Mild Cognitive Impairment and Endurance Exercise in Parkinson's Disease

Mean change in cognitive function from baseline to 6-months as measured by global statistical test (GST) for cognitive domains. This will be a composite score reported as Z-scores. The Z-score indicates the number of standard deviations away from the mean, which is based on normative (healthy control) data. A Z-score of 0 is equal to the mean of the normative data with negative numbers indicating values lower than the mean and positive values higher. A positive change in Z-scores indicates a favorable outcome.

The GSTs will be calculated from the following neuropsychological tests administered in the cognitive test battery reflecting specific cognitive domains:

• Attention/Working Memory - Trail Making Test-Part A
• Executive Function - Trail Making Test-Part B, Clock Draw, Raven's Progressive Matrices
• Memory - Hopkin Verbal Learning Test-Revised, Free and Cued Selective Reminding Test, Figural Memory Test
• Processing Speed - Symbol Digit Modality Test

Mean change in total MDS-UPDRS score. This is a summed total from Part I (non-motor experiences of daily living), Part II (motor experiences of daily living, Part III (motor examination) and Part IV (motor complications). The minimum score on the MDS-UPDRS is 0 and the maximum is 260 with higher scores representing worse symptoms.

Mean change in total MDS-UPDRS Part II (motor experiences of daily living) score. Part II comprises 13 items evaluating the impact of PD on patients' activities of daily living (ADL) over the week prior to the visit such as speech, salivation, swallowing, eating, handwriting, dressing, turning in bed, walking. The total score, being the sum of all these items, can be between 0 to 52. Higher scores represent worse symptoms.

Mean change in total MDS-UPDRS Part I (non-motor experiences of daily living) score. Part I assesses 15 items of non-motor aspects of experiences of daily living. Part IA is assessed by a qualified rater, Part IB is completed by the patient. The total score, being the sum of all these items, can be between 0 to 60. Higher scores represent worse symptoms.

Mean change in total MDS-UPDRS Part IV (motor complications) score. Part IV assesses motor complications of therapy, such as dyskinesias, motor fluctuations. This part (6 items) is completed by a qualified rater. The total score, being the sum of all these items, can be between 0 to 24. Higher scores represent worse symptoms.

Mean change in total MDS-UPDRS Part III (motor examination) score. The minimum score on the MDS-UPDRS Part III is 0 and the maximum is 132 with higher scores representing worse motor symptoms.

The ESS assesses the overall level of daytime sleepiness. Eight items describe normative daily situations known to vary in their soporific qualities. Patients rate the likelihood of dozing off or falling asleep. The test is rated on a 4-point scale (0=would never doze off to 3=high chance of dozing off).

The Pittsburgh Sleep Quality Index (PSQI) contains 19 self-rated questions and 5 questions rated by the bed partner or roommate (if one is available). Only self-rated questions are included in the scoring. The 19 self-rated items are combined to form seven "component" scores, each of which has a range of 0-3 points.The global PSQI score is then calculated by totaling the seven component scores, providing an overall score ranging from 0 to 21, where lower scores denote a healthier sleep quality.

A 9-item questionnaire with questions related to how fatigue interferes with certain activities and rates its severity according to a self-report scale. The items are scored on a 7 point scale with 1 = strongly disagree and 7= strongly agree. The minimum score = 9 and maximum score possible = 63. Higher the score = greater fatigue severity.

Although the HAM-D form lists 21 items, the scoring is based on the first 17. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2. Higher scores represent more severe depression.

The NeuroQOL is a self-report of health related quality of life in 17 domains and sub-domains for adults. Item banks consist of 302 items in total (range from 5 to 45) which are used adaptively to test a variable number and content of items in a computer assisted testing format. All items are rated on a five option scale based on intensity (e.g. 1 = not at all, 2 = a little bit, 3 = somewhat, 4 = quite a bit, 5 = very much) or frequency ("never" to "always"). Raw scores are converted based on consistent metric (T-distribution) with data from the US general population with a T-score mean of 50 and standard deviation of 10.

The PDQ-39 is a 39-item self-report questionnaire, which assesses Parkinson's disease-specific health related quality over the last month covering 8 dimensions 1) Mobility (10, #1-10) 2) Activities of daily living (ADL) (6, #11-16) 3) Emotional well-being (6, #17-22) 4) Stigma (4, #23-26) 5) Social support (3, #27-29) 6) Cognition (4, #30-33) 7) Communication (3, #34-36) 8) Bodily discomfort (3, #37-39) on a 5 point ordinal system (0=never, 4=always). Dimension score = sum of scores of each item in the dimension divided by the maximum possible score of all the items in the dimension, multiplied by 100. Each dimension total score range from 0 (never have difficulty) to 100 (always have difficulty). Lower scores reflect better QoL. Overall score can be summarized in the Parkinson's Disease Summary Index (PDSI) or PDQ-39 Summary Index (PDQ-39 SI).PDSI or PDQ-39 SI = sum of dimension total scores divided by 8.

The examiner begins with Item 1 and continues through Item 60, unless the patient is in distress or refuses to continue. The patient is told to tell the examiner the name of each picture and is given about 20 seconds to respond for each trial. The examiner writes down the patient's responses in detail, using codes. If the patient fails to give the correct response, the examiner at her or his discretion may give the patient a phonemic cue, which is the initial sound of the target word. After the patient completes the test, the examiner scores each item + or - according to the response coding and scoring procedures.

The Verbal Fluency Test has two conditions, Letter Verbal Fluency and Category Verbal Fluency. Letter Verbal Fluency assesses the number of words beginning with certain letters that participants can generate within 60 seconds, the Category Verbal Fluency assesses the number of words within particular categories participants can generate within 60 seconds.

Benton Judgment of Line Orientation Test is a standardized test with 30 items that is specific for visual spatial cognition. Tests will be administered at baseline, after 3, 6, 9 and 12 months of treatment.

The minimum score is 0, indicating low visual spatial cognition. The maximum score is 30, indicating high visual spatial cognition

This involves the participant copying an intersecting double pentagon and is given a maximum score of 1 point based on the correctness of copying. The IPC addresses visuospatial constructional skills and executive function.

Measure of dynamic balance, scores range from 0 (no Balance) to 28 good dynamic balance

This measures the time (in seconds) taken by a patient to rise to their feet from a sitting position, walk 3 metres in a straight line, turn around, walk back to the seat and sit down again

Distance traveled during 6 minute walk

The activities specific balance confidence scale is used to assess the level of fear of falling. It consists of 16 items reflecting the level of balance confidence from 0% (no confidence) to 100% (complete confidence)

The New Freezing of Gait Questionnaire (NFOG-Q) is a clinician-administered tool that aims to assess both the clinical aspects of FOG as well as its subsequent impairments on quality of life. The task ratings and scales are calculated into a summed NFOG-Q score. Part I detected the presence of FOG using a dichotomous item in which individuals were classified as a freezer (FR) or a non-freezer (NFR) if they had experienced FOG-episodes during the past month. Parts II and III were designed for FRs only, providing a total summed score between 0 and 28. Part II (items 2-6, scoring range 0-19) rated the severity of FOG based on its duration and frequency in its most common manifestation, i.e. during turning and initiation of gait. Part III rated the impact of FOG on daily life (items 7-9, scoring range 0-9). No separate on and off rating of parts II and III was considered to avoid unreliable assessment.

Change in hippocampus volumes on structural MRI

Change in Microstructural integrity of white matter pathways on diffusion tensor imaging

Change in Functional connectivity among brain networks on resting state fMRI

Change in salivary cortisol levels between baseline and 6 months post exercise. Cortisol samples were taken before the exercise intervention (Pre) and after the exercise intervention (Post) at 8 different time points: At awakening (0), 15 minutes post awakening (0.25), 30 minutes post awakening (0.5), 45 minutes post awakening (0.75), 3 hours post awakening (3), 6 hours post awakening (6), 9 hours post awakening (9), and 12 hours post awakening (12).

Change in soluble inflammatory biomarkers in plasma between baseline and 6 months post exercise

Change in peripheral levels of neurotrophic factors in plasma between baseline and 6 months post exercise