Neurodegenerative Disease Alzheimer’s Disease
Molecular Imaging in Alzheimer’s Disease Karl Herholz
Professor of Clinical Neuroscience, Wolfson Molecular Imaging Centre, University of Manchester
Abstract
The most sensitive and accurate method for molecular imaging in human Alzheimer’s disease (AD) is positron emission tomography (PET). The most widely available PET tracer, which is also used in clinical oncology, is 18F-2-fluoro-2-deoxy-D-glucose (FDG). FDG is an imaging biomarker for early and differential diagnosis of AD. Even higher molecular specificity and sensitivity for detection of AD before dementia onset is provided by high-affinity ligands for fibrillary amyloid. 11C-Pittsburgh Compound B is widely being used in research laboratories, while new 18F-labelled ligands are currently undergoing formal clinical trials as amyloid imaging agents and are expected to become commercially available for clinical use in the near future. A large variety of tracers is being developed and used in dementia research for activated microglia and multiple neurotransmitter systems to study disease pathophysiology, biological correlates of clinical symptoms and new possibilities for treatment. Current studies in humans are investigating cholinergic, serotonergic and dopaminergic neurotransmission.
Keywords
Alzheimer’s disease (AD), dementia, positron emission tomography (PET), 18F-2-fluoro-2-deoxy-D-glucose (FDG), amyloid, microglia, acetylcholine, serotonin, dopamine
Disclosure: Karl Herholz has received a research grant from AVID Radiopharmaceuticals. Received: 19 October 2010 Accepted: 6 December 2010 Citation: European Neurological Review, 2011;6(1):16–20 Correspondence: Karl Herholz, Professor of Clinical Neuroscience, Wolfson Molecular Imaging Centre, University of Manchester, 27 Palatine Road, Manchester, M20 3LJ, UK. E:
karl.herholz@manchester.ac.uk
Neurodegenerative dementia has become the most rapidly growing cause of severe disability in the world. The most important risk factor is old age, while genetics and lifestyle also contribute. Therefore, better treatment and effective intervention are urgently needed at an early stage before the onset of severe disability. This requires further research into the risk factors and pathophysiological determinants of disease manifestation in humans and better, specific diagnosis at an early stage before dementia develops. Molecular imaging can provide the tools to achieve these goals.
Positron Emission Tomography
The most sensitive and accurate method for molecular imaging in humans is positron emission tomography (PET) and therefore this article focuses on this technique. It employs minute amounts (in the micromolar range) of short-lived radioactive tracers. They are labelled with either:
• •
carbon-11 (physical half-life 20 minuntes), which requires a cyclotron and associated radiopharmacy on site and is therefore not practical for widespread clinical use; or
fluorine-18 (physical half-life 90 minutes), which allows remote regional tracer production and delivery to clinical nuclear medicine departments.
Clinical PET scans typically involve intravenous tracer injection and subsequent brain scanning for 10–30 minutes at resting state. PET scans are associated with very low radiation exposure of approximately 5mSv.1
This article discusses imaging biomarkers that are provided by clinical PET for early diagnosis of disease and 16
monitoring of disease progression.2,3
It describes the clinical utility of
glucose and amyloid scanning. It also provides a brief overview of current research investigating possible determinants of disease progression, such as neuroinflammation, and changes in major neurotransmitter systems and their relation to clinical symptoms.
Amyloid Imaging The deposition of amyloid-β (Aβ) is an early event in the pathogenesis of AD and is central in the amyloid cascade hypothesis. The first tracer to be used to label fibrillary Aβ selectively with high affinity in vivo was 11C-labelled Pittsburgh compound B (11C-PIB).4,5
Many
research studies and recent multicentre studies have demonstrated that this tracer has a very high sensitivity of 90% for detecting fibrillary amyloid plaques in patients with Alzheimer’s disease (AD).6–9
The apolipoprotein E (APOE) e4 allele is a genetic risk factor for increased PIB uptake10–12
and cortical PIB binding is correlated
negatively with amyloid beta-protein 42 (abeta42) in cerebrospinal fluid.13–15
Similar results have been obtained with quantification of tracer binding by dynamic measurement and by simplified static imaging protocols recording cortical tracer uptake in a single scan lasting for 40 to 60 minutes following intravenous injection of 11C-PIB.16,17
These results demonstrate the robustness and clinical applicability of the method. The cerebellar cortex, which may exhibit diffuse but not fibrillary amyloid in AD, is generally used as a reference region without specific PIB binding.
Most normal control subjects exhibit very low cortical binding of PIB, with less than 1.5-fold PIB uptake relative to the cerebellar cortex. In
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