Movement disorders: Limbic system serotonergic plasticity that contributes to apathy in Parkinson's disease

Serotonergic lesions in Parkinson's disease (PD) are closely associated with motor and non-motor symptoms throughout the disease course, and according to postmortem histopathological staging, serotonergic lesions may predate the disappearance of substantia nigra dopaminergic projections
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However, the longitudinal evolution of serotonergic pathology in early PD and its relationship to symptoms and progression of dopaminergic pathology remain unclear
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Previous studies have demonstrated that newly diagnosed untreated (de novo) Parkinson's disease patients with apathy, depression, and anxiety have prominent seroergic dysfunction compared with patients without neuropsychiatric symptoms, and medial limbic cortex- Early striatal-pallidal-thalamic circuits are associated with specific microstructural alterations, whereas substantia nigra dopaminergic degeneration is similar
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In particular, in addition to midbrain white matter reorganization, microstructural disorganization and dysfunction of serotonergic terminals in the head of the caudate nucleus and the anterior cingulate cortex were co-existed
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These findings identify early changes in long-range serotonergic projections originating from the median and dorsal xiphoid nuclei, consistent with other studies showing early serotonergic dysfunction in patients with PD and rapid eye movement (REM) sleep behavior disorder
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Furthermore, in advanced non-demented patients, apathy, depression, and anxiety associated with PD were associated with dopaminergic dysregulation of the central cortical limb system and were conceptualized as hypodopaminergic behaviors responsive to dopamine replacement therapy
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Overall, it is suspected that apathy, depression, and anxiety in Parkinson's disease have distinct pathophysiological underpinnings, depending on the stage of PD and the sequential dysfunction of limbic monoaminergic and cholinergic circuits
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In addition, listless patients had greater non-motor burden and lower cognitive performance at diagnosis, even among patients with persistent listlessness for the first two years
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However, the long-term prognostic significance of apathy in the early stages of Parkinson's disease has so far been unclear
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Thus, Stéphane Prange, et al, of the National Centre for Scientific Research in Lyon, France, compared the longitudinal evolution of dyskinesia and non-motor psychiatric symptoms with depression and anxiety in a cohort of patients with new Parkinson's disease with and without apathy at diagnosis.
Correlation of symptoms
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Core hypothesis: At diagnosis, analgesic and non-analgesic patients develop different neuropsychiatric symptoms and serotonergic lesions within 5 years of diagnosis, and may exhibit plastic changes in the limbic serotonergic system
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In a longitudinal dual-trace positron emission tomography cohort study, they recruited 13 new patients with sleepy and non-drowsy PD
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They found that after initiation of dopamine replacement therapy, patients with apathy at diagnosis (n = 10) had improvements in apathy, depression, and anxiety at follow-up, to levels seen in patients without apathy (n = 11)
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The patients' dyskinesia progression was similar, while mild impulsive behavior was seen in both groups
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The progression of striatal and mesocortical presynaptic dopaminergic loss was similar in both groups.

The same is true for serotonergic lesions of the caudate nucleus and globus pallidus
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Original source:

[Prange S, Metereau E, Maillet A, et al.