Neuroprotection in Parkinson's Disease: Are We Getting Close?
MEASURING PROGRESSION OF PARKINSON'S DISEASE
Assessments using neuroimaging
Positron emission photography and SPECT imaging have been used as endpoints to measure progression of PD in clinical trials assessing levodopa and dopamine agonists as potential neuroprotective therapies for PD.47,80 The REAL-PET (Requip® [ropinirole; GlaxoSmithKline, Research Triangle Park, NC] as Early Therapy versus L-dopa-PET) study demonstrated a significantly slower decrease in [18F]dopa uptake over 2 years during treatment with the dopamine receptor agonist ropinirole compared with levodopa.90 However, at 2 years, motor function was more improved in the levodopa group than in the ropinirole group. Similarly, the CALM-PD (Comparison of the Agonist Pramipexole With Levodopa on Motor Complications of Parkinson's Disease) study demonstrated that over 4 years, initial treatment with pramipexole was associated with a reduction in loss of striatal β-CIT uptake on SPECT imaging compared with treatment with levodopa,86 but clinical improvement was greater in the levodopa group.91,92 Results from the ELLDOPA (Earlier Versus Later Levodopa Therapy in Parkinson's Disease) trial, which examined the effects of levodopa therapy versus placebo over 40 weeks, found that levodopa was associated with a greater decline in [123I] β-CIT uptake but significantly better clinical improvement than placebo.47
While it remains possible that a medication (levodopa) could provide greater symptomatic benefit and be associated with faster loss of dopaminergic neurons, the lack of clinical correlation suggests that imaging assessments should be interpreted cautiously. It is possible that other imaging methods such as FDG PET may be more reliable surrogate markers for PD progression. Changes in the activity of the PDCP and PDRP have been observed as PD progresses.83 However, the utility of FDG PET results as endpoints in clinical trials assessing potential neuroprotective therapies remains to be determined.
Physical symptom scales
Because of questions regarding the validity of imaging studies to assess disease progression, trials assessing therapies with potential neuroprotective actions have tended to use clinical rather than imaging endpoints. Various symptom scales have been developed to measure PD severity and progression, with the Unified Parkinson's Disease Rating Scale (UPDRS) being the most commonly used.32 However, the UPDRS focuses mainly on motor features of the disease and does not account very well for nonmotor features.93 In light of this, the Movement Disorder Society (MDS) is currently developing and validating the MDS-UPDRS, a modified UPDRS that includes nonmotor symptoms and allows for more sensitive measurement of mild deficits and small changes in disability.94
