Nat Commun. 2023 Aug 21;14(1):5080. doi: 10.1038/s41467-023-40917-3.
Amyotrophic lateral sclerosis causes degeneration of motor neurons, resulting in progressive muscle weakness and impairment in motor function. Promising drug development efforts have accelerated in amyotrophic lateral sclerosis, but are constrained by a lack of objective, sensitive, and accessible outcome measures. Here we investigate the use of wearable sensors, worn on four limbs at home during natural behavior, to quantify motor function and disease progression in 376 individuals with amyotrophic lateral sclerosis. We use an analysis approach that automatically detects and characterizes submovements from passively collected accelerometer data and produces a machine-learned severity score for each limb that is independent of clinical ratings. We show that this approach produces scores that progress faster than the gold standard Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (-0.86 ± 0.70 SD/year versus -0.73 ± 0.74 SD/year), resulting in smaller clinical trial sample size estimates (N = 76 versus N = 121). This method offers an ecologically valid and scalable measure for potential use in amyotrophic lateral sclerosis trials and clinical care.
Cerebellum. 2023 Apr 28. doi: 10.1007/s12311-023-01559-9. Online ahead of print.
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.
OBJECTIVE: Objective, sensitive, and meaningful disease assessments are critical to support clinical trials and clinical care. Speech changes are one of the earliest and most evident manifestations of cerebellar ataxias. The purpose of this work is to develop models that can accurately identify and quantify these abnormalities.
METHODS: We use deep learning models such as ResNet 18 , that take the time and frequency partial derivatives of the log-mel spectrogram representations of speech as input, to learn representations that capture the motor speech phenotype of cerebellar ataxia. We train classification models to separate patients with ataxia from healthy controls as well as regression models to estimate disease severity.
RESULTS: Our model was able to accurately distinguish healthy controls from individuals with ataxia, including ataxia participants with no detectable clinical deficits in speech. Furthermore the regression models produced accurate estimates of disease severity, were able to measure subclinical signs of ataxia, and captured disease progression over time in individuals with ataxia.
CONCLUSION: Deep learning models, trained on time and frequency partial derivatives of the speech signal, can detect sub-clinical speech changes in ataxias and sensitively measure disease change over time.
SIGNIFICANCE: Such models have the potential to assist with early detection of ataxia and to provide sensitive and low-burden assessment tools in support of clinical trials and neurological care.
Cerebellum. 2023 Apr 11. doi: 10.1007/s12311-023-01539-z. Online ahead of print.
Dysarthria is a common manifestation across cerebellar ataxias leading to impairments in communication, reduced social connections, and decreased quality of life. While dysarthria symptoms may be present in other neurological conditions, ataxic dysarthria is a perceptually distinct motor speech disorder, with the most prominent characteristics being articulation and prosody abnormalities along with distorted vowels. We hypothesized that uncertainty of vowel predictions by an automatic speech recognition system can capture speech changes present in cerebellar ataxia. Speech of participants with ataxia (N=61) and healthy controls (N=25) was recorded during the "picture description" task. Additionally, participants' dysarthric speech and ataxia severity were assessed on a Brief Ataxia Rating Scale (BARS). Eight participants with ataxia had speech and BARS data at two timepoints. A neural network trained for phoneme prediction was applied to speech recordings. Average entropy of vowel tokens predictions (AVE) was computed for each participant's recording, together with mean pitch and intensity standard deviations (MPSD and MISD) in the vowel segments. AVE and MISD demonstrated associations with BARS speech score (Spearman's rho=0.45 and 0.51), and AVE demonstrated associations with BARS total (rho=0.39). In the longitudinal cohort, Wilcoxon pairwise signed rank test demonstrated an increase in BARS total and AVE, while BARS speech and acoustic measures did not significantly increase. Relationship of AVE to both BARS speech and BARS total, as well as the ability to capture disease progression even in absence of measured speech decline, indicates the potential of AVE as a digital biomarker for cerebellar ataxia.
Brain Commun. 2023 Mar 13;5(2):fcad064. doi: 10.1093/braincomms/fcad064. eCollection 2023.
Novel disease-modifying therapies are being evaluated in spinocerebellar ataxias and multiple system atrophy. Clinician-performed disease rating scales are relatively insensitive for measuring disease change over time, resulting in large and long clinical trials. We tested the hypothesis that sensors worn continuously at home during natural behaviour and a web-based computer mouse task performed at home could produce interpretable, meaningful and reliable motor measures for potential use in clinical trials. Thirty-four individuals with degenerative ataxias (spinocerebellar ataxia types 1, 2, 3 and 6 and multiple system atrophy of the cerebellar type) and eight age-matched controls completed the cross-sectional study. Participants wore an ankle and wrist sensor continuously at home for 1 week and completed the Hevelius computer mouse task eight times over 4 weeks. We examined properties of motor primitives called 'submovements' derived from the continuous wearable sensors and properties of computer mouse clicks and trajectories in relationship to patient-reported measures of function (Patient-Reported Outcome Measure of Ataxia) and ataxia rating scales (Scale for the Assessment and Rating of Ataxia and the Brief Ataxia Rating Scale). The test-retest reliability of digital measures and differences between ataxia and control participants were evaluated. Individuals with ataxia had smaller, slower and less powerful ankle submovements during natural behaviour at home. A composite measure based on ankle submovements strongly correlated with ataxia rating scale scores (Pearson's r = 0.82-0.88), strongly correlated with self-reported function (r = 0.81), had high test-retest reliability (intraclass correlation coefficient = 0.95) and distinguished ataxia and control participants, including preataxic individuals (n = 4) from controls. A composite measure based on computer mouse movements and clicks strongly correlated with ataxia rating scale total (r = 0.86-0.88) and arm scores (r = 0.65-0.75), correlated well with self-reported function (r = 0.72-0.73) and had high test-retest reliability (intraclass correlation coefficient = 0.99). These data indicate that interpretable, meaningful and highly reliable motor measures can be obtained from continuous measurement of natural movement, particularly at the ankle location, and from computer mouse movements during a simple point-and-click task performed at home. This study supports the use of these two inexpensive and easy-to-use technologies in longitudinal natural history studies in spinocerebellar ataxias and multiple system atrophy of the cerebellar type and shows promise as potential motor outcome measures in interventional trials.
Cerebellum. 2023 Jan 14. doi: 10.1007/s12311-023-01514-8. Online ahead of print.
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.
Sensors (Basel). 2022 Dec 3;22(23):9454. doi: 10.3390/s22239454.
Wearable sensor data is relatively easily collected and provides direct measurements of movement that can be used to develop useful behavioral biomarkers. Sensitive and specific behavioral biomarkers for neurodegenerative diseases are critical to supporting early detection, drug development efforts, and targeted treatments. In this paper, we use autoregressive hidden Markov models and a time-frequency approach to create meaningful quantitative descriptions of behavioral characteristics of cerebellar ataxias from wearable inertial sensor data gathered during movement. We create a flexible and descriptive set of features derived from accelerometer and gyroscope data collected from wearable sensors worn while participants perform clinical assessment tasks, and use these data to estimate disease status and severity. A short period of data collection (<5 min) yields enough information to effectively separate patients with ataxia from healthy controls with very high accuracy, to separate ataxia from other neurodegenerative diseases such as Parkinson’s disease, and to provide estimates of disease severity.
IEEE Access. 2022;10:34022-34031. doi: 10.1109/access.2022.3156964. Epub 2022 Mar 4.
Eye movement assessments have the potential to help in diagnosis and tracking of neurological disorders. Cerebellar ataxias cause profound and characteristic abnormalities in smooth pursuit, saccades, and fixation. Oculomotor dysmetria (i.e., hypermetric and hypometric saccades) is a common finding in individuals with cerebellar ataxia. In this study, we evaluated a scalable approach for detecting and quantifying oculomotor dysmetria. Eye movement data were extracted from iPhone video recordings of the horizontal saccade task (a standard clinical task in ataxia) and combined with signal processing and machine learning approaches to quantify saccade abnormalities. Entropy-based measures of eye movements during saccades were significantly different in 72 individuals with ataxia with dysmetria compared with 80 ataxia and Parkinson's participants without dysmetria. A template matching-based analysis demonstrated that saccadic eye movements in patients without dysmetria were more similar to the ideal template of saccades. A support vector machine was then used to train and test the ability of multiple signal processing features in combination to distinguish individuals with and without oculomotor dysmetria. The model achieved 78% accuracy (sensitivity= 80% and specificity= 76%). These results show that the combination of signal processing and machine learning approaches applied to iPhone video of saccades, allow for extraction of information pertaining to oculomotor dysmetria in ataxia. Overall, this inexpensive and scalable approach for capturing important oculomotor information may be a useful component of a screening tool for ataxia and could allow frequent at-home assessments of oculomotor function in natural history studies and clinical trials.
Sensors (Basel). 2022 Oct 20;22(20):7993. doi: 10.3390/s22207993.
The study presents a novel approach to objectively assessing the upper-extremity motor symptoms in spinocerebellar ataxia (SCA) using data collected via a wearable sensor worn on the patient's wrist during upper-extremity tasks associated with the Assessment and Rating of Ataxia (SARA). First, we developed an algorithm for detecting/extracting the cycles of the finger-to-nose test (FNT). We extracted multiple features from the detected cycles and identified features and parameters correlated with the SARA scores. Additionally, we developed models to predict the severity of symptoms based on the FNT. The proposed technique was validated on a dataset comprising the seventeen (n = 17) participants' assessments. The cycle detection technique showed an accuracy of 97.6% in a Bland-Altman analysis and a 94% accuracy (F1-score of 0.93) in predicting the severity of the FNT. Furthermore, the dependency of the upper-extremity tests was investigated through statistical analysis, and the results confirm dependency and potential redundancies in the upper-extremity SARA assessments. Our findings pave the way to enhance the utility of objective measures of SCA assessments. The proposed wearable-based platform has the potential to eliminate subjectivity and inter-rater variabilities in assessing ataxia.
Cerebellum. 2022 Oct 3:1-21. doi: 10.1007/s12311-022-01471-8. Online ahead of print.
Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.
Front Neurol. 2022 Feb 28;12:795258. doi: 10.3389/fneur.2021.795258. eCollection 2021.
Digital assessments enable objective measurements of ataxia severity and provide informative features that expand upon the information obtained during a clinical examination. In this study, we demonstrate the feasibility of using finger tapping videos to distinguish participants with Ataxia (N = 169) from participants with parkinsonism (N = 78) and from controls (N = 58), and predict their upper extremity and overall disease severity. Features were extracted from the time series representing the distance between the index and thumb and its derivatives. Classification models in ataxia archived areas under the receiver-operating curve of around 0.91, and regression models estimating disease severity obtained correlation coefficients around r = 0.64. Classification and prediction model coefficients were examined and they not only were in accordance, but were in line with clinical observations of ataxia phenotypes where rate and rhythm are altered during upper extremity motor movement.
Cerebellum. 2023 Apr;22(2):261-271. doi: 10.1007/s12311-022-01385-5. Epub 2022 Mar 16.
Sensitive motor outcome measures are needed to efficiently evaluate novel therapies for neurodegenerative diseases. Devices that can passively collect movement data in the home setting can provide continuous and ecologically valid measures of motor function. We tested the hypothesis that movement patterns extracted from continuous wrist accelerometer data capture motor impairment and disease progression in ataxia-telangiectasia. One week of continuous wrist accelerometer data were collected from 31 individuals with ataxia-telangiectasia and 27 controls aged 2-20 years old. Longitudinal wrist sensor data were collected in 14 ataxia-telangiectasia participants and 13 controls. A novel algorithm was developed to extract wrist submovements from the velocity time series. Wrist sensor features were compared with caregiver-reported motor function on the Caregiver Priorities and Child Health Index of Life with Disabilities survey and ataxia severity on the neurologist-performed Brief Ataxia Rating Scale. Submovements became smaller, slower, and less variable in ataxia-telangiectasia compared to controls. High-frequency oscillations in submovements were increased, and more variable and low-frequency oscillations were decreased and less variable in ataxia-telangiectasia. Wrist movement features correlated strongly with ataxia severity and caregiver-reported function, demonstrated high reliability, and showed significant progression over a 1-year interval. These results show that passive wrist sensor data produces interpretable and reliable measures that are sensitive to disease change, supporting their potential as ecologically valid motor biomarkers. The ability to obtain these measures from a low-cost sensor that is ubiquitous in smartwatches could help facilitate neurological care and participation in research regardless of geography and socioeconomic status.
IEEE Trans Biomed Eng. 2022 Jul;69(7):2314-2323. doi: 10.1109/TBME.2022.3142504. Epub 2022 Jun 17.
OBJECTIVE: Assessment of motor severity in cerebellar ataxia is critical for monitoring disease progression and evaluating the effectiveness of therapeutic interventions. Though wearable sensors have been used to monitor gait tasks in order to enable frequent assessment, existing solutions only estimate gait performance severity rather than comprehensive motor severity. In this study, we propose a new approach that analyzes sub-second movement profiles of the lower-limbs during gait to estimate overall motor severity in cerebellar ataxia.
METHODS: A total of 37 ataxia subjects and 12 healthy subjects performed a 5 m walk-and-turn task with two ankle-worn inertial sensors. Lower-limb movements were decomposed into one-dimensional sub-movements, namely movement elements. Supervised regression models trained on data features of movement elements estimated the Brief Ataxia Rating Scale (BARS) and its sub-scores evaluated by clinicians. The proposed models were also compared to models trained on widely-accepted spatiotemporal gait features.
RESULTS: Estimated total BARS showed strong agreement with clinician-evaluated scores with r2 = 0.72 and a root mean square error of 2.6 BARS points. Movement element-based models significantly outperformed conventional, spatiotemporal gait feature-based models.
CONCLUSION: The proposed algorithm accurately assessed overall motor severity in cerebellar ataxia using inertial data collected from bilaterally-placed ankle sensors during a simple walk-and-turn task.
SIGNIFICANCE: Our work could support fine-grained monitoring of disease progression and patients' responses to medical/clinical interventions.