The Personalized Parkinson Project

Parkinson*s disease (PD) is the second most prevalent degenerative brain
disease. Our understanding of the basic pathology, etiology, and progression of
PD has stagnated, partly due to the limited patient diversity captured in study
cohorts. Additionally, we lack sufficient biological insight into the
underlying etiologies and pathophysiological mechanisms to develop new
interventions that can slow down or arrest disease progression. As a result,
patients do not receive the best care they deserve, leading to unnecessary
disability, and to mounting costs for society.

Currently biomarker studies have been especially valuable for the differential
diagnostics (distinguishing PD patients from healthy controls, and to
differentiate PD from the different forms of atypical parkinsonism). There are
currently no reliable biomarkers that can help to predict the widely varying
differences between patients in prognosis, rate of progression, time to
development of important milestones (such as development of falls), or
treatment response. Additionally, an important limitation of the ongoing
research is that biomarkers are often investigated in isolation, for instance
with one measurement per patient, and not combined with other disease-specific
characteristics, and often not longitudinally. The few available longitudinal
studies typically have had brief follow-up periods.

Furthermore, the clinical presentation of PD varies considerably within and
across days. Patients perform paradoxically well when being observed in
clinical or in research settings, so this offers a biased view of their
real-life performance. Consequently, it has to date not been possible for
researchers to capture a truly accurate picture of the diverse day-to-day
experiences of people living with PD. Today, a new field of technology called
*wearable devices* has the potential to revolutionize how we collect this
critical information from patients.

The primary objective of the study is to perform a set of hypothesis-driven
analyses on the study data set, aiming to correlate established biomarkers
(obtained clinically, from brain MRI, from CSF, from known genetic factors, and
from monitoring of biosensors signals) to the rate of disease progression, and
to responses to treatment (both pharmacological and behavioral, such as
participation in exercise). Additionally, we aim to identify biomarkers that
can assist in predicting differences in prognosis and treatment response
between patients. Finally, by developing novel etiological and
pathophysiological insights, we aim to improve existing treatments and to
develop new therapeutic approaches, as a basis for development of a more
precise and personalized disease management approach.

The secondary objective of the study is to evaluate the Verily Study Watch, to
assess how these devices could provide information about the function of
patients with PD.

The tertiary objective of this study is to create an extensive longitudinal
dataset describing the genetic, clinical, functional, and phenotypic
characteristics of a representative Parkinson*s disease (PD) subject cohort (n
= 520) to allow researchers to investigate important unanswered questions in
PD.

Prospective, longitudinal, single-center cohort study.

Nature and extent of the burden to patients
Participants are invited to come to the study site in Nijmegen for a full (up
to 1.5) day of data collection three times during the 2-year study duration. As
is common practice in any clinical trial with PD patients, the initial
assessments are performed in the OFF-medications state, i.e., after PD
medications have been withheld for 12 hours. Subjects* Parkinson symptoms may
temporarily worsen, but medications will be resumed immediately after the
initial clinical assessments. This is a widely accepted and safe procedure in
the Parkinson research field. All study assessments are routine exams done in
standard clinical practice and are generally well tolerated. The noise in the
MRI scanner, and lying in a small space for approximately 1 hour, may lead to
minor discomfort; however, subjects with claustrophobia will be excluded from
the study to avoid burden for the patients. The lumbar puncture to obtain CSF
is optional, although based on our extensive prior experience in large
Parkinson studies, we strive for a 75% acceptance rate of lumbar punctures by
patients. The risks of the lumbar puncture are outlined In Section *Risks and
Benefits* of the Protocol.

The Verily Study Watch will be worn daily for up to 23 hours. This small,
unobtrusive electronic device is easily applied and poses no significant safety
issues. Data collection does not require patient intervention, and data
transfer does not require connection to a mobile phone or computer. The Study
Watch requires minimum care (daily charge and sync, remove when near water).

Risks
There are limited risks for the patients during the data collection. The
diagnostic measurements (MRI, Holter ECG) are standard non-invasive tests that
are routinely performed in clinical practice.
Tests that may lead to discomfort / risk are the following:
• Local hematoma can occur related to the venipuncture for blood collection.
• The lumbar puncture is an optional assessment. It can be uncomfortable,
although local anesthesia will be used. Radboudumc*s extensive experience shows
that patients greatly value this, as it markedly diminishes local discomfort. A
small percentage of patients may suffer from prolonged and severe headache
after CSF collection. However, this risk will be further reduced by using
atraumatic needles.
• The Verily Study Watch is a low risk non-invasive device (class IIa) used as
an adjunct tool and not to guide diagnosis or therapy, therefore it does not
pose significant risks.

Benefits
Because data collection is not performed for immediate diagnostic or
therapeutic purposes, there will be no direct benefits for the subjects
enrolled in this study. As a service in return for their efforts for research,
participants will be offered an educational program (voluntarily) on
Parkinson*s disease and how to handle the disease in daily life. Moreover,
patients will indirectly benefit from the study, as their data contribute to
gain novel etiological insights for improvement of existing treatments,
development of new therapeutic approaches, and more precise and personalized
disease management. This will provide future benefit for all patients affected
by the disease.

The Study Watch supplements and enhances the information available to the
physician, providing continuous measurement and quantitative (rather than
subjective) data. The device detects important physiologic parameters that are
expected to change with disease conditions or behavioral patterns (e.g.,
electrodermal activity [EDA], physical movement of the body in three dimensions
[acceleration], skin temperature, heart rhythm). As such, by wearing the Study
Watch, patients are providing unprecedented insight into the evolution of PD
and potentially allowing to identify better ways to treat the disease. In
addition to collecting data, the device also functions as a wristwatch.