Best Oculomotor Endpoints for Clinical Trials in Hereditary Ataxias: A Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital‑Motor Biomarkers.

Oculomotor deficits are common in hereditary cerebellar ataxias (HCAs) and their quantitative assessment offers a sensitive and reliable manner to capture disease-severity and progression. As a group of experts of the Ataxia Global Initiative to support trial readiness, we previously established harmonized methodology for quantitative oculomotor assessments in HCAs. Here, we aimed to identify to most promising oculomotor/vestibular outcomes as endpoints for future trials.

Verbal fluency is associated with Gait impairment in Progressive Supranuclear Palsy.

Introduction: Gait impairment is an important diagnostic criterion for Progressive Supranuclear Palsy (PSP) and may be modulated by specific cognitive domains such as executive function. This study aims to investigate the relationship between executive function and gait in PSP, using verbal fluency tasks as a cognitive measure alongside clinical assessments and objective gait analysis with wearable sensors. We explore whether these relationships are sustained longitudinally.

Pathway to Regulatory Approval of Digital Health Technologies in Progressive Supranuclear Palsy: A Scoping Review.

Progressive supranuclear palsy (PSP) is an atypical Parkinsonian disorder characterized by Parkinsonism with gait imbalance, vertical gaze palsy, and frontal cognitive dysfunction. Though digital health technologies (DHTs) are widely used both clinically and in research as outcome measures, there is a lack of consistency applied to these devices and their resulting metrics. This scoping review aims to identify efforts taken to validate wearable DHTs for use in PSP, identify gaps in research, and discuss the steps needed to expand their use and acceptance as primary trial endpoints.

Decoding dynamic brain networks in Parkinson's disease with temporal attention.

Detecting brief, clinically meaningful changes in brain activity is crucial for understanding neurological disorders. Conventional imaging analyses often overlook these subtle events due to computational demands. IMPACT (Integrative Multimodal Pipeline for Advanced Connectivity and Time-series) addresses this challenge by converting 3D/4D fMRI scans into time-series signals using a standardized brain atlas.

A novel machine learning based framework for developing composite digital biomarkers of disease progression.

Background: Current methods of measuring disease progression of neurodegenerative disorders, including Parkinson's disease (PD), largely rely on composite clinical rating scales, which are prone to subjective biases and lack the sensitivity to detect progression signals in a timely manner. Digital health technology (DHT)-derived measures offer potential solutions to provide objective, precise, and sensitive measures that address these limitations. However, the complexity of DHT datasets and the potential to derive numerous digital features that were not previously possible to measure pose challenges, including in selection of the most important digital features and construction of composite digital biomarkers.

Quantitative Oculomotor and Vestibular Profile in Spinocerebellar Ataxia Type 6 - Systematic Review and Meta-Analysis.

Whereas several studies have reported on quantitative oculomotor and vestibular measurements in spinocerebellar ataxia type 6 (SCA6), selecting the most suitable paradigms remains challenging. We aimed to address this knowledge gap through a systematic literature review and providing disease-specific recommendations for a tailored set of eye-movement recordings in SCA6. A literature search (MEDLINE, Embase) was performed focusing on studies reporting on quantitative oculomotor and/or vestibular measurements in SCA6-patients.

The oculomotor microcosm.

This scientific commentary refers to 'Noradrenergic modulation of saccades in Parkinson's disease', by  Orlando . (https://doi.org/10.

Naturalistic Eye Movement Tasks in Parkinson's Disease: A Systematic Review.

Background: Eye tracking assessments in the laboratory have previously highlighted clear differences in eye movements between Parkinson's disease (PD) and healthy aging. However, laboratory-based eye movement tasks are artificial and limit the ecological validity of observed results. Eye movement tasks utilizing more naturalistic scenarios may provide more accurate insight into cognitive function but research in this area is limited.

Differential effects of bilateral hippocampal CA3 damage on the implicit learning and recognition of complex event sequences.

Learning regularities in the environment is a fundament of human cognition, which is supported by a network of brain regions that include the hippocampus. In two experiments, we assessed the effects of selective bilateral damage to human hippocampal subregion CA3, which was associated with autobiographical episodic amnesia extending ~50 years prior to the damage, on the ability to recognize complex, deterministic event sequences presented either in a spatial or a non-spatial configuration. In contrast to findings from related paradigms, modalities, and homologue species, hippocampal damage did not preclude recognition memory for an event sequence studied and tested at four spatial locations, whereas recognition memory for an event sequence presented at a single location was at chance.

Eye movements in Parkinson's disease: from neurophysiological mechanisms to diagnostic tools.

Movement disorders such as Parkinson's disease (PD) impact oculomotor function - the ability to move the eyes accurately and purposefully to serve a multitude of sensory, cognitive, and secondary motor tasks. Decades of neurophysiological research in monkeys and behavioral studies in humans have characterized the neural basis of healthy oculomotor control. This review links eye movement abnormalities in persons living with PD to the underlying neurophysiological mechanisms and pathways.

Using Smartphone Sensors for Ataxia Trials: Consensus Guidance by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers.

Smartphone sensors are used increasingly in the assessment of ataxias. To date, there is no specific consensus guidance regarding a priority set of smartphone sensor measurements, or standard assessment criteria that are appropriate for clinical trials. As part of the Ataxia Global Initiative Digital-Motor Biomarkers Working Group (AGI WG4), aimed at evaluating key ataxia clinical domains (gait/posture, upper limb, speech and oculomotor assessments), we provide consensus guidance for use of internal smartphone sensors to assess key domains.

Identification of motor progression in Parkinson's disease using wearable sensors and machine learning.

Wearable devices offer the potential to track motor symptoms in neurological disorders. Kinematic data used together with machine learning algorithms can accurately identify people living with movement disorders and the severity of their motor symptoms. In this study we aimed to establish whether a combination of wearable sensor data and machine learning algorithms with automatic feature selection can estimate the clinical rating scale and whether it is possible to monitor the motor symptom progression longitudinally, for people with Parkinson's Disease.

Retinal Optical Coherence Tomography Features Associated With Incident and Prevalent Parkinson Disease.

Background And Objectives: Cadaveric studies have shown disease-related neurodegeneration and other morphological abnormalities in the retina of individuals with Parkinson disease (PD); however, it remains unclear whether this can be reliably detected with in vivo imaging. We investigated inner retinal anatomy, measured using optical coherence tomography (OCT), in prevalent PD and subsequently assessed the association of these markers with the development of PD using a prospective research cohort.

Methods: This cross-sectional analysis used data from 2 studies.

Antiparkinsonian medication masks motor signal progression in de novo patients.

Patients not yet receiving medication provide insight to drug-naïve early physiology of Parkinson's Disease (PD). Wearable sensors can measure changes in motor features before and after introduction of antiparkinsonian medication. We aimed to identify features of upper limb bradykinesia, postural stability, and gait that measurably progress in de novo PD patients prior to the start of medication, and determine whether these features remain sensitive to progression in the period after commencement of antiparkinsonian medication.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital-motor Biomarkers.

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes.

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response.

Parkinson's disease deficits in time perception to auditory as well as visual stimuli - A large online study.

Cognitive deficits are common in Parkinson's disease (PD) and range from mild cognitive impairment to dementia, often dramatically reducing quality of life. Physiological models have shown that attention and memory are predicated on the brain's ability to process time. Perception has been shown to be increased or decreased by activation or deactivation of dopaminergic neurons respectively.

Longitudinal Monitoring of Progressive Supranuclear Palsy using Body-Worn Movement Sensors.

Background: We have previously shown that wearable technology and machine learning techniques can accurately discriminate between progressive supranuclear palsy (PSP), Parkinson's disease, and healthy controls. To date these techniques have not been applied in longitudinal studies of disease progression in PSP.

Objectives: We aimed to establish whether data collected by a body-worn inertial measurement unit (IMU) network could predict clinical rating scale scores in PSP and whether it could be used to track disease progression.

Oculomotor deficits in Parkinson's disease: Increasing sensitivity using multivariate approaches.

Parkinson's disease (PD) affects several domains of neurological function, from lower-level motor programs to higher cognitive processing. As certain types of eye movements (saccades) are fast, non-fatiguing, and can be measured objectively and non-invasively, they are a promising candidate for quantifying motor and cognitive dysfunction in PD, as well as other movement disorders. In this pilot study, we evaluate the latency (reaction time), damping (resistance to oscillation), and amplitude of saccadic movements in two tasks performed by 25 PD patients with mild to moderate disease and 26 age-matched healthy controls.

Deep Brain Stimulation and Levodopa Affect Gait Variability in Parkinson Disease Differently.

Background: Both dopaminergic medication and subthalamic nucleus (STN) deep brain stimulation (DBS) can improve the amplitude and speed of gait in Parkinson disease (PD), but relatively little is known about their comparative effects on gait variability. Gait irregularity has been linked to the degeneration of cholinergic neurons in the pedunculopontine nucleus (PPN).

Objectives: The STN and PPN have reciprocal connections, and we hypothesized that STN DBS might improve gait variability by modulating PPN function.

Longitudinal changes of early motor and cognitive symptoms in progressive supranuclear palsy: the OxQUIP study.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative condition characterised by a range of motor and cognitive symptoms. Very little is known about the longitudinal change in these symptoms over time. Moreover, the effectiveness of clinical scales to detect early changes in PSP is still a matter of debate.

Discriminating progressive supranuclear palsy from Parkinson's disease using wearable technology and machine learning.

Background: Progressive supranuclear palsy (PSP), a neurodegenerative conditions may be difficult to discriminate clinically from idiopathic Parkinson's disease (PD). It is critical that we are able to do this accurately and as early as possible in order that future disease modifying therapies for PSP may be deployed at a stage when they are likely to have maximal benefit. Analysis of gait and related tasks is one possible means of discrimination.