Synucleinopathies

The main purpose of this study is to evaluate whether treatment with donanemab slows the progression of cognitive (how we think, learn, remember, pay attention, and make decisions) and functional (how we are able to perform daily activities) decline. For each participant, the study will last one and a half years.

This observational study aims to systematically characterize a cohort of patients with early-stage Parkinson's disease (PD) attending the Movement Disorders Center of AUSL-IRCCS Reggio Emilia, Italy. PD is the second most common neurodegenerative disorder, affecting about 1% of individuals over 60 years of age. The project will explore clinical and biological differences between the recently proposed "Brain-First" and "Body-First" phenotypes of PD. Patients will undergo detailed clinical evaluation, neuroimaging, and biomarker assessments (including neurodegeneration and neuroinflammation markers). Particular attention will be given to the progression of axial and cognitive symptoms, which represent major contributors to disability. Findings from this study are expected to improve early patient stratification, clarify disease mechanisms, and support the development of precision medicine strategies and future disease-modifying therapies.

BioFINDER-Sleep study was established in 2021 and will include patients with early Parkinson´s disease (PD) and persons with iRBD to provide essential insights into the underlying mechanisms of the progressive neurodegenerative processes in central and peripheral nervous systems. Briefly polysomnography will be used to establish the presence of RBD in both the early PD cohort and in the iRBD cohort. Then, state of the art multimodal imaging techniques will be used, including, magnetic resonance imaging (MRI), positron emission tomography (PET) of the dopamine transporters (DAT-PET) to quantify dopamine terminal loss, and \[123I\] MIBG scintigraphy of the heart will be performed to quantify the loss noradrenaline terminals to the heart. In addition to this, synuclein seed amplification assays (SSAs) will be applied to cerebrospinal fluid (CSF) and skin samples to establish synuclein pathology status. Further, CSF and blood biomarkers will be developed that can be used to as prognostic markers. These investigations will be done in parallel to clinical assessments of motor and non-motor symptoms as well as assessment of cognitive function in a longitudinal setting.

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.

The goal of this clinical trial is two-fold. First to investigate the feasibility of whether a remotely administered smartphone app can increase the volume and intensity of physical activity in daily life in individuals with a LRRK2 G2019S or GBA1 N370S genetic mutation over a long period of time (24 months). Second, to explore the preliminary efficacy of exercise on markers for prodromal Parkinson's disease progression in individuals with a LRRK2 G2019S or GBA1 N370S genetic mutation. Participants will be tasked to achieve an incremental increase of daily steps (volume) and amount of minutes exercised at a certain heart rate (intensity) with respect to their own baseline level. Motivation with regards to physical activity will entirely be communicated through the study specific Slow Speed smartphone app. A joint primary objective consists of two components. First to determine the longitudinal effect of an exercise intervention in LRRK2 G2019S or GBA1 N370S variant carriers on a prodromal load score, comprised of digital biomarkers of prodromal symptoms. The secondary component of the primary outcome is to determine the feasibility of a remote intervention study. The secondary objective is the effect of a physical activity intervention on digital markers of physical fitness. Exploratory outcomes entail retention rate, completeness of remote digital biomarker assessments, digital prodromal motor and non-motor features of PD. Using these biomarkers, the investigators aim to develop a composite score (prodromal load score) to estimate the total prodromal load. An international exercise study with fellow researchers in the United Kingdom are currently in preparation (Slow-SPEED-UK) and active in the Netherlands (Slow-SPEED-NL). Our intention is to analyse overlapping outcomes combined where possible through a meta-analysis plan, to obtain insight on (determinants of) heterogeneity in compliance and possible efficacy across subgroups

The goal of this clinical trial is to investigate the feasibility if a remotely administered smartphone app can increase the volume and intensity of physical activity in daily life in patients with isolated Rapid Eye Movement (REM) sleep behaviour disorder over a long period of time (24 months). Participants will be tasked to achieve an incremental increase of daily steps (volume) and amount of minutes exercised at a certain heart rate (intensity) with respect to their own baseline level. Motivation with regards to physical activity will entirely be communicated through the study specific Slow Speed smartphone app. Primary outcomes will be compliance expressed as longitudinal change in digital measures of physical activity (step count) measured using a Fitbit smartwatch. Exploratory outcomes entail retention rate, completeness of remote digital biomarker assessments, digital prodromal motor and non-motor features of PD, blood biomarkers and brain imaging markers. Using these biomarkers, we aim to develop a composite score (prodromal load score) to estimate the total prodromal load. An international exercise study with fellow researchers in the United States and United Kingdom are currently in preparation (Slow-SPEED). Our intention is to analyse overlapping outcomes combined where possible through a meta-analysis plan, to obtain insight on (determinants of) heterogeneity in compliance and possible efficacy across subgroups

Synucleinopathies are a group of severe neurodegenerative diseases, including Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). A common feature of these diseases is the pathological aggregation of α-synuclein (α-Syn), which forms Lewy Bodies (LBs), directly causing neuronal damage and death. Clinically, these diseases can present similar parkinsonian syndromes, making differential diagnosis more challenging. However, they may exhibit significant differences in the distribution and morphology of α-Syn pathology. For example, in MSA, the pathological α-Syn primarily accumulates in oligodendrocytes, particularly in the brainstem and cerebellar white matter, which differs significantly from the neuronal Lewy Body formation seen in PD and DLB. Currently, imaging biomarkers related to β-amyloid (Aβ) and tau proteins have been widely used in clinical diagnosis and research. However, imaging biomarkers targeting α-Syn are still relatively lacking, which limits the early diagnosis and accurate subtyping of these diseases. In recent years, some PET imaging agents targeting α-Syn have demonstrated good affinity in vitro and in animal experiments, significantly outperforming other common neurodegenerative biomarkers, including Aβ and tau proteins. These agents show promising potential in aiding the diagnosis of synucleinopathies. Professor Ye Keqiang's team at Shenzhen University of Technology has previously developed a small molecule compound (F0502B) with high affinity and selectivity for α-Syn aggregates. Early in vivo and in vitro experiments showed that it could specifically bind to LBs and quantify the amount of LBs in the brain, aiding the early detection of preclinical PD patients and dynamic monitoring of disease progression. Further optimization of the F0502B compound led to the development of its derivative, CP6A. The 18F-labeled probe of CP6A preferentially highlights α-Syn deposition in the brains of animal models and has demonstrated good safety in both mice and monkeys. Based on the above, this project intends to include clinically diagnosed or highly probable synucleinopathy patients and healthy volunteers, using the 18F-labeled derivative of the α-synuclein-specific imaging agent, 18F-CP6A, to perform integrated PET imaging. The goal is to explore the in vivo safety, pharmacokinetics, and clinical application value of 18F-CP6A in synucleinopathies.

MARKERS-NDD is a prospective, observational, longitudinal study, which aims to collect data from patients affected by neurodegenerative diseases (NDD) followed longitudinally for routine examinations performed as part of normal clinical practice. Data collected from clinical evaluations, movement analysis, brain imaging, neuropsychological and electroencephalographic assessments, blood chemistry tests will be analysed to carry out statistical investigations and predictive analyses, also using artificial intelligence systems, which allow the identification of new early markers of diagnosis and prognosis of neurodegenerative diseases.

People with Parkinson's have infrequent clinical consultation (once every 12-18 months) and limited rehabilitation. Assessment play an important role in these consultations to help clinicians understand patients' health status and disease progression necessary to adjust treatment plans. The current way of measuring is the UPDRS which needs a clinician to do this and takes 30 minutes. There is a strong need for more frequent and accurate Parkinson's assessments in the clinic and at home to detect changes early and then give appropriate support and drug and physiotherapy quickly. There is a need to develop good home digital physiotherapy tools to increase the amount of therapy. Here the investigators are testing new digital technologies to do these assessments in the home and clinic and a new digital physiotherapy device in the home. The investigators aim to conduct a clinical study with 50 people with Parkinson's (50 from UK) with the UPDRS, (a rating scale that is commonly used in clinical settings to evaluate the progression of Parkinson's disease) and 30 healthy adults. The investigators will develop and investigate if two new digital devices, one the MachineMD that measures eye movement and one the gaitQ that measures gait can be used instead of the MDS-UPDRS (motor) using digital gait and ophthalmic features in the clinic setting. The investigators will investigate the effect of a physiotherapy gait intervention gaitQ Tempo in the home context for two weeks and of doing the gait measure at home. The investigators will determine the potential of the gaitQ intervention to improve key gait metrics in order to collect clinical evidence and of using the gaitQ as a cuing system over a 2-week period on gait and other movement measures in the home and community