CSF Dopa Decarboxylase Reflects Dopaminergic Dysfunction of Multiple Causes in Dementia with Lewy Bodies

Abstract Background: Cerebrospinal fluid (CSF) dopa decarboxylase (DDC) is elevated across parkinsonian disorders and is emerging as a diagnostic biomarker, but whether it reflects dopaminergic pathway impairment remains uncertain, particularly in dementia with Lewy bodies (DLB), where parkinsonism is inconsistent and drugs acting on dopaminergic signaling are frequently prescribed. We aimed to assess whether and how CSF DDC reflects dopaminergic signaling in DLB. Methods: Retrospective multicenter study of 104 patients with probable DLB from routine clinical practice. CSF DDC, measured by proximity extension assay, was analyzed according to parkinsonian syndrome and its onset, dopamine transporter single-photon emission computed tomography (DAT-SPECT), treatments, amyloid/tau (AT) profile and α-synuclein real-time quaking-induced conversion (RT-QuIC). Associations with parkinsonism and treatments were tested by multivariable linear regression adjusted for age and sex, with AT profile and RT-QuIC added in a sensitivity analysis. Results: DDC was higher in patients with parkinsonian syndrome (n = 61 vs 35; median 103.4 vs 70.0 pg/mL), independently of age, sex and treatments (p < 0.001). Its elevation mainly concerned patients sampled after or shortly before motor onset. Dopaminergic therapy and selective serotonin reuptake inhibitors were not associated with DDC. Neuroleptic use showed a trend in the multivariable analysis (p = 0.07) and was associated with higher DDC after additional adjustment for AT profile and RT-QuIC (p = 0.03). Among patients without parkinsonism, DDC was higher under neuroleptics (n = 4, p = 0.01). DDC was higher with abnormal DAT-SPECT (n = 31, p = 0.018) and RT-QuIC positivity (n = 90, p < 0.001), and was unrelated to AT profile. Conclusions: CSF DDC seems to reflect dopaminergic hypoactivity from multiple causes, degenerative and possibly iatrogenic. Neuroleptic exposure should therefore be taken into account when interpreting CSF DDC, as it may limit its ability to distinguish drug-induced from degenerative parkinsonism.