Spatial evolution of microglial phenotypes and iron accumulation in CSF1R ‐associated leukoencephalopathy

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Abstract
Colony‐stimulating factor 1 receptor (CSF1R)‐associated leukoencephalopathy (CSF1R‐LE) is a fatal genetic white matter disease, whose onset is most commonly in mid‐age adulthood, and is characterized by rapid neurological decline and premature death within a few years after disease onset. CSF1R is exclusively expressed by microglia in the parenchyma of the adult central nervous system, thus defining CSF1R‐LE as a paradigmatic primary microgliopathy. However, the cellular alterations that drive the sudden onset and rapid progression of the disease remain largely unknown. Therefore, the investigation of microglia phenotypes in human histopathological tissue, particularly considering the spatial evolution of the pathology, can provide crucial insights into the disease‐causing mechanisms. In this study, we (immuno‐) histochemically characterized myeloid cell pathology in relation to the extent of damage to the axon‐myelin unit in five autopsy cases of CSF1R‐LE. A particular focus was on the relationship between microglia phenotypes and the pronounced iron accumulation observed in this disease. Our findings provide evidence that the early loss of homeostatic microglia and inflammatory activation of remaining myeloid cells are key components of areas with mild tissue pathology. Furthermore, we demonstrate a marked and progressive accumulation of iron within myeloid cells paralleling increasing white matter damage. This process is associated with ongoing myelin degeneration and occurs in the apparent absence of efficient remyelination. In summary, our study reveals stage‐specific myeloid cell pathology in CSF1R‐LE and highlights a specific spatial heterogeneity that should be considered when studying this disease. Moreover, our findings suggest that cellular iron accumulation may not only contribute to disease progression but may also represent a promising and clinically accessible biomarker for CSF1R‐LE.
Funding Information
  • Medizinische Fakultät, Universität Leipzig
  • Deutsche Forschungsgemeinschaft (500301720)

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