Cerebral amyloid PET imaging in Alzheimer's disease

Abstract

The devastating effects of the still incurable Alzheimer's disease (AD) project an ever increasing shadow of burden on the health care system and society in general. In this ominous context, amyloid (Aβ) imaging is considered by many of utmost importance for progress towards earlier AD diagnosis and for potential development of effective therapeutic interventions. Amyloid imaging positron emission tomography procedures offer the opportunity for accurate mapping and quantification of amyloid-Aβ neuroaggregate deposition in the living brain of AD patients. This review analyzes the perceived value of current Aβ imaging probes and their clinical utilization and, based on amyloid imaging results, offers a hypothesis on the effects of amyloid deposition on the biology of AD and its progression. It also analyzes lingering questions permeating the field of amyloid imaging on the apparent contradictions between imaging results and known neuropathology brain regional deposition of Aβ aggregates. As a result, the review also discusses literature evidence as to whether brain Aβ deposition is truly visualized and measured with these amyloid imaging agents, which would have significant implications in the understanding of the biological AD cascade and in the monitoring of therapeutic interventions with these surrogate Aβ markers.

Fig. 1

Model of dynamic biomarkers of the Alzheimer's disease pathological cascade. The severity of biomarker abnormality is indicated on the y axis and time on the x axis. Neurodegeneration is measured by FDG PET and structural MRI, which are drawn concordantly (dark blue). By definition, all curves converge at the top right-hand corner of the plot, the point of maximum abnormality. Cognitive impairment is illustrated as a zone (light green-filled area) with low- and high-risk borders. People who are at high risk of cognitive impairment due to Alzheimer's disease pathophysiology are shown with a cognitive impairment curve that is shifted to the left. By contrast, the cognitive impairment curve is shifted to the right in people with a protective genetic profile, high cognitive reserve, and the absence of comorbid pathological changes in the brain, showing that two patients with the same biomarker profile can have different cognitive outcomes. Aβ beta-amyloid, FDG fluorodeoxyglucose, MCI mild cognitive impairment. Reprinted from [46]

Fig. 2

Topographic differences between amyloid and neurodegeneration. Alzheimer's disease versus cognitively normal voxel mapping. PIB (left) statistic parametric mapping (SPM) of PIB retention ratio. MRI (right) voxel-based morphometry (VBM) of MRI grey matter density. Plaque deposition but not grey matter loss is seen in the prefrontal cortex while grey matter loss but not plaque deposition is seen in the medial and basal temporal lobes. Reprinted from [40]

Fig. 3

Phases of Aβ deposition in medial temporal lobe structures during evolution of Alzheimer's disease. Phases as defined by Thal et al. [106, 107] and adopted by NIA-AA. OTG occipitotemporal gyrus, PHG parahippocampal gyrus, H hippocampus

Fig. 4

Lack of binding in medial temporal lobe structures in ¹¹C-PIB PET scan of an AD patient. Comparison of ¹¹C-PIB PET scan (upper left) and MRI scan (lower left) reveals that medial temporal lobe ¹¹C-PIB signal is significantly lower than in other cortical structures. Detailed view of temporal lobe (middle column) clearly shows that ¹¹C-PIB signal is low not only in hippocampus but also in hippocampal gyrus and occipitotemporal gyrus, both areas of medial temporal lobe that have Aβ levels comparable to the levels observed in other parts of temporal lobe as shown on examples from AD pathology studies. Examples from Price and Morris [86] (upper right) and Thal et al. [107] (lower right). Distribution volume ratio (DVR) ¹¹ C-PIB image in reference to cerebellum is shown. Warmer colors represent higher DVR values. MTL medial temporal lobe