Slowing Cognitive Decline in Alpha-synucleinopathies by Enhancing Physical Activity

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?observational A study in which researchers do not assign participants to a treatment or other intervention. They observe or measure what happens, which may include study visits, tests, questionnaires or a review of medical records. studies, and clinical trials with up to six months of follow-up?follow-up The period after treatment or enrolment during which participants are observed or contacted, for example to record side effects or outcomes. 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?