Loss of Presynaptic Terminal Integrity in the Substantia Nigra in Early Parkinson's Disease

Background: It has been hypothesized that the pathology of Parkinson's disease (PD) primarily affects presynaptic terminals and spreads trans-synaptically.

Objectives: The main objective of this study was to assess the magnitude and anatomical extent of presynaptic terminal loss across the brain in early PD. A second objective was to compare loss of presynaptic terminals and cell bodies within the nigrostriatal tract.

Methods: A total of 30 patients with early PD and 20 age- and gender-matched healthy controls underwent positron emission tomography with ¹¹ C-UCB-J, a ligand for the universal presynaptic terminal marker synaptic vesicle protein 2A (SV2A), and with the Dopamine Transporter ligand ¹⁸ F-FE-PE2I, as well as a detailed clinical assessment. Volumes of interest were delineated based on individual 3-dimensional T1 magnetic resonance imaging. BP_ND images were calculated.

Results: Patients with PD showed significant loss of SV2A binding in the substantia nigra only. Loss of Dopamine Transporter binding in the PD group was much greater in the putamen than in the substantia nigra. We found no correlations between SV2A or Dopamine Transporter binding and any of the clinical motor or nonmotor scores. Homologous voxel-based analysis in the PD group showed significant correlations between SV2A and Dopamine Transporter binding in the caudate and substantia nigra.

Conclusions: Presynaptic terminals appear to be the most heavily affected subcellular compartment of nigrostriatal neurons in early PD. Moreover, early PD causes loss of presynaptic terminals that innervate the nigrostriatal neurons. This loss of presynaptic boutons in the substantia nigra may reflect an axonal response to target deprivation or could possibly point to a trans-synaptic mode of propagation of the disease process. © 2020 International Parkinson and Movement Disorder Society.