Objective: To evaluate the relationship of CSF DDC with levodopa (L-DOPA) treatment and determine its feasibility as a biomarker in clinical trials based on sample size estimates.

Background: DDC, an enzyme converting L-DOPA to dopamine, has recently been considered as a biomarker with increased levels observed in PD cases compared to controls. We investigated whether CSF DDC levels are influenced by L-DOPA and estimated the required sample sizes for DDC-based assessments compared to other PD biomarkers, including UPDRS, DaTscan, and NfL.

Method: We analyzed longitudinal CSF DDC levels from Olink in the PPMI. First, we compared DDC levels in PD cases with and without L-DOPA treatment over two years. At baseline (n=35), none had started treatment, and 12 and 28 PD cases were on treatment by year 1 and 2, respectively. Correlation analyses between DDC levels and L-DOPA equivalent daily doses (LEDD) across all visits from baseline to year 4 were performed in PD subgroups stratified by LEDD dose categories (none: 0, low: 1–300, mid: 301–699, high: ≥700). We examined correlations between LEDD and DDC, together with CSF NFL, at each visit. Additionally, sample size estimates for detecting significant CSF DDC changes for one year were compared to those for UPDRS, DaTscan, and serum NfL.

Results: No significant differences in CSF DDC levels were observed between treated and untreated PD cases during the first two years (P>0.75). DDC measures across all time points from baseline to year 4 significantly correlated with LEDD in all PD cases (P=5.0×10^-5) but not within LEDD subgroups (P-value: low=0.34, mid=0.71, high=0.42). Comparing LEDD with DDC and NfL at each year, nominal associations were observed only at year 2 (P-value: DDC=0.03, NfL=0.01). The similar association strengths for DDC and NfL suggest that DDC levels reflect disease progression, like NfL, and is not influenced by treatment. Our sample size estimates indicated that CSF DDC required 65-72% fewer samples compared to UPDRS III (off medication) and serum NfL, while being comparable to DaTscan.

Conclusion: Our analysis suggests that increased CSF DDC levels in PD are less likely driven by treatment and require fewer sample size compared to UPDRS III and NfL as end-points. Taken together, CSF DDC is a promising biomarker, requiring fewer participants to detect disease-related changes.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dopa-decarboxylase-as-a-biomarker-for-parkinsons-disease-and-its-relationship-to-l-dopa-influence-and-sample-size-estimates/