Patients with de novo Parkinson’s disease (PD) who demonstrate apathy have substantial limbic serotonergic dysfunction and microstructural disarray. It was uncertain if this unique lesion profile upon diagnosis results in a different prognosis. For a study, researchers sought to determine the evolution of dopaminergic and serotonergic dysfunction and its relationship to motor and nonmotor impairment in Parkinson’s disease patients with or without apathy at the time of diagnosis.

A longitudinal double-tracer positron emission tomography cohort research included 13 de novo apathetic and 13 nonapathetic Parkinson’s disease patients. They used linear mixed-effect models and mediation analysis to compare the longitudinal evolution of clinical impairment and region-of-interest-based analysis to quantify the progression of presynaptic dopaminergic and serotonergic pathology using [11C]PE2I for dopamine transporter and [11C]DASB for serotonin transporter at baseline and 3 to 5 years later. 

Apathy, sadness, and anxiety improved in patients with apathy at diagnosis (n=10) to the level of those without apathy (n=11) after starting dopamine replacement medication. Patients’ motor impairment progressed similarly, and both groups showed minor impulsive behaviors. Striato-pallidal and mesocorticolimbic presynaptic dopaminergic loss, as well as serotonergic dysfunction in the putamen, caudate nucleus, and pallidum, advanced equally in both groups. In contrast to dopamine replacement treatment, serotonergic innervation was specifically augmented in the ventral striatum and anterior cingulate cortex of apathetic patients, contributing to apathy reversal.

Within 5 years of diagnosis, patients with apathy display compensatory alterations in limbic serotonergic innervation, providing hopeful evidence that serotonergic plasticity contributes to apathy recovery. More research on the link between serotonergic plasticity and dopaminergic therapies is needed.