Clinical correlates of raphe serotonergic dysfunction in early Parkinson’s disease

Abstract

Post-mortem and neuroimaging studies suggest that the serotonergic system, which originates from the brainstem raphe nuclei, is disrupted in Parkinson's disease. This could contribute to the occurrence of non-motor symptoms and tremor, which are only partially explained by dopamine loss. However, the level of involvement of the serotonergic raphe nuclei in early Parkinson's disease is still debated. (123)I-FP-CIT single photon emission computed tomography is a marker of dopamine and serotonin transporter availability. While (123)I-FP-CIT binds primarily to dopamine transporters in the striatum, its binding in the brainstem raphe nuclei reflects serotonin transporter availability. We interrogated baseline single photon emission computed tomography scans of subjects recruited by the Parkinson's Progression Markers Initiative to determine: (i) the integrity of the brainstem raphe nuclei in early Parkinson's disease; and (ii) whether raphe serotonin transporter levels correlate with severity of tremor and symptoms of fatigue, depression, and sleep disturbance. Three hundred and forty-five patients with early drug-naïve Parkinson's disease, 185 healthy controls, and 56 subjects with possible Parkinson's disease without evidence of dopaminergic deficit were included. In the Parkinson's disease cohort, 37 patients had a tremulous, 106 patients had a pure akinetic-rigid, and 202 had a mixed phenotype. Patients with Parkinson's disease had significantly lower serotonin transporter availability in the brainstem raphe nuclei compared to controls (P < 0.01) and subjects without evidence of dopaminergic deficit (P < 0.05). However, only 13% of patients with Parkinson's disease individually had reduced signals. Raphe serotonin transporter availability over the entire Parkinson's disease cohort were associated with rest tremor amplitude (β = -0.106, P < 0.05), rest tremor constancy (β = -0.109, P < 0.05), and index of rest tremor severity (β = -0.104, P < 0.05). The tremulous Parkinson's disease subgroup had significantly lower raphe serotonin transporter availability but less severe striatal dopaminergic deficits compared to akinetic-rigid patients with no resting tremor (P < 0.05). In tremulous patients, raphe serotonin transporter availability was also associated with rest tremor constancy (β = -0.380, P < 0.05) and index of rest tremor severity (β = -0.322, P < 0.05). There was no association between raphe serotonin transporter availability and fatigue, depression, excessive daytime sleepiness, or rapid eye movement sleep behaviour disorder in early Parkinson's disease. We conclude that the raphe nuclei are affected in a subgroup of early drug-naïve Parkinson's disease patients and that reduced raphe serotonin transporter availability is associated with the severity of resting tremor but not non-motor symptoms.

Depression, anxiety, and apathy in Parkinson's disease: insights from neuroimaging studies

“…Of the 38 studies on depression, 33 reported findings from one single imaging modality: 19 used either PET [11, 12, 13,15, 16, 17, 18, 19] or SPECT 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 techniques, four used T1‐weighted imaging 31, 32, 33, three used DTI 34, 35, 36, six used resting state functional MRI (RS‐FMRI) 37, 38, 39, 40, 41, 42 and two used TCS methods 43, 44. The remaining four of the 38 studies reported findings from structural T1‐weighted imaging plus another imaging method, including PET 14, DTI 45, task FMRI 46 and RS‐FMRI 47, respectively.…”

The prominent role of serotonergic degeneration in apathy, anxiety and depression inde novoParkinson’s disease

“…The serotonergic system is altered from the early stages of Parkinson's disease A growing body of evidence, provided by neuroimaging studies, points towards global serotonergic disruption in Parkinson's disease (Doder et al, 2003;Boileau et al, 2008;Pavese et al, 2010;Politis et al, 2010b;Ballanger et al, 2012;Qamhawi et al, 2015).…”

“…This may be because most of the neuroimaging studies performed so far have included patients with Parkinson's disease who have been treated chronically with dopaminergic medication or have been exposed to serotonergic drugs, which may consequently hinder the pathophysiological interpretation of the associated results (Brooks et al, 1990;Doder et al, 2003;Kerenyi et al, 2003;Remy et al, 2005;Weintraub et al, 2005;Albin et al, 2008;Boileau et al, 2008;Pavese et al, 2010;Politis et al, 2010a, b;Thobois et al, 2010;Strecker et al, 2011;Ballanger et al, 2012;Joutsa et al, 2015). In addition, the delineation of nonmotor signs is not always detailed, which limits the clinical interpretation of these investigations (Qamhawi et al, 2015). Furthermore, post-mortem and neuroimaging studies performed in early-stage patients have sometimes reported conflicting results, either showing serotonergic disruption at Parkinson's disease onset (Albin et al, 2008;Politis et al, 2010a;Joutsa et al, 2015;Qamhawi et al, 2015) or not (Beucke et al, 2011;Strecker et al, 2011).…”

“…In addition, the delineation of nonmotor signs is not always detailed, which limits the clinical interpretation of these investigations (Qamhawi et al, 2015). Furthermore, post-mortem and neuroimaging studies performed in early-stage patients have sometimes reported conflicting results, either showing serotonergic disruption at Parkinson's disease onset (Albin et al, 2008;Politis et al, 2010a;Joutsa et al, 2015;Qamhawi et al, 2015) or not (Beucke et al, 2011;Strecker et al, 2011). Finally, most of these previous works have explored the dopaminergic or the serotonergic systems separately, but not simultaneously in the same patients suffering from Parkinson's disease.…”

Parkinson';s Disease, Diabetes and Cognitive Impairment

“…The cardinal pathological characteristic of PD is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta [7], however, lines of evidence from in vivo molecular imaging research has demonstrated that PD pathology involves also non-dopaminergic systems such as the serotonergic [8][9][10]. Serotonergic pathology in PD has been associated with the development of tremor [11,12], dyskinesias [13][14][15] and various non-motor symptoms [16][17][18].…”