Uncovering Transdiagnostic Dimensions of Neurodegeneration: A Multimodal Approach to Primary Progressive Aphasia and Related Syndromes (360G-Wellcome-324220_Z_25_Z)

Growing scientific literature recognises the broad cognitive and linguistic variation across dementia. This project aims to explore a data-driven, transdiagnostic approach to understanding clinical heterogeneity in primary progressive aphasia (PPA) and related dementias. Using principal component analysis (PCA) and clinical data, we will derive dimensions of phenotypical variation. This approach seeks to explore how different syndromes, including PPA, Alzheimer’s disease, and behavioural frontotemporal dementia, are positioned along a gradient of clinical symptoms. We will examine associations with brain volume changes and graph theory based network connectivity patterns to explore the underlying neuropathological mechanisms. Additionally, we will investigate how data-driven phenotypic profiles relate to clinical biomarkers in blood samples and explore their longitudinal impact on disease progression. The study will assess whether these profiles, in combination with connectivity changes, can predict post-mortem brain pathology. By integrating neuroimaging, cognitive, and biomarker data, this project aims to refine our understanding of disease mechanisms, inform potential biomarkers, and provide insights into language network vulnerability in PPA.