Synapse loss in frontotemporal lobal degeneration: disease mechanisms and biomarker validation

Summary

Synapse loss occurs early in neurodegenerative diseases and is directly linked to clinical symptoms. Insights into synapse loss in neurodegeneration open the way to multiple therapeutic strategies, new clinical trials, and tools for monitoring or stratification of patients. However, this requires validated biomarkers and a better understanding of synapse loss and its relation to other disease processes such as protein accumulation and inflammation.

PET imaging studies at Cambridge using the synaptic tracer 11C-UCBJ suggest that synapse loss is occurring early and is predictive clinical severity and disease progression across the spectrum of clinical syndromes associated with frontotemporal lobal degeneration (FTLD). However, the relationship with post-mortem neuropathology and disease etiopathogenesis needs clarification to validate these biomarkers and develop therapeutic strategies. 

Project aims

This project builds on the extensive collection of FTLD brains in the Cambridge Brain Bank with complementary ante-mortem clinical, neurophysiological and PET-imaging-based characterisation coming from longstanding clinical cohorts at the Cambridge Centre for Parkinson-Plus.

The host lab has developed a novel, AI-powered quantitative pathology pipeline to visualise and measure synapses in post-mortem brain tissue. With a cross-disciplinary approach, we will use post-mortem brain tissue from brain donors to validate the clinical utility of UCB-J PET-imaging as a synapse biomarker, by cross-validating post-mortem synapse metrics with in vivo PET imaging in the same regions of the same patients.

We will also study the vulnerability of specific subtypes of synapses, and will determine whether regional synapse loss predicts clinical and pathological heterogeneity. Finally, we will investigate the relationship between synapse loss, neuroinflammation, tau pathology and neuronal cell loss.

Contact details

Dr Annelies Quaegebeur - aq244@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD
• MPhil