Pharmacologically Modulating the Noradrenergic Arousal System to Reduce Freezing of Gait in Parkinson's Disease: Study Protocol of the International AnTi-FREEZE Study.

Franka M Goossens, Kaylena A Ehgoetz Martens, Bastiaan R Bloem, Rick C Helmich, Erika E Howe, Roy P C Kessels, Melvyn Roerdink, Annie G Bryant, James M Shine, Anouk Tosserams, Simon J G Lewis, Jorik Nonnekes

Journal: The European journal of neuroscience 2026;64(2):e70630

PMID: 42460839

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Abstract

Freezing of gait (FOG) is a burdensome Parkinson's disease (PD) symptom. Gait control in people with PD relies on compensation from cognitive, sensory and limbic networks. Their integration is influenced by the noradrenergic ascending arousal system, modulated by the locus coeruleus. In PD, locus coeruleus degeneration has been linked to increased FOG severity. Atomoxetine, a selective noradrenaline reuptake inhibitor, may provide a novel therapeutic approach for FOG. However, to date, studies on atomoxetine's effect on FOG have been inconsistent and had small sample sizes. This study will evaluate the effects of atomoxetine on FOG severity, both in the dopaminergic OFF- and ON-states. Moreover, we will investigate its mode of action by examining its influence on functional network topology. Additionally, we will examine clinical and imaging markers associated with an individual's treatment response. Sixty patients with frequent FOG will be recruited for a multicentre, single-dose, double-blind, placebo-controlled, crossover clinical trial. Assessments include clinimetrics, cognition, MDS-UPDRS III, gait assessments, pupillometry and neuroimaging, conducted in the dopaminergic OFF- and ON-states. The primary outcome is FOG severity in the dopaminergic OFF-state, quantified based on the percentage of time spent frozen during gait assessments. Resting-state fMRI is conducted to assess network integration and segregation across brain regions and task-fMRI to reveal neural circuitry changes during FOG. Lastly, locus coeruleus and substantia nigra integrity will be assessed using structural MRI. This study will provide insights into the role of the noradrenergic ascending arousal system and potentially identify a novel pharmaceutical treatment pipeline for FOG in PD.

Address: Department of Rehabilitation, Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.; Donders Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.; Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.; Department of Neurology, Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.; Donders Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.; Department of Neurology, Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.; Donders Centre of Cognition, Donders Institute for Brain, Cognition, and Behaviour, Radboud University, Nijmegen, the Netherlands.; Vincent van Gogh Institute for Psychiatry, Venray, the Netherlands.; Klimmendaal Rehabilitation Specialists, Arnhem, the Netherlands.; Radboudumc Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands.; Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands.; Department of Nutrition and Movement Sciences, NUTRIM Institute of Nutrition and Translational Research in Metabolism & MHeNs Institute of Mental Health and Neurosciences, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.; Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.; Department of Rehabilitation, Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.; Department of Neurology, Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.; Parkinson's Disease Research Clinic, Macquarie Medical School, Macquarie University, Sydney, New South Wales, Australia.; Department of Rehabilitation, Center of Expertise for Parkinson and Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.

DOI: 10.1111/ejn.70630

MeSH Terms: Humans, Parkinson Disease, Atomoxetine Hydrochloride, Gait Disorders, Neurologic, Adrenergic Uptake Inhibitors, Arousal, Double-Blind Method, Locus Coeruleus, Male, Female, Cross-Over Studies, Magnetic Resonance Imaging