Parkinson's disease is characterized by different clinical subtypes but the pathophysiological mechanisms underlying the clinical subtypes are unknown. The aim of the present study is to provide the first neurophysiological, neuroradiological and neurobiological characterization of PD clinical subtypes. A further aim of the study will be to identify the neurophysiological correlates of the various types of PD tremor (rest, re-emergent and postural). For this project 150 patients with PD will be enrolled. For each patient we will collect demographic and clinical data. The clinical variables will include motor as well non-motor symptoms. PD clinical subtypes will be identified by using a `data-driven¿ cluster analysis of patients based on clinical and demographic featuires . For the neurophysiological assessment motor and sensory functions weill be investigated. For the assessement of primary motor cortex excitability and plasticity we will use different single pulse and repetitive transcranial magnetic stimulation (TMS) techniques. To test motor performance, we will measure the kinematic parameters of index finger abductions performed with maximum velocity. Sensory function and sensorimotor investigations will be assessed with somatosensory temporal discrimination threshold (STDT) at rest and during voluntary finger movements . All patients will undergo a magnetic brain resonance imaging standardized scan. In order to provide a neurobiological profile of PD subtypes we will also measure a-synuclein concentration in the saliva of patients with PD. Finally the neurophysiological correlates of the different types of tremor will use the recent developed technique of TMS-electroencephalogram.
The present study will allow to understand whether the various subtypes in PD rae due to different pathophysiological mechanisms and to provide useful biomarkers for PD subtype.
Although several authors have suggested that PD is characterized by different clinical subtypes no previous studies have specifically investigated the pathophysiology of the clinical subtypes. In 2014, the National Institutes of Health suggested that subtype identification is one of the top 3 clinical research priorities in PD. The definition of subtypes based only on clinical features, however, does not add usefull information on the mechanisms and causes underlying PD. In the present study, we will provide, for the first time, a comprehensive neurophysiological, neuroradiological and biomarker characterization of PD clinical subtypes. By using this approach, we will verify whether PD subtypes reflect differences in clinical features only without differences in pathophysiological mechanisms, or whether specific clinical subtypes are generated by different pathophysiological mechanisms. The different involvement of motor and sensory functions, as tested by neurophysiological techniques as welle as differences in neuroradiological and neurobiological markers profile may characterize the clinical subtypes. By thie approach we propose it would be possible to demonstrate the involvement of specific structures and circuits in brain areas.
A further aim of the project is to investigate the pathophysiology of tremor by using advanced neurophysiological techniques. Specific neurophysiologiocal changes may characterize the various types of tremor present in PD (rest, postural and reemergent).
Overall, the results of the present project will provide a major understanding in the pathophysiology of PD and will give new opportunities for personalized and interventional treatment in PD.