title: 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.
authors.affiliation: 1 Division of Brain Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.
authors.forename: Zahi
authors.initials: Z
authors.lastname: Qamhawi
authors.affiliation: 1 Division of Brain Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Towey
authors.affiliation: 1 Division of Brain Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.
authors.forename: Bina
authors.initials: B
authors.lastname: Shah
authors.affiliation: 1 Division of Brain Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Pagano
authors.affiliation: 2 Institute for Neurodegenerative Disorders, 60 Temple Street, Connecticut 06510, USA.
authors.forename: John
authors.initials: J
authors.lastname: Seibyl
authors.affiliation: 2 Institute for Neurodegenerative Disorders, 60 Temple Street, Connecticut 06510, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Marek
authors.affiliation: 3 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Borghammer
authors.affiliation: 1 Division of Brain Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK 3 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus, Denmark.
authors.forename: David James
authors.initials: DJ
authors.lastname: Brooks
authors.affiliation: 1 Division of Brain Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK 3 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus, Denmark nicola.pavese@imperial.ac.uk.
authors.forename: Nicola
authors.initials: N
authors.lastname: Pavese
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009778:Occipital Lobe / Q000000981:diagnostic imaging / Q000473:pathology; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000473:pathology*; D011903:Raphe Nuclei / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D012720:Severity of Illness Index; D013223:Statistics as Topic; D018709:Statistics, Nonparametric; D015899:Tomography, Emission-Computed, Single-Photon; D014326:Tropanes / Q000493:pharmacokinetics
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes; C087552:2-carbomethoxy-8-(3-fluoropropyl)-3-(4-iodophenyl)tropane; D012701:Serotonin
keywords: Parkinson; SPECT; non-motor; serotonin; tremor