Dissecting the biological and clinical heterogeneity of Lewy body disease

• Applicant: Julia Schumacher, Ph.D.
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555954864

The current project proposes a shift of the research focus on Lewy body disease (LBD) which will be critical for achieving a better biological characterisation of the LBD spectrum, ultimately enabling individualised treatment and more targeted recruitment of patients into clinical trials. Neurodegenerative diseases such as LBD are characterised by large heterogeneity across patients in terms of symptomatology and disease progression. The previous focus on the study of group average differences is likely to have slowed our understanding of pathophysiological mechanisms and impacted outcomes of clinical trials. The project is based on the overall hypothesis that the differential breakdown of different neurotransmitter systems leads to patient-specific patterns of brain neurotransmitter alterations that can be assessed in vivo and constitute an important biological driver of heterogeneity in LBD. A central part of this project will be the development and validation of robust neuroimaging biomarkers that assess the integrity of the dopaminergic, cholinergic, serotonergic, and noradrenergic systems in vivo and are derived from imaging data that are readily available in clinical practice to ensure widespread future applicability. While most previous work in this field has focused on studying the integrity of relevant source nuclei of the different neurotransmitter systems, we showed in two recent studies that an assessment of the ascending pathways that provide (cortical) cholinergic innervation can yield additional disease-relevant information. We aim to extend this approach to the other neurotransmitter systems and develop a reference atlas of neurotransmitter pathways which will also be of relevance for the study of other neurodegenerative diseases that show neurotransmitter changes, e.g. Alzheimer’s disease. Based on the developed neurotransmitter markers, the second aim is to identify subgroups of patients with similar patterns of neurotransmitter changes using data-driven subtyping and to characterise them with respect to symptomatology and longitudinal disease progression. Thirdly, we aim to study how the breakdown of different neurotransmitter systems relates to neuropathological changes, including the occurrence of Alzheimer’s disease co-pathology in LBD and how the interaction of neurotransmitter and pathological heterogeneity influences the clinical phenotype. This project will contribute to a better understanding of the neurotransmitter biology of LBD, leading to the definition of clinically relevant biological subtypes which will ultimately help to individualise treatment approaches, providing a first step towards precision neurology. The developed methods will be applicable beyond the field of LBD and will have value in the study of other neurodegenerative diseases and ageing.

• DFG Programme: Research Grants