Longitudinal Positron Emission Tomography in Preventive Alzheimer's Disease Drug Trials, Critical Barriers from Imaging Science Perspective

Abstract

Recent Alzheimer’s trials have recruited cognitively normal people at risk for Alzheimer’s dementia. Due to the lack of clinical symptoms in normal population, conventional clinical outcome measures are not suitable for these early trials. While several groups are developing new composite cognitive tests that could serve as potential outcome measures by detecting subtle cognitive changes in normal people, there is a need for longitudinal brain imaging techniques that can correlate with temporal changes in these new tests and provide additional objective measures of neuropathological changes in brain. Positron emission tomography (PET) is a nuclear medicine imaging procedure based on the measurement of annihilation photons after positron emission from radiolabeled molecules that allow tracking of biological processes in body, including the brain. PET is a well-established in vivo imaging modality in Alzheimer’s disease diagnosis and research due to its capability of detecting abnormalities in three major hallmarks of this disease. These include 1) amyloid beta plaques, 2) neurofibrillary tau tangles and 3) decrease in neuronal activity due to loss of nerve cell connection and death. While semi-quantitative PET imaging techniques are commonly used to set discrete cut-points to stratify abnormal levels of amyloid accumulation and neurodegeneration, they are sub-optimal for detecting subtle longitudinal changes. In this study, we have identified and discussed four critical barriers in conventional longitudinal PET imaging that may be particularly relevant for early Alzheimer’s disease studies. These include within and across subject heterogeneity of AD-affected brain regions, PET intensity normalization, neuronal compensations in early disease stages and cerebrovascular amyloid deposition.

Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease

“…Tau-PET outcomes may thus permit more rapid assessment of pharmacodynamic effects and thereby facilitate early phase proof-of-concept trials. 37 Furthermore, serial tau-PET measures could identify individuals at risk of rapid cognitive decline ( Table 2 ; model 9). Probably because Aβ increases long before cognition declines, Aβ changes did not add information compared with a baseline Aβ-PET to predict cognition; however, Aβ changes were associated with tau changes, suggesting that the effect of Aβ accumulation could be more easily assessed with tau-PET outcomes than with cognitive measures.…”

Imaging Techniques in Alzheimer’s Disease: A Review of Applications in Early Diagnosis and Longitudinal Monitoring

“…For instance, FDG uptake is also diminished in certain brain regions after a stroke or other brain injuries [ 171 ]. Since approximately 30% of elderly people suffer from a silent infarct, lacking any clinical manifestations [ 172 ], alterations in cerebral glucose metabolism are not surprising in this aged population [ 173 ]. It is, therefore, suggested to consider FDG-PET as an independent biomarker rather than a biomarker of neurodegeneration in the “A/T/N” framework, because, as mentioned before, FDG uptake is likely to reflect the glucose consumption by astrocytes instead of neurons [ 80 , 174 ].…”

Complexity across scales: a walkthrough to linking neuro-imaging readouts to molecular processes

“…However, the characteristics of these imaging biomarkers are not yet adequate for diagnosis of patients at an individual level. This is largely due to the lack of longitudinal imaging data [70,71]. Combining known genetic biomarkers with imaging data could improve the prediction pattern across all patients [72][73][74].…”