Alzheimer’s disease (AD)
Alzheimer’s disease is a neurodegenerative disorder, and the most common form of dementia.
Histopathological examination of AD brain reveals extracellular parenchymal deposits of amyloid-β (plaques), and intraneuronal deposits of tau protein as neurofibrillary tangles. Tau protein may also surround plaques as straight or paired helical filaments. In most cases of AD, amyloid deposits are also seen in the walls of small blood vessels in cerebral and cerebellar cortex. Brain amyloid-β levels are not directly associated with synaptic loss and cognitive functions. Instead, amyloid-β accumulation may incite neurodegeneration before cognitive decline. Cytosolic [Ca2+] may have an important role in apoptosis and cell death and early development of synaptic pathology, as the elevated [Ca2+] can increase amyloid-β production, amyloid-β increases [Ca2+], and ryanodine receptors (RyR) on endoplasmic reticulum amplify the signalling by releasing more Ca2+ (Briggs et al., 2017). RAGE may mediate the influx of circulating amyloid-β into the brain (Deane et al., 2003).
PET in AD diagnosis
PET imaging with amyloid-β tracers provides information about the extent of Aβ plaque burden to support the AD diagnosis, although positive Aβ-PET is often seen in asymptomatic elderly individuals. AD is the most common tauopathy, and PET imaging with tau protein tracers may be useful in AD diagnosis; again, tau lesions can be seen in other neurodegenerative diseases and in subjects with repeated head trauma.
Glucose metabolism in the brain can be measured using FDG PET, and due to its wide availability, it is the most commonly used PET tracer. Reduction of FDG uptake in parietotemporal cortex, precuneus, and posterior cingulate is the most characteristic finding in AD. Hypoperfusion is seen in the same brain areas, and can be detected with PET using for example [15O]H2O. Transgenic mouse models for AD provide different FDG uptake results, and FDG uptake is only weakly correlated with Aβ distribution (Snellman et al., 2019).
PET in drug development
Amyloid-β and tau protein tracers can be used to assess possible effects of new drugs for AD. Since neuroinflammatory processes are important in development of neurodegenerative processes, TSPO radioligands are useful in studying glial activation in these diseases, especially in the early phases, but amyloid-β tracers may be better suited for following long-term progression (López-Picón et al., 2018). Mitochondrial dysfunction and oxidative stress induced apoptotic processes are central to neurodegenerative diseases, including AD and Parkinson’s disease.
Synapse loss correlates best with cognitive impairment, and PET imaging can be used to measure synaptic density. Synaptic vesicle glycoprotein 2A (SV2A), a marker of synaptic density, is reduced in hippocampus in AD (Chen et al., 2018). In a mouse model of AD, hippocampal uptake of [11C]UCB-J, a SV2A radioligand, is reduced but normalized after treatment with saracatinib (Toyonaga et al., 2019).
Cholinergic neurotransmission is decreased in AD and already in mild cognitive impairment (MCI) (Rinne et al., 2003; Haense et al., 2012). Inhibitors of acetylcholinesterase (AChE), such as donepezil and rivastigmine, have been studied with PET using tracers [11C]MP4A and [11C]MP4P. PET radioligands for nicotinic acetylcholine receptors (nAcRs) have also been used to assess the efficacy of AChE inhibitors in increasing the synaptic concentration of acetylcholine.
Serotonergic system is impaired especially in early-onset AD, and several serotonin system targeting PET tracers could be used to study the effects of AD medications.
Dopaminergic system is implicated in many symptoms of AD, and can be studied using a wide repertoire of PET tracers.
Monoamine oxidases (MAO-A and MAO-B) remove monoamine neurotransmitters (dopamine, serotonin, noradrenaline), and MAO inhibitors can therefore be used to treat the symptoms of AD. MAO-B occupancy can be studied using [11C]L-deprenyl-D2.
GABA system contributes to the BPSD in AD, and modulates other neurotransmitters. GABAA receptor modulating drugs, such as benzodiazepines, have been used for symptomatic treatment of AD induced anxiety, and can be studied with PET using [11C]flumazenil.
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Updated at: 2019-05-23
Created at: 2017-11-16
Written by: Vesa Oikonen