title: Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: Evidence for clinico-pathologic subtypes.
abstract: Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are types of major TDP-43 (43-kDa TAR DNA-binding protein) proteinopathy. Cortical TDP-43 pathology has been analyzed in detail in cases of FTLD-TDP, but is still unclear in cases of ALS. We attempted to clarify the cortical and subcortical TDP-43 pathology in Japanese cases of sporadic ALS (n = 96) using an antibody specific to phosphorylated TDP-43 (pTDP-43). The cases were divided into two groups: those without pTDP-43-positive neuronal cytoplasmic inclusions in the hippocampal dentate granule cells (Type 1, n = 63), and those with such inclusions (Type 2, n = 33). Furthermore, the Type 2 cases were divided into two subgroups based on semi-quantitative estimation of pTDP-43-positive dystrophic neurites (DNs) in the temporal neocortex: Type 2a (accompanied by no or few DNs, n = 22) and Type 2b (accompanied by abundant DNs, n = 11). Clinico-pathologic analysis revealed that cognitive impairment was a feature in patients with Type 2a and Type 2b, but not in those with Type 1, and that importantly, Type 2b is a distinct subtype characterized by a poor prognosis despite the less severe loss of lower motor neurons, the unusual subcortical dendrospinal pTDP-43 pathology, and more prominent glial involvement in cortical pTDP-43 pathology than other two groups. Considering the patient survival time and severity of motor neuron loss in each group, transition from Type 1 to Type 2, or from Type 2a to Type 2b during the disease course appeared unlikely. Therefore, each of these three groups was regarded as an independent subtype.
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan.|Department of Neurology, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takeuchi
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Tada
authors.affiliation: Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiga
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Toyoshima
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Konno
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan.|Department of Neurology, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nozaki
authors.affiliation: Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kato
authors.affiliation: Division of Neurobiology and Anatomy, Graduate School of Medicine and Dental Sciences, Niigata University, Chuo-ku, Niigata, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Horie
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Division of Neurobiology and Anatomy, Graduate School of Medicine and Dental Sciences, Niigata University, Chuo-ku, Niigata, Japan.
authors.forename: Hirohide
authors.initials: H
authors.lastname: Takebayashi
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan.
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan. hitoshi@bri.niigata-u.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000145:classification / Q000378:metabolism* / Q000473:pathology* / Q000523:psychology; D000073885:C9orf72 Protein; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D011506:Proteins / Q000235:genetics
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; C000598624:TARDBP protein, human
keywords: Amyotrophic lateral sclerosis; Cerebral cortex; Dendrites; Dystrophic neurite; Frontotemporal lobar degeneration; Globus pallidus; Putamen; TDP-43