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:
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.
