Predicting Parkinson's Disease Before It Strikes: A Brain Imaging Study in At-Risk Individual

Parkinson's disease (PD) is a chronic, debilitating neurodegenerative disorder characterized by progressive motor dysfunction and various non-motor features. Better understanding and prediction of PD progression from the earliest stage will improve disease management and clinical trial design.

Idiopathic REM sleep behavior disorder (iRBD) is the most specific marker of prodromal PD, since the majority of individuals with iRBD eventually develop PD or a related synucleinopathy. Longitudinal studies have shown that the estimated risk for the clinical diagnosis of a synucleinopathy from the time of iRBD diagnosis is about 35% at 5 years, 75% at 10 years, and 90% at 14 years. Therefore, studying iRBD provides a unique window to observe neurodegenerative synucleinopathies in their prodromal stages, before parkinsonism or dementia becomes fully manifest.

This is a national, monocentric, longitudinal observational study with additional procedures. Patients with iRBD will be screened to evaluate eligibility: patients will be included if they have PSG-confirmed longstanding iRBD duration since diagnosis equal or greater than 5 years, without a clinically defined PD.

All patients undergo clinical and cognitive assessments, quantitative PSG, and MRI visits at baseline (T0) and every year for 3 years. PSG is performed to diagnose iRBD and investigate PSG changes over time. MRI evaluations investigate structural alterations and resting-state (RS) functional connectivity. Longitudinal measures of cortical/subcortical atrophy, white matter damage, and RS connectivity will be assessed.

A group of 50 healthy subjects similar for age (50-75 years old) and sex to patients with iRBD will be recruited. They will undergo clinical evaluation and PSG at study entry (to exclude sleep disorders), and motor, neuropsychological and MRI assessments at baseline and every year for 3 years.

Clinical assessments include: Unified Parkinson's Disease Rating Scale (UPDRS), Single-Question Screen for REM sleep behavior disorder, REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Beck Depression Inventory-II (BDI-II).

Motor assessments include: Five Times Sit-To-Stand, Ten-Meter Walking Test (10MWT), Timed Up and Go Test (TUG), TUG with cognitive task, Nine Hole Peg Test.

Neuropsychological assessments include: MMSE, Digit span forward and backward, Corsi block-tapping test, Rey's List, Raven's Progressive Matrices, Trail Making Test A and B (TMT-A and TMT-B), Attentive Matrices, Verbal Fluency (phonemic and semantic cues), Token Test, Copy of Rey-Osterrieth complex figure.

PSG recording includes: electroencephalogram (six channels), electrooculogram, electromyography (submentalis muscle and bilateral tibialis anterior muscles), electrocardiogram, and sleep respiratory pattern.

Brain MRI sequences include: 3D sagittal T1-weighted fast field echo (structural MRI), diffusion tensor (DT) MRI, and T2*-weighted EPI sequence for resting-state fMRI.

Statistical analyses include: t-test, Mann-Whitney U-test or Pearson chi-square for between-group comparisons; longitudinal linear generalized models for repeated measures or Wilcoxon test for within-group changes over time; multivariable linear mixed-effects models for predictors of motor/nonmotor progression; multivariable Cox model for predictors of conversion to full clinical disease in iRBD.

Inclusion criteria

(both patients and healthy controls):

• Right-handed participants.
• Monolingual native Italian speakers.
• Age between 50 and 75 years old.
• Normal or corrected-to-normal visual acuity.
• Mini Mental State Examination (MMSE) score greater than 24.
• Oral and written informed consent to study participation.

Additional inclusion criteria for iRBD patients:

• Diagnosis of iRBD based on International Classification of Sleep Disorders, 3rd Edition (ICSD-3) criteria: presence of REM sleep without atonia; presence of sleep-related injurious-disruptive behaviors by history or abnormal sleep behaviors documented during PSG monitoring; absence of EEG epileptiform activity during REM sleep; presence of sleep disturbance not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder.
• PSG-confirmed iRBD duration since diagnosis equal or greater than 5 years.
• Absence of clinically defined Parkinson's disease.

Exclusion criteria

for iRBD patients:

• Secondary forms of RBD on the basis of historical data, neurologic examination, and cerebral MRI findings.
• History of other systemic, neurologic, or psychiatric diseases, head injury, cardiovascular events, and cerebrovascular alterations visible at MRI scan.
• Alcohol and/or psychotropic drugs abuse.
• Contraindications to MRI scan (cardiac pace-maker or other types of cardiac catheters, splinters or metallic shards, metallic prosthesis not compatible with the magnetic field generated by MRI, claustrophobia).

Exclusion criteria

for Healthy Controls:

• Sleep disorders on the basis of clinical evaluation.
• History of systemic, neurologic, or psychiatric diseases, head injury, cardiovascular events, and cerebrovascular alterations visible at MRI scan.
• Alcohol and/or psychotropic drugs abuse.
• Contraindications to MRI scan (cardiac pace-maker or other types of cardiac catheters, splinters or metallic shards, metallic prosthesis not compatible with the magnetic field generated by MRI, claustrophobia).
• Hypnotic or benzodiazepine medication.