Objective: To determine the magnitude and anatomical extent of presynaptic terminal damage in early Parkinson’s disease (PD) in vivo, we performed a PET study with the dopamine transporter radioligand ¹⁸F-FE-PE2I and with ¹¹C-UCB-J, a ligand for the universal presynaptic terminal marker SV2A.

Background: It has been hypothesized that the pathology of  PD primarily affects presynaptic terminals and spreads trans-synaptically between anatomically connected brain regions. However, this hypothesis is mostly based on human postmortem data and on studies in animal and cell culture models.

Method: Thirty patients with early PD (60.5 ± 9.2 years; nine female; disease duration 37.9 ± 13.4 months since first motor symptoms) and twenty age- and gender-matched healthy controls (59.6 ± 8.2 years; six female) underwent ¹¹C-UCB-J and ¹⁸F-FE-PE2I PET and a detailed clinical assessment of motor and non-motor manifestations. Volumes of interest were delineated based on individual 3D T1 magnetic resonance imaging. For both tracers, BP_ND images were calculated and a region-based partial volume correction (PVC) was done. Data were analyzed with and without PVC.

Results: ¹⁸F-FE-PE2I PET showed a loss of dopamine transporter binding in the PD group in the putamen (-76.4%, p < 0.0001) that was much greater than in the substantia nigra (-36.9%, p < 0.0001). ¹¹C-UCB-J PET showed that loss of SV2A binding was most prominent in the substantia nigra (-14.4%, p = 0.002) and less pronounced and only borderline significant in the caudate (-7.4%, p = 0.02), while a trend towards decreased SV2A binding was found in the putamen (-5.6%, p = 0.09). We found no correlations between ¹¹C-UCB-J or ¹⁸F-FE-PE2I binding and any of the clinical motor or non-motor scores. However, homologous voxel-based analysis in the PD group showed significant correlations between ¹⁸F-FE-PE2I and ¹¹C-UCB-J binding in the caudate (r = 0.40-0.97, p < 0.05) and substantia nigra (r = 0.40-0.68, p < 0.05).

Conclusion: The data showed that presynaptic terminals are the most heavily affected subcellular compartment of nigrostriatal neurons in early PD. In addition, early PD causes loss of presynaptic terminals that innervate the nigrostriatal neurons. This loss of presynaptic terminals in the substantia nigra may reflect an axonal response to target deprivation or may point to a trans-synaptic mode of propagation of the disease process.

References: 1. Del Tredici K, Braak H 2016, ‘Review: Sporadic Parkinson’s disease: development and distribution of alphasynuclein pathology’, Neuropathol Appl Neurobiol, 42, 33-50. 2. Fazio P, Svenningsson P, Cselenyi Z, Halldin C, Farde L, Varrone A 2018, ‘Nigrostriatal dopamine transporter availability in early Parkinson’s disease’, Mov Disord, 33, 592-599. 3. Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, et al 2016, ‘Imaging synaptic density in the living human brain’, Sci Transl Med, 8, 348ra96.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/in-vivo-imaging-of-presynaptic-terminal-loss-in-early-parkinsons-disease/