Eye tracking paradigm to identify disease-specific behavioral biomarkers in neurodegeneration

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) has been identified as the most specific and common prodromal stage of α-synucleinopathies (αSYN) such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and the sporadic disease multiple system atrophy (MSA). Within 10...

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Bibliographic Details
Main Author: Habibi, Mahboubeh
Contributors: Oertel, Wolfgang (Prof. Dr. Dr. h.c.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2023
Online Access:PDF Full Text
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Summary:Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) has been identified as the most specific and common prodromal stage of α-synucleinopathies (αSYN) such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and the sporadic disease multiple system atrophy (MSA). Within 10 to 20 years, patients with this dream-sleep disorder convert in up to 85 % of cases to a neurodegenerative disease of the type of αSYN. Hence, iRBD is an ideal group for testing a disease-modifying therapy to postpone or even prevent phenoconversion. The latency, however, from diagnosis to phenoconversion is prolonged, lasting years to decades. Therefore, identifying iRBD patients more likely to phenoconvert needs highly sensitive and specific prodromal biomarkers and progression markers. The goal of this study was to contribute to the identification of biomarkers in manifest and prodromal αSYNs for their future selection as participants in protection trials. Furthermore, comparing patients with αSYN and Tauopathy is the second objective of this dissertation, aimed at identifying the underlying differences between the two disorders. To date, most of the biomarkers and progression markers for manifest αSYN relate to the motor and cognitive dysfunctions and imaging of the central nervous system but less to sensory and autonomic dysfunction. For iRBD, a recent review paper has summarized the state-of-the-art that confirms the above statement that most of the works in the field of biomarkers are performed on motor and cognitive functions and imaging. Until 2022, little has been published on oculomotor and pupillomotor dysfunctions in manifest and prodromal αSYN, but rather on the Tauopathy; progressive supranuclear palsy (PSP). The methodologies for studying eye movements and pupillary responses are highly developed. They offer a high resolution and precision in time and space for measuring sensory, autonomic, motor, and cognitive functions. Therefore, we systematically investigated the saccade, pupil, and blink behaviors in the manifest αSYN PD and MSA and their prodrome iRBD compared to healthy age and gender-matched controls. As a ”disease control” and for comparison, we also studied patients suffering from Tauopathy PSP. PSP is well-known for its oculomotor abnormalities, particularly for its characteristic symptom of relative vertical gaze palsy. PSP is – like MSA – another atypical parkinsonian disorder with multiple brain tissue losses, for example, in the frontal cortex. Because the early diagnosis of PD and MSA from PSP is difficult, PSP patients have been recruited for this study. As methods, we employed a structured saccade task that is called the Interleaved Pro/ Anti Saccade Task (IPAST) and a free viewing task (FV) to investigate oculomotor and pupillomotor function along with blink behavior in SYN and PSP. The IPAST is a structured saccade task that requires strong cognitive control, alertness, and attention. Previous studies on the manifest SYN have shown that patients with PD have systemic abnormalities in oculomotor, pupillometric parameters, and blink behavior in the IPAST. In order to simplify our method and broaden our ability to collect a wide range of eye movement parameters, we additionally employed another task, the unstructured free viewing of video clips (FV). Therefore, the research question is whether oculomotor and pupillomotor abnormalities and blinking during the IPAST and FV in iRBD patients differ from healthy controls, PD, MSA, and PSP. This study represents the first use of FV for the investigation of eye movement and pupil responses in subjects suffering from prodromal and manifest SYN. It is also the first study comparing prodromal and manifest SYN (PD, MSA) with PSP in FV. This dissertation has been performed in the context of the evolving disease-modifying therapy trials for manifest SYN, which are currently ongoing in patients with Parkinson’s disease. The next challenge will be to test these therapies in people with iRBD to slow or even prevent the full manifestation of the SYN. It will be essential to enrich prodromal populations with biomarkers of short-term conversion and to be able to monitor disease progression with serial measurements. Developing neurodegenerative disease treatments is becoming increasingly important as the population ages and the burden on families and society increases. In summary, we identified potential prodromal biomarkers in iRBD and differences between αSYN and the Tauopathy PSP, suggesting that the IPAST and especially FV task may be a tool to identify prodromal SYN and help to distinguish early manifest αSYN from early PSP. The future goal is intra-individual follow-up studies in iRBD patients to determine whether the so far observed subtle changes in oculo/pupillo-motor measures will progressively increase over time and allow the prediction of the phenoconversion of iRBD into manifest αSYN. These longitudinal studies will show whether oculo/pupillo-motor parameters can reliably distinguish the different neurodegenerative movement disorders in the manifest stages, and even more challenging, during their prodromal progression towards phenoconversion.