Slowing Cognitive Decline in Alpha-synucleinopathies by Enhancing Physical Activity

Basal Ganglia Diseases, Brain Diseases, Central Nervous System Diseases, Cerebral Disorder, Nervous System Diseases, Neurodegenerative Diseases, Parkinson Disease, Parkinsonian Disorders, Prodromal Stage, Synucleinopathies

intervention, movement, iRBD, prodromal parkinson's, non-pharmacologic, alpha-synucleinopathy, biomarker, cognitive decline, executive function, MRI, lifestyle, prevention, RCT, motor decline, smartphone, smartwatch, accelerometer, scalable, prodromal, PD, Parkinson, Lewy-body, MSA, multiple system atrophy, dementia

α-Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are the second most common neurodegenerative diseases. In addition to progressive motor deterioration, cognitive decline is a key element of the non-motor symptom complex of these diseases. Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) indicates an early stage of α-synucleinopathies, even before relevant motor or cognitive disorders are present. Therapeutic interventions in individuals with iRBD therefore have great preventive potential. In particular, increasing physical activity could have a relevant effect on neurodegenerative processes, including the preservation of cognitive functions. The aim of the study is therefore to investigate the effects of increased physical activity in everyday life on cognitive functions in individuals with iRBD. In this randomized, double-blind, actively controlled study, an increase in physical activity will be implemented over a period of one year with the help of a motivational smartphone application. The intervention and control conditions are the same as those used in the Slow-SPEED trials, making the connection between the trials concrete. The primary outcome parameter is the change in cognitive performance in a neuropsychological test battery over one year. Eighty individuals with iRBD and 50 age- and gender-matched individuals are being recruited at the University Hospital Bonn and the "Deutsches Zentrum für Neurodegenerative Erkrankungen" (DZNE) Bonn (German branch only). In addition to classic neuropsychological tests as the primary endpoint, magnetic resonance imaging (MRI) and blood-based markers of brain aging are being examined as secondary endpoints. This study is in close collaboration with the Slow-SPEED study (https://clinicaltrials.gov/study/NCT06993142). In addition, selected data from three separate trials-Alpha-Fit, Slow-SPEED-NL, and a sister trial in Austria currently in preparation-are planned to be synthesized into a meta-analysis.

α-Synucleinopathies are the second most common group of neurodegenerative diseases after Alzheimer's disease (AD). Their prevalence is expected to increase significantly, with more than 12 million people worldwide likely to be affected by 2040. Clinical manifestations include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). These diseases are characterized by neuronal inclusions of α-synuclein aggregates and Lewy bodies, which lead to premature aging of the brain. In addition to motor impairments, cognitive decline is a central element of non-motor symptoms, which not only occurs in DLB but also affects up to 80% of people with PD. Cognitive deficits can often occur in the early stages of the disease and significantly impair social functioning and quality of life. Despite their high prevalence, there are currently only a few therapeutic approaches for treating cognitive impairments in α-synucleinopathies. Therefore, easily accessible, early preventive interventions are crucial to counteract cognitive decline. Isolated REM sleep behavior disorder (iRBD) is considered an early sign of α-synucleinopathy and can be reliably diagnosed using video polysomnography. Over 90% of individuals with iRBD develop either PD or DLB within 20 years of diagnosis, with an approximately equal distribution between the two entities. It is noteworthy that executive functions can often already be impaired in iRBD, which is associated with an increased risk of early conversion to PD or DLB. Thus, iRBD represents a phase of early neurodegeneration in which there is a high risk of cognitive decline. For this reason, individuals with iRBD are a particularly suitable target group for investigating the effects of lifestyle modifications that could slow the progression of the disease at an early stage. Increasing physical activity could offer a promising way to slow the progression of neurodegenerative processes in the early stages of α-synucleinopathies. Since motor impairments are a central feature of PD and DLB, many affected individuals-even in the early stages of the disease-do not achieve the recommended level of physical activity. Studies on increasing physical activity have shown that physical training has positive effects on cerebrovascular function and cognitive performance, both in healthy aging and in various neurodegenerative diseases. For α-synucleinopathies in particular, there is evidence from animal models, observational studies, and clinical trials with up to six months of follow-up that physical activity may have disease-modifying effects. A recent meta-analysis in PD found that various interventions to increase physical activity have moderate effects on global cognition and even strong effects on executive functions. Therefore, promoting a more active lifestyle could be a promising strategy to positively influence the early course of α-synucleinopathies. Motivational mobile apps offer a novel way to increase physical activity, as they can be used completely independently, allowing for a high degree of scalability of the intervention. Derivation of research questions The following key questions will be addressed in the research project: * Can the progression of motor and cognitive changes in individuals with iRBD be influenced by increasing physical activity? * Does this intervention also affect biological and imaging markers of pathological brain aging? * Does this intervention also have an effect on healthy older people?

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