Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Nasu-Hakola disease: lesion staging and dynamic changes of axons and microglial subsets.
The brains of 10 Japanese patients with adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) and eight Japanese patients with Nasu-Hakola disease (N-HD) and five age-matched Japanese controls were examined neuropathologically with special reference to lesion staging and dynamic changes of microglial subsets. In both diseases, the pathognomonic neuropathological features included spherically swollen axons (spheroids and globules), axon loss and changes of microglia in the white matter. In ALSP, four lesion stages based on the degree of axon loss were discernible: Stage I, patchy axon loss in the cerebral white matter without atrophy; Stage II, large patchy areas of axon loss with slight atrophy of the cerebral white matter and slight dilatation of the lateral ventricles; Stage III, extensive axon loss in the cerebral white matter and dilatation of the lateral and third ventricles without remarkable axon loss in the brainstem and cerebellum; Stage IV, devastated cerebral white matter with marked dilatation of the ventricles and axon loss in the brainstem and/or cerebellum. Internal capsule and pontine base were relatively well preserved in the N-HD, even at Stage IV, and the swollen axons were larger with a higher density in the ALSP. Microglial cells immunopositive for CD68, CD163 or CD204 were far more obvious in ALSP, than in N-HD, and the shape and density of the cells changed in each stage. With progression of the stage, clinical symptoms became worse to apathetic state, and epilepsy was frequently observed in patients at Stages III and IV in both diseases. From these findings, it is concluded that (i) shape, density and subsets of microglia change dynamically along the passage of stages and (ii) increase of IBA-1-, CD68-, CD163- and CD204-immunopositive cells precedes loss of axons in ALSP.
Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan.|Brain Research Laboratory, Hatsuishi Hospital, Chiba, Japan.
Kiyomitsu
K
Oyanagi
Department of Neurology, Suwa Red Cross Hospital, Nagano, Japan.
Michiaki
M
Kinoshita
Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan.
Emi
E
Suzuki-Kouyama
Department of Neurology, Daigo Hospital, Miyazaki, Japan.
Teruhiko
T
Inoue
Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan.|Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
Asa
A
Nakahara
Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan.
Mika
M
Tokiwai
Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Nobutaka
N
Arai
Department of Bioinfomatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan.
Jun-Ichi
JI
Satoh
Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.|Psychiatric Center, Yokohama City University Medical Center, Kanagawa, Japan.
Naoya
N
Aoki
Department of Neurology, National Hospital Organization Hyogo-Chuo-Hospital, Hyogo, Japan.
Kenji
K
Jinnai
Laboratory of Research Resources, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan.
Ikuru
I
Yazawa
Department of Neurology, National Hospital Organization Chiba-East Hospital, Chiba, Japan.
Kimihito
K
Arai
Department of Neurology, Showa University School of Medicine, Tokyo, Japan.|Department of Internal Medicine, Ushioda General Hospital, Kanagawa, Japan.
Kenji
K
Ishihara
Department of Neurology, Showa University School of Medicine, Tokyo, Japan.
Mitsuru
M
Kawamura
Departments of Neurology and Pathology, Saitama Medical University, Saitama, Japan.
Keisuke
K
Ishizawa
Department of Neurology, Sagamihara National Hospital, Kanagawa, Japan.
Kazuko
K
Hasegawa
Kanagawa Rehabilitation Center, Kanagawa, Japan.
Saburo
S
Yagisita
Department of Psychiatry, Shinshu University School of Medicine, Nagano, Japan.
Naoji
N
Amano
Division of Neurogenetics, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan.
Kunihiro
K
Yoshida
Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Seishi
S
Terada
Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.
Mari
M
Yoshida
Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Haruhiko
H
Akiyama
Department of Neurology, Daigo Hospital, Miyazaki, Japan.
Yoshio
Y
Mitsuyama
Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan.
Shu-Ichi
SI
Ikeda
D000328:Adult; D001284:Atrophy / Q000473:pathology; D001344:Autopsy; D001369:Axons / Q000473:pathology; D001921:Brain / Q000473:pathology; D005260:Female; D006801:Humans; D007564:Japan; D056784:Leukoencephalopathies / Q000175:diagnosis / Q000473:pathology*; D008060:Lipodystrophy / Q000175:diagnosis / Q000473:pathology*; D008297:Male; D017628:Microglia / Q000473:pathology; D008875:Middle Aged; D009457:Neuroglia / Q000473:pathology; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000473:pathology*; D013344:Subacute Sclerosing Panencephalitis / Q000175:diagnosis / Q000473:pathology*; D066127:White Matter / Q000473:pathology
ALSP; HDLS; Hakola; Nasu; lesion staging; microglia