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 ([11C]‐N‐(3‐iodoprop‐2E‐enyl)‐2‐beta‐carbomethoxy‐3‐beta‐(4‐methylphenyl)‐nortropane) ([11C]PE2I) and serotonin ([11C]‐N,N‐dimethyl‐2‐(‐2‐amino‐4‐cyanophenylthio)‐benzylamine) ([11C]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

Depression in Patients with Parkinson’s Disease: Current Understanding of its Neurobiology and Implications for Treatment

“…Contrastingly, depression in de novo, drug-naïve patients with apathy, depression and anxiety was associated with decreased [11C]DASB in the limbic system and greater severity specifically correlated to greater serotonergic dysfunction in the bilateral subgenual anterior cingulate cortex (ACC) [171]. Moreover, greater serotonergic pathology related to depression was recently demonstrated across PD stages, underlying the major influence of serotonergic dysfunction in limbic corticostriatal circuits [198], which may specifically underpin microstructural alterations in the caudate nucleus [45]. Regarding postsynaptic dysfunction, patients with PD depression had lower binding of [18F] MPPF to the 5HT1A receptor in the left hippocampus, right insula, left superior temporal cortex, and the orbitofrontal cortex [199].…”

Imaging the Limbic System in Parkinson’s Disease—A Review of Limbic Pathology and Clinical Symptoms

“…In turn, functional connectivity between the anterior cingulate and the temporo-parietal junction was positively correlated with a higher quality of life in PD [ 158 ]. Furthermore, PET studies have reported serotonergic dysfunction in the cingulate of PD patients [ 159 , 160 , 161 , 162 ]. Notably, increased serotonergic innervation in the ACC and ventral striatum was recently demonstrated in PD patients who were apathetic at diagnosis and reverted apathy under dopamine replacement therapy, suggesting compensatory plasticity in early PD [ 163 ].…”

Apathy in Parkinson’s Disease: Defining the Park Apathy Subtype

“…Co-occurrence of apathy and impulse disorders was also reported in other neurological disorders [ 82 ]. Lastly, animal models and imaging studies in patients have shown the involvement of other neurotransmitter systems [ 83 , 84 , 85 ]. To further study the complex underlying physiology of apathy, the definition of the neuroanatomical correlates is an important starting point.…”

“…Yet, some studies found no difference in dopaminergic uptake between apathetic and non-apathetic patients [ 84 ]. Serotonin could act as a modulator, with reduced uptake found in critical parts of the mesocorticolimbic pathway in apathetic PD patients [ 84 , 85 ]. The uptake reduction was proportional to apathy’s severity [ 84 ].…”