Biomarkers of Neurodegeneration and Neuroplasticity in Parkinson's Disease Patients Treated by Bilateral M1-iTBS

Movement Disorders Society (MDS) Unified Parkinson's Disease Rating Scale (UPDRS) Part III (MDS-UPDRS III). Part III assessed the motor signs of PD and was administered by the rater (Range 0-132). Part III contained 33 scores based on 18 items. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe.

MDS-UPDRS (parts II - IV). Part II assessed motor experiences of daily living (Range 0-52). Part IV assessed motor complications and contained 6 items. Score range: 0-24, 4 and below is mild, 13 and above is severe

Change in Levodopa and Dopamine Equivalent Daily Dosages (LEDD). The dosages of these medications are calculated using standardized conversion factors to obtain LEDD. This outcome aims to measure any changes in the daily dosages of these medications over the course of the study or intervention.

The PFS-16 is a 16-item patient-rated scale based on recent feelings and experiences over the past two weeks. Nine items address the impact of fatigue on daily functioning and activities, including socialization and work but not exercise specifically and seven items tap the presence or absence of the subjective experience of fatigue with an emphasis on the physical effects of fatigue. The scoring possibilities are 1 for "strongly disagree" and 5 for "strongly agree". Based on the total of the scores, an ordinal PFS score ranging from 16 to 80 will be applied.

Mobility impact as assessed by PDQ-39 mobility dimension (questions #1-10 from the total PDQ-39 questionnaire). Scores are on a 0-4 Likert Scale (lower scores equaling better quality of life), summed, and then transformed into the total PDQ-39 that ranges from 0-100. Lower scores represent better quality of life.

Mini Mental Parkinson (MMP) is a brief questionnaire derived from the Mini Mental State Examination and used for the assessment of general cognitive function in PD patients. This test is evaluated on a maximum of 32 points. The presence of severe or moderate cognitive impairment comparable to dementia is indicated by a score of ≤ 24.

Frontal Assessment Battery (FAB) is a short battery consisting of 6 subtests related to different frontal lobe functions. The maximum score to be obtained in this test is 18 points. To consider that the subject presents alterations in the frontal lobe and, therefore, altered executive functions, his score must be equal to or less than 11 points.

Benton Visual Retention Test (BVRT) is a test used for the evaluation of visuospatial memory. In our protocol, we plan to use the multiple choice format of administration, which consists of stimulus presentation followed by concealment for immediate recognition of one item out of four answer options (specifically, the M form). The performance is scored 0-10 based on correct drawing reconstruction.

In the BDI-II, a score of 0-13 indicates absence of depression, 14-19 mild depression, 20-28 moderate depression, and 29-63 severe depression.

In the HAM-A has a score range of 0 to 56, where higher scores are associated with higher severity anxiety.

The SAS has 14 items, rated on a 4-point scale with higher values indicating more apathy

The SEND-PD is a 12-item scale divided into three subscales: psychotic symptoms, mood/apathy, and impulse control behaviors. Items are rated from 0 (not present) to 4 (very severe)

The PPQ is a screening tool used to measure the frequency and severity of early signs and psychotic symptoms of PD and consists of six items, each rated from 1 (no symptoms) to 4 (extreme symptoms); the total score ranges from 6 to 24 points.

The FrSBe is a self-report scale designed to assess the changes in behavior that may occur in relation to frontal system dysfunction. Each item is rated on a 1-5 Likert scale. Raw scores for the three subscales (Apathy, Disinhibition, and Executive Dysfunction) and the Total are reported as T scores.

The QUIP is a screening questionnaire developed for the assessment of Impulsive-Compulsive Disorders (ICDs) and related behaviors. It uses a 5-point Likert scale (score 0-4 for each question) to gauge the frequency of behaviors. Scores for each ICDs and related disorder range from 0 to 16 and the total QUIP score for all ICDs and related disorders combined ranges from 0 to 112, with a higher score indicating greater severity (ie, frequency) of symptoms.

The CNS-LS is a screening instrument composed of seven items that are scored by the patient according to the perceived frequency of pseudobulbar affect (PBA) episodes during the last week. A CNS-LS score of 13 or higher may suggest PBA.

The following transcranial magnetic stimulation (TMS)-derived measures of cortical excitability using electromyography (EMG) parameters of cortical excitability will be obtained after stimulation of the first dorsal interosseous (FDI) muscle hotspot of the mapping grid: the resting motor threshold (rMT); the active motor threshold (aMT); twenty single pulses ("20t"); and the cortical silent period (cSP)

Power spectral density (PSD) analysis of delta, theta, alpha, beta, gamma rhythms, and functional connectivity measures (e.g., coherence, synchronization measures from graph theory metrics) of EEG signal recorded during eyes-closed (4 min) and eyes-open (4 min) conditions

Measures of global and regional gray matter (GM) volume and cortical thickness (CT) changes in magnetic resonance imaging (MRI) by voxel-based morphometry (VBM) measures

Using baseline iTBS resting-state functional magnetic resonance imaging (fMRI), altered brain networks associated with PD will be identified by independent component analysis (ICA) and Seed-to-voxel and seed-to-seed functional connectivity measures between patients and controls.

Quantification of serum NfL levels by Single-molecule assay (Simoa; SR-X™ biomarker detection system)

Quantification of serum GFAP levels by Single-molecule assay (Simoa; SR-X™ biomarker detection system)

Quantification of serum BDNF levels by Single-molecule assay (Simoa; SR-X™ biomarker detection system)