A normative model for dopamine transporter laterality in PD
Poster No:
154
Submission Type:
Abstract Submission
Authors:
Ted Alushani1, Manuela Moretto1, Marco Pinamonti1, Lucia Batzu2, Silvia Rota2, Chih-Mao Huang3, Mattia Veronese1
Institutions:
1Department of Information Engineering, University of Padua, Padua, Italy, 2Institute of Psychiatry, Psychology & Neuroscience, Department of Neuroimaging, King’s College, London, United Kingdom, 3Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Taiwan
First Author:
Co-Author(s):
Lucia Batzu
Institute of Psychiatry, Psychology & Neuroscience, Department of Neuroimaging, King’s College
London, United Kingdom
Institute of Psychiatry, Psychology & Neuroscience, Department of Neuroimaging, King’s College
London, United Kingdom
Silvia Rota
Institute of Psychiatry, Psychology & Neuroscience, Department of Neuroimaging, King’s College
London, United Kingdom
Institute of Psychiatry, Psychology & Neuroscience, Department of Neuroimaging, King’s College
London, United Kingdom
Chih-Mao Huang
Department of Biological Science and Technology, National Yang Ming Chiao Tung University
Taiwan
Department of Biological Science and Technology, National Yang Ming Chiao Tung University
Taiwan
Introduction:
Dopamine function in Parkinson's disease (PD) is commonly assessed using [123I] FP-CIT single-photon-emission computed tomography imaging (DATSCAN). While standard analysis uses striatal binding as a diagnostic biomarker, preliminary studies have suggested the presence of clinically relevant left-right dopamine lateralization in PD (Kaasinen et al., 2015; Fiorenzato et al., 2021; Murtomäki et al., 2022). However, these approaches are limited by the use of purely empirical cutoffs, lacking a clear rationale to guide the stratification process. Here we investigate the value of dopamine laterality in PD patients, by developing a normative model of dopamine lateralization developed from healthy control (HC) individuals.
Methods:
A total of 1,038 DATSCAN data were analyzed, including 191 HC and 847 early-stage PD patients. The average disease duration from diagnosis was 1.05±1.52 years. Among PD patients, Hoehn & Yahr stages were distributed as follows: stage 0 (1 patient, <0.1%), stage 1 (280 patients, 33%), stage 2 (534 patients, 63%), and stage 3 (12 patients, 1.4%). Missing data accounted for 20 patients (2.4%). All data were collected from the PPMI database from the baseline scans. Inclusion criteria included: i) idiopathic PD, ii) no other neurological conditions, iii) "good" or "adequate" quality of DATSCAN data. Analysis was further restricted to right-handed subjects, to avoid the potential bias induced by dopamine laterality and individual handness (Johnstone et. al., 2021). Starting from the already available signal-to-background ratio (SBR) metric, we computed the Asymmetry Index (AI) (Kaasinen et al., 2015) in the putamen, as follows:
AI=(Right SBR-Left SBR)/(Right SBR+Left SBR)
Then, we analyzed the distribution of the Dopamine AI in HC, establishing the upper and lower extremes of this distribution as the limits for normal lateralization (NL). Comparing this to the AI distribution in PD patients, we classified patients as Extreme Lateralized (EL), when their AI exceeded these boundaries. Finally, we performed a univariate analysis on EL patients, to assess the relationship between AI and i) baseline motor, non-motor, and cognitive scores, ii) longitudinal scores collected at two, four and six years following the initial visit.
AI=(Right SBR-Left SBR)/(Right SBR+Left SBR)
Then, we analyzed the distribution of the Dopamine AI in HC, establishing the upper and lower extremes of this distribution as the limits for normal lateralization (NL). Comparing this to the AI distribution in PD patients, we classified patients as Extreme Lateralized (EL), when their AI exceeded these boundaries. Finally, we performed a univariate analysis on EL patients, to assess the relationship between AI and i) baseline motor, non-motor, and cognitive scores, ii) longitudinal scores collected at two, four and six years following the initial visit.
Results:
The normative model showed dopamine function is not perfectly symmetrical in healthy controls (Fig.1). Moreover, approximately 26% of PD patients exceed normal dopamine lateralization (Fig.1). Interestingly, greater asymmetry in dopamine function was associated with higher SBR values, alongside better cognitive, motor, and autonomic performance: EL patients outperformed NL PD subjects in cognitive assessments (MDS-UPDRS Part I, Symbol Digit Modalities Test, p<.001) and autonomic function scores (urinary and gastrointestinal-related problems, p<.001). Additionally, EL patients exhibited significantly higher SBR signals (p<.001) in the right hemisphere and the average signal.
Furthermore, longitudinal analysis highlighted a growing disparity between the groups over time. EL patients showed a less pronounced progression of motor symptoms, as observed at the six-year follow-up visit. In MDS-UPDRS Part II scores, EL patients had significantly lower scores (mean=8.93±5.83) compared to NL patients (mean=11.59±7.07, p<.001). Similarly, in MDS-UPDRS Part III scores, EL patients performed better (mean=29.70±11.87) than NL patients (mean=33.22±14.47, p<.001) as shown in Fig.2. Cognitive and autonomic symptoms followed a similar trend, with EL patients showing slower progression over time.
Furthermore, longitudinal analysis highlighted a growing disparity between the groups over time. EL patients showed a less pronounced progression of motor symptoms, as observed at the six-year follow-up visit. In MDS-UPDRS Part II scores, EL patients had significantly lower scores (mean=8.93±5.83) compared to NL patients (mean=11.59±7.07, p<.001). Similarly, in MDS-UPDRS Part III scores, EL patients performed better (mean=29.70±11.87) than NL patients (mean=33.22±14.47, p<.001) as shown in Fig.2. Cognitive and autonomic symptoms followed a similar trend, with EL patients showing slower progression over time.
·Fig 1: Distribution of the AI in the putamen for HC and PD patients. The AI distribution comparison aids in distinguishing between "Extreme Laterality" (EL) and "Normal Laterality" (NL).
Conclusions:
This finding opens the possibility of using AI as a potential prognostic marker, providing the foundation for more personalized rehabilitation or therapeutic strategies. However, understanding the underlying neurobiology of these processes remains essential. With further research, this understanding could help develop treatments that focus on each patient's unique dopamine distribution, improving the precision of PD therapies.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
PET Modeling and Analysis 2
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Transmitter Systems
Keywords:
Data analysis
Dopamine
Movement Disorder
Single Photon Emission Computed Tomography (SPECT)
Statistical Methods
1|2Indicates the priority used for review
·Fig.2: Evolution of MDS-UPDRS Part II and III, SDMT and Urine related-problems scores over time for both the groups. Data were collected during 2 years follow-up visits after the baseline.
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[2] Fiorenzato, E., Antonini, A., Bisiacchi, P., Weis, L., & Biundo, R. (2021). Asymmetric Dopamine Transporter Loss Affects Cognitive and Motor Progression in Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society, 36(10), 2303–2313. https://doi.org/10.1002/mds.28682
[3] Murtomäki, K., Mertsalmi, T., Jaakkola, E., Mäkinen, E., Levo, R., Nojonen, T., Eklund, M., Nuuttila, S., Lindholm, K., Pekkonen, E., Joutsa, J., Noponen, T., Ihalainen, T., Kaasinen, V., & Scheperjans, F. (2022). Gastrointestinal Symptoms and Dopamine Transporter Asymmetry in Early Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society, 37(6), 1284–1289. https://doi.org/10.1002/mds.28986
[4] Johnstone, L. T., Karlsson, E. M., & Carey, D. P. (2021). Left-Handers Are Less Lateralized Than Right-Handers for Both Left and Right Hemispheric Functions. Cerebral cortex (New York, N.Y. : 1991), 31(8), 3780–3787. https://doi.org/10.1093/cercor/bhab048