Increased PK11195-PET binding in normal-appearing white matter in clinically isolated syndrome

Abstract

The most accurate predictor of the subsequent development of multiple sclerosis in clinically isolated syndrome is the presence of lesions at magnetic resonance imaging. We used in vivo positron emission tomography with (11)C-(R)-PK11195, a biomarker of activated microglia, to investigate the normal-appearing white matter and grey matter of subjects with clinically isolated syndrome to explore its role in the development of multiple sclerosis. Eighteen clinically isolated syndrome and eight healthy control subjects were recruited. Baseline assessment included: history, neurological examination, expanded disability status scale, magnetic resonance imaging and PK11195-positron emission tomography scans. All assessments except the PK11195-positron emission tomography scan were repeated over 2 years. SUPERPK methodology was used to measure the binding potential relative to the non-specific volume, BPND. We show a global increase of normal-appearing white matter PK11195 BPND in clinically isolated syndrome subjects compared with healthy controls (P = 0.014). Clinically isolated syndrome subjects with T2 magnetic resonance imaging lesions had higher PK11195 BPND in normal-appearing white matter (P = 0.009) and their normal-appearing white matter PK11195 BPND correlated with the Expanded Disability Status Scale (P = 0.007; r = 0.672). At 2 years those who developed dissemination in space or multiple sclerosis, had higher PK11195 BPND in normal-appearing white matter at baseline (P = 0.007 and P = 0.048, respectively). Central grey matter PK11195 BPND was increased in subjects with clinically isolated syndrome compared to healthy controls but no difference was found in cortical grey matter PK11195 BPND. Microglial activation in clinically isolated syndrome normal-appearing white matter is diffusely increased compared with healthy control subjects and is further increased in those who have magnetic resonance imaging lesions. Furthermore microglial activation in clinically isolated syndrome normal-appearing white matter is also higher in those subjects who developed multiple sclerosis at 2 years. Our finding, if replicated in a larger study, could be of prognostic value and aid early treatment decisions in clinically isolated syndrome.

Neuroinflammatory component of gray matter pathology in multiple sclerosis

“…In line with previous observations, we found increased TSPO levels in WM lesions 43, 44 and NAWM 16, 43, 45 . We found that TPSO levels in WM lesions, measured with both SUVR and DVR, were generally lower than those in cortical lesions.…”

“…In our MS cohort, neurological disability correlated with microglial/macrophages activation in deep GM, in addition to neuroinflammation in the cortex and WM as previously reported 14, 16 . Here, we also demonstrated that microglia/macrophages activation correlated with reduced cognitive performance in MS.…”

“…In MS, 11 C-PK11195 studies reported increased TSPO levels in the cortex 14 , thalamus 15 and central deep GM 16 , however, knowledge of microglia/macrophages activation in MS cortical lesions is still lacking due to the low sensitivity of clinical imaging tools to detect cortical demyelination. Seven Tesla (T) T 2 *-weighted gradient-echo protocols demonstrate increased sensitivity to in vivo visualization of focal cortical lesions in MS, confirmed pathologically to correspond to cortical areas with the greatest degree of demyelination 17, 18 .…”

Recent imaging advances in neurology

“…[ 11 C]PK11195 PET has showed increased microglial activation in the cortical grey matter (GM) of relapsingremitting (RR) and secondary progressive (SP) MS patients, which correlated with levels of neurological disability [139]. Patients with clinically isolated syndrome showed a global increase of [ 11 C]PK11195 binding in normal-appearing white matter (NAWM), and the binding was higher in subjects who developed lesions that were disseminated in space or MS at 2 years follow-up [140]. [ 11 C]PK11195 PET has been found to be increased in chronic hypointense T1-weighted MRI lesions (black holes) and this has been associated with worse prognosis at 2 years of follow-up in progressive MS [141].…”

Enhancing our understanding of white matter changes in early multiple sclerosis

“…Studies using magnetization transfer imaging suggest loss of macromolecules such as myelin, while diffusion imaging measures correlate with injured structural components within the tissue, including axons, myelin, and the tissue matrix. A recent study using PET showed that microglia are globally activated in the normal-appearing white matter and deep grey matter of patients with CIS compared to control subjects (Giannetti et al, 2015), and that the global increase in microglial activation is predictive of earlier development of multiple sclerosis over the next 2 years. This PET study is in accord with studies of autopsied multiple sclerosis tissues that have revealed activated microglia throughout normal-appearing white matter.…”