Objective: To investigate interactions between the serotonergic and dopaminergic systems in early PD as related to (i) response to treatment and (ii) dopamine (DA) release, a predictor of future treatment related motor complications (1).

Background: The serotonergic system can contribute to DA release but lacks regulatory feedback (2). A relative preservation of serotonergic function may thus increase therapeutic efficacy in early disease, while becoming a risk factor as disease progresses. Identification of a relevant serotonergic/dopaminergic pattern in early disease may help to identify progression phenotypes. A novel joint multimodal analysis approach (3)  was used to explore this hypothesis

Method: 15 early stable PD subjects (disease duration 56±34 months) were scanned in the Siemens High Resolution Research Tomograph with: a) [11]C-DTBZ (VMAT2 marker) and [11]C-MP (DAT marker) to assess dopaminergic integrity; b) [11]C-DASB (SERT marker) to examine serotonergic integrity and c) double [11]C-RAC (D2 receptor marker) to estimate levodopa-induced DA release. Multiset canonical correlation analysis (MCCA) (3) applied to tracers’ binding values (BPND) (4) was used to extract highly correlated subject scores (SS)  along each canonical variate for each tracer. MCCA loadings (ROI weights) visualized the spatial patterns which were validated with permutation tests and leave-one-out cross validation.

Results: A significant (p=0.004) relevant pattern was identified: SS for DA release correlated positively with DASB (p=0.024), positively with change in Unified PD Rating Scale after LD administration (p=0.045) and negatively with LD equivalent dose (p=0.042) after correcting for age of disease onset and duration. The associated spatial patterns comprised reduced dopaminergic function, increased serotonergic function and increased DA release in the putamen.

Conclusion: These results support the hypothesis that early PD subjects with relatively preserved serotonergic innervation in the putamen respond better to LD therapy. Higher DA release was associated with relatively preserved serotonergic function in the presence of a relatively higher dopaminergic deficit indicating that (i) the impact of the serotonergic system on DA release is already relevant in early disease and (ii) subjects strongly expressing this pattern may be at higher risk of complications – to be verified with longitudinal clinical observations

References: 1. de la Fuente-Fernandez R, Lu JQ, Sossi V, et al. Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover. Ann Neurol. 2001;49:298-303. 2. Carta M, Carlsson T, Kirik D, Bjorklund A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain. 2007;130:1819-1833. 3. Correa NM, Li YO, Adali T, Calhoun VD. Canonical Correlation Analysis for Feature-Based Fusion of Biomedical Imaging Modalities and Its Application to Detection of Associative Networks in Schizophrenia. IEEE J Sel Top Signal Process. 2008;2:998-1007. 4. Innis RB, Cunningham VJ, Delforge J, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27:1533-1539.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/relative-preservation-of-serotonergic-function-increases-response-to-treatment-in-early-pd/