The goal of the present study is to explore the diagnostic and prognostic value of neurophysiological biomarkers obtained through paired-pulse Transcranial Magnetic Stimulation (TMS) techniques in individuals affected by Parkinson's disease (PD) with and without cognitive decline.

The main questions it aims to answer are:

• TMS measures of cortical excitability are able to distinguish between PD patients cognitively normal, PD-Mild Cognitive Impairment (PD-MCI) and PD-Dementia (PD-D)?
• TMS measures of cortical excitability are able to predict progression of PD patient cognitive status from cognitively normal to PD-MCI and PD-D?

Parkinson's disease (PD) is the second most common degenerative disease in the world, affecting approximately 10 million people globally. Cognitive decline is considered one of the most frequent non-motor symptoms, reaching a prevalence of 80% in patients with advanced stages of the disease. Cognitive impairment represents one of the most challenging symptoms for patients, caregivers, and society. The pathophysiology underlying cognitive impairment in PD is still not fully understood.

From a neuro-transmission system perspective, cognitive decline appears to be caused predominantly by dysfunction of three systems: dopaminergic, noradrenergic, and cholinergic. Transcranial Magnetic Stimulation (TMS) is able to explore cortico-spinal pathway functionality, cortical excitability, as well as the integrity of different intra-cortical, transcortical, and cortico-subcortical neuro-transmission circuits. Paired-pulse techniques such as Short Interval Cortical Inhibition (SICI), Short Latency Afferent Inhibition (SAI), and Intracortical Facilitation (ICF) pair a conditioning and a test stimulus with different inter-stimulus intervals (ISI), permitting the exploration of transmission in neural circuits dependent on different neurotransmitters.

In the last 20 years, TMS has been applied to the study of patients with Alzheimer's dementia (AD), Fronto-temporal dementia (FTD), and Lewy Body dementias (LBD), in order to better understand their pathophysiological mechanisms and identify potential biomarkers to be used as surrogate endpoints in clinical trials for disease-modifying therapies. Conversely, dementia related to PD has been much less studied compared to AD, FTD, and LBD (7 studies in total and 176 patients with PD-related cognitive decline enrolled vs >40 studies in total and >1000 patients with AD, FTD, and LBD enrolled).

In PD patients with PD-related cognitive decline, cortical measures of excitability evaluated through TMS protocols included Resting Motor Threshold (RMT), Activated Motor Threshold (AMT), Silent Period (SP) from contralateral (CSP) and ipsilateral (ISP) activation, SAI, SICI, and ICF. A preliminary review of these studies revealed that the most commonly evaluated TMS measures were RMT and SAI (6 studies out of 8), and the measures that were significantly different, with a large effect size (expressed as Cohen's d > 0.7), comparing PD patients with and without cognitive decline (defined as MCI or dementia), were SAI and ICF (both reduced in patients with cognitive decline), while SICI was significantly increased only in PD patients with dementia compared to cognitively intact PD patients. No study has explored the value of these measures in predicting the evolution of cognitive decline to MCI or dementia.

The aim of the present study is to explore the diagnostic and prognostic value of neurophysiological biomarkers obtained through paired-pulse TMS techniques in individuals affected by PD. Comprehensive neurological and neuro-psychological evaluations will be performed after enrollment, in addition to a set of paired-pulse TMS tests including SAI, SICI, and ICF. Patients will be categorized according to cognitive status (cognitively normal - CN, MCI, dementia) and assessed at T0, after T1 (one year), T2 (two years), and T3 (three years). SAI, SICI, and ICF measures will be compared cross-sectionally among PD patients cognitively normal, with MCI, and dementia to assess their diagnostic value in differential diagnosis of cognitive status. Moreover, SAI, SICI, and ICF measures of patients manifesting a progression of cognitive status from cognitively normal to MCI, and from MCI to dementia at follow-ups, will be compared with those of patients not manifesting a progression of cognitive status, to assess their value in predicting the evolution of cognitive status.

Inclusion Criteria:

• Age > 18 years
• Ability to undergo an extensive neuropsychological evaluation
• Ability to sign informed consent for the study
• Diagnosed with idiopathic PD according to the latest revision of the MDS criteria
• On stable and optimal antiparkinsonian therapy for at least four weeks

Exclusion Criteria:

• Systemic diseases of significant severity, including cardiovascular and cerebrovascular conditions (e.g., active neoplasms requiring chemotherapy, or end-stage heart failure)
• Presence of any active neurological disease, in addition to PD
• Presence of a cochlear implant, ferromagnetic brain device or near the site of brain stimulation, pacemaker, brain electrodes for DBS, electromechanical devices with IPG, or any other implantable stimulator, including peripheral ones
• History of epilepsy
• History of cerebrovascular, tumor-related, infectious, or metabolic brain conditions predisposing to seizures or causing symptomatic epilepsy
• Pregnancy or breastfeeding
• Alcoholism
• Treatment with anticholinesterase drugs, benzodiazepines, neuroleptics, anticholinergics, or antidepressants in the last month
• Treatment with drugs that lower the seizure threshold (e.g., imipramine, amitriptyline, doxepin, nortriptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, cocaine, MDMA, ecstasy, phencyclidine, ketamine, gamma-hydroxybutyrate, alcohol, theophylline)
• Active cochlear pathology (especially if currently receiving ototoxic drugs, such as aminoglycoside antibiotics)
• Dementia according to the latest revision of the MDS criteria for PDD