An in vivo Pig Model for Testing Novel Positron Emission Tomography Radioligands Targeting Cerebral Protein Aggregates & nbsp;

Positron emission tomography (PET) has become an essential clinical tool for diagnosing neurodegenerative diseases with abnormal accumulation of proteins like amyloid-beta or tau. Despite many attempts, it has not been possible to develop an appropriate radioligand for imaging aggregated alpha-synuclein in the brain for diagnosing, e.g., Parkinson's Disease. Access to a large animal model with alpha-synuclein pathology would critically enable a more translationally appropriate evaluation of novel radioligands. We here establish a pig model with cerebral injections of alpha-synuclein preformed fibrils or brain homogenate from postmortem human brain tissue from individuals with Alzheimer's disease (AD) or dementia with Lewy body (DLB) into the pig's brain, using minimally invasive surgery and validated against saline injections. In the absence of a suitable alpha-synuclein radioligand, we validated the model with the unselective amyloid-beta tracer [C-11]PIB, which has a high affinity for beta-sheet structures in aggregates. Gadolinium-enhanced MRI confirmed that the blood-brain barrier was intact. A few hours post-injection, pigs were PET scanned with [C-11]PIB. Quantification was done with Logan invasive graphical analysis and simplified reference tissue model 2 using the occipital cortex as a reference region. After the scan, we retrieved the brains to confirm successful injection using autoradiography and immunohistochemistry. We found four times higher [C-11]PIB uptake in AD-homogenate-injected regions and two times higher uptake in regions injected with alpha-synuclein-preformed-fibrils compared to saline. The [C-11]PIB uptake was the same in non-injected (occipital cortex, cerebellum) and injected (DLB-homogenate, saline) regions. With its large brain and ability to undergo repeated PET scans as well as neurosurgical procedures, the pig provides a robust, cost-effective, and good translational model for assessment of novel radioligands including, but not limited to, proteinopathies.& nbsp;