Nonamyloid PET Biomarkers and Alzheimer's Disease: Current and Future Perspectives

Lucas Porcello Schilling; Antoine Leuzy; Eduardo Rigon Zimmer; Serge Gauthier; Pedro Rosa-Neto

Disclosures

Future Neurology. 2014;9(6):597-613. 

In This Article

Abstract and Introduction

Abstract

Recent advances in neurobiology and PET have helped redefine Alzheimer's disease (AD) as a dynamic pathophysiological process, clinically characterized by preclinical, mild cognitive impairment due to AD and dementia stages. Though a majority of PET studies conducted within these populations have to date focused on β-amyloid, various 'nonamyloid' radiopharmaceuticals exist for evaluating neurodegeneration, neuroinflammation and perturbations in neurotransmission across the spectrum of AD. Importantly, findings using such tracers have been shown to correlate with various clinical, cognitive and behavioral measures. In the context of a growing shift toward early diagnosis and symptomatic and disease-modifying clinical trials, nonamyloid PET radiotracers will prove of use, and, potentially, contribute to improved therapeutic prospects for AD.

Introduction

Alzheimer's disease (AD) is the leading cause of dementia[1] and is characterized by an insidious onset, progressive impairment in memory, attention and language and by the presence of neuropathological hallmarks, including the extracellular deposition of β-amyloid (Aβ) and the intracellular accumulation of hyperphosphorylated tau.[2] Criteria for the clinical diagnosis of AD were first put forth in 1984 by a work group jointly established by the National Institute of Neurological and Communicative Disorders and Stroke, and the Alzheimer's Disease and Related Disorders Association.[3] These criteria assumed that the clinical and neuropathological features of AD were related in a one-to-one manner, such that AD pathology was either present in an individual – producing dementia – or absent, in which case dementia, if present, was not due to AD.[4]

Though useful and widely adopted, important advances in the characterization of AD along clinical and neuropathological lines, as well as in our ability to detect AD pathophysiology in vivo via biomarkers, led to a consensus position that the criteria should be revised.[4] These revisions, initiated by an International Working Group,[5,6] were further elaborated by several National Institute of Aging and Alzheimer's Association working groups, resulting in novel diagnostic criteria addressing asymptomatic, 'preclinical',[7] mild cognitive impairment (MCI) due to AD[8] and AD dementia stages.[9] This revised conceptual framework posits a conceptual distinction between AD neuropathology and resulting clinical phenomenology. Specifically, AD has been conceptualized as a progressive pathophysiological process in which Aβ toxicity is believed to result in sequence of dynamic changes, including the accumulation of intracellular neurofibrillary tangles (NFTs), synaptic loss,[10,11] neuroinflammatory processes[12] and disrupted neurotransmission.[13] Importantly, these changes are thought to accumulate during a protracted preclinical phase, with the acceleration of such changes marking the transition to MCI, the symptomatic predementia phase of AD.

Increasingly, quantitative imaging of functional and molecular processes in the living human brain has become possible using neuroimaging techniques, in particular PET (see Figure 1). Noninvasive in nature, PET allows for the quantification of brain biological processes by modeling interactions between short-lived radiopharmaceuticals and a biological process of interest, with sensitivity in the nano to pico molar (10 9–10−12 M) range. While the majority of PET studies conducted in AD have to date focused on the characterization of amyloid fibrillary deposits, a growing number of 'nonamyloid radiopharmaceuticals are available for visualization and quantification of neurodegeneration (glucose metabolism and hyperphosphorylated tau), neuroinflammation (astrocytosis, microgliosis and phospholipase) and perturbations in neurotransmission (cholinergic, dopaminergic, serotonergic and others; see Table 1 & Figure 2). This article aims to review the role of nonamyloid PET biomarkers in improving our understanding of AD neurobiology.

Figure 1.

Steps involved in PET imaging. An on-site cyclotron (A) inside the radiochemistry facility produces short-lived positron-emitting isotopes (B) which, after quality control, are delivered as PET molecular probes (C) to hospital or research facilities. Molecular probes are injected intravenously at tracer concentrations (D) before PET scanning (E). During the scan, the PET camera records the distribution of radioactivity, which, following reconstruction, (F), can be analyzed and read by imaging experts or clinicians.
For color images please see online at http://www.futuremedicine.com/doi/full/10.2217/fnl.14.40

Figure 2.

Alzheimer's disease pathophysiological events amenable to quantification using PET. Hypothetical models of Alzheimer's disease suggest that the pathophysiological cascade of events culminating in dementia begins many years before detectable cognitive impairment. These models have provided the framework necessary to test various nonamyloid biomarkers addressing processes believed to be secondary to amyloid toxicity, including neurodegeneration, neuroinflammation and disruptions within neurotransmitter system.

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