Navigating the therapeutic landscape in advanced Parkinson’s disease: a comprehensive review from infusion therapies to stem cells

Oral dopaminergic treatment is the cornerstone of Parkinson's disease (PD) management. However, progressive shortening of oral levodopa's effect, along with the limited efficacy of enzyme inhibitors and dopamine agonists, does not allow to adequately control motor and non-motor complications characterizing advanced PD. At this stage, device-aided therapies (DATs), including infusion treatments, are warranted to guarantee an adequate quality of life. We review current and upcoming infusion therapies for PD, with a particular focus on their efficacy and safety data. Moreover, we provide an overview of current knowledge and open issues on patient selection and specific DAT choice. Recent EAN/MDS-ES guidelines suggest infusion therapies for advanced PD, yet several challenges remain, including limited access, delayed referrals, and patients' hesitancy. The'5-2-1' criteria and tools like MANAGE-PD aid early identification of eligible candidates, but treatment decisions often do not account for patients' preferences. Current trends favor early DATs implementation, as soon as motor fluctuations appear and before the disability onset. Emerging infusion therapies (e.g. foslevodopa-foscarbidopa) will boost this tendency. Enhancing DATs accessibility and inclusivity in clinical trials are key priorities. Finally, regenerative therapies including putaminal infusion of neurotrophic factors and dopaminergic neuron precursors may transform advanced PD care.