Table 2.

Examples of potential endpoints for disease-modification trials in prodromal PD

Type of marker	Outcome (endpoint)	Availability of data from studies in prodromal cohorts	Availability of data from studies in early PD patients	Advantages	Disadvantages
Clinical marker	Phenoconversion to clinically defined PD	Assessed in many unselected and preselected population-based cohorts [27, 33, 34, 38, 43], assessed in iRBD [13, 37, 44, 73]	NA	Represents the essence of prophylactic therapies	May require long trial duration of 5 or more years, difficulties in determining the exact time point of phenoconversion
	Motor progression (e.g., motor parts of the MDS-UPDRS/UPDRS)	Assessed in population-based [74] and iRBD cohorts [75, 76]	Assessed in early PD patients [77–79]; MDS-UPDRS Part II scores increased 1.0 point per year, and Part III scores increased 2.4 points per year, steepest increment observed in year 1	Shorter intervals due to continuous outcome	Motor progression might be slow in the early “premotor” phase (but accelerates shortly before diagnosis and in very early PD)
	Non-motor progression	Assessed in population-based [74] and iRBD cohorts [75, 76]	Assessed in early PD patients [78, 80]	Non-motor progression may be faster in “premotor” stages than motor progression	Heterogeneous outcome
	Progression of the prodromal PD score	Assessed in TREND [33], PMPP [81], and in a LRRK2 cohort [38]; results suggest the progression may only be seen in true prodromal PD cases that may indeed go on to develop PD	NA	Universal outcome that seems to be very different in true prodromal cases versus healthy controls	Large interindividual variability [33]
Imaging marker	Decline in striatial dopaminergic binding	Assessed in the PARS cohort (5% decline per year) [43] and in iRBD patients (6% decline per year) [82]	Assessed in early PD patients in the PPMI cohort [79] and in disease-modification trials [64, 66]	Objective, quantifiable, correlates with disease severity	Represents surrogate marker, expensive, requires multiple resources
	Progression of MRI markers [53]	NA	Free-water imaging [83] Neuromelanin imaging [84, 85]	Objective, quantifiable, correlates with disease severity	Represents surrogate marker, expensive, requires specialized MRI
Biochemical marker	Change in alpha-synuclein in CSF	Assessed in individuals with prodromal PD in the PPMI cohort [86]	Assessed in the PPMI cohort [86, 87]	Lower in PD patients and individuals with prodromal PD	No change over time observed in early PD patients; no correlation with disease progression or ongoing neurodegeneration in MDS-UPDRS and DAT-Scan results; contradicting results
	RT-QuIC-assessed alpha-synuclein	Assessed only as disease state biomarker [58, 62]; but not yet as progression biomarker	Assessed only as disease state biomarker [57, 59–61]; but not yet as progression biomarker	Highly sensitive	Not yet assessed in term of progression marker. Specialized lab equipment

CSF, cerebrospinal fluid; DAT, dopamine transporter; iRBD, idiopathic REM-sleep behaviour disorder; LRRK2, leucine-rich repeat kinase 2; MDS, Movement Disorders Society; MRI, magnetic resonance imaging; NA, not assessed; PMPP, Progression Markers in the Premotor Phase study; PPMI, Parkinson’s progression marker initiative; TREND, Tuebinger evaluation of Risk factors for Early detection of NeuroDegeneration study; UPDRS, Unified Parkinson’s Disease Rating Scale; RT-QuIC, Real-time quaking-induced conversion