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. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

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. Guidance was developed by means of a literature review and a two stage Delphi study conducted by an Expert panel, which surveyed members of AGI WG4, representing clinical, research, industry and patient-led experts, and consensus meetings by the Expert panel to agree on standard criteria and map current literature to these criteria. Seven publications were identified that investigated ataxias using internal smartphone sensors. The Delphi 1 survey ascertained current practice, and systems in use or under development. Wide variations in smartphones sensor use for assessing ataxia were identified. The Delphi 2 survey identified seven measures that were strongly endorsed as priorities in assessing 3/4 domains, namely gait/posture, upper limb, and speech performance. The Expert panel recommended 15 standard criteria to be fulfilled in studies. Evaluation of current literature revealed that none of the studies met all criteria, with most being early-phase validation studies. Our guidance highlights the importance of consensus, identifies priority measures and standard criteria, and will encourage further research into the use of internal smartphone sensors to measure ataxia digital-motor biomarkers.

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. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias.

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. Dopaminergic medication should not do this, and we therefore sought to compare the effects of medication and STN DBS on gait variability. MATERIALS AND METHODS: We studied 11 patients with STN DBS systems on and off with no alteration to their medication, and 15 patients with PD without DBS systems on and off medication. Participants walked for two minutes in each state, wearing six inertial measurement units. Variability has previously often been expressed in terms of SD or coefficient of variation over a testing session, but these measures conflate long-term variability (eg, gradual slowing, which is not necessarily pathological) with short-term variability (true irregularity). We used Poincaré analysis to separate the short- and long-term variability. RESULTS: DBS decreased short-term variability in lower limb gait parameters, whereas medication did not have this effect. In contrast, STN DBS had no effect on arm swing and trunk motion variability, whereas medication increased them, without obvious dyskinesia. CONCLUSIONS: Our results suggest that STN DBS acts through a nondopaminergic mechanism to reduce gait variability. We believe that the most likely explanation is the retrograde activation of cholinergic PPN projection neurons.

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. METHODS: We studied gait and postural stability in 17 participants with PSP over five visits at 3-month intervals. Participants performed a 2-minute walk and an assessment of postural stability by standing for 30 seconds with their eyes closed, while wearing an array of six IMUs. RESULTS: Thirty-two gait and posture features were identified, which progressed significantly with time. A simple linear regression model incorporating the three features with the clearest progression pattern was able to detect statistically significant progression 3 months in advance of the clinical scores. A more complex linear regression and a random forest approach did not improve on this. CONCLUSIONS: The reduced variability of the models, in comparison to clinical rating scales, allows a significant change in disease status from baseline to be observed at an earlier stage. The current study sheds light on the individual features that are important in tracking disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pallidal Deep Brain Stimulation Improves Higher Control of the Oculomotor System in Parkinson's Disease.

The frontal cortex and basal ganglia form a set of parallel but mostly segregated circuits called cortico-basal ganglia loops. The oculomotor loop controls eye movements and can direct relatively simple movements, such as reflexive prosaccades, without external help but needs input from "higher" loops for more complex behaviors. The antisaccade task requires the dorsolateral prefrontal cortex, which is part of the prefrontal loop. Information flows from prefrontal to oculomotor circuits in the striatum, and directional errors in this task can be considered a measure of failure of prefrontal control over the oculomotor loop. The antisaccadic error rate (AER) is increased in Parkinson's disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has no effect on the AER, but a previous case suggested that DBS of the globus pallidus interna (GPi) might. Our aim was to compare the effects of STN DBS and GPi DBS on the AER. We tested eye movements in 14 human DBS patients and 10 controls. GPi DBS substantially reduced the AER, restoring lost higher control over oculomotor function. Interloop information flow involves striatal neurons that receive cortical input and project to pallidum. They are normally silent when quiescent, but in PD they fire randomly, creating noise that may account for the degradation in interloop control. The reduced AER with GPi DBS could be explained by retrograde stimulation of striatopallidal axons with consequent activation of inhibitory collaterals and reduction in background striatal firing rates. This study may help explain aspects of PD pathophysiology and the mechanism of action of GPi DBS. Significance statement: Parkinson's disease causes symptoms including stiffness, slowness of movement, and tremor. Electrical stimulation of specific areas deep in the brain can effectively treat these symptoms, but exactly how is not fully understood. Part of the cause of such symptoms may be impairments in the way information flows from one circuit within the brain to another, as a result of overactivity of certain nerve cells. By demonstrating that stimulation of an area called the globus pallidus interna partially reverses deficits in voluntary control of eye movements, this study shows that stimulation can improve information flow between circuits, probably by calming down the overactive cells.

Eye movements and deep brain stimulation.

PURPOSE OF REVIEW: Deep brain stimulation (DBS) is an established treatment for several neurological conditions, and is most commonly used to treat Parkinson's disease by implanting electrodes in the basal ganglia. Despite the fact that circuits involved in eye movement control traverse the basal ganglia and are thus likely to be affected by DBS, studies combining DBS with eye movement analysis have been infrequent. This review focuses on recent research studies that examine the relationship between DBS and various types of eye movements and which highlight the potential of this approach. RECENT FINDINGS: Recent work shows that DBS in the subthalamic nucleus (STN) can improve smooth pursuit in Parkinson's disease. STN DBS has also been shown to modulate visuospatial attention, and has provided experimental evidence backing a Bayesian model of basal ganglia function. DBS in the pallidum can improve antisaccadic performance in Parkinson's disease, suggesting improvement in higher control of oculomotor function, and implying retrograde striatal stimulation as part of the mechanism of action. SUMMARY: These studies show that the combination of DBS with eye movement analysis is a powerful research tool. It may be used to study oculomotor physiology, basal ganglia pathophysiology, and the mechanism of action of DBS.

Deep brain stimulation abolishes slowing of reactions to unlikely stimuli.

The cortico-basal-ganglia circuit plays a critical role in decision making on the basis of probabilistic information. Computational models have suggested how this circuit could compute the probabilities of actions being appropriate according to Bayes' theorem. These models predict that the subthalamic nucleus (STN) provides feedback that normalizes the neural representation of probabilities, such that if the probability of one action increases, the probabilities of all other available actions decrease. Here we report the results of an experiment testing a prediction of this theory that disrupting information processing in the STN with deep brain stimulation should abolish the normalization of the neural representation of probabilities. In our experiment, we asked patients with Parkinson's disease to saccade to a target that could appear in one of two locations, and the probability of the target appearing in each location was periodically changed. When the stimulator was switched off, the target probability affected the reaction times (RT) of patients in a similar way to healthy participants. Specifically, the RTs were shorter for more probable targets and, importantly, they were longer for the unlikely targets. When the stimulator was switched on, the patients were still faster for more probable targets, but critically they did not increase RTs as the target was becoming less likely. This pattern of results is consistent with the prediction of the model that the patients on DBS no longer normalized their neural representation of prior probabilities. We discuss alternative explanations for the data in the context of other published results.

Antisaccades and executive dysfunction in early drug-naive Parkinson's disease: The discovery study.

BACKGROUND: Cognitive impairment is well recognized in Parkinson's disease (PD), but when it begins to develop is unclear. The aim of this study was to identify early signs of cognitive impairment along with abnormalities in saccadic behavior in newly diagnosed unmedicated PD patients. METHODS: Nineteen drug-naive PD patients and 20 controls were examined using a battery of tests, including an antisaccade task, phonemic and semantic verbal fluencies, and a switching and rule finding task. RESULTS: With simple tasks, no differences were found between the two groups. However, cognitive performance of the two groups diverged with more complex tasks, occurring independently of PD-related motor impairment. Patients exhibited higher antisaccadic error rates and switch costs in the task switching test, and performed significantly worse in the rule finding task. CONCLUSIONS: Certain cognitive domains and saccadic parameters are already significantly impoverished in newly diagnosed Parkinson's patients, even before the initiation of medication.

The effect of acetazolamide on saccadic latency at 3459 meters.

OBJECTIVE: The effect of altitude on brain function is not yet well understood, nor is the influence of height and speed of ascent. Additionally, the relationship between acute mountain sickness (AMS) symptoms and brain function at altitude is unclear. We hypothesized that a deterioration from baseline measures of brain function occurs after rapid, mechanical ascent to 3459 m and would be less pronounced in persons taking acetazolamide. METHODS: In this double blind, randomized, placebo-controlled study, 20 healthy volunteers (14 men, 6 women; mean age [±SD] 43 ± 16 years) were alternately allocated to acetazolamide 250 mg or to placebo, taken every 12 hours commencing 3 days before ascent. Prosaccadic and antisaccadic eye movements, heart rate, arterial saturation, and Lake Louise AMS scores were assessed at sea level and 15 to 22 hours after ascent to 3459 m. RESULTS: Arterial oxygen saturation was significantly lower in the placebo group compared to the acetazolamide group at altitude (Wilcoxon signed-rank test, median [interquartile range]: acetazolamide vs placebo: 92% [5] vs 85% [5]; P = .007), with no differences in prosaccadic latency, heart rate, or Lake Louise score. No differences in saccadic latencies from baseline to altitude were observed in the placebo group, whereas prosaccadic latencies were significantly longer at altitude with acetazolamide (altitude vs baseline: 153 ms [41] vs 176 ms [52], P = .008). CONCLUSIONS: Brain function, measured by saccadic eye movements, appears to be unimpaired after rapid ascent to 3459 m. Although acetazolamide improves oxygen saturations, it may worsen prosaccades, possibly indicating adverse effects of acetazolamide on brain function at moderate altitude.

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. Building on this foundation, we highlight recent progress in using eye movements to gauge symptom severity, assess treatment effects, and serve as potential precision biomarkers. We conclude that whereas eye movements provide insights into PD mechanisms, based on current evidence they appear to lack sufficient sensitivity and specificity to serve as a standalone diagnostic tool. Their full potential may be realized when combined with other disease indicators in big datasets.

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. In two additional experiments, recognition memory for novel single-items was intact, whereas the ability to recognize novel single-items in a different location from that presented at study was at chance. The results are at variance with a general role of the hippocampus in the learning and recognition of complex event sequences based on non-adjacent spatial and temporal dependencies. We discuss the impact of the results on established theoretical accounts of the hippocampal contributions to implicit sequence learning and episodic memory.

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. Upper limb motion was measured using an inertial sensor worn on a finger, while postural stability and gait were recorded using an array of six wearable sensors. Patients were tested over nine visits at three monthly intervals. The timepoint of start of medication was noted. Three upper limb bradykinetic features (finger tapping speed, pronation supination speed, and pronation supination amplitude) and three gait features (gait speed, arm range of motion, duration of stance phase) were found to progress in unmedicated early-stage PD patients. In all features, progression was masked after the start of medication. Commencing antiparkinsonian medication is known to lead to masking of progression signals in clinical measures in de novo PD patients. In this study, we show that this effect is also observed with digital measures of bradykinetic and gait motor features.

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. Seventy-four patients visited the lab seven times at 3-month intervals. Their walking (2-minutes) and postural sway (30-seconds,eyes-closed) were recorded using six Inertial Measurement Unit sensors. Simple linear regression and Random Forest algorithms were utilised together with different routines of automatic feature selection or factorisation, resulting in seven different machine learning algorithms to estimate the clinical rating scale (Movement Disorder Society- Unified Parkinson's Disease Rating Scale part III; MDS-UPDRS-III). Twenty-nine features were found to significantly progress with time at group level. The Random Forest model revealed the most accurate estimation of the MDS-UPDRS-III among the seven models. The model estimations detected a statistically significant progression of the motor symptoms within 15 months when compared to the first visit, whereas the MDS-UPDRS-III did not capture any change. Wearable sensors and machine learning can track the motor symptom progression in people with PD better than the conventionally used clinical rating scales. The methods described in this study can be utilised complimentary to the clinical rating scales to improve the diagnostic and prognostic accuracy.

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. For the detection of retinal markers in prevalent PD, we used data from AlzEye, a retrospective cohort of 154,830 patients aged 40 years and older attending secondary care ophthalmic hospitals in London, United Kingdom, between 2008 and 2018. For the evaluation of retinal markers in incident PD, we used data from UK Biobank, a prospective population-based cohort where 67,311 volunteers aged 40-69 years were recruited between 2006 and 2010 and underwent retinal imaging. Macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layer (INL) thicknesses were extracted from fovea-centered OCT. Linear mixed-effects models were fitted to examine the association between prevalent PD and retinal thicknesses. Hazard ratios for the association between time to PD diagnosis and retinal thicknesses were estimated using frailty models. RESULTS: Within the AlzEye cohort, there were 700 individuals with prevalent PD and 105,770 controls (mean age 65.5 ± 13.5 years, 51.7% female). Individuals with prevalent PD had thinner GCIPL (-2.12 µm, 95% CI -3.17 to -1.07, p = 8.2 × 10-5) and INL (-0.99 µm, 95% CI -1.52 to -0.47, p = 2.1 × 10-4). The UK Biobank included 50,405 participants (mean age 56.1 ± 8.2 years, 54.7% female), of whom 53 developed PD at a mean of 2,653 ± 851 days. Thinner GCIPL (hazard ratio [HR] 0.62 per SD increase, 95% CI 0.46-0.84, p = 0.002) and thinner INL (HR 0.70, 95% CI 0.51-0.96, p = 0.026) were also associated with incident PD. DISCUSSION: Individuals with PD have reduced thickness of the INL and GCIPL of the retina. Involvement of these layers several years before clinical presentation highlight a potential role for retinal imaging for at-risk stratification of PD.

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. As well as general increases in reaction time caused by PD, the damping of saccadic eye movements was found to be task-dependent and affected by disease. Finally, we introduce a proof-of-concept multivariate model to demonstrate how information from saccadometry can be combined to infer disease status.

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. Here we investigate differences in time perception between patients with PD and healthy controls. We have measured differences in sub-second- and second-time intervals. Sensitivity and error in perception as well as the response times are calculated. Additionally, we investigated intra-individual response variability and the effect of participant devices on both reaction time and sensitivity. Patients with PD have impaired sensitivity in discriminating between durations of both visual and auditory stimuli compared to healthy controls. Though initially designed as an in-person study, because of the pandemic the experiment was adapted into an online study. This adaptation provided a unique opportunity to enroll a larger number of international participants and use this study to evaluate the feasibility of future virtual studies focused on cognitive impairment. To our knowledge this is the only time perception study, focusing on PD, which measures the differences in perception using both auditory and visual stimuli. The cohort involved is the largest to date, comprising over 800 participants.

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. OBJECTIVE: We aimed to determine longitudinal changes in PSP features using multiple closely spaced follow-up time points over a period of 2 years. Methods 28 healthy control and 28 PSP participants, with average time since onset of symptoms of 1.9 years, were prospectively studied every 3 months for up to 24 months. Changes from baseline scores were calculated at each follow-up time point using multiple clinical scales to identify longitudinal progression of motor and cognitive symptoms. RESULTS: The Montreal Cognitive Assessment, but not the Mini-Mental State Examination, detected cognitive decline at baseline. Both scales revealed poor longitudinal sensitivity to clinical change in global cognitive symptoms. Conversely, the Movement Disorders Society Unified Parkinson's disease Rating Scale - part III and the PSP Rating Scale (PSPRS) reliably detected motor decline less than 2 years after disease onset. The 'Gait/Midline' PSPRS subscore consistently declined over time, with the earliest change being observed 6 months after baseline assessment. CONCLUSION: While better cognitive screening tools are still needed to monitor cognitive decline in PSP, motor decline is consistently captured by clinical rating scales. These results support the inclusion of multiple follow-up time points in longitudinal studies in the early stages of PSP.

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. RESEARCH QUESTION: Here we investigate a wearable sensor array coupled with machine learning approaches as a means of disease classification. METHODS: 21 participants with PSP, 20 with PD, and 39 healthy control (HC) subjects performed a two minute walk, static sway test, and timed up-and-go task, while wearing an array of six inertial measurement units. The data were analysed to determine what features discriminated PSP from PD and PSP from HC. Two machine learning algorithms were applied, Logistic Regression (LR) and Random Forest (RF). RESULTS: 17 features were identified in the combined dataset that contained independent information. The RF classifier outperformed the LR classifier, and allowed discrimination of PSP from PD with 86 % sensitivity and 90 % specificity, and PSP from HC with 90 % sensitivity and 97 % specificity. Using data from the single lumbar sensor only resulted in only a modest reduction in classification accuracy, which could be restored using 3 sensors (lumbar, right arm and foot). However for maximum specificity the full six sensor array was needed. SIGNIFICANCE: A wearable sensor array coupled with machine learning methods can accurately discriminate PSP from PD. Choice of array complexity depends on context; for diagnostic purposes a high specificity is needed suggesting the more complete array is advantageous, while for subsequent disease tracking a simpler system may suffice.