{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:09:52Z","timestamp":1792465792368,"version":"4.5.0"},"reference-count":29,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,22]],"date-time":"2020-06-22T00:00:00Z","timestamp":1592784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["16768966"],"award-info":[{"award-number":["16768966"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer\u2019s disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid \u03b2 (A\u03b2) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between A\u03b2, tau and neurodegeneration, we performed tau and A\u03b2 PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer\u2019s disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (&gt;2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (&gt;2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle A\u03b2 accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that A\u03b2 can induce tau accumulation and neuronal degeneration without forming senile plaques.<\/jats:p>","DOI":"10.3390\/ijms21124443","type":"journal-article","created":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T06:11:02Z","timestamp":1592892662000},"page":"4443","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Heavy Tau Burden with Subtle Amyloid \u03b2 Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer\u2019s Disease with APP Osaka Mutation"],"prefix":"10.3390","volume":"21","author":[{"given":"Hiroyuki","family":"Shimada","sequence":"first","affiliation":[{"name":"Department of Radiology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinobu","family":"Minatani","sequence":"additional","affiliation":[{"name":"Department of Neurology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4911-9320","authenticated-orcid":false,"given":"Akitoshi","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Neurology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4828-743X","authenticated-orcid":false,"given":"Joji","family":"Kawabe","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2096-1602","authenticated-orcid":false,"given":"Yasuhiro","family":"Wada","sequence":"additional","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Mawatari","sequence":"additional","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyoshi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7139-7178","authenticated-orcid":false,"given":"Hitoshi","family":"Shimada","sequence":"additional","affiliation":[{"name":"Department of Functional Brain Imaging Research (DOFI), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba 263-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Higuchi","sequence":"additional","affiliation":[{"name":"Department of Functional Brain Imaging Research (DOFI), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba 263-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Suhara","sequence":"additional","affiliation":[{"name":"Department of Functional Brain Imaging Research (DOFI), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba 263-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takami","family":"Tomiyama","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-798X","authenticated-orcid":false,"given":"Yoshiaki","family":"Itoh","sequence":"additional","affiliation":[{"name":"Department of Neurology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,22]]},"reference":[{"key":"ref_1","first-page":"11","article-title":"Association between Abeta and tau accumulations and their influence on clinical features in aging and Alzheimer\u2019s disease spectrum brains: A [11C]PBB3-PET study","volume":"6","author":"Shimada","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/j.neuron.2013.07.037","article-title":"Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls","volume":"79","author":"Maruyama","year":"2013","journal-title":"Neuron"},{"key":"ref_3","first-page":"764","article-title":"Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies","volume":"140","author":"Ono","year":"2017","journal-title":"Brain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/S1474-4422(14)70090-0","article-title":"Advancing research diagnostic criteria for Alzheimer\u2019s disease: The IWG-2 criteria","volume":"13","author":"Dubois","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/416535a","article-title":"Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo","volume":"416","author":"Walsh","year":"2002","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Tomiyama, T., and Shimada, H. (2020). APP osaka mutation in familial Alzheimer\u2019s disease-its discovery, phenotypes, and mechanism of recessive inheritance. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041413"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/nn1372","article-title":"Natural oligomers of the amyloid-\u03b2 protein specifically disrupt cognitive function","volume":"8","author":"Cleary","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/nature04533","article-title":"A specific amyloid-\u03b2 protein assembly in the brain impairs memory","volume":"440","author":"Koh","year":"2006","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/nm1782","article-title":"Amyloid-\u03b2 protein dimers isolated directly from Alzheimer\u2019s brains impair synaptic plasticity and memory","volume":"14","author":"Shankar","year":"2008","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/ana.21321","article-title":"A new amyloid beta variant favoring oligomerization in Alzheimer\u2019s-type dementia","volume":"63","author":"Tomiyama","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4845","DOI":"10.1523\/JNEUROSCI.5825-09.2010","article-title":"A mouse model of amyloid beta oligomers: Their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo","volume":"30","author":"Tomiyama","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s00401-014-1259-1","article-title":"Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice","volume":"127","author":"Umeda","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1159\/000330017","article-title":"Clinical course of patients with familial early-onset Alzheimer\u2019s disease potentially lacking senile plaques bearing the E693Delta mutation in amyloid precursor protein","volume":"32","author":"Shimada","year":"2011","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1007\/s00259-016-3591-2","article-title":"Inter-rater variability of visual interpretation and comparison with quantitative evaluation of (11)C-PiB PET amyloid images of the Japanese Alzheimer\u2019s Disease Neuroimaging Initiative (J-ADNI) multicenter study","volume":"44","author":"Yamane","year":"2017","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/ncn3.12366","article-title":"Staging of tau distribution by positron emission tomography may be useful in clinical staging of Alzheimer disease","volume":"8","author":"Aohara","year":"2020","journal-title":"Neurol. Clin. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1093\/brain\/awz268","article-title":"The bivariate distribution of amyloid-beta and tau: Relationship with established neurocognitive clinical syndromes","volume":"142","author":"Jack","year":"2019","journal-title":"Brain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1126\/science.1079469","article-title":"Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis","volume":"300","author":"Kayed","year":"2003","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1056\/NEJMoa1705971","article-title":"Trial of solanezumab for mild dementia due to Alzheimer\u2019s disease","volume":"378","author":"Honig","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1126\/science.366.6471.1298","article-title":"Doubts persist for claimed Alzheimer\u2019s drug","volume":"366","author":"Servick","year":"2019","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/nm1096-1146","article-title":"The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology","volume":"2","author":"Lemere","year":"1996","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1111\/j.1750-3639.2010.00469.x","article-title":"Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer\u2019s disease","volume":"21","author":"Matschke","year":"2011","journal-title":"Brain Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0022-510X(97)05399-9","article-title":"Cerebellar pathology in sporadic and familial Alzheimer\u2019s disease including APP 717 (Val-->Ile) mutation cases: A morphometric investigation","volume":"149","author":"Fukutani","year":"1997","journal-title":"J. Neurol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s00702-018-1850-z","article-title":"Neuropathology and biochemistry of early onset familial Alzheimer\u2019s disease caused by presenilin-1 missense mutation Thr116Asn","volume":"125","author":"Sutovsky","year":"2018","journal-title":"J. Neural. Transm. (Vienna)"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1093\/brain\/awx194","article-title":"The cerebellum in Alzheimer\u2019s disease: Evaluating its role in cognitive decline","volume":"141","author":"Jacobs","year":"2017","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"351","DOI":"10.2214\/ajr.149.2.351","article-title":"MR signal abnormalities at 1.5 T in Alzheimer\u2019s dementia and normal aging","volume":"149","author":"Fazekas","year":"1987","journal-title":"AJR Am. J. Roentgenol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.2967\/jnumed.115.160127","article-title":"PET Quantification of Tau Pathology in Human Brain with 11C-PBB3","volume":"56","author":"Kimura","year":"2015","journal-title":"J. Nucl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.2967\/jnumed.114.139550","article-title":"Radiosynthesis, photoisomerization, biodistribution, and metabolite analysis of 11C-PBB3 as a clinically useful PET probe for imaging of tau pathology","volume":"55","author":"Hashimoto","year":"2014","journal-title":"J. Nucl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.jalz.2010.03.003","article-title":"The ADNI PET Core","volume":"6","author":"Jagust","year":"2010","journal-title":"Alzheimers Dement."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1007\/s12149-016-1115-6","article-title":"Automated quantification of amyloid positron emission tomography: A comparison of PMOD and MIMneuro","volume":"30","author":"Choi","year":"2016","journal-title":"Ann. Nucl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/12\/4443\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:41:24Z","timestamp":1760175684000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/12\/4443"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,22]]},"references-count":29,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21124443"],"URL":"https:\/\/doi.org\/10.3390\/ijms21124443","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,22]]}}}