Parkinson s disease (PD) is a progressive neurodegenerative disorder and current treatment options only tackle symptoms. We aimed to evaluate the effect of intracranial photobiomodulation (iPBM) on dopaminergic neurons and its consequences on motor symptoms in de novo PD patients. This randomised open label study included 6 de novo PD patients, 3 served as control and 3 were treated by chronic iPBM during 2 years. They were included from december 2020 to april 2022. Researcher analysing the PET data was unaware of patients iPBM status but clinical examinator was aware of it. Data analysis was performed on June 2024. De novo PD patients were recruited and randomized (1:1) to receive iPBM or medical treatment alone for 4 years. PD diagnosis was < 2 years, and no medication was allowed at inclusion. PET scan was performed at baseline and at 1 year This randomized clinical trial was performed in France, at Clinatec-CEA research center and University Hospital, Grenoble and in CERMEP, Lyon, France. Primary outcome was safety. The secondary outcome measure was the evolution at 2 years of motor scales using the MDS-UPDRS part III and the evolution of PET scan (using the [11C]-PE2I ligand) at 1 year. Six patients (1f, 5m) were recruited with a mean age (SD) of 55.3 years (7.6). We showed that iPBM was feasible and safe on the first 3 operated patients. The first novelty of the study was that iPBM improved motor scores in average at 2 years whereas the control group followed the natural clinical decline. Mean (SD) clinical outcome with iPBM was -6.2% (32.9%) improvement on the MDS-UPDRS (part III) compared to baseline versus +130% (143%) for control group. The second novelty was that in the iPBM group, [11C]-PE2I PET scans showed an unusual mean increase in tracer binding within the caudate +21.3%(15.9), nucleus accumbens +22.2%(23.7%), pallidum +89.7% (94.8%) and putamen +26.1%(34%). in the control group, as expected, tracer binding was decreased (SD) on average in the caudate -16.9%(-16.3%), nucleus accumbens -27.5%(-28.4%), and putamen -19.5%(-11.4%), but slightly increased in the pallidum +10.7%(+39.6%). Because of the small number of patients, no statistical test was performed at this stage. Conclusions: iPBM was feasible and safe in this small group of patients. It showed an unusual improvement of motor scores at 2 years that was associated with striking increase of dopamine transporter in the basal ganglia observed on the [11C]-PE2I PET. These preliminary data suggest a possible modifying disease effect related to iBPM. A larger number of patients with longer follow up is mandatory to validate our preliminary results.

SC is consultant for Medtronic and Boston Scientific ST has received consultant fees from Abbvie, Boston Scientific, Medtronic and payements for lectures from MERZ, Movement Disorders Society, NHC, Aguettant

NCT04261569

This study was funded by Boston Scientific and the Edmond J Safra Foundation

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The details of the Institutional Review Board (IRB) or oversight body that approved or provided exemption for the research described in this manuscript are outlined below: All analyses conducted as part of the present study were approved by the Comite de Protection des Personnes Phones Alpes Auvergne (2019-A02097-50) April 2020 and received additional authorization from the French National Agency for the Safety of Medicines and Health Products (ANSM) in January 2020. The treatment and handling of data adhered to all applicable ethical regulations.

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