The Superior Colliculus in De Novo Parkinson's Disease: A Prodromal Dysfunction?

Abstract

Background: The dual hit hypothesis about the pathogenesis of Parkinson's disease (PD) suggests that the brainstem can convey pathological entries to the brain. However, information about the involvement of different brainstem structures are difficult to collect in living PD patients. We have filled this gap by studying with functional brain MRI the superior colliculus (SC), a brainstem sensorimotor structure. Starting with the discovery that the SC shows abnormal visual responses in PD rat models, we aimed at studying the SC also in de novo PD patients. Methods: De novo PD patients and controls were studied using a recently developed fMRI protocol to stimulate and visualize the SC, the lateral geniculate nucleus (LGN) and the primary visual cortex (V1). The visual responses modulation of these structures was studied using luminance contrasts from 1% to 9%. We compared SC, LGN, and V1 BOLD responses of de novo PD patients with matching controls. The effects of dopaminergic treatment in PD patients were further evaluated. Findings: In the 22 enrolled PD patients, there was no modulation of the SC responses to the luminance contrasts, and the LGN was only modulated by 3%-9% luminance contrasts compared to the 22 controls. No major differences were found in V1 between both groups. Moreover, SC lack of modulation was more frequent in less affected de novo PD patients (Hoehn & Yahr stage 1). Dopaminergic treatment had no effect on SC and LGN modulation. Interpretation: De novo PD patients showed pathological responses to the luminance contrasts in the SC, suggesting that SC dysfunction could be diagnostic of PD. Since the SC seems to be more affected at stage 1 of PD, its dysfunction might be detected even earlier, supporting its potential role as a prodromal biomarker of PD. Clinical Trial Number: ClinicalTrial.gov (NCT02488395). Funding Statement: The work was funded by the University Grenoble Alpes, “La Fondation de l’Avenir” and “France Parkinson”. The Grenoble MRI facility IRMaGe was partly funded by the French program ‘Investissement d’Avenir” run by the Agence Nationale pour la Recherche (ANR-11-INBS-0006). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All participants provided written informed consent to the study. The study was approved by the local ethical committee (ID RCB- 2014-A01835-42).