Measuring Synaptic Density and Dopamine Transporter Availability in Parkinson's Disease: A PET Imaging Study with 11C-UCB-J and 18F-FE-PE2I
Faranak Ebrahimian Saadabad1, Tommaso Volpi1, Praveen Honhar1, Mika Naganawa1, Salih Cayir1, Sule Tinaz2, Jean-Dominique Gallezot1, Gustavo angarita3, Sophie Holmes3, Richard Carson1, Sjoerd Finnema4, David Matuskey1
1Department of Radiology and Biomedical Imaging, Yale University, 2Department of Neurology, Yale University, 3Department of Psychiatry, Yale University, Yale University, 4AbbVie, North Chicago, IL
Objective:
To relate synaptic density and presynaptic dopaminergic terminal integrity along the nigrostriatal tract using in vivo PET imaging in individuals with Parkinson's disease (PD) and healthy controls (HCs).
Background:
The pathophysiology of PD involves the degeneration of dopaminergic neurons in the substantia nigra, leading to reduced striatal dopamine signaling. This study employs 11C-UCB-J, targeting synaptic vesicle glycoprotein 2A (SV2A), to assess presynaptic loss, and 18F-FE-PE2I, a highly selective dopamine transporter (DaT) ligand, to evaluate dopaminergic loss.
Design/Methods:
Twenty PD patients (11 women, 61.0±5.3 years) and thirteen HCs (7 women, 57.8±5.4 years) underwent PET imaging with 11C-UCB-J and 18F-FE-PE2I on separate days using a high-resolution research tomograph (HRRT). Binding potential (BPND) was quantified employing the Simplified Reference Tissue Model 2 (SRTM2) with the cerebellum as a reference region for 18F-FE-PE2I and the centrum semiovale for 11C-UCB-J. Four regions of interest (ROIs) (caudate, substantia nigra, putamen, ventral striatum) were delineated from a standardized template. Across-subject Spearman correlations between 11C-UCB-J and 18F-FE-PE2I BPND values were computed and corrected for false discovery rate (FDR). For the PD group, correlations with motor severity scores (i.e., MDS-UPDRS part III) were also explored.
Results:
In the PD group, a significant positive correlation between 11C-UCB-J and 18F-FE-PE2I BPND was observed in the caudate (r=0.59,p-FDR=0.02), but not in the other regions. This correlation remained significant (p-FDR<0.05) even after controlling for covariates (i.e., age, gender, BMI, and the interval between scans) via partial correlation. Additionally, there was a trend toward significance in the caudate and substantia nigra in HCs (r=0.62 and r=0.61,p-FDR=0.06 for both), but not if covariates were accounted for. A negative relationship between 18F-FE-PE2I putamen BPND and MDS-UPDRS part III was also observed (r=-0.79,p-FDR=5·10-4).
Conclusions:
Our findings point to a clinically meaningful relationship between striatal DaT binding and synaptic density, and its impact on PD clinical symptoms needs to be further elucidated.