{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T13:50:48Z","timestamp":1782568248613,"version":"3.54.5"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T00:00:00Z","timestamp":1704672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18H02743"],"award-info":[{"award-number":["18H02743"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Kii amyotrophic lateral sclerosis (ALS) is a unique disease that occurs in the southern portion of the Kii Peninsula and exhibits a dual pathology of TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy and tauopathy. The incidence of ALS in this region was very high in the 1960s, briefly decreased through the 1980s, but began increasing again after 2000 with a change of high-concentration geographic foci. It is unclear, however, whether the unique pathological features have changed along with the incidence changes. This study analyzed postmortem specimens from neuropathologically confirmed Kii ALS cases from the 1970s (n\u2009=\u20094) and those after 1999 (n\u2009=\u200912) from the southern Kii Peninsula or outside of the area. Our results confirm the continued occurrence of Kii ALS after 2000 in the southern Kii Peninsula and the preservation of disease-specific neuronal tau pathology, including the widespread occurrence throughout the brain and spinal cord, sparse neuropil threads, and predominance in superficial layers. Furthermore, we assessed the glial tau pathology of Kii and non-Kii ALS in accordance with the aging-related tau astrogliopathy classification method for the first time and detected a unique brainstem predominant appearance of gray matter aging-related tau astrogliopathy in Kii ALS cases, which may provide clues to pathogenetic mechanisms.<\/jats:p>","DOI":"10.1093\/jnen\/nlad113","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T10:28:03Z","timestamp":1704796083000},"page":"79-93","source":"Crossref","is-referenced-by-count":2,"title":["Persistence of Kii amyotrophic lateral sclerosis after the 2000s and its characteristic aging-related tau astrogliopathy"],"prefix":"10.1093","volume":"83","author":[{"given":"Kazumi","family":"Tsuji","sequence":"first","affiliation":[{"name":"Department of Neurology, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3010-7741","authenticated-orcid":false,"given":"Yoshiaki","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Neurology, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Taruya","sequence":"additional","affiliation":[{"name":"Department of Neurology, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidefumi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Neurology, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,8]]},"reference":[{"key":"2024032523552980200_nlad113-B1","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1056\/NEJM200105313442207","article-title":"Amyotrophic lateral sclerosis","volume":"344","author":"Rowland","year":"2001","journal-title":"N Engl J Med"},{"key":"2024032523552980200_nlad113-B2","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3109\/17482960802566824","article-title":"Prognostic factors in ALS: A critical review","volume":"10","author":"Chi\u00f2","year":"2009","journal-title":"Amyotroph Lateral Scler"},{"key":"2024032523552980200_nlad113-B3","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.3389\/fnins.2019.01310","article-title":"ALS genetics, mechanisms, and therapeutics: Where are we now?","volume":"13","author":"Mejzini","year":"2019","journal-title":"Front Neurosci"},{"key":"2024032523552980200_nlad113-B4","first-page":"61","article-title":"Pathology of amyotrophic lateral sclerosis","volume":"36","author":"Hughes","year":"1982","journal-title":"Adv Neurol"},{"key":"2024032523552980200_nlad113-B5","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/j.1440-1789.2007.00873.x","article-title":"Bunina bodies in amyotrophic lateral sclerosis","volume":"28","author":"Okamoto","year":"2008","journal-title":"Neuropathology"},{"key":"2024032523552980200_nlad113-B6","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.bbrc.2006.10.093","article-title":"TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"351","author":"Arai","year":"2006","journal-title":"Biochem Biophys Res Commun"},{"key":"2024032523552980200_nlad113-B7","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/0014-4886(79)90129-8","article-title":"Degeneration of the human Betz cell due to amyotrophic lateral sclerosis","volume":"63","author":"Hammer","year":"1979","journal-title":"Exp Neurol"},{"key":"2024032523552980200_nlad113-B8","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1212\/WNL.5.4.249","article-title":"Epidemiologic investigations of amyotrophic lateral sclerosis. 2. Familial aggregations indicative of dominant inheritance. I","volume":"5","author":"Kurland","year":"1955","journal-title":"Neurology"},{"key":"2024032523552980200_nlad113-B9","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1212\/WNL.4.6.438","article-title":"Epidemiologic investigations of amyotrophic lateral sclerosis: I. Preliminary report on geographic distribution, with special reference to the Mariana Islands, including clinical and pathologic observations","volume":"4","author":"Kurland","year":"1954","journal-title":"Neurology"},{"key":"2024032523552980200_nlad113-B10","first-page":"1724","article-title":"Neurologic diseases on the island of Guam","volume":"5","author":"Mulder","year":"1954","journal-title":"US Armed Forces Med J"},{"key":"2024032523552980200_nlad113-B11","first-page":"353","volume-title":"Handbook of Clinical Neurology","author":"Shiraki","year":"1975"},{"key":"2024032523552980200_nlad113-B12","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1212\/WNL.32.2.107","article-title":"Amyotrophic lateral sclerosis and parkinsonian syndromes in high incidence among the Auyu and Jakai people of West New Guinea","volume":"32","author":"Gajdusek","year":"1982","journal-title":"Neurology"},{"key":"2024032523552980200_nlad113-B13","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1212\/WNL.61.3.291","article-title":"Western Pacific ALS\/PDC and flying foxes: What\u2019s next?","volume":"61","author":"Armon","year":"2003","journal-title":"Neurology"},{"key":"2024032523552980200_nlad113-B14","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1093\/brain\/84.4.642","article-title":"Parkinsonism-dementia complex, an endemic disease on the island of Guam. I. Clinical features","volume":"84","author":"Hirano","year":"1961","journal-title":"Brain"},{"key":"2024032523552980200_nlad113-B15","doi-asserted-by":"crossref","first-page":"S108","DOI":"10.1002\/mds.20548","article-title":"Atypical parkinsonism of Japan: Amyotrophic lateral sclerosis-parkinsonism-dementia complex of the Kii peninsula of Japan (Muro disease): An update","volume":"20 Suppl 12","author":"Kuzuhara","year":"2005","journal-title":"Mov Disord"},{"key":"2024032523552980200_nlad113-B16","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1093\/jnen\/62.7.791","article-title":"Biochemical and ultrastructural study of neurofibrillary tangles in amyotrophic lateral sclerosis\/parkinsonism-dementia complex in the Kii Peninsula of Japan","volume":"62","author":"Itoh","year":"2003","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024032523552980200_nlad113-B17","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s00401-008-0439-2","article-title":"Enduring involvement of tau, \u03b2-amyloid, \u03b1-synuclein, ubiquitin and TDP-43 pathology in the amyotrophic lateral sclerosis\/parkinsonism\u2013dementia complex of Guam (ALS\/PDC)","volume":"116","author":"Miklossy","year":"2008","journal-title":"Acta Neuropathol"},{"key":"2024032523552980200_nlad113-B18","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1093\/aje\/kwf175","article-title":"Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: Changing incidence rates during the past 60 years","volume":"157","author":"Plato","year":"2003","journal-title":"Am J Epidemiol"},{"key":"2024032523552980200_nlad113-B19","doi-asserted-by":"crossref","first-page":"347","DOI":"10.3109\/17482968.2012.674140","article-title":"An increase in ALS incidence on the Kii Peninsula, 1960\u20132009: A possible link to change in drinking water source","volume":"13","author":"Kihira","year":"2012","journal-title":"Amyotroph Lateral Scler"},{"key":"2024032523552980200_nlad113-B20","doi-asserted-by":"crossref","first-page":"178","DOI":"10.3109\/17482968.2011.622405","article-title":"Widespread neuronal and glial hyperphosphorylated tau deposition in ALS with cognitive impairment","volume":"13","author":"Yang","year":"2012","journal-title":"Amyotroph Lateral Scler"},{"key":"2024032523552980200_nlad113-B21","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1212\/WNL.0000000000009729","article-title":"Tau deposition in the spinal cord is not specific for CTE-ALS","volume":"95","author":"Fournier","year":"2020","journal-title":"Neurology"},{"key":"2024032523552980200_nlad113-B22","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1097\/00005072-199703000-00010","article-title":"Distinct pathological features of the Gallyas- and tau-positive glia in the parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam","volume":"56","author":"Oyanagi","year":"1997","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024032523552980200_nlad113-B23","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s00401-015-1509-x","article-title":"Aging-related tau astrogliopathy (ARTAG): Harmonized evaluation strategy","volume":"131","author":"Kovacs","year":"2016","journal-title":"Acta Neuropathol"},{"key":"2024032523552980200_nlad113-B24","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/jnen\/nlx041","article-title":"Multisite assessment of aging-related tau astrogliopathy (ARTAG)","volume":"76","author":"Kovacs","year":"2017","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024032523552980200_nlad113-B25","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s40478-018-0552-y","article-title":"Sequential stages and distribution patterns of aging-related tau astrogliopathy (ARTAG) in the human brain","volume":"6","author":"Kovacs","year":"2018","journal-title":"Acta Neuropathol Commun"},{"key":"2024032523552980200_nlad113-B26","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1093\/jnen\/63.9.911","article-title":"Staging of argyrophilic grains: An age-associated tauopathy","volume":"63","author":"Saito","year":"2004","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024032523552980200_nlad113-B27","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/ana.23937","article-title":"Stages of pTDP-43 pathology in amyotrophic lateral sclerosis","volume":"74","author":"Brettschneider","year":"2013","journal-title":"Ann Neurol"},{"key":"2024032523552980200_nlad113-B28","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00401-011-0845-8","article-title":"A harmonized classification system for FTLD-TDP pathology","volume":"122","author":"Mackenzie","year":"2011","journal-title":"Acta Neuropathol"},{"key":"2024032523552980200_nlad113-B29","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00401-006-0127-z","article-title":"Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry","volume":"112","author":"Braak","year":"2006","journal-title":"Acta Neuropathol"},{"key":"2024032523552980200_nlad113-B30","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1126\/science.278.5337.412","article-title":"Life and death of neurons in the aging brain","volume":"278","author":"Morrison","year":"1997","journal-title":"Science"},{"key":"2024032523552980200_nlad113-B31","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/neup.12143","article-title":"Astrocytic inclusions in progressive supranuclear palsy and corticobasal degeneration","volume":"34","author":"Yoshida","year":"2014","journal-title":"Neuropathology"},{"key":"2024032523552980200_nlad113-B32","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1093\/jnen\/61.11.935","article-title":"Office of Rare Diseases neuropathologic criteria for corticobasal degeneration","volume":"61","author":"Dickson","year":"2002","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024032523552980200_nlad113-B33","doi-asserted-by":"crossref","first-page":"S16","DOI":"10.1212\/WNL.56.suppl_4.S16","article-title":"Neuropathology of Pick\u2019s disease","volume":"56","author":"Dickson","year":"2001","journal-title":"Neurology"},{"key":"2024032523552980200_nlad113-B34","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/bpa.12248","article-title":"The neuropathology of chronic traumatic encephalopathy","volume":"25","author":"McKee","year":"2015","journal-title":"Brain Pathol"},{"key":"2024032523552980200_nlad113-B35","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1212\/WNL.41.4.479","article-title":"The consortium to establish a registry for Alzheimer\u2019s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer\u2019s disease","volume":"41","author":"Mirra","year":"1991","journal-title":"Neurology"},{"key":"2024032523552980200_nlad113-B36","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1093\/jnen\/nlx007","article-title":"Evaluating the patterns of aging-related tau astrogliopathy unravels novel insights into brain aging and neurodegenerative diseases","volume":"76","author":"Kovacs","year":"2017","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024032523552980200_nlad113-B37","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s40478-016-0330-7","article-title":"ARTAG in the basal forebrain: Widening the constellation of astrocytic tau pathology","volume":"4","author":"Liu","year":"2016","journal-title":"Acta Neuropathol Commun"},{"key":"2024032523552980200_nlad113-B38","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s00401-018-1824-0","article-title":"Mechanical disruption of the blood\u2013brain barrier following experimental concussion","volume":"135","author":"Johnson","year":"2018","journal-title":"Acta Neuropathol"},{"key":"2024032523552980200_nlad113-B39","doi-asserted-by":"crossref","first-page":"e2306767120","DOI":"10.1073\/pnas.2306767120","article-title":"Tau filaments from amyotrophic lateral sclerosis\/parkinsonism-dementia complex (ALS\/PDC) adopt the CTE fold","volume":"120","author":"Qi","year":"2023","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Journal of Neuropathology &amp; Experimental Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jnen\/article-pdf\/83\/2\/79\/56253745\/nlad113.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jnen\/article-pdf\/83\/2\/79\/56253745\/nlad113.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T00:47:38Z","timestamp":1711414058000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jnen\/article\/83\/2\/79\/7513119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,8]]},"references-count":39,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1,8]]},"published-print":{"date-parts":[[2024,1,19]]}},"URL":"https:\/\/doi.org\/10.1093\/jnen\/nlad113","relation":{},"ISSN":["0022-3069","1554-6578"],"issn-type":[{"value":"0022-3069","type":"print"},{"value":"1554-6578","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,2,1]]},"published":{"date-parts":[[2024,1,8]]}}}