Brain scans to study inflammation over time

Intervention: Group 1: Single-center, scientific-experimental, prospective observational study with serial PET imaging. As the study does not aim to assess the diagnostic efficacy of PET within an interventional setting, neither a placebo arm nor randomization or blinding is planned. A control group without neurodegenerative disease is required because both the extent of reactive astrogliosis and baseline tracer uptake may be subject to age-related changes. Measurements obtained in the patient groups must therefore be evaluated in relation to largely healthy brain tissue. Complete individual age matching between control participants and all investigated disease groups is not feasible throughout, owing to the different typical ages of onset of the various neurodegenerative diseases. Accordingly, age-adjusted normalization of the PET measurements using the control group is planned. Without such normalization, the assessment of longitudinal changes in reactive astrogliosis over a period of 1.5 years, the analysis of its spatial and quantitative association with a-synuclein deposition, and the temporal comparison between astrocyte and microglial activation could be biased by group-specific differences in baseline tracer uptake and age distribution. Primary outcome: Study Objectives The present study aims to use positron emission tomography (PET) to quantify reactive astrogliosis in the brains of patients and, in particular, to address the following research questions: Primary and Secondary Objectives a) Does the regional and quantitative extent of reactive astrogliosis differ between patients with different phenotypes of multiple system atrophy? b) Does the regional and quantitative extent of reactive astrogliosis differ between other manifestations of a-synucleinopathies, including idiopathic Parkinson’s syndrome (IPS), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and rapid eye movement sleep behavior disorder (RBD)? c) Does reactive astrogliosis differ between patients with Alzheimer’s disease at the clinical stages of subjective cognitive decline, mild cognitive impairment, and manifest dementia? d) Does reactive astrogliosis differ between patients with primary tauopathies within the frontotemporal disease spectrum, including progressive supranuclear palsy and corticobasal degeneration, and patients with presumed tau-negative disorders within the frontotemporal disease spectrum, including the behavioral variant of frontotemporal dementia and the semantic variant of primary progressive aphasia? e) How does the extent of reactive astrogliosis in the brain change over a disease course of 1.5 years in patients with the disease entities described under objectives a–d? Do the quantitative changes differ depending on the underlying neuropathological characteristics? f) At study inclusion, does the quantitative and regional extent of reactive astrogliosis correlate with a-synuclein deposition in the disease entities described under objectives a and b? How does reactive astrogliosis change longitudinally in relation to a-synuclein deposition in these disease entities? g) Does astrocyte activation, referred to as the “astrocyte burst,” occur earlier than microglial activation in the stages of Alzheimer’s disease described under objective c and in the presumed tau-negative disorders described under objective d? In addition to investigating these primary outcome parameters, we aim to monitor the measured extent of reactive astrogliosis over time in order to precisely characterize the dynamics of signal changes within the individual groups. A key advantage of PET is its ability to capture individual longitudinal trajectories through serial examinations. This is particularly relevant in the context of clinical trials investigating immunomodulatory therapies. These longitudinal measurements are intended to establish a quantitative basis for this type of treatment monitoring, as is already used, for example, in amyloid antibody-based therapies for Alzheimer’s disease. As an additional secondary objective, associations with clinically established and approved parameters and imaging procedures, including clinical scores, magnetic resonance imaging, cerebrospinal fluid proteins, FDG, amyloid and tau PET, and electroencephalography, will be assessed. This will enable investigation of the temporal and spatial relationship between astrogliosis and functional and structural damage to the nervous system. In particular, the early-phase images obtained from astrocyte PET will be evaluated in conjunction with the early-phase images obtained from amyloid and tau PET examinations. Where technically feasible, additional neuroinflammation-specific analyses will be performed using clinically available blood and cerebrospinal fluid samples, and the resulting parameters will be correlated with the imaging findings. Outcome Measures Primary and Secondary Outcome Measures •For primary objectives a–d, the PET-derived quantitative measure of reactive astrogliosis will be expressed as the percentage deviation from the control group without neurodegenerative disease. This outcome measure will be used to assess regional and quantitative differences between the different phenotypes of multiple system atrophy, other a-synucleinopathies, the different clinical stages of Alzheimer’s disease, and primary tauopathies compared with presumed tau-negative disorders within the frontotemporal disease spectrum. •For primary objective e, the change in the above-mentioned quantitative outcome measure between the baseline and follow-up examinations will be assessed. For primary objective f, the quantitative and regional measure of reactive astrogliosis will be correlated with quantitatively assessed a-synuclein deposition, both at baseline and longitudinally. •For primary objective g, the quantitative measure of reactive astrogliosis obtained at baseline or follow-up will be compared with quantitatively assessed microglial activation in predefined subgroups of the study population. Secondary outcome: Secondary outcome measures are correlation parameters between PET imaging and established diagnostic methods.