Metabotropic Receptors For Glutamate Type 3 In Parkinson's Disease: Clinical And Neurophysiological Correlations

In recent years, numerous neurophysiological studies have characterized the alterations of voluntary movement and the pathophysiological mechanisms of MP. Kinematic studies have shown that in addition to bradykinesia, which literally means slowing of movement, voluntary movements in PD are characterized by reduced amplitude (hypokinesia), altered rhythmicity (dysrhythmia) and progressive decrease in amplitude and speed during the execution of repetitive movements (sequence effect). Recent evidence also suggests that the characteristics of voluntary movement can vary in the various stages of PD, it has been observed, for example, that in early stages of disease, i.e. in newly diagnosed patients not previously treated with dopaminergic drugs repetitive finger-tapping movements are characterized by reduced amplitude and speed and the effect sequence, without significant changes in the rhythm of movement. In the advanced stages of PD, movement is characterized by a marked decrease in amplitude and velocity and by an altered rhythm of movement but not by the sequence effect.

TMS is a neurophysiological technique that allows the non-invasive study of different physiological mechanisms of M1 in humans. Stimulation, delivered in single stimuli, allows for example to evaluate neurophysiological parameters such as motor thresholds, the amplitude of motor evoked potentials (MEPs) and the so-called input-output recruitment curve of MEPs, i.e. parameters that reflect the overall excitability of the corticospinal system. TMS delivered in pairs of magnetic stimuli allows additional parameters to be evaluated, such as intracortical inhibition at short intervals (SICI) and intracortical facilitation (ICF), i.e. parameters that reflect the excitability of inhibitory and facilitator cortical interneurons. In recent years, further protocols have been developed using the repetitive stimulation of M1 to induce lasting changes in the amplitude of MEPs that are thought to reflect the mechanisms of synaptic plasticity, similar to similar phenomena observed in the experimental animal. In particular, the technique of associative stimulation (PAS), is based on percutaneous electrical stimulation of the peripheral nerve and concomitant stimulation of M1 by TMS at certain inter-stimulation intervals (25ms or 10ms) to induce lasting changes, in a facilitatory or inhibitory sense, in the amplitude of MEPs. Numerous TMS studies have been performed in PD patients in recent years. Among the main results observed are altered excitability of M1, especially a reduced SICI and reduced synaptic plasticity, tested with the PAS technique or other methods. Recently, we have also observed that some alterations of excitability and plasticity of M1 correlate with specific kinematic alterations of movement in PD patients, suggesting therefore that neurophysiological changes of M1 contribute to the pathophysiology of bradykinesia. In addition to the central role played by a dopaminergic deficit in MP, recent evidence suggests a possible involvement of the neurotransmitter glutamatergic system.

MAIN ASSUMPTIONS AND OBJECTIVES

Hypothesis:

Previous studies have observed relationships between the reduced cortical inhibition and reduced synaptic plasticity of M1 and the overall severity of PD evaluated with standardized clinical scales and kinematic motion analysis techniques. In the present study, we will relate metabotropic type 3 glutamate receptor polymorphisms (mGlu3) to the severity of motor and non-motor symptoms, cortical plasticity and other neurophysiological parameters in patients with PD.