¹¹C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

Abstract

Objective Neuroinflammation is considered a key driver for neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 20% of familial ALS, and related pathology might generate microglial activation triggering neurodegeneration. 11C‐PK11195 is the prototypical and most validated PET radiotracer, targeting the 18‐kDa translocator protein which is overexpressed in activated microglia. In this study, we investigated microglia activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 mutated carriers, by using 11C‐PK11195 and PET imaging. Methods We included 20 subjects: 4 ASYM‐carriers, neurologically normal, 6 SYM‐carriers with probable ALS, and 10 healthy controls. A receptor parametric mapping procedure estimated 11C‐PK11195 binding potentials and voxel‐wise statistical comparisons were performed at group and single‐subject levels. Results Both the SYM‐ and ASYM‐carriers showed significant microglia activation in cortical and subcortical structures, with variable patterns at individual level. Clusters of activation were present in occipital and temporal regions, cerebellum, thalamus, and medulla oblongata. Notably, SYM‐carriers showed microglia activation also in supplementary and primary motor cortices and in the somatosensory regions. Interpretation In vivo neuroinflammation occurred in all SOD1 mutated cases since the presymptomatic stages, as shown by a significant cortical and subcortical microglia activation. The involvement of sensorimotor cortex became evident at the symptomatic disease stage. Although our data indicate the role of in vivo PET imaging for assessing resident microglia in the investigation of SOD1‐ALS pathophysiology, further studies are needed to clarify the temporal and spatial dynamics of microglia activation and its relationship with neurodegeneration.

Non-neuronal cells in amyotrophic lateral sclerosis — from pathogenesis to biomarkers

“…In human ALS 31,32 , and in pre-symptomatic carriers of SOD1 mutations 33 , widespread cerebral microglial activation was demonstrated by PET imaging in vivo. In post mortem ALS, elevated levels of microglial transcripts, increased microglial density, and activated microglial morphology have been found in addition to motor neuron degeneration 34,35 .…”

Cytokine Signalling at the Microglial Penta-Partite Synapse

“…Some studies have explored the role of microglial activation in ALS [36,37], AD [38,39] and MS [40][41][42]. While these studies report significantly increased microglial activation, as inferred from increased TSPO binding, some studies have demonstrated no correlation between microglial activation and increased TSPO binding [40][41][42].…”

Heterogeneity of Neuroinflammatory Responses in Amyotrophic Lateral Sclerosis: A Challenge or an Opportunity?

“…More recently, specific increased expression of cannabinoid receptor type 2 (CB2r) and purinergic P2X7 (P2X7r) receptors have been reported in activated microglia cells in ALS rodent models and patients' post-mortem samples. CD68 immunostaining and TSPO-ligand binding were increased in CNS areas displaying positivity for CB2r and P2X7r, supporting the association of these markers with compromised CNS districts characterized by ongoing neuroinflammatory processes and microglia cell activation [103]. This has prompted the development of radioligands targeted to CB2r and P2X7r as sensitive PET tracers alternative/complementary to TSPO-ligands, with some promising candidate compounds already validated at pre-clinical level [104].…”