{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T10:25:55Z","timestamp":1785925555553,"version":"3.56.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T00:00:00Z","timestamp":1724198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100013083","name":"Xuzhou Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013083","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005878","name":"Research Foundation of Xuzhou Commission of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005878","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012217","name":"Xuzhou Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012217","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The expansion of GGC repeats within NOTCH2NLC leads to translation of the uN2CpolyG protein, the primary pathogenic factor in neuronal intranuclear inclusion disease (NIID). The aim of this study was to explore the deposition of uN2CpolyG as an amyloid in the vessel wall, leading to uN2CpolyG cerebral amyloid angiopathy-related cerebral microbleeds (CMBs).<\/jats:p>\n               <jats:p>A total of 97 patients with genetically confirmed NIID were enrolled in this study. We analysed the presence of CMBs using susceptibility-weighted imaging sequences and compared general clinical information, cerebrovascular risk factors, stroke history, antiplatelet medication use and MRI features between NIID patients with and without CMBs. We also performed haematoxylin and eosin, Perl\u2019s, Congo red and Thioflavin S staining, ubiquitin, p62 and uN2CpolyG immunostaining on brain tissue obtained from four NIID patients.<\/jats:p>\n               <jats:p>A total of 354 CMBs were detected among 41 patients with NIID, with nearly half located in the deep brain, one-third in the lobes and \u223c20% in the infratentorial area. No significant differences in cerebrovascular disease risk factors or history of antiplatelet drug use were observed between patients with and without CMBs. However, patients with CMBs had suffered a higher incidence of previous ischaemic and haemorrhagic stroke events. This group also had a higher incidence of recent subcortical infarcts and a higher proportion of white matter lesions in the external capsule and temporal pole. Conversely, patients without CMBs showed higher detection of high signals at the corticomedullary junction on diffusion-weighted imaging and more pronounced brain atrophy.<\/jats:p>\n               <jats:p>Haematoxylin and eosin staining showed blood vessel leakage and haemosiderin-laden macrophage clusters, and Prussian blue staining revealed iron deposition in brain tissue. CMBs occurred more frequently in small vessels lacking intranuclear inclusions, and extensive degeneration of endothelial cells and smooth muscle fibres was observed mainly in vessels lacking inclusions. Congo red-positive amyloid deposition was observed in the cerebral vessels of NIID patients, with disordered filamentous fibres appearing under an electron microscope. Additionally, the co-localization of Thioflavin S-labelled amyloid and uN2CpolyG protein in the cerebral vascular walls of NIID patients further suggested that uN2CpolyG is the main pathogenic protein in this form of amyloid angiopathy.<\/jats:p>\n               <jats:p>In conclusion, we reviewed patients with GGC repeat expansion of NOTCH2NLC from a new perspective, providing initial clinical, neuroimaging and pathological evidence suggesting that uN2CpolyG might contribute to a distinct type of cerebral amyloid angiopathy.<\/jats:p>","DOI":"10.1093\/brain\/awae274","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T02:15:15Z","timestamp":1724292915000},"page":"467-479","source":"Crossref","is-referenced-by-count":10,"title":["GGC repeat expansions in <i>NOTCH2NLC<\/i> cause uN2CpolyG cerebral amyloid angiopathy"],"prefix":"10.1093","volume":"148","author":[{"given":"Lei","family":"Bao","sequence":"first","affiliation":[{"name":"Department of Neurology, the Affiliated Hospital of Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]},{"name":"Department of Neurology, Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Affiliated Hospital of Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]},{"name":"Department of Neurology, Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Affiliated Hospital of Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]},{"name":"Department of Neurology, Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, the Affiliated Hospital of Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Affiliated Hospital of Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]},{"name":"Department of Neurology, Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pathology, the Affiliated Hospital of Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei 230000 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xuanwu Hospital, Capital Medical University , Beijing 100000 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Neurological Intensive Care, Yantai Yuhuangding Hospital , Yantai 264000 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinyi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Geriatric Neurology, Nanjing Brain Hospital Affiliated to Nanjing Medical University , Nanjing 210000 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9675-8497","authenticated-orcid":false,"given":"Guiyun","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Affiliated Hospital of Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]},{"name":"Department of Neurology, Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Affiliated Hospital of Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"key":"2025020305060729900_awae274-B1","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1038\/s41588-019-0459-y","article-title":"Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease","volume":"51","author":"Sone","year":"2019","journal-title":"Nat Genet"},{"key":"2025020305060729900_awae274-B2","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1136\/jnnp-2022-329772","article-title":"Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease","volume":"93","author":"Tian","year":"2022","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2025020305060729900_awae274-B3","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1002\/acn3.51189","article-title":"Re-defining the clinicopathological spectrum of neuronal intranuclear inclusion disease","volume":"7","author":"Chen","year":"2020","journal-title":"Ann Clin Transl Neurol"},{"key":"2025020305060729900_awae274-B4","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1161\/STROKEAHA.122.041848","article-title":"NOTCH2NLC GGC repeat expansion in patients with vascular leukoencephalopathy","volume":"54","author":"Liao","year":"2023","journal-title":"Stroke"},{"key":"2025020305060729900_awae274-B5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.12779\/dnd.2018.17.3.73","article-title":"Characteristics of cerebral microbleeds","volume":"17","author":"Lee","year":"2018","journal-title":"Dement Neurocogn Disord"},{"key":"2025020305060729900_awae274-B6","doi-asserted-by":"crossref","first-page":"3991","DOI":"10.1093\/brain\/awad193","article-title":"Clinical considerations in early-onset cerebral amyloid angiopathy","volume":"146","author":"Banerjee","year":"2023","journal-title":"Brain"},{"key":"2025020305060729900_awae274-B7","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1093\/jnen\/62.9.885","article-title":"Cerebral amyloid angiopathies: A pathologic, biochemical, and genetic view","volume":"62","author":"Revesz","year":"2003","journal-title":"J Neuropathol Exp Neurol"},{"key":"2025020305060729900_awae274-B8","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1093\/brain\/awx047","article-title":"Emerging concepts in sporadic cerebral amyloid angiopathy","volume":"140","author":"Charidimou","year":"2017","journal-title":"Brain"},{"key":"2025020305060729900_awae274-B9","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1007\/s00401-021-02375-3","article-title":"Upstream open reading frame with NOTCH2NLC GGC expansion generates polyglycine aggregates and disrupts nucleocytoplasmic transport: Implications for polyglycine diseases","volume":"142","author":"Zhong","year":"2021","journal-title":"Acta Neuropathol"},{"key":"2025020305060729900_awae274-B10","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1016\/j.neuron.2021.03.038","article-title":"Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases","volume":"109","author":"Boivin","year":"2021","journal-title":"Neuron"},{"issue":"5B","key":"2025020305060729900_awae274-B11","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1111\/j.1582-4934.2008.00411.x","article-title":"Parenchymal and vascular A\u03b2-deposition and its effects on the degeneration of neurons and cognition in Alzheimer's disease","volume":"12","author":"Thal","year":"2008","journal-title":"J Cell Mol Med"},{"key":"2025020305060729900_awae274-B12","doi-asserted-by":"crossref","first-page":"1085283","DOI":"10.3389\/fneur.2022.1085283","article-title":"Unraveling rare form of adult-onset NIID by characteristic brain MRI features: A single-center retrospective review","volume":"13","author":"Li","year":"2022","journal-title":"Front Neurol"},{"key":"2025020305060729900_awae274-B13","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":"2025020305060729900_awae274-B14","first-page":"929","article-title":"Large Virchow-Robin spaces: MR-clinical correlation","volume":"10","author":"Heier","year":"1989","journal-title":"AJNR Am J Neuroradiol"},{"key":"2025020305060729900_awae274-B15","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1002\/ana.410300503","article-title":"Cerebral amyloid angiopathy without and with cerebral hemorrhages: A comparative histological study","volume":"30","author":"Vonsattel","year":"1991","journal-title":"Ann Neurol"},{"key":"2025020305060729900_awae274-B16","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/0003-2697(89)90046-8","article-title":"Fluorometric determination of amyloid fibrils in vitro using the fluorescent dye, thioflavin T","volume":"177","author":"Naiki","year":"1989","journal-title":"Anal Biochem"},{"key":"2025020305060729900_awae274-B17","doi-asserted-by":"crossref","first-page":"e003477","DOI":"10.1161\/JAHA.116.003477","article-title":"Cerebral microbleeds, vascular risk factors, and magnetic resonance imaging markers: The Northern Manhattan Study","volume":"5","author":"Caunca","year":"2016","journal-title":"J Am Heart Assoc"},{"key":"2025020305060729900_awae274-B18","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1080\/10641963.2019.1665673","article-title":"Cerebral microbleeds are associated with blood pressure levels in individuals with hypertension","volume":"42","author":"Lyu","year":"2020","journal-title":"Clin Exp Hypertens"},{"key":"2025020305060729900_awae274-B19","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1093\/brain\/awx156","article-title":"Neuronal intranuclear (hyaline) inclusion disease and fragile X-associated tremor\/ataxia syndrome: A morphological and molecular dilemma","volume":"140","author":"Gelpi","year":"2017","journal-title":"Brain"},{"key":"2025020305060729900_awae274-B20","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1046\/j.1440-1789.2003.00524.x","article-title":"Neuronal intranuclear hyaline inclusion disease","volume":"23","author":"Takahashi-Fujigasaki","year":"2003","journal-title":"Neuropathology"},{"issue":"Pt 12","key":"2025020305060729900_awae274-B21","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1093\/brain\/aww249","article-title":"Clinicopathological features of adult-onset neuronal intranuclear inclusion disease","volume":"139","author":"Sone","year":"2016","journal-title":"Brain"},{"key":"2025020305060729900_awae274-B22","doi-asserted-by":"crossref","first-page":"6355","DOI":"10.3390\/ijms22126355","article-title":"Neurotoxic soluble amyloid oligomers drive Alzheimer\u2019s pathogenesis and represent a clinically validated target for slowing disease progression","volume":"22","author":"Tolar","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2025020305060729900_awae274-B23","doi-asserted-by":"crossref","first-page":"e2210766119","DOI":"10.1073\/pnas.2210766119","article-title":"Early diagnosis and treatment of Alzheimer\u2019s disease by targeting toxic soluble A\u03b2 oligomers","volume":"119","author":"Habashi","year":"2022","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2025020305060729900_awae274-B24","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1007\/s12035-015-9143-0","article-title":"The essential role of soluble A\u03b2 oligomers in Alzheimer\u2019s disease","volume":"53","author":"Wang","year":"2016","journal-title":"Mol Neurobiol"},{"key":"2025020305060729900_awae274-B25","doi-asserted-by":"crossref","first-page":"e2208649119","DOI":"10.1073\/pnas.2208649119","article-title":"CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model","volume":"119","author":"Yu","year":"2022","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2025020305060729900_awae274-B26","doi-asserted-by":"crossref","first-page":"e16102","DOI":"10.1111\/ene.16102","article-title":"Utility of labial salivary gland biopsy in the histological diagnosis of neuronal intranuclear inclusion disease","volume":"31","author":"Bao","year":"2024","journal-title":"Eur J Neurol"},{"key":"2025020305060729900_awae274-B27","doi-asserted-by":"crossref","first-page":"e202100658","DOI":"10.1002\/cbic.202100658","article-title":"Rippled sheets: The early polyglycine days and recent developments in nylons","volume":"23","author":"Lotz","year":"2022","journal-title":"Chembiochem"},{"key":"2025020305060729900_awae274-B28","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1021\/acs.biochem.1c00501","article-title":"Glycine-rich peptides from FUS have an intrinsic ability to self-assemble into fibers and networked fibrils","volume":"60","author":"Kar","year":"2021","journal-title":"Biochemistry"},{"key":"2025020305060729900_awae274-B29","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1021\/jp111501d","article-title":"Aggregation of capped hexaglycine strands into hydrogen-bonding motifs representative of pleated and rippled beta-sheets, collagen, and polyglycine I and II crystal structures. A density functional theory study","volume":"115","author":"Plumley","year":"2011","journal-title":"J Phys Chem B"},{"key":"2025020305060729900_awae274-B30","first-page":"100124","article-title":"Main features of hereditary cerebral amyloid angiopathies: A systematic review","volume":"3","author":"Biffi","year":"2022","journal-title":"Cereb Circ Cogn Behav"},{"key":"2025020305060729900_awae274-B31","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s00018-009-0182-4","article-title":"Cerebral amyloidosis: Amyloid subunits, mutants and phenotypes","volume":"67","author":"Rostagno","year":"2010","journal-title":"Cell Mol Life Sci"},{"key":"2025020305060729900_awae274-B32","doi-asserted-by":"crossref","first-page":"a023572","DOI":"10.1101\/cshperspect.a023572","article-title":"The three-dimensional structures of amyloids","volume":"9","author":"Riek","year":"2017","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2025020305060729900_awae274-B33","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/aps.2017.28","article-title":"Amyloid beta: Structure, biology and structure-based therapeutic development","volume":"38","author":"Chen","year":"2017","journal-title":"Acta Pharmacol Sin"},{"key":"2025020305060729900_awae274-B34","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1007\/s00330-021-08288-9","article-title":"Spatial distribution of cerebral microbleeds reveals heterogeneous pathogenesis in CADASIL","volume":"32","author":"Chen","year":"2022","journal-title":"Eur Radiol"},{"key":"2025020305060729900_awae274-B35","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1161\/STROKEAHA.120.030664","article-title":"Intracerebral hemorrhage in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: Prevalence, clinical and neuroimaging features and risk factors","volume":"52","author":"Liao","year":"2021","journal-title":"Stroke"},{"key":"2025020305060729900_awae274-B36","doi-asserted-by":"crossref","first-page":"375","DOI":"10.5414\/NP300961","article-title":"Pathological background of subcortical hyperintensities on diffusion-weighted images in a case of neuronal intranuclear inclusion disease","volume":"35","author":"Yokoi","year":"2016","journal-title":"Clin Neuropathol"},{"key":"2025020305060729900_awae274-B37","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1136\/svn-2022-001631","article-title":"NOTCH2NLC expanded GGC repeats in patients with cerebral small vessel disease","volume":"8","author":"Wang","year":"2023","journal-title":"Stroke Vasc Neurol"},{"key":"2025020305060729900_awae274-B38","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1212\/WNL.56.5.628","article-title":"MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL","volume":"56","author":"O'Sullivan","year":"2001","journal-title":"Neurology"},{"key":"2025020305060729900_awae274-B39","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3988\/jcn.2023.19.1.12","article-title":"Update on the epidemiology, pathogenesis, and biomarkers of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy","volume":"19","author":"Yamamoto","year":"2023","journal-title":"J Clin Neurol"},{"key":"2025020305060729900_awae274-B40","doi-asserted-by":"crossref","first-page":"e200057","DOI":"10.1212\/NXG.0000000000200057","article-title":"Clinical features and classification of neuronal intranuclear inclusion disease","volume":"9","author":"Tai","year":"2023","journal-title":"Neurol Genet"},{"key":"2025020305060729900_awae274-B41","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1212\/WNL.0000000000012234","article-title":"Cerebral amyloid angiopathy-related transient focal neurologic episodes","volume":"97","author":"Smith","year":"2021","journal-title":"Neurology"},{"key":"2025020305060729900_awae274-B42","doi-asserted-by":"crossref","first-page":"116496","DOI":"10.1016\/j.jns.2019.116496","article-title":"Cerebral amyloid angiopathy-related transient focal neurological episodes (CAA-TFNEs): A well-defined clinical-radiological syndrome","volume":"406","author":"Charidimou","year":"2019","journal-title":"J Neurol Sci"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awae274\/60833139\/awae274.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/148\/2\/467\/60833139\/awae274.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/148\/2\/467\/60833139\/awae274.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T05:06:24Z","timestamp":1738559184000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/148\/2\/467\/7738208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,21]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,8,21]]},"published-print":{"date-parts":[[2025,2,3]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awae274","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,2]]},"published":{"date-parts":[[2024,8,21]]}}}