Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis

Abstract

Objective:In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants.Methods:Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [11C]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [11C]-PBR28 uptake.Results:In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [11C]-PBR28 binding in the left motor cortex was correlated with FA (r = −0.68, p < 0.05) and cortical thickness (r = −0.75, p < 0.05). UMNB was correlated with glial activation (r = +0.75, p < 0.05), FA (r = −0.77, p < 0.05), and cortical thickness (r = −0.75, p < 0.05) in the motor cortex.Conclusions:Increased uptake of the glial marker [11C]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS.

Ultra-High Field Proton MR Spectroscopy in Early-Stage Amyotrophic Lateral Sclerosis

“…In ALS, gliosis is commonly seen on post-mortem exam and includes increased numbers of reactive astrocytes and activated microglia in the motor cortex [19,59]. Prior work in ALS using a positron emission tomography (PET) tracer that binds specifically to these cells has shown evidence of gliosis in the motor cortex in vivo [60–62]. This PET biomarker also positively correlates with mIns levels, according to a recent pilot investigation [63].…”

Modulation of Microglial Activity by Rho-Kinase (ROCK) Inhibition as Therapeutic Strategy in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

“…In human postmortem studies, reactive microglia were detected in regions which play an important role in motor function (motor cortex, motor nuclei of the brainstem, corticospinal tract, spinal cord; Kawamata et al, 1992; Moisse and Strong, 2006). Recently, microglia were also visualized in ALS patients using integrated MR/PET and the radioligand [ 11 C]-PBR28 that also binds to TSPO (Alshikho et al, 2016). …”

Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis

“…4 Neuroinflammation undoubtedly occurs in ALS, though whether this is pathogenic or a secondary consequence of neurodegeneration is uncertain. 6,7 Differential expression of cytokines, including factors specifically involved in microglial activation, have been observed in enzyme-linked immunosorbent assay (ELISA)-based studies of CSF from ALS patients. Both animal models and postmortem tissue from ALS patients shows infiltration of activated microglia and T cells into affected areas, which correlates with progression rate.…”