Table 1 Sites of microglia activation on MS lesions (Peterson et al. 2001; Kutzelnigg and Lassmann 2014; Calabrese et al. 2015; Kuhlmann et al. 2017) and corresponding potential application of neuroinflammation TSPO-PET tracers

WM lesions

Active lesions: activated macrophages or microglia throughout the lesions with synchronous myelin destruction.

Inactive lesions: lack of microglia or macrophages within the MS lesion.

Mixed active/inactive lesions: hypocellular

core and activated microglia or macrophages at the lesion border. The so-called “smoldering/slowly expanding lesions” are considered a subtype of mixed lesions and are typical in patients affected by progressive forms of MS.

(P) reactive lesions: microglial activation prior to the formation of the WM lesions (preactive) or in response to remyelination of older WM lesions (reactive).

Heterogeneous PK11195 uptake pattern within the WM lesions has been described (core versus periphery and lesional vs perilesional (Kaunzner et al. 2019; Datta et al. 2017b; Colasanti et al. 2014)). Lesional and perilesional binding of vinpocetine has been shown to be higher than PK11195 but with small overlap in areas of high uptake between ligands (Park et al. 2015).

PK11195, PBR28 and PBR111 uptake pattern has been shown to potentially track disease progression as well response to therapy in RRMS patients (Colasanti et al. 2014; Colasanti et al. 2016; Datta et al. 2017a; Datta et al. 2017b; Datta et al. 2017c; Kaunzner et al. 2017; Kaunzner et al. 2019; Oh et al. 2011; Park et al. 2015).

Non-lesional WM

Activated microglia can be seen in the areas immediately surrounding zones of active demyelination plaques, particularly in progressive forms of MS (periplaque WM, PPWM). This finding is associated with initial myelin loss and apoptosis of oligodendrocytes.

In the areas of WM that are distant from plaques, which appear normal on MRI and gross

pathology (normal appearing WM, NAWM), diffuse microglial activation and occasionally small microglial nodules has been described.

Increased PK11195 and PBR28 binding has been described in NAWM (Datta et al. 2017b; Rissanen et al. 2014), preceding gadolinium enhancement by 4 weeks (Oh et al. 2011).

Enlarging T2 lesion volumes at 1-year MRI follow-up correlated with higher NAWM PBR28 uptake at baseline in RRMS (Datta et al. 2017a).

Lesionals and non-lesionals GM

GM lesions are fewer and usually characterized by lower density of T lymphocytes and microglia or macrophages with respect to WM lesions. However, apoptotic cells are increased, and microglia/macrophages retain an activated morphology irrespective of lesion stage or location of these cells (lesion center versus periphery). These peculiar features of GM lesions might at least partially justify the disproportionately selective GM versus WM atrophy.

Increased non-uniform PK11195 (Politis et al. 2012) and 11C-PBR28 (Herranz et al. 2016) GM binding has been described in MS suggesting the occurrence of neuroinflammation in the cortex. This finding is closely linked to poor clinical outcome and, to a lesser extent, to 7neurodegeneration (Politis et al. 2012; Herranz et al. 2016).