Radiology - Research Publications

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    Sodium selenate as a disease-modifying treatment for progressive supranuclear palsy: protocol for a phase 2, randomised, double-blind, placebo-controlled trial
    Vivash, L ; Bertram, KL ; Malpas, CB ; Marotta, C ; Harding, IH ; Kolbe, S ; Fielding, J ; Clough, M ; Lewis, SJG ; Tisch, S ; Evans, AH ; O'Sullivan, JD ; Kimber, T ; Darby, D ; Churilov, L ; Law, M ; Hovens, CM ; Velakoulis, D ; O'Brien, TJ (BMJ PUBLISHING GROUP, 2021-12)
    INTRODUCTION: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP. METHODS AND ANALYSIS: This will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain-3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures. ETHICS AND DISSEMINATION: The study was approved by the Alfred Health Ethics Committee (594/20). Each participant or their legally authorised representative and their study partner will provide written informed consent at trial commencement. The results of the study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620001254987).
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    Speech metrics, general disability, brain imaging and quality of life in multiple sclerosis
    Noffs, G ; Boonstra, FMC ; Perera, T ; Butzkueven, H ; Kolbe, SC ; Maldonado, F ; Cofre Lizama, LE ; Galea, MP ; Stankovich, J ; Evans, A ; van Der Walt, A ; Vogel, AP (WILEY, 2021-01)
    BACKGROUND AND PURPOSE: Objective measurement of speech has shown promising results to monitor disease state in multiple sclerosis. In this study, we characterize the relationship between disease severity and speech metrics through perceptual (listener based) and objective acoustic analysis. We further look at deviations of acoustic metrics in people with no perceivable dysarthria. METHODS: Correlations and regression were calculated between speech measurements and disability scores, brain volume, lesion load and quality of life. Speech measurements were further compared between three subgroups of increasing overall neurological disability: mild (as rated by the Expanded Disability Status Scale ≤2.5), moderate (≥3 and ≤5.5) and severe (≥6). RESULTS: Clinical speech impairment occurred majorly in people with severe disability. An experimental acoustic composite score differentiated mild from moderate (P < 0.001) and moderate from severe subgroups (P = 0.003), and correlated with overall neurological disability (r = 0.6, P < 0.001), quality of life (r = 0.5, P < 0.001), white matter volume (r = 0.3, P = 0.007) and lesion load (r = 0.3, P = 0.008). Acoustic metrics also correlated with disability scores in people with no perceivable dysarthria. CONCLUSIONS: Acoustic analysis offers a valuable insight into the development of speech impairment in multiple sclerosis. These results highlight the potential of automated analysis of speech to assist in monitoring disease progression and treatment response.
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    Novel Functional MRI Task for Studying the Neural Correlates of Upper Limb Tremor
    Boonstra, FMC ; Perera, T ; Noffs, G ; Marotta, C ; Vogel, AP ; Evans, AH ; Butzkueven, H ; Moffat, BA ; van der Walt, A ; Kolbe, SC (FRONTIERS MEDIA SA, 2018-07-02)
    Introduction: Tremor of the upper limbs is a disabling symptom that is present during several neurological disorders and is currently without treatment. Functional MRI (fMRI) is an essential tool to investigate the pathophysiology of tremor and aid the development of treatment options. However, no adequately or standardized protocols for fMRI exists at present. Here we present a novel, online available fMRI task that could be used to assess the in vivo pathology of tremor. Objective: This study aims to validate the tremor-evoking potential of the fMRI task in a small group of tremor patients outside the scanner and assess the reproducibility of the fMRI task related activation in healthy controls. Methods: Twelve HCs were scanned at two time points (baseline and after 6-weeks). There were two runs of multi-band fMRI and the tasks included a "brick-breaker" joystick game. The game consisted of three conditions designed to control for most of the activation related to performing the task by contrasting the conditions: WATCH (look at the game without moving joystick), MOVE (rhythmic left/right movement of joystick without game), and PLAY (playing the game). Task fMRI was analyzed using FSL FEAT to determine clusters of activation during the different conditions. Maximum activation within the clusters was used to assess the ability to control for task related activation and reproducibility. Four tremor patients have been included to test ecological and construct validity of the joystick task by assessing tremor frequencies captured by the joystick. Results: In HCs the game activated areas corresponding to motor, attention and visual areas. Most areas of activation by our game showed moderate to good reproducibility (intraclass correlation coefficient (ICC) 0.531-0.906) with only inferior parietal lobe activation showing poor reproducibility (ICC 0.446). Furthermore, the joystick captured significantly more tremulous movement in tremor patients compared to HCs (p = 0.01) during PLAY, but not during MOVE. Conclusion: Validation of our novel task confirmed tremor-evoking potential and reproducibility analyses yielded acceptable results to continue further investigations into the pathophysiology of tremor. The use of this technique in studies with tremor patient will no doubt provide significant insights into the treatment options.
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    Subclinical speech signs correlate with MS disease severity and differentiates patients with and without clinical cerebellar dysfunction
    Noffs, G ; Boonstra, F ; Perera, T ; Kolbe, S ; Shanahan, C ; Evans, A ; Butzkueven, H ; Vogel, A ; van der Walt, A (SAGE PUBLICATIONS LTD, 2017-10-01)
    Background: Dysarthria is highly prevalent in Multiple Sclerosis (MS). The relationship between dysarthria, MS disease severity and other cerebellar manifestations (such as tremor) is poorly understood. Aim: To examine the relationship between objective markers of speech, disease severity and upper limb tremor in relapsing-remitting and secondary progressive MS. Method: An experienced neurologist determined A) the presence of upper limb tremor, B) the Expanded Disability Status Scale (EDSS) score and C) the degree of dysarthria (from 0, no disturbance to 4, unintelligible). We used acoustic analysis to investigate 4 speech domains: 1) stability of vocal pitch, in sustained utterance of the vowel /a/; 2) stability of loudness, in the same sustained vowel; 3) diadochokinetic speed, in fast repetition of the meaningless word /pa/ta/ka/ and 4) maximum speed of vocal tract movement (i.e. change in pharynx and mouth cavity shape), measured through change in the second formant frequency in the word “always”, from reading of the “Grandfather Passage”. After adjustment for multiple comparisons, a p< 0.0125 was considered for statistical significance. Results: We assessed 24 MS patients with upper limb tremor (47.2±12.3years, 75% female, EDSS=3.7±1.6) and 24 matched patients without tremor (51.2±10.7years, 75% female, EDSS=3.6±1.7). Clinical dysarthria (median=0, mean=0.375±0.76) moderately correlated with EDSS scores (Spearman's rho =.586, p< .001) and with syllable repetition rates (/pa/ta/ka/ rho=.561, p< .001), marginally correlated with speed of tract movement (rho=.363, p=.012), pitch stability (rho=.37, p=.011), loudness stability (rho=.37, p=.01) but not with upper limb tremor presence (p=.039). Only /pa/ta/ka/ rate correlated with EDSS (rho=.529, p< .001) and speed of tract movement differentiated tremor and non-tremor groups (2-tailed t-test p=0.002, rho=.418). Conclusion: Acoustic speech measurements correlate with MS disease severity and can differentiate overt cerebellar dysfunction. Further study is needed to understand the significance of this relationship longitudinally.
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    Pathophysiology of MS tremor: an fMRI study
    Boonstra, F ; Noffs, G ; Perera, T ; Shanahan, C ; Vogel, A ; Evans, A ; Butzkueven, H ; van der Walt, A ; Kolbe, S (SAGE PUBLICATIONS LTD, 2017-11)
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    Validation of a precision tremor measurement system for multiple sclerosis
    Perera, T ; Lee, W-L ; Yohanandan, SAC ; Ai-Lan, N ; Cruse, B ; Boonstra, FMC ; Noffs, G ; Vogel, AP ; Kolbe, SC ; Butzkueven, H ; Evans, A ; van der Walt, A (ELSEVIER SCIENCE BV, 2019-01-01)
    BACKGROUND: Tremor is a debilitating symptom of Multiple Sclerosis (MS). Little is known about its pathophysiology and treatments are limited. Clinical trials investigating new interventions often rely on subjective clinical rating scales to provide supporting evidence of efficacy. NEW METHOD: We present a novel instrument (TREMBAL) which uses electromagnetic motion capture technology to quantify MS tremor. We aim to validate TREMBAL by comparison to clinical ratings using regression modelling with 310 samples of tremor captured from 13 MS participants who performed five different hand exercises during several follow-up visits. Minimum detectable change (MDC) and test-retest reliability were calculated and comparisons were made between MS tremor and data from 12 healthy volunteers. RESULTS: Velocity of the index finger was most congruent with clinical observation. Regression modelling combining different features, sensor configurations, and labelling exercises did not improve results. TREMBAL MDC was 84% of its initial measurement compared to 91% for the clinical rating. Intra-class correlations for test-retest reliability were 0.781 for TREMBAL and 0.703 for clinical ratings. Tremor was lower (p =  0.002) in healthy subjects. COMPARISON WITH EXISTING METHODS: Subjective scales have low sensitivity, suffer from ceiling effects, and mitigation against inter-rater variability is challenging. Inertial sensors are ubiquitous, however, their output is nonlinearly related to tremor frequency, compensation is required for gravitational artefacts, and their raw data cannot be intuitively comprehended. CONCLUSIONS: TREMBAL, compared with clinical ratings, gave measures in agreement with clinical observation, had marginally lower MDC, and similar test-retest reliability.
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    What speech can tell us: A systematic review of dysarthria characteristics in Multiple Sclerosis
    Noffs, G ; Perera, T ; Kolbe, SC ; Shanahan, CJ ; Boonstra, FMC ; Evans, A ; Butzkueven, H ; van der Walt, A ; Vogel, AP (ELSEVIER SCIENCE BV, 2018-12)
    IMPORTANCE: Multiple sclerosis produces neurological impairments that are variable in duration, severity and quality. Speech is frequently impaired, resulting in decreased communication skills and quality of life. Advancements in technology now makes it possible to use quantitative acoustic assessment of speech as biomarkers of disease progression. OBSERVATIONS: Four domains of speech have been identified: articulation (slow articulation and imprecise consonants), voice (pitch and loudness instability), respiration (decreased phonatory time and expiratory pressure) and prosody (longer and frequent pauses, deficient loudness control). Studies also explored I) predictive models for diagnosis of MS and of ataxia using speech variables, II) the relationship of dysarthria with cognition and III) very few studies correlated neuroimaging with dysarthria. We could not identify longitudinal studies of speech or dysarthria in Multiple Sclerosis. CONCLUSION AND RELEVANCE: Refinement of objective measures of speech has enhanced our understanding of Multiple Sclerosis-related deficits in cross-sectional analysis while both integrative and longitudinal studies are identified as major gaps. This review highlights the potential for using quantitative acoustic assessments as clinical endpoints for diagnosing, monitoring progression and treatment in disease modifying trials.
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    Tremor in multiple sclerosis is associated with cerebello-thalamic pathology
    Boonstra, F ; Florescu, G ; Evans, A ; Steward, C ; Mitchell, P ; Desmond, P ; Moffat, B ; Butzkueven, H ; Kolbe, S ; van der Walt, A (SPRINGER WIEN, 2017-12)
    Tremor in people with multiple sclerosis (MS) is a frequent and debilitating symptom with a relatively poorly understood pathophysiology. To determine the relationship between clinical tremor severity and structural magnetic resonance imaging parameters. Eleven patients with clinically definite MS and right-sided upper limb tremor were studied. Tremor severity was assessed using the Bain score (overall severity, writing, and Archimedes spiral drawing). Cerebellar dysfunction was assessed using the Scale for the Assessment and Rating of Ataxia. Dystonia was assessed using the Global Dystonia Scale adapted for upper limb. For all subjects, volume was calculated for the thalamus from T1-weighted volumetric scans using Freesurfer. Superior cerebellar peduncle (SCP) cross-sectional areas were measured manually. The presence of lesions was visually determined and the lesion volumes were calculated by the lesion growth algorithm as implemented in the Lesion Segmentation Toolbox. Right thalamic volume negatively correlated with Bain tremor severity score (ρ = - 0.65, p = 0.03). Left thalamic volume negatively correlated with general Bain tremor severity score (ρ = - 0.65, p = 0.03) and the Bain writing score (ρ = - 0.65, p = 0.03). Right SCP area negatively correlated with Bain writing score (ρ = - 0.69, p = 0.02). Finally, Bain Archimedes score was significantly higher in patients with lesions in the contralateral thalamus. Whole brain lesion load showed no relationship with tremor severity. These results implicate degeneration of key structures within the cerebello-thalamic pathway as pathological substrates for tremor in MS patients.