Comparative ccf-mtDNA levels in PPMI-PD cases and controls. a CSF ccf-mtDNA levels are reduced in PPMI-PD patients compared to controls at 36 months (mean ccf-mtDNA in 176 PD patients 2.0 (95%CI = 1.99–2.16), versus 2.2 (95%CI = 2.11–2.32) in 87 controls, Student’s t-test p = 0.045, Cohen’s d = 0.35), but not at 0 months (mean ccf-mtDNA in 291 PD patients 2.1 (95%CI = 2.10–2.22), versus 2.2 (95%CI = 2.16–2.34) in 132 controls, Student’s t-test p = 0.101). After regression, adjusting for age, sex and BMI as covariates, group differences remained significant at 36 months (p = 0.047) and non-significant at 0 months (p = 0.233). b The reduction in CSF ccf-mtDNA between 0 to 36 months appears specific to PPMI-PD cases (Change in mean CSF ccf-mtDNA levels calculated from 0 to 36 months where both timepoints were available, mean change in 130 PD patients − 0.15 (95%CI = 0.274--0.026), Student’s t-test p = 0.045; in 58 controls − 0.02 (95%CI = -0.224–0.184), Student’s t-test p = 0.858). c Elevated CSF ccf-mtDNA levels are associated with cognitive impairment in PPMI-PD patients at 0 months (mean ccf-mtDNA in 230 PD cases without cognitive impairment 2.1 (95%CI = 2.05–2.19), versus 2.3 (95%CI = 2.19–2.45) in 61 PD cases with cognitive impairment, Student’s t-test p = 0.012, Cohen’s d = 0.38), but not at 36 months (mean ccf-mtDNA in 138 PD cases without cognitive impairment 2.1 (95%CI = 2.03–2.21), versus 1.9 (95%CI = 1.79–2.11) in 38 PD cases with cognitive impairment, Student’s t-test p = 0.44). Error bars indicate mean and 95% confidence interval (95%CI)