will show more durable tremor control. In contrast, dopamine-responsive patients with higher raphe/putamen ratios may be more prone to relapse as nigrostriatal degeneration progresses.

Objective To increase understanding of tremor relapse following MRgFUSth in PD and to identify clinical and imaging biomarkers associated with sustained tremor control, thereby supporting improved patient selection and optimized therapeutic outcomes.

Study design This is a prospective, interventional cohort study conducted at Aarhus University Hospital.

Eligible participants are 50-80 years old and have established diagnosis of PD and tremor unsatisfactory controlled with conventional standard doses of dopamine replacement therapy.

All screened patients undergo a standardized levodopa test using an oral suprathreshold levodopa/carbidopa dose (300/75 mg) to classify dopaminergic responsiveness of tremor.

The test is performed after ≥8 hours of dopaminergic medication withdrawal ("OFF" state). The Movement Disorder Society version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III will be administered before and after levodopa/carbidopa administration.

A total of 20 participants will be enrolled, equally divided into two predefined groups based on the outcomes of the levodopa test:

• Dopamine-responsive group (n=10) >30% improvement in MDS-UPDRS III tremor subscore (items 3.15-18)
• Dopamine-resistant group (n=10) ≤30% improvement in MDS-UPDRS III tremor subscore

Although all enrolled participants have tremor insufficiently controlled by their usual dopaminergic treatment, some demonstrate marked tremor improvement under the standardized suprathreshold levodopa/carbidopa challenge ('dopamine-responsive'), while others do not ('dopamine-resistant'). These classifications apply solely to the high-dose test conditions and do not reflect real-world treatment effectiveness

A ¹⁸F-DOPA PET (along with an MRI for PET co-registration) will be performed at baseline to further characterize individual serotonergic and dopaminergic specific binding ratios (raphe/putamen ratio) in these patients. A repeat ¹⁸F-DOPA PET will be performed 18 months after MRgFUSth to assess progression of nigrostriatal and/or serotonergic dysfunctions.

All participants will receive unilateral MRgFUSth targeting the ventral intermediate (VIM) nucleus contralateral to the most affected limb.

The procedure is performed using the Exablate Neuro 4000 system (Insightec Ltd.) under MR guidance within its CE-marked clinical indication.

Clinical assessment will be performed at baseline (pre-MRgFUSth) and 24 hours, 6, 12, 18 and 24 month post-MRgFUSth.

Assessment battery:

• MDS-UPDRS Parts I-IV
• Fahn-Tolosa-Marin Tremor Rating Scale (FTM)
• Mini-BESTest, 20-meter walk test and Timed Up and Go (TUG) for balance and gait
• Montreal Cognitive Assessment (MoCA)
• Patient and Clinician Global Impression of Change (PGIC, CGI-I)
• Quality of life (QoL) questionnaires
• Neuropsychological evaluations

Clinical assessment of FTM part A and B and MDS-UPDS part III will be video recorded.

MDS UPDRS tremor scores (item 3.15-3.18) and FTM part A and B of upper extremities will be rated by a movement disorder specialist blinded to dopamine-responsiveness status of the participant.

Safety and ethics Adverse events, neurological symptoms, and medication adjustments will be recorded at each time point.

Safety monitoring is coordinated by the study's clinical research coordinator, and all events will be reviewed by the investigator team.

All participants will provide written informed consent before enrollment. Data will be recorded in REDCap (Research Electronic Data Capture) hosted by Aarhus University Hospital, where participant data will be anonymized by randomly assigned project ID. Only the clinical investigators will have access to the data. Data handling complies with the EU General Data Protection Regulation (GDPR) and the Danish Data Protection Act.

Inclusion Criteria:

• Established diagnosis of idiopathic Parkinson's disease
• Tremor not manageable with optimal medication
• Clinical Indication for MRgFUSth
• Able to understand study requirements and provide consent
• HOEHN and YAHR <3

Exclusion Criteria:

• Dementia or severe cognitive impairment
• The presence of another significant neurological/psychiatric disorder or significant disease
• Severe psychopathology, not medically managed
• Poor balance and gait function based on neurological examination
• Epilepsy
• Active drug abuse
• History of stroke or structural lesions on MRI that could interfere with image analysis.
• Contraindications for MRI
• Cardiac pacemaker
• Pregnancy or breast-feeding
• Claustrophobia
• Patients unable to lie on the back for 2-4 hours in the MR-scanner-setting
• Patients who do not want information about findings of unknown disease during the trial
• SDR (Skull density rate) lower than 0.35