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 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?

Inclusion criteria

iRBD:

• Age: 50-80 years
• Polysomnographically confirmed diagnosis of iRBD
• Maximum of 120 minutes of sports/outdoor activities per day
• Less than an average of 10,000 steps per day during the 4-week eligibility and baseline phase
• Basic smartphone skills
• Sufficient knowledge of German (native language, C1 or C2)
• Ownership of a suitable smartphone (minimum screen size 4.6 inches, Android version 9 or iOS version 15 or newer)
• Consent to be informed of any additional findings

Healthy controls:

• Age: 50-80 years
• Maximum of 120 minutes of sports/outdoor activities per day
• Less than an average of 10,000 steps per day during the 4-week eligibility and baseline phase
• Basic smartphone skills
• Sufficient knowledge of German (native language, C1 or C2)
• Ownership of a suitable smartphone (minimum screen size 4.6 inches, Android version 9 or iOS version 15 or newer)
• Consent to be informed of any additional findings

Exclusion criteria

iRBD:

• Relevant cardiovascular diseases
• Problems with dexterity or cognitive impairments that make it difficult to use a smartphone
• Cognitive impairments that limit the ability to make informed decisions and consent to participate in the study
• Ownership of one of the following devices: Huawei P8 Lite, Huawei P9 Lite, Xiaomi Mi 6, Huawei P20 Lite (FitBit is not compatible)

Healthy controls:

• Relevant cardiovascular diseases
• Problems with dexterity or cognitive impairments that make it difficult to use a smartphone
• Cognitive impairments that limit the ability to make informed decisions and consent to participate in the study
• Ownership of one of the following devices: Huawei P8 Lite, Huawei P9 Lite, Xiaomi Mi 6, Huawei P20 Lite (FitBit is not compatible)
• clinically diagnosed iRBD