To Evaluate the Dose-response Effects of a Defined Volume of Physical Exercise on the Change of Peripheral Biomarkers, Clinical Response and Brain Connectivity in Parkinson's Disease: a Prospective, Observational, Cohort Pilot Study

This is a prospective, observational, cohort pilot study of standardize volume of aerobic exercise on changes in BDNF concentration at 4-weeks of exercise training among Parkinson disease patients.

Thirty (N=30) participants will be consecutively enrolled and assigned to 2 groups: 1) Extensive Rehabilitation Group (exercise volume: 180 METs-min/week) or 2) Intensive Rehabilitation Group (exercise volume: 1350 METs-min/week).

The primary objective is to evaluate the dose-response effects of two different rehabilitation settings, characterized by different workload (measured as energy expenditure), on blood BDNF levels.

This pilot observational study will evaluate the dose-response relationship between the volume of exercise, measured as METs-minutes/week, of two different rehabilitation settings to quantify the change in BDNF concentration in PD patients.

The study will also compare the changes induced by extensive and intensive rehabilitation settings in other neurotrophic factors and peripheral biomarkers, on motor and non-motor symptoms, kinematic parameters of gait, cognitive function, quality of life and the changes in cortical activity assessed with electroencephalogram (EEG) and in brain connectivity by functional magnetic resonance imaging (fMRI).

Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of Parkinson's Disease according to the United Kingdom (UK) Parkinson's Disease Society Brain Bank
* Aged between 30 and 80 years
* Disease stage II-III in "ON" phase according to modified Hoehn and Yahr (H\&Y)
* Having no severe cognitive impairment:

  * Mini-Mental State Examination-MMSE ≥24
  * Montreal Cognitive Assessment - MoCA ≥ 17/30
* Under stable dopaminergic pharmacological treatment
* Motor condition that permits to execute 6-Minutes Walking Test (6MWT)
* Willing to participate in the study, understand the procedures and sign the informed consent.

Exclusion Criteria:

* Diagnosis of neurological disorders not related to Parkinson's disease
* Musculoskeletal diseases that could impair gait and execution of exercise program
* Presence of known cardiovascular disease that can compromise the performance required by the protocol
* Presence of diabetes or other metabolic and endocrine disease
* Uncontrolled hypertension (resting blood pressure \>150/90 mmHg)
* Individuals with orthostatic hypotension and systolic pressure in feet below 100 will be excluded. Orthostatic hypotension (OH) is a reduction in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 minutes of standing.
* Hypo- or hyperthyroidism (TSH \<0.5 or \>5.0 mU/L), abnormal liver function (AST or ALT more than 2 times the upper limit of normal, ULN), alteration of kidney function.
* Values of complete blood test out of range and abnormal value clinically significant as per clinical judgment.
* Recent use of psychotropic drugs (e.g. anxiolytics, hypnotics, benzodiazepines, antidepressants) in which the dosage was not stable for 28 days before screening
* Severe disease (requiring systemic treatment and/or hospitalization) in the last 4 weeks.
* Any other clinically significant medical condition, psychiatric condition, drug or alcohol abuse, laboratory evaluation or abnormality that, in the opinion of the investigators, would interfere with the subject's ability to participate in the study.
* Beck Depression Inventory II (BDI) score \> 28, indicating a severe depression that precludes the ability to exercise.
* (Only for women) State of pregnancy.
* Other disorders, injuries, diseases or conditions that may interfere with the ability to perform exercises (e.g. history of stroke, breathing problems, traumatic brain injury, orthopaedic injury or neuromuscular disease).