title: Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids.
abstract: To clarify the histopathological alterations of microglia in the brains of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) caused by mutations of the gene encoding the colony stimulating factor-1 receptor (CSF-1R).
  
  
  
  We examined 5 autopsied brains and 1 biopsy specimen from a total of 6 patients with CSF-1R mutations. Detailed immunohistochemical, biochemical, and ultrastructural features of microglia were examined, and quantitative analyses were performed.
  
  
  
  In layers 3 to 4 of the frontal cortex in HDLS brains, microglia showed relatively uniform and delicate morphology, with thin and winding processes accompanying knotlike structures, and significantly smaller areas of Iba1 immunoreactivity and lower numbers of Iba1-positive cells were evident in comparison with control brains. On the other hand, in layers 5 to 6 and the underlying white matter, microglia were distributed unevenly; that is, in some areas they had accumulated densely, whereas in others they were scattered. Immunoblot analyses of microglia-associated proteins, including CD11b and DAP12, revealed that HDLS brains had significantly lower amounts of these proteins than diseased controls, although Ki-67-positive proliferative microglia were not reduced. Ultrastructurally, the microglial cytoplasm and processes in HDLS showed vesiculation of the rough endoplasmic reticulum and disaggregated polyribosomes, indicating depression of protein synthesis. On the other hand, macrophages were immunonegative for GLUT-5 or P2ry12, indicating that they were derived from bone marrow.
  
  
  
  The pathogenesis of HDLS seems to be associated with microglial vulnerability and morphological alterations. Ann Neurol 2016;80:554-565.
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata. tadamari@bri.niigata-u.ac.jp.
authors.forename: Mari
authors.initials: M
authors.lastname: Tada
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata.
authors.forename: Takuya
authors.initials: T
authors.lastname: Konno
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tada
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tezuka
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata.|Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miura
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata.|Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata.
authors.forename: Naomi
authors.initials: N
authors.lastname: Mezaki
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Okazaki
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata.
authors.forename: Musashi
authors.initials: M
authors.lastname: Arakawa
authors.affiliation: Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Department of Neurology, Saiseikai Nakatsu Hospital and Medical Center, Osaka.
authors.forename: Toru
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Human Pathology, Gunma University, Maebashi, Gunma.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yokoo
authors.affiliation: Department of Neurology, Gifu University, Gifu.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yoshikura
authors.affiliation: Department of Neurology, Showa University, Tokyo.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishihara
authors.affiliation: Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata.
authors.forename: Masao
authors.initials: M
authors.lastname: Horie
authors.affiliation: Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata.
authors.forename: Hirohide
authors.initials: H
authors.lastname: Takebayashi
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Toyoshima
authors.affiliation: Department of Pathology, Niigata Medical Center, Niigata, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Naito
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata.
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata.
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
mesh_terms: D001344:Autopsy; D001706:Biopsy; D002525:Cerebellar Cortex / Q000473:pathology*; D005625:Frontal Lobe / Q000473:pathology*; D006801:Humans; D056784:Leukoencephalopathies / Q000378:metabolism / Q000473:pathology*; D017628:Microglia / Q000473:pathology* / Q000648:ultrastructure; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D066127:White Matter / Q000473:pathology*
chemical_list: D016186:Receptor, Macrophage Colony-Stimulating Factor