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.

In a postmortem study of frontal cortex, phosphorylated tau (pTau) protein levels were positively correlated with TSPO (representing neuroinflammation) and negatively correlated with SV2A (representing synaptic density) (Metaxas et al., 2019). Brain amyloid-β levels are not directly associated with synaptic loss and cognitive functions. Instead, amyloid-β accumulation may incite neurodegeneration before cognitive decline. At early stages of amyloid pathology, neuroinflammation and amyloid accumulation are associated (Toppala et al., 2021). Reactive astrocytes play a role at the initial stages of AD pathogenesis (Rodriguez-Vieitez & Nordberg, 2018). Microglia may contribute to the propagation of amyloid-β from plaques into surrounding tissue (d’Errico et al., 2022). TSPO PET studies have given controversial results in mild cognitive impairment and Alzheimer's disease, but when genetic and environmental effects were controlled by studying twin pairs, increased TSPO radioligand uptake was seen in twins with worse episodic memory performance (Lindgren et al., 2020).

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). In clinical FDG PET studies of AD, assessment is usually based on semiquantitative "metabolic ratio" (Herholz et al., 1990, 1993, and 1999; Mosconi et al., 2007), calculated as FDG uptake ratio during late scan using a set of well-preserved brain regions such as pons or cerebellar vermis as reference region (Jagust et al., 2009; Dukart et al., 2010; Landau et al., 2010 and 2011; Jack Jr et al., 2012; Rasmussen et al., 2012; Roberts et al., 2014). For SPM analysis, voxels have traditionally been normalized using global cerebral mean, possibly including only grey matter, but cluster normalization provides more reliable classification (Yakushev et al., 2009; Dukart et al., 2013).

Multiple system atrophy (MSA) has clinically overlapping symptoms with PD. Pattern of TSPO binding may support clinical MSA diagnosis (Jucaite et al., 2022).

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 AD in several cortical areas, including thalamus, and especially hippocampus (Chen et al., 2018; Bastin et al., 2020; Mecca et al., 2020). 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. Elevated MAO-B is a marker of astrocytosis, observed in the early stage of AD pathology (Rodriguez-Vieitez et al., 2016).

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: 2022-03-29
Created at: 2017-11-16
Written by: Vesa Oikonen