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1Division of Neurology, Department of Brain Sciences, Imperial College London, United Kingdom, London, London, United Kingdom.
Background:
Microglia can take on proinflammatory or anti-inflammatory phenotypes, but it is unclear how these phenotypes play out along the Alzheimer's disease (AD) continuum. The purpose was to assess regional variances of microglial activation in distinct stages of the disease, and the role of microglial responses on grey matter volume and mean diffusivity in different brain areas and on cognition across the course of AD.
Method:
48 subjects (23 AD patients, 14 mild cognitive impairment [MCI], and 11 healthy controls [HC]) underwent TSPO-PET, diffusion tensor imaging (DTI) and extensive neuropsychometric assessment. SPM (Statistical parametric mapping) analysis was conducted for single subject analysis. GM volume for each subject was derived from T1 volumetric MRI using the FreeSurfer pipeline, mean diffusivity (DTI), alongside voxel-based morphometric analysis. Using postmortem brain tissue from 26 AD subjects, we evaluated CD32a and CD163 anti-bodies, markers of proinflammatory and anti-inflammatory microglia, respectively.
Result:
Voxel-wise analyses identified positive and negative clusters of associations for IRF90 with GM volume and mean diffusivity. The presence of pro- and anti-inflammatory phenotypes was confirmed in human postmortem brain, in the frontal, parietal and entorhinal cortices. In addition, higher TSPO, signal in temporal lobes associated with lower hippocampal volume and mean diffusivity, and higher TSPO, signal across the cortex, correlated with poorer performance on neuropsychometric tests.
Conclusion:
There may be protective and deleterious microglial phenotypes in an individual, region specific and disease stage dependent. Therapeutic modulation of microglia is warranted to promote anti-inflammatory functions while suppressing pro-inflammatory functions.
Insights
Microglia exhibit both protective and harmful phenotypes in Alzheimer's disease (AD), varying by brain region and disease stage. Modulating these microglial responses could offer new therapeutic strategies for AD.
Area of Science:
- Neuroscience
- Immunology
- Neuropathology
Background:
- Microglia, the brain's immune cells, can adopt proinflammatory or anti-inflammatory roles.
- The specific roles of these microglial phenotypes across the Alzheimer's disease (AD) spectrum remain unclear.
Purpose of the Study:
- To investigate regional variations in microglial activation at different stages of AD.
- To determine the impact of microglial responses on brain structure (grey matter volume, mean diffusivity) and cognitive function throughout AD progression.
Main Methods:
- Utilized Positron Emission Tomography (PET) with TSPO tracers, diffusion tensor imaging (DTI), and neuropsychometric assessments in 48 participants (AD, mild cognitive impairment, healthy controls).
- Performed voxel-based morphometry and analyzed postmortem brain tissue for microglial markers (CD32a, CD163).
Main Results:
- Found associations between microglial activation markers and grey matter volume/mean diffusivity.
- Confirmed the presence of both pro- and anti-inflammatory microglial phenotypes in postmortem AD brains.
- Higher microglial activation in temporal lobes correlated with reduced hippocampal volume and poorer cognitive performance.
Conclusions:
- Microglial phenotypes in AD are complex, being region-specific, individual-dependent, and stage-specific.
- Targeting microglial functions to enhance anti-inflammatory and suppress pro-inflammatory activities presents a potential therapeutic avenue for AD.
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