Molecular Imaging of Microglial Activation in Amyotrophic Lateral Sclerosis

Abstract

There is growing evidence of activated microglia and inflammatory processes in the cerebral cortex in amyotrophic lateral sclerosis (ALS). Activated microglia is characterized by increased expression of the 18 kDa translocator protein (TSPO) in the brain and may be a useful biomarker of inflammation. In this study, we evaluated neuroinflammation in ALS patients using a radioligand of TSPO, 18F-DPA-714. Ten patients with probable or definite ALS (all right-handed, without dementia, and untreated by riluzole or other medication that might bias the binding on the TSPO), were enrolled prospectively and eight healthy controls matched for age underwent a PET study. Comparison of the distribution volume ratios between both groups were performed using a Mann-Whitney’s test. Significant increase of distribution of volume ratios values corresponding to microglial activation was found in the ALS sample in primary motor, supplementary motor and temporal cortex (p = 0.009, p = 0.001 and p = 0.004, respectively). These results suggested that the cortical uptake of 18F-DPA-714 was increased in ALS patients during the “time of diagnosis” phase of the disease. This finding might improve our understanding of the pathophysiology of ALS and might be a surrogate marker of efficacy of treatment on microglial activation.

High-Resolution 7T MR Imaging of the Motor Cortex in Amyotrophic Lateral Sclerosis

“…PET with radioligand-binding biomarkers of activated microglia revealed that areas with the highest microglial activation in patients with ALS were the motor cortices, 39 thus corresponding to the distribution of signal changes and atrophy that we have detected in our group of patients.…”

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

“…In patients with ALS, microgliosis occurs specifically with motor neuron injury in the motor cortex, along the corticospinal tract, and in the ventral horn of the spinal cord [24,53,[69][70][71][72] radioligands that bind microglia, has been used to image microglial activation corresponding with the location motor neuron injury in patients with ALS [72,73]. This radiographic evidence in humans correlates the with evidence in the G93A mSOD1 transgenic mouse, which demonstrates microglial activation even before motor neuron cell death [74,75].…”

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

“…Uptake of TSPO ligands in the brain is generally low in normal healthy adults, but overall uptake is increased with age (146). An increase in TSPO expression has been observed during the onset of disease in amytrophic lateral sclerosis (ALS) patients (147). Similarly, brains of subjects with mild cognitive impairment (MCI), who are at an increased risk of developing Alzheimer's disease (AD), or subjects with mild and early forms of AD, exhibit higher ligand binding compared to age-matched controls (148,149) although other studies contradict this observation (150).…”