Neurodegenerative proteinopathies, such as Parkinson’s disease, progressive supranuclear palsy, dementia with Lewy bodies, frontotemporal dementia, among others, are characterized by progressive protein accumulation and degeneration of nerve cells, leading to a wide range of motor and non-motor symptoms. While motor symptoms like tremors and muscle stiffness are well-recognized in these conditions, non-motor symptoms (NMS) also play an important role in patient well-being, disease progression, and overall quality of life. NMS cover a wide range of disruptions, including mood disorders, anxiety, perceptual disturbances, sleep impairments and pain. They can affect daily functioning and are often the main determinants of institutionalization and quality of life; yet there is limited understanding of their underlying mechanisms.
Over a 36-month period, we aim to determine the neural correlates of NP subjects experiencing each NMS by comparing them with NP patients without that NMS, individuals living with the NMS but without NP, and healthy controls. For this purpose, we will analyze the structural and resting functional brain MRI studies that are available for both NP patients and non-NP subjects within the UK Biobank database, accounting also for clinical information obtained through medical questionnaires, neuropsychological tests, wearable accelerometers and biological samples. We will then employ advanced statistical techniques paired with machine learning algorithms to identify specific brain regions or structures that correlate with the severity and manifestation of NMS.
Our main anatomical hypothesis is that (a) subjects with NP, among the four groups, have the lowest cortical thickness in the regions associated with each NMS, and that (b) there are differences in functional connectivity between NP subjects with NMS and subjects with NMS of same severity but without an NP diagnosis. Overall, this project represents an important step toward understanding the complex relationship between neurodegenerative proteinopathies and non-motor symptoms. We expect that this work will provide further directions for mechanistic and clinical research that may open possibilities for the development of novel interventions to improve non-motor symptoms management in NP patients.