Sodium selenate as a disease-modifying treatment for progressive supranuclear palsy: Protocol for a phase 2, randomised, double-blind, placebo-controlled trial

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).Lucy Vivash, Kelly L Bertram, Charles B Malpas, Cassandra Marotta, Ian H Harding, Scott Kolbe, Joanne Fielding, Meaghan Clough, Simon J G Lewis, Stephen Tisch, Andrew H Evans, John D O, Sullivan, Thomas Kimber, David Darby, Leonid Churilov, Meng Law, Christopher M Hovens, Dennis Velakoulis, Terence J O, Brie

Anxiety is associated with freezing of gait and attentional set-shifting in Parkinson’s disease : a new perspective for early intervention

Previous research has shown that anxiety in Parkinson's disease (PD) is associated with freezing of gait (FOG), and may even contribute to the underlying mechanism. However, limited research has investigated whether PD patients with FOG (PD\ua0+\ua0FOG) have higher anxiety levels when compared directly to non-freezing PD patients (PD-NF) and moreover, how anxiety might contribute to FOG. The current study evaluated whether: (i) PD\ua0+\ua0FOG have greater anxiety compared to PD-NF, and (ii) anxiety in PD is related to attentional set-shifting, in order to better understand how anxiety might be contributing to FOG. In addition, we explored whether anxiety levels differed between those PD patients with mild FOG (PD\ua0+\ua0MildFOG) compared to PD-NF. Four hundred and sixty-one patients with PD (231 PD-NF, 180 PD\ua0+\ua0FOG, 50 PD\ua0+\ua0MildFOG) were assessed using the Freezing of Gait Questionnaire item 3 (FOG-Q3), Hospital Anxiety and Depression Scale (HADS), Digit Span Test, Logical Memory Retention Test and Trail Making Tests. Compared to PD-NF, PD\ua0+\ua0FOG had significantly greater anxiety (p\ua

Predicting the Onset of Freezing of Gait Using EEG Dynamics

Freezing of gait (FOG) severely incapacitates the mobility of patients with advanced Parkinson’s disease (PD). An accurate prediction of the onset of FOG could improve the quality of life for PD patients. However, it is imperative to distinguish the possibility of the onset of FOG from that of voluntary stopping. Our previous work demonstrated the neurological differences between the transition to FOG and voluntary stopping using electroencephalogram (EEG) signals. We employed a timed up-and-go (TUG) task to elicit FOG in PD patients. Some of these TUG tasks had an additional voluntary stopping component, where participants stopped walking based on verbal instruction to “stop”. The performance of the convolutional neural network (CNN) in identifying the transition to FOG from normal walking and the transition to voluntary stopping was explored. To the best of our knowledge, this work is the first study to propose a deep learning method to distinguish the transition to FOG from the transition to voluntary stop in PD patients. The models, trained on the EEG data from 17 PD patients who manifested FOG episodes, considering a short two-second transition window for FOG occurrence or voluntary stopping, achieved close to 75% classification accuracy in distinguishing transition to FOG from the transition to voluntary stopping or normal walking. Our results represent an important step toward advanced EEG-based cueing systems for smart FOG intervention, excluding the potential confounding of voluntary stopping.Alka Rachel John, Zehong Cao, Hsiang-Ting Chen, Kaylena Ehgoetz Martens, Matthew Georgiades, Moran Gilat, Hung T. Nguyen, Simon J. G. Lewis, and Chin-Teng Li

Modulating arousal to overcome gait impairments in Parkinson's disease: How the noradrenergic system may act as a double-edged sword

In stressful or anxiety-provoking situations, most people with Parkinson's disease (PD) experience a general worsening of motor symptoms, including their gait impairments. However, a proportion of patients actually report benefits from experiencing-or even purposely inducing-stressful or high-arousal situations. Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight (USA) and ParkinsonNEXT (NL) cohorts, we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment. Crucially, these strategies differ along an axis of arousal-some act to heighten, whereas others diminish, overall sympathetic tone. Together, our observations suggest that arousal may act as a double-edged sword for gait control in PD. We propose a theoretical, neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals, while alleviating them in others. Specifically, we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system: namely, that arousal is related to task performance by an inverted u-shaped curve (the so-called Yerkes and Dodson relationship). We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression, by regulating arousal and by mediating network-level functional integration across the brain. The ability of the locus coeruleus to facilitate dynamic 'cross-talk' between distinct, otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD. In the presence of suboptimal arousal, compensatory networks may be too segregated to allow for adequate compensation. Conversely, with supraoptimal arousal, increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional. Because the locus coeruleus degenerates with disease progression, finetuning of this delicate balance becomes increasingly difficult, heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub- or supraoptimal state of arousal to improve gait performance. Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50–70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN− and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10–12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.Gabrielle Todd, Caroline D. Rae, Janet L. Taylor, Nigel C. Rogasch, Jane E. Butler, Michael Hayes, Robert A. Wilcox, Simon C. Gandevia, Karl Aoun, Adrian Esterman, Simon J. G. Lewis, Julie M. Hall, Elie Matar, Jana Godau, Daniela Berg, Christian Plewnia, Anna-Katharina von Thaler, Clarence Chiang, Kay L. Doubl