Imaging of glia activation in people with primary lateral sclerosis

Abstract

Background: Glia activation is thought to contribute to neuronal damage in several neurodegenerative diseases based on preclinical and human post-mortem studies, but its role in primary lateral sclerosis (PLS) is unknown.

Objectives: To localize and measure glia activation in people with PLS compared to healthy controls (HC).

Methods: Ten participants with PLS and ten age-matched HCs underwent simultaneous magnetic resonance (MR) and proton emission tomography (PET). The radiotracer [¹¹C]-PBR28 was used to obtain PET-based measures of 18 kDa translocator protein (TSPO) expression, a marker of activated glial cells. MR techniques included a structural sequence to measure cortical thickness and diffusion tensor imaging (DTI) to assess white matter integrity.

Results: PET data showed increased [¹¹C]-PBR28 uptake in anatomically-relevant motor regions which co-localized with areas of regional gray matter atrophy and decreased subcortical fractional anisotropy.

Conclusions: This study supports a link between glia activation and neuronal degeneration in PLS, and suggests that these disease mechanisms can be measured in vivo in PLS. Future studies are needed to determine the longitudinal changes of these imaging measures and to clarify if MR-PET with [¹¹C]-PBR28 can be used as a biomarker for drug development in the context of clinical trials for PLS.

Keywords: Amyotrophic lateral sclerosis; Diffusion; PET; Primary lateral sclerosis; TSPO; [11C]-PBR28.

Fig. 1

[¹¹C]-PBR28 uptake images and statistical maps for between-group differences. Panel A and B: Mean [¹¹C]-PBR28 uptake (expressed as SUVR_60–90 min) in ten PLS individuals (A) and ten healthy controls (HC) (B). The color bar represents [¹¹C]-PBR28 uptake. Panel C: Statistical maps comparing PLS and HC shows significantly higher [¹¹C]-PBR28 uptake in the motor regions in PLS compared to HC (p_FWE < 0.05). The color bar (red to yellow) represents higher [¹¹C]-PBR28 uptake in PLS as compared to HC. All images are shown at MNI coordinates x = − 10, y = − 20, and z = + 55. Panel D: Tract-based spatial statistics analysis of FA maps shows decreased FA values in multiple white matter tracts in 10 PLS participants compared to 10 healthy controls. The color bar red-yellow represents decreased FA in PLS compared to controls. The mean FA white matter skeleton generated by TBBS for all participants in the study is shown in green. Data is shown using the standard template FMRIB58 at coordinates x = − 10, y = − 22, z = + 55. Panel E: [¹¹C]-PBR28 uptake (expressed as SUVR_60–90 min) in ten healthy controls (HC) and ten individuals with PLS. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Surface based analyses (SBA). Panel A: SBA of cortical thickness shows cortical thinning in PLS compared to HC. The color bar (blue to cyan) represent the difference in cortical thickness between PLS and HC. Panel B: SBA of [¹¹C]-PBR28 uptake shows increased [¹¹C]-PBR28 uptake in PLS compared to HC. The color bar (red to yellow) represent the difference in [¹¹C]-PBR28 uptake between PLS and HC. Statistical maps were overlaid onto the pial surface of the left and the right hemispheres. The results of all SBA analyses were cluster-wise corrected for multiple comparisons (p < 0.01). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Region of Interest (ROI) analyses. Panel A: Representation of the ROI overlaid onto MNI152-1 mm standard space, and shown at MNI coordinates x = − 10, y = − 20, and z = + 55. The ROI includes the bilateral precentral and paracentral gyri. Contribution from gray and subcortical white matter to the ROI is indicated in maroon and purple, respectively. Panel B: Box plots showing [¹¹C]-PBR28 uptake, FA and RD values in PLS (orange circles) and HC (blue circles) within the ROI. The horizontal white line in each box plot represents the median (the box contains median, 25th, and 75th percentiles). The asterisk denotes significant group differences, at p < 0.05. The scale of RD values is divided by 1000. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)