Serotonergic and Dopaminergic Lesions Underlying Parkinsonian Neuropsychiatric Signs

Abstract Background Parkinson's disease (PD) is characterized by heterogeneous motor and nonmotor manifestations related to alterations in monoaminergic neurotransmission systems. Nevertheless, the characterization of concomitant dopaminergic and serotonergic dysfunction after different durations of Parkinson's disease, as well as their respective involvement in the expression and severity of neuropsychiatric signs, has gained little attention so far. Methods To fill this gap, we conducted a cross‐sectional study combining clinical and dual‐tracer positron emission tomography (PET) neuroimaging approaches, using radioligands of dopamine ([ 11 C]‐N‐(3‐iodoprop‐2E‐enyl)‐2‐beta‐carbomethoxy‐3‐beta‐(4‐methylphenyl)‐nortropane) ([ 11 C]PE2I) and serotonin ([ 11 C]‐N,N‐dimethyl‐2‐(‐2‐amino‐4‐cyanophenylthio)‐benzylamine) ([ 11 C]DASB) reuptake, after different durations of Parkinson's disease (ie, in short‐disease duration drug‐naive de novo (n = 27, 0–2 years‐duration), suffering from apathy (n = 14) or not (n = 13); intermediate‐disease duration (n = 15, 4–7 years‐duration) and long‐disease duration, non‐demented (n = 15, 8–10 years‐duration) patients). Fifteen age‐matched healthy subjects were also enrolled. Results The main findings are threefold: (1) both dopaminergic and serotonergic lesions worsen with the duration of Parkinson's disease, spreading from midbrain/subcortical to cortical regions; (2) the presence of apathy at PD onset is associated with more severe cortical and subcortical serotonergic and dopaminergic disruption, similar to the denervation pattern observed in intermediate‐disease duration patients; and (3) the severity of parkinsonian apathy, depression, and trait‐anxiety appears primarily related to serotonergic alteration within corticostriatal limbic areas. Conclusions Altogether, these findings highlight the prominent role of serotonergic degeneration in the expression of several neuropsychiatric symptoms occurring after different durations of Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society