Multiple sclerosis (MS)

Multiple sclerosis is an immune system mediated demyelinating neurodegenerative disease of central nervous system (CNS), which usually affects young adults (age 20-40, mostly women). The pathophysiology of MS is associated with loss of anatomic and physiologic integrity of the BBB. Peripheral immune cells infiltrate the CNS, damaging myelin, oligodendrocytes (that produce myelin and support axonal metabolism), and neurons and their axons. The medications are also mostly modulating the peripheral immune response. MS lesions (plaques) can develop in various areas of the CNS, including spinal cord, leading to variable symptoms. MS lesions can be easily detected with MRI, and therefore MRI is currently a routine clinical tool in MS diagnosis and development monitoring. Demyelination and axonal loss is not confined to the plaques, but apparent in macroscopically normal appearing white matter (NAWM). Most newly diagnosed MS patients have relapsing-remitting form of MS (RRMS), characterized by periods of development of new neurological deficits followed by complete or partial improvement. RRMS may later advance into a secondary progressive phase (SPMS) with continuous development of neurological deficits and symptoms. Minority of patients (∼10%) have primary progressive MS (PPMS) that progresses continuously without remission. ∼5% of patients have progressive relapsing form of MS (PRMS), in which the periods between relapses are characterized by continuous progression.

Acute disseminated encephalomyelitis (ADEM) is also a heterogeneous inflammatory demyelinating disorder of the CNS, affecting children. It is usually caused by viral or bacterial infections, including measles, rubella, H1N1 influenza, mumps, enterovirus, Epstein-Barr virus, adenovirus, dengue, and rotavirus. Pediatric MS is defined by onset prior to 18 years of age.

Demyelination is usually accompanied by remyelination, driven by oligodendrocytes and anti-inflammatory cytokines, and mediated by integrins. Remyelination can be extensive even in PPMS and SPMS, so that most of the plaques are "shadow plaques", areas of uniformly thin myelin sheets. Premyelinating oligodendrocytes are present in chronic MS lesions and associate with demyelinated axons, but axonal injury may prevent the cell interactions that are needed for myelination. Remyelinating capacity decreases with time, especially in SPMS. PET imaging with myelin radioligands can be used to follow demyelination and remyelination processes. Both [11C]PIB PET and MRI based myelin water fraction (MWF) show reduced, and correlated, myelin content in MS lesions compared to NAWM (Vavasour et al., 2022). Apoptotic neuronal cell bodies can be found in chronic MS lesions.

Infiltrated macrophages (and/or microglia, the resident macrophages) actively break down myelin and phagocytoze myelin remnants, and release proinflammatory factors such as prostaglandins, IL-1β, and TNF-α. Microglial activation, and the effects of treatment, can be studied using PET with TSPO (de Paula Faria et al., 2014a; Airas et al., 2015a and 2017; Sucksdorff et al., 2017 and 2019; Vomacka et al., 2017), P2X7 (Beaino et al., 2017), and CB2 receptor tracers. TSPO radioligands have shown that neuroinflammation takes place in NAWM, outside of MS lesions (Datta et al., 2017; Rissanen et al., 2018; Bezukladova et al., 2020), and TSPO PET can be used to assess smouldering inflammation in MS brain (Laaksonen et al., 2023; Lehto et al., 2023). TSPO and FRβ expression is highest in the chronic active MS lesions; the typical hyperintense rim of iron-enriched activated microglia and macrophages can be detected using quantitative susceptibility mapping MRI (Kaunzner et al., 2019). TSPO PET can predict MS disease progression (Sucksdorff et al., 2020). Interaction between astrocytes and innate immune system has a pivotal role in neuroinflammation and demyelinating diseases (Mayo et al., 2012).

The increased metabolism of activated astrocytes in MS can be assessed using [11C]acetate (Takata et al., 2014; Kato et al., 2021). [18F]FDG may not be optimal for studying acute (hyper-metabolism) or chronic (hypometabolism) white matter lesions because of high glucose consumption of the brain. Amino acid uptake may be somewhat increased in MS lesions (Tarkkonen et al., 2016; Nakajima et al., 2017; Tomura et al., 2022).

The reversible clinical deficits in MS are caused by decreased number of Na+ channels in the demyelinated axons. Impulse conduction is restored only after new sodium channels are formed or redistributed into the demyelinated area. Voltage-gated K+ channels normally localize in the axons hidden beneath the myelin sheath. Following demyelination, K+ channels are exposed, and overexpressed. MS drug 4-aminopyridine (4AP) enhances conduction by blocking K+ channels. Action potential in demyelinated area leads to higher Na+ influx into axon, and higher K+ efflux, and the achievement of resting potential by Na+/K+-ATPase requires more ATP and increased mitochondrial respiration. Increased mitochondrial respiration, and the inflammatory processes, lead to increased production of reactive oxygen species (ROS). Increased number of mtDNA deletions have been observed in cortical neurons of SPMS patients. Failed mitochondrial function may lead to glutamate mediated axonal injury; glutamate concentrations in CNS and CSF are increased in MS patients. Activity of system xc- (cystine/glutamate antiporter) is increased in rat model of MS, as seen with [18F]FSPG PET (Martín et al., 2016), and in NAWM tissue samples from MS patients (Merckx et al., 2017). Increased intracellular [Na+] causes increase in cytosolic [Ca2+], which may lead to activation of proteases and degradation of microtubules and microfilaments, and impaired axonal transport. IL-1β increases the expression of P2X7 receptors on astrocytes, augmenting Ca2+ influx. Increased binding of P2X7 tracer [11C]SMW139 was seen in NAWM of MS patients (Hagens et al., 2020). IL-1β also promotes BBB disruption via several mechanisms.

Integrin α4β1 is crucial for the initial contact and firm adhesion of lymphocytes to endothelial cells in CNS, and modified monoclonal antibodies targeting the α4 subunit are being used in treatment of certain forms of MS. Integrin PET tracers could be useful in development of new pharmaceuticals. Mechanism of action of the monoclonal antibodies can be studied by labelling the mAbs; for example, 89Zr-labelled rituximab was found to not penetrate BBB even in MS lesions (Hagens et al., 2017).

Adenosine receptors are involved in neuroinflammatory processes. Increased binding of A2AR tracer [11C]TMSX was seen in NAWM of MS patients (Rissanen et al, 2013).

Cortical damage in MS patients has been demonstrated using GABAA receptor tracer [11C]flumazenil (Freeman et al., 2015).

MS drug 4AP is a K+-channel blocker, used as a drug in severe MS. [18F]3F4AP is its recently developed fluorinated derivative, which has increased uptake in demyelinated brain regions in mice, rats, and Rhesus monkeys (Brugarolas et al., 2018; Guehl et al., 2021).

Sphingosine-1-phosphate (S1P) and its receptors are involved in MS, and some of the MS drugs are S1P receptor modulators. PET tracers targeting S1P receptor 1 have been used in animals model of MS.

Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model for MS. Most of the knowledge about the in vivo mechanisms of neurodegeneration in MS are based on EAE, and it is also used in PET imaging studies (Abourbeh et al., 2012; Xie et al., 2012; Wu et al., 2013; Mattner et al., 2013; Airas et al., 2015b; Martín et al., 2016; Han et al., 2017; Válles-García et al., 2017; Elo et al., 2019). Focal delayed-type hypersensitivity EAE (fDTH-EAE) elicits large, predictable lesions that are easy to evaluate in small animal PET, and the contralateral hemisphere can be used as reference tissue in the analysis of PET data (Vainio et al., 2019). Vascular adhesion protein-1 (VAP-1) is actively involved in the development of lesions in the EAE model (Elo et al., 2018). Folate and TSPO radioligands have been shown to bind their targets in EAE lesions (Elo et al., 2019).

Lysolecithin induced demyelination has also been used as animal model of MS in PET imaging (de Paula Faria et al., 2014b; de Paula Faria et al., 2014c), and cuprizone feeding as demyelination and remyelination model (de Paula Faria et al., 2014d).

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Updated at: 2023-09-22
Created at: 2017-11-16
Written by: Vesa Oikonen