From: Prodromal Parkinson's disease: hype or hope for disease-modification trials?
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 early PD patients [77,76,79]; 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 | 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] | 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] | 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, 59,60,61]; but not yet as progression biomarker | Highly sensitive | Not yet assessed in term of progression marker. Specialized lab equipment |