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 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

Objective evaluation of Parkinson's disease bradykinesia

Bradykinesia is the fundamental motor feature of Parkinson’s disease - obligatory for diagnosis and central to monitoring. It is a complex clinicalsign that describes movements with slow speed, small amplitude, irregular rhythm, brief pauses and progressive decrements. Clinical ascertainment of the presence and severity of bradykinesia relies on subjective interpretation of these components, with considerable variability amongst clinicians, and this may contribute to diagnostic error and inaccurate monitoring in Parkinson’s disease. The primary aim of this thesis was to assess whether a novel non-invasive device could objectively measure bradykinesia and predict diagnostic classification of movement data from Parkinson’s disease patients and healthy controls. The second aim was to evaluate how objective measures of bradykinesia correlate with clinical measures of bradykinesia severity. The third aim was to investigate the characteristic kinematic features of bradykinesia. Forty-nine patients with Parkinson’s disease and 41 healthy controls were recruited in Leeds. They performed a repetitive finger-tapping task for 30 seconds whilst wearing small electromagnetic tracking sensors on their finger and thumb. Movement data was analysed using two different methods - statistical measures of the separable components of bradykinesia and a computer science technique called evolutionary algorithms. Validation data collected independently from 13 patients and nine healthy controls in San Francisco was used to assess whether the results generalised. The evolutionary algorithm technique was slightly superior at classifying the movement data into the correct diagnostic groups, especially for the mildest clinical grades of bradykinesia, and they generalised to the independent group data. The objective measures of finger tapping correlated well with clinical grades of bradykinesia severity. Detailed analysis of the data suggests that a defining feature of Parkinson’s disease bradykinesia called the sequence effect may be a physiological rather than a pathological phenomenon. The results inform the development of a device that may support clinical diagnosis and monitoring of Parkinson’s disease and also be used to investigate bradykinesia

Smooth Pursuit and Antisaccade Eye Movements as Endophenotypes in Schizophrenia Spectrum Research

Smooth pursuit eye movement (SPEM) and antisaccade deficits have been proposed as schizophrenia spectrum endophenotypes. An endophenotype is a behavioural or biological deficit thought to represent, more closely than the disease phenotype, the effects of an underlying disease gene. Oculomotor endophenotypes possess phenotypic homogeneity, well-understood neural correlates and objective assessment and may thus be used as phenotypes in linkage studies. This thesis investigated a number of issues concerning the reliability and validity of the SPEM and antisaccade tasks as schizophrenia spectrum endophenotypes (and two tasks thought to be unimpaired in the schizophrenia spectrum, visual fixation and prosaccades). The schizophrenia spectrum encompasses not only people with schizophrenia but any population with an increased frequency of schizophrenia-related phenotypes or genotypes, such as schizotypal individuals or first-degree relatives of schizophrenia patients. A valid endophenotype should thus be detected in these populations. Study I investigated reliability, namely internal consistency and temporal stability, of eye movements in healthy individuals. Study II utilised first-episode psychosis patients and healthy controls, aiming to detect behavioural oculomotor deficits in the absence of secondary confounds that may be encountered in chronic schizophrenia. Study III assessed performance in siblings discordant for schizophrenia. Study IV explored the relationship between psychometric schizotypy and oculomotor performance. Study V examined possible state effects of procyclidine, an anticholinergic compound often administered to schizophrenia patients, on performance in a patient group. The results generally confirmed the validity of the SPEM and antisaccade deficits as schizophrenia spectrum endophenotypes: Oculomotor performance was mostly stable both within and between assessments. SPEM and antisaccade impairments were observed in first­episode psychosis patients and schizophrenia patients and their healthy siblings. Antisaccade, but not SPEM, impairments were associated with high levels of schizotypy. State effects of procyclidine on SPEM and antisaccade performance were observed, suggesting the need to consider the influence of pharmacological treatment in future patient studies. These findings suggest that SPEM and antisaccade deficits may be studied profitably as endophenotypes in schizophrenia spectrum research

AI and Non AI Assessments for Dementia

Current progress in the artificial intelligence domain has led to the development of various types of AI-powered dementia assessments, which can be employed to identify patients at the early stage of dementia. It can revolutionize the dementia care settings. It is essential that the medical community be aware of various AI assessments and choose them considering their degrees of validity, efficiency, practicality, reliability, and accuracy concerning the early identification of patients with dementia (PwD). On the other hand, AI developers should be informed about various non-AI assessments as well as recently developed AI assessments. Thus, this paper, which can be readable by both clinicians and AI engineers, fills the gap in the literature in explaining the existing solutions for the recognition of dementia to clinicians, as well as the techniques used and the most widespread dementia datasets to AI engineers. It follows a review of papers on AI and non-AI assessments for dementia to provide valuable information about various dementia assessments for both the AI and medical communities. The discussion and conclusion highlight the most prominent research directions and the maturity of existing solutions.Comment: 49 page

The utility of the auditory brainstem response in children with atypical saccadic eye movements

Full version unavailable due to 3rd party copyright restrictionsLesions in the brainstem result in widespread damage to a number of sensorimotor systems including oculomotor and auditory neural circuits. Although these systems are spatially separate and highly specialised, they are also co-located. This thesis, investigates whether lesions in the oculomotor system will also cause co-morbid dysfunction in the auditory pathways. Specifically, we investigated the usefulness of the Auditory Brainstem Response (ABR) in two oculomotor conditions: slow saccades in Gaucher disease (GD) and opsoclonus in Dancing Eye Syndrome (DES). We present four empirical studies. In our first study we systematically investigated the ABR in GD. We found that multimodal testing can better delineate underlying neurological deficits in neuronopathic GD (nGD) and distinguish between phenotypes. In the second study we examined the ABR's utility as a longitudinal, objective marker of disease burden and in a randomised clinical control trial. ABRs continued to deteriorate regardless of treatment. In our third study we assessed audiological function in DES. We found that at least 43% of DES patients have hyperacusis. We also found subtle abnormalities in the auditory brainstem, as shown by the ABR. Our final study explored the onset-offset response in the ABR and assessed its utility as a clinical marker. Overall, this thesis provides new evidence that auditory pathways are also affected in diseases which are traditionally assumed to be ‘oculomotor’ in nature. We believe that there is sufficient evidence to warrant the inclusion of audiological testing, such as the ABR, as part of the standard assessment of newly diagnosed GD patients and that they undergo these tests prior to commencing treatment. These tests may also have a wider application as longitudinal outcome measures for use in clinical trials or as markers of neurological burden in GD and we believe may be useful in other metabolic diseases; we found that current therapies for GD have low efficacy. Understanding the underlying neurological deficits in these debilitating illnesses can only help to improve treatments and the long-term outlook for these patients

Dementia in Parkinson’s Disease

An estimated 50% to 80% of individuals with Parkinson’s disease experience Parkinson’s disease dementia (PDD). Based on the prevalence and clinical complexity of PDD, this book provides an in-depth update on topics including epidemiology, diagnosis, and treatment. Chapters discuss non-medical therapies and examine views on end-of-life issues as well. This book is a must-read for anyone interested in PDD whether they are a patient, caregiver, or doctor

Pathophysiology and clinical aspects of eye movements in basal ganglia disorders.

Tato dizertační práce je souborem celkem 7 publikací, které se zabývají poruchami očních pohybů u pacientů s extrapyramidovými poruchami hybnosti. Pomocí videookulografického vyšetření jsme získali normativní data u zdravých osob. Zjistili jsme, že se vzrůstajícím věkem zdravé osoby se prodlužuje latence, oční pohyby se zpomalují, zhoršuje se přesnost a pohyby se stávají hypometrickými, rovněž vzrůstá chybovost u antisakád. Prokázali jsme, že pohlaví a vzdělání provádění očních pohybů neovlivňují. Naše studie také popsala asymetrii ve výsledcích pro levé a pravé oko, čímž klade důraz na význam vyšetření obou očí. Jako první jsme studovali vergenci u pacientů s Parkinsonovou nemocí (PN) za pomocí videookulografie (VOG). Vymysleli jsme a definovali paradigma pro toto vyšetření a zjistili, že u pacientů s PN je prodloužená latence a rovněž dochází k rozvoji hypometrie u divergence. U pacientů s abúzem efedronu (EP) jsme jako první vyšetřili oční pohyby a zjistili jsme, že je možné na základě okulografického vyšetření rozlišit mezi tímto toxicky navozeným parkinsonským syndromem a PN. U EP pacientů jsme popsali nižší rychlost a hypometrii u horizontálních sakád, prodlouženou latenci u horizontálních sakád a vyšší chybovost u antisakadického úkolu. Porucha chování v REM spánku (RBD) jako prodromální...This dissertation is a collection of a total of seven publications that deal with eye movement disorders in patients with basal ganglia disorders. We obtained normative data for videooculography in healthy individuals. We have described the eye movement evolution during a human life such as the increase of latency, movements become hypometric and antisaccadic error rate increases. We have shown that sex and education do not affect the eye movements. Our study highlighted the asymmetry in the eye movement performance. As the first, we studied the vergence in patients with Parkinson's disease (PN) using videooculography (VOG). We devised and defined a paradigm for this examination and saw that in patients with PN there is a prolonged latency and hypometry of divergence. In patients with ephedrone induced parkinsonism (EP), we were the first who examined eye movements and found that it was possible to identify between this toxic Parkinson's syndrome and PN on the basis of a videooculography. In EP patients, we described velocity decsrease and hypometry in horizontal saccades, prolonged latency in horizontal saccades, and higher error rate in the antisacadic task. Behavioral disorder in REM sleep (RBD) as a prodromal stage of PN leads to impaired eye movement. In the evaluation with PN patients, we...Department of Neurology First Faculty of Medicine and General University HospitalNeurologická klinika 1. LF UK a VFN1. lékařská fakultaFirst Faculty of Medicin

Evaluating Digital Health Technologies to Advance Parkinson's Disease Care

Parkinson’s disease (PD) is a common progressive neurological disorder characterised by a complex range of motor and non-motor symptoms (NMS). Current PD service provision does not meet the needs of patients, and puts pressure on services with limited capacity. Digital Health Technologies (DHTs), including body-worn sensors and portable devices, may provide advantages, by enabling continual and objective monitoring of symptoms, and facilitating patient self-management. I carried out a series of studies and evaluations of DHTs for use in PD, to evaluate their ability to identify and monitor symptoms in both a clinical and research context. These included: 1. The evaluation of a computerised paced finger tapping task (PFT) that was found to correlate with a measure of verbal fluency, suggesting there may be potential to implement the PFT as part of a wider finger tapping battery to be used as a screening tool for PD executive dysfunction. 2. The iterative, user-centred design and formative evaluation of NMS Assist, a smartphone-based app to enable regular assessment of NMS as well as provide education for patients. The app was found to be highly usable, and key areas of amendment were identified. 3. A clinical service evaluation of the PKGTM, a PD remote monitoring device. The findings revealed the PKGTM is useful for identifying patients with unmet treatment need, even in newly diagnosed people with Parkinson’s (PwP) who experience more frequent clinic review. 4. A systematic review of neuroprotective trial design in PD. The results demonstrated a wide range of primary outcome measures is used across trials, and there is little evidence of patient stratification. The findings highlighted the potential for DHTs to improve various aspects of clinical trial design. I discuss the potential value of DHTs, as well as challenges associated with their use, identified as a result of this research

Low-Cost Objective Measurement of Prehension Skills

This thesis aims to explore the feasibility of using low-cost, portable motion capture tools for the quantitative assessment of sequential 'reach-to-grasp' and repetitive 'finger-tapping' movements in neurologically intact and deficit populations, both in clinical and non-clinical settings. The research extends the capabilities of an existing optoelectronic postural sway assessment tool (PSAT) into a more general Boxed Infrared Gross Kinematic Assessment Tool (BIGKAT) to evaluate prehensile control of hand movements outside the laboratory environment. The contributions of this work include the validation of BIGKAT against a high-end motion capture system (Optotrak) for accuracy and precision in tracking kinematic data. BIGKAT was subsequently applied to kinematically resolve prehensile movements, where concurrent recordings with Optotrak demonstrate similar statistically significant results for five kinematic measures, two spatial measures (Maximum Grip Aperture – MGA, Peak Velocity – PV) and three temporal measures (Movement Time – MT, Time to MGA – TMGA, Time to PV – TPV). Regression analysis further establishes a strong relationship between BIGKAT and Optotrak, with nearly unity slope and low y-intercept values. Results showed reliable performance of BIGKAT and its ability to produce similar statistically significant results as Optotrak. BIGKAT was also applied to quantitatively assess bradykinesia in Parkinson's patients during finger-tapping movements. The system demonstrated significant differences between PD patients and healthy controls in key kinematic measures, paving the way for potential clinical applications. The study characterized kinematic differences in prehensile control in different sensory environments using a Virtual Reality head mounted display and finger tracking system (the Leap Motion), emphasizing the importance of sensory information during hand movements. This highlighted the role of hand vision and haptic feedback during initial and final phases of prehensile movement trajectory. The research also explored marker-less pose estimation using deep learning tools, specifically DeepLabCut (DLC), for reach-to-grasp tracking. Despite challenges posed by COVID-19 limitations on data collection, the study showed promise in scaling reaching and grasping components but highlighted the need for diverse datasets to resolve kinematic differences accurately. To facilitate the assessment of prehension activities, an Event Detection Tool (EDT) was developed, providing temporal measures for reaction time, reaching time, transport time, and movement time during object grasping and manipulation. Though initial pilot data was limited, the EDT holds potential for insights into disease progression and movement disorder severity. Overall, this work contributes to the advancement of low-cost, portable solutions for quantitatively assessing upper-limb movements, demonstrating the potential for wider clinical use and guiding future research in the field of human movement analysis