Activation of microglia is considered a crucial step in response to injury in central nervous system. In multiple sclerosis (MS), activated microglia are found not only related to focal demyelinating lesions, but also diffusely in the normal appearing white matter (NAWM), especially in progressive MS. Measuring microglial activation in vivo is possible using PET imaging and radioligands binding to 18 kDa translocator protein (TSPO) expressed on outer mitochondrial membrane of activated, but not resting, microglia. Thus, TSPO-PET imaging provides tools for the evaluation of molecular mechanisms associated with progression of MS.

The aim of this study was to investigate how activation of microglia relates to certain milestones in MS progression. MS patients with secondary progressive (SPMS, n=10) or relapsing remitting (RRMS, n=10) disease and healthy controls (n=8) were imaged using PET and TSPO-binding [11C]PK11195. Diffusion tensor imaging was performed for assessment of structural integrity of NAWM tracts. In addition, tissue binding characteristics of [11C]PK11195 in cryosections of post mortem autopsy samples from progressive MS patients (n=5) were evaluated. [11C]PK11195 binding in the autoradiography was paralleled to microglial activation, astrocytosis and myelin density in serial sections immunostained using CD68 and GFAP antibodies, and after LFB staining.

[11C]PK11195 binding was significantly increased in the perilesional white matter of SPMS compared to RRMS patients (p=0.011). Similarly, the radioligand binding in NAWM was significantly higher in SPMS compared to RRMS (p< 0.001) and control (p< 0.001) groups. A distribution volume cut-off value of 1.02 in [11C]PK11195 binding in NAWM separated the RRMS and SPMS groups from each other. The increased radioligand binding in perilesional WM and NAWM correlated to increasing clinical disability measured using EDSS (p=0.030 and p< 0.001 respectively). Lower fractional anisotropy in NAWM also correlated to higher EDSS (p=0.002). In the post mortem autoradiography and immunohistochemistry evaluation, there was increased perilesional [11C]PK11195 signal co-localised with increased microglial/macrophage activation around, but not within, the chronic demyelinating lesions. 

In conclusion, TSPO PET imaging may be used as a biomarker of diffuse neuroinflammation related to disease progression in MS, and can potentially be utilised to help identify patients entering the progressive phase of the disease.