Evaluating PET Imaging Biomarkers in Chronic Traumatic Encephalopathy
Year: 2023
Type: dissertation
Abstract: This work aims to characterize novel and existing radioligands to assess their utility for positron emission tomography (PET) imaging of chronic traumatic encephalopathy (CTE). Two pathological mechanisms were targeted: 1) neuroinflammation and 2) tau protein aggregates. Neuroinflammatory PET biomarkers were evaluated in Chapter 2 in CTE post-mortem tissues compared to controls and no significance in target density (Bmax) of the 18 kDa translocator protein (TSPO) or monoamine oxidase-B (MAO-B) was determined. Further validation of TSPO as a PET imaging biomarker in CTE was performed in a young cohort (19-29 year-olds). The activated microglial marker, CD68, and TSPO cell density was significantly higher in the calcarine cortex compared to the dorsolateral frontal cortex (DLFC), in individuals with repetitive head impacts (RHIs), regardless of CTE pathology. There was no significant difference found in TPSO density or in the percentage of CD68+ cells co-expressing TPSO in CTE or RHI groups. Upon evaluation of five tau-PET radiotracers in CTE in Chapter 3, a Bmax and affinity (Kd) for CTE-tau was determined with [3H]flortaucipir and off-target binding to MAO-A with this radiotracer was identified. [3H]MK-6240, [3H]PI-2620 and [3H]APN-1607 bound in late-stage CTE cases with mixed Alzheimer’s disease (AD) pathology and [3H]APN-1607 demonstrated off-target binding to amyloid-b. In a case study of a cognitively impaired former National Football League player, [18F]MK-6240 PET imaging was performed, and radiotracer binding was observed in regions that generally show CTE-related tau pathology at autopsy. Evaluation of PI-2620 derivatives toward the identification of a radioligand suitable for imaging tau beyond AD was performed. Radiotracer development including autoradiography and in vivo PET imaging was performed in Chapter 4 to image other neurodegenerative targets, namely metabotropic glutamate receptor subtype 5 (mGluR5) with [18F]FPEB and glycogen synthase kinase-3 (GSK-3) in which [18F]OCM-50 was identified as a potent, selective GSK-3 targeting radiotracer displaying good brain uptake, quick washout and retention in non-human primate. Kinetic modelling of this radiotracer has now been performed and first-in-human studies are planned. This thesis has contributed to understanding the underlying pathological mechanisms associated with head injuries with PET imaging towards the goal of imaging CTE in life.
Source: TSpace (University of Toronto)
Author: Varlow, Cassis
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7132985846