Abstract
Objective
To investigate the utility of ‘dual-phase’ positron emission tomography (PET) imaging as a measure of cerebral perfusion and metabolism and pathological protein burden in cognitive impairment associated with neurodegenerative disorders.
Background
Neurodegenerative disorders pose significant clinical and financial challenges to patients and caregivers alike. PET imaging with amyloid beta (Aβ) and tau tracers have been invaluable for visualising molecular pathology, especially in Alzheimer’s disease (AD). Complementary measures of perfusion and metabolism such as 18F-Fluorodeoxyglucose (FDG) PET and arterial spin labelling (ASL MRI) provide critical information on disease severity and prognosis. However, the need for multiple imaging sessions burdens both patients and healthcare systems. Emerging evidence suggests that the acquisition within the first few minutes of Aβ and tau PET tracers (early-phase) may serve as surrogate measures for brain metabolism and perfusion, streamlining imaging protocols. This thesis comprehensively reviews the literature on early-phase PET imaging and investigates dual acquisitions of Aβ and tau PET. Specifically, we investigated early-phase Aβ PET in individuals with cognitive impairment – a vulnerable population at risk for conversion to dementia. We further validated early-phase Aβ PET in Parkinson’s disease (PD) across a broad cognitive spectrum. Finally, we investigated early- and late-phase tau PET in PD, where tau pathology and its association with cognitive decline remains unclear
Methods
In the first study, 20 participants with varying levels of cognitive impairment (AD dementia, amnestic and non-amnestic mild cognitive impairment, subjective cognitive decline, non-neurodegenerative impairment, controls) underwent dual-phase acquisition of 18F-Florbetaben (FBB) Aβ PET, FDG PET and ASL MRI. We compared the within-subject and regional associations between the early-phase FBB (eFBB), FDG, and ASL MRI and also their relationship with cognitive performance. In the second study, we further investigated eFBB in 115 PD participants across a broad spectrum of cognitive impairment. We utilised multiple linear regression models to compare eFBB uptake with cognitive performance and ASL MRI perfusion. Finally, as part of an ongoing study, 17 PD participants underwent dual-phase imaging with second-generation tau tracer PI-2620, and we analysed early- and late-phase associations with cognitive performance.
Results
In our first study, eFBB PET showed strong correlations with FDG PET both within-subject (median r [range] = 0.86 [0.69–0.95], p<;0.001), and across atlas-defined regions (median r [range] = 0.81 [0.62–0.95], p < 0.001). ASL perfusion exhibited weaker correlations with both eFBB (median r = 0.36) and FDG (median r = 0.4). Furthermore, eFBB and FDG PET showed associations with cognitive performance in regions previously associated with AD hypometabolism. In our second study, reduced early-phase Aβ PET uptake was associated with cognitive performance in brain regions where hypometabolism was previously associated with cognitive decline in PD, independent of amyloid status. Furthermore, eFBB uptake correlated with cerebral perfusion across widespread cortical and subcortical regions (r=0.27-0.49, corrected p<0.005). Finally, in our third study, tau burden was not highly prevalent in our interim PD cohort, with only one participant displaying an AD-like tau uptake. Early-phase PI-2620 images visually resembled the perfusion-metabolism images. Neither early-phase nor late-phase PI-2620 was associated with cognitive performance.
Conclusions
Early-phase PET imaging shows strong potential as a perfusion and metabolism surrogate and may potentially FDG PET, providing valuable insights into metabolism, perfusion, and cognitive decline in AD and PD. This approach may help to reduce scan burden, costs, and radiation exposure, and to help streamline diagnosis, patient selection and progress monitoring in both clinical and research settings.