A novel biomarker for Ataxia-Telangiectasia: Evaluating the lack of hypointensity of the dentate nuclei

A novel biomarker for Ataxia-Telangiectasia: Evaluating the lack of hypointensity of the dentate nuclei | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report A novel biomarker for Ataxia-Telangiectasia: Evaluating the lack of hypointensity of the dentate nuclei May Yung Tiet, Daniel J Scoffings, Caroline Blanchard, Robert A Dineen, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2842224/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Ataxia-Telangiectasia (A-T) is a very rare autosomal recessive disease characterised by cerebellar ataxia, extrapyramidal movements and cancer predisposition. Delayed diagnosis is common due to clinical heterogeneity. The development of clinical trials in A-T is limited by a lack of suitable biomarkers. Abnormal hypointensity of the dentate nuclei (DN) has been demonstrated in some genetic ataxias. We assess the degree of hypointensity of the DN in paediatric and adult A-T patients using the Gupta visual ranking score and report a novel observation of a lack of hypointensity of the DN in adults. Adult A-T patients had significantly lower visual rating scores than paediatric patients (0.07 versus 0.55 respectively). Our findings demonstrate that the normal process leading to hypointensity of the DN is initiated in children with A-T, but the physiological DN hypointensity is lost by adulthood. Ataxia-Telangiectasia Dentate nuclei MRI Figures Figure 1 Introduction Ataxia-Telangiectasia (A-T) is a very rare incurable autosomal recessive multisystemic disease. In the absence of ATM kinase function, classic A-T patients have a neurodegenerative phenotype with cerebellar ataxia, peripheral neuropathy and extrapyramidal symptoms ( 1 ). Residual ATM kinase function leads to an often later-onset milder disease, variant A-T, without immunodeficiency but with disabling neurological symptoms. Cerebellar ataxia is a universal and incapacitating symptom in classic A-T; however, in variant A-T, the neurological presentation can be heterogeneous and extrapyramidal symptoms sometimes dominate. The clinical presentation of A-T can be clinically difficult to distinguish from other neurological disorders and delayed diagnosis is common. The susceptibility to malignancies in A-T means that a timely diagnosis is vital ( 1 ) and the characterization of typical MRI features of the disease is important. Furthermore, the current lack of A-T biomarkers, including imaging biomarkers, limits the development and evaluation of novel therapies. We have previously reported microbleeds in supratentorial regions in A-T ( 2 , 3 ). Abnormal hypointensity of the DN has recently been reported in other genetic ataxias ( 4 ), including DNA repair disorder Ataxia with Oculomotor Apraxia ( 5 , 6 ). Lack of hypointensity of the DN has been previously reported in a single case report of A-T with microbleeds ( 7 ). The iron-rich DN is the largest of the deep cerebellar nuclei. Most efferents from the cerebellum synapse at the DN. Acquired pathology in the dentate nucleus is uncommon and leads to complex and non-specific symptoms which are difficult to localise ( 8 ) but recent studies demonstrate DN territories in default mode, attentional motor and visual networks ( 9 ). The development of the Gupta visual rating scale enables objective grading of the variability of DN hypointensity ( 10 ). We assess the hypointensity of the DN from our UK National A-T centres as a potential diagnostic imaging signature for A-T. Patients And Methods Our cohort of 26 A-T patients are reviewed annually or biannually at the National Paediatric or Adult A-T clinics in Nottingham and Cambridge, UK. Uncontrasted MRI brain imaging was performed as part of routine clinical care for adult patients (Health Research Authority Integrated Research Application System 204229). Paediatric patients were scanned as part of the Childhood A-T Neuroimaging Assessment Project (CATNAP; UK National Research Ethics Service references 14/EM/1175 and 18/SW/0078) ( 11 ), including age-matched healthy controls. The cohort included 16 classic A-T (age range 4.6–25.4 years, mean 16.3 years, median 17.0 years), 10 variant A-T (age range 11.3–55.7 years, mean 34.0 years, median 34.2 years) patients (Fig. 1 ) and 14 age- and sex-matched paediatric healthy controls (age range 5.5–17.6 years, mean 13.6 years, median 14.6 years). The classic A-T patients presented with a typical phenotype of early-onset cerebellar ataxia, axonal peripheral neuropathy and extrapyramidal symptoms. As previously published, our variant A-T cohort often had a milder and late-onset disease, and some patients had a predominant extrapyramidal phenotype ( 12 ). Dentate nuclei hypointensity The MRI acquisition for the CATNAP study participants was performed on a 3T unit (Discovery MR750, GE Healthcare) and included susceptibility weighted acquisition using 3D multiecho gradient SWAN sequence with parameters of TR 39.3 ms, effective TE 24.68 ms, flip angle = 15° section thickness 1 mm with 0.5 mm overlap, FOV 25.6 cm, matrix 256 × 256. Adult patients were imaged at 3T (Skyra, Siemens) with SWI parameters of TR 34 ms, TE 15 ms, flip angle 15°, section thickness 1.2 mm, FOV 23 cm, matrix 320 x 294. The Gupta visual rating score for DN hypointensity is calculated by the region of interest graded as 0, 1, 2 or 3 relative to signal intensity (SI), with grade 0 as SI similar to cerebrospinal fluid and grade 3 as severe hypointensity ( 10 ). In our cohort MRIs, evaluation of DN hypointensity using the Gupta visual rating scale was performed by two independent assessors at each study site who were blinded to the subject’s phenotype. Each site had an experienced neuroradiologist as a rater. The raters each had a minimum of 3 years of experience in reviewing MRIs in A-T patients. For discrepancies in rating, after discussions between the raters, a unified rating was decided. Where available, the presence or absence of DN hypointensity in FLAIR sequences were also assessed. White matter hyperintensities (WMH) and cerebral microbleeds (CMB) were evaluated using visual rating scales Fazekas ( 13 ) and Brain Observer MicroBleeds Scale (BOMBS) ( 14 ). Some of the adult AT cohort were previously described ( 3 ). Statistical analysis of the visual rating scores between patient groups and controls was performed using the Mann Whitney test or Spearman rank correlation using GraphPad Prism version 9.3.1. Results The mean DN visual rating score for patients was 0.55 in paediatric subjects (N = 11) and 0.64 in age- and sex-matched controls (N = 14) compared to adult A-T subjects with an average score of 0.07 (N = 15) (Fig. 2). Adult A-T patients had significantly lower visual rating scores than paediatric patients (p = 0.01). The presence or absence of DN hypointensity in SWI imaging was confirmed with FLAIR sequences (data not shown). WMH were absent in the paediatric cohort. The frequency of CMB was numerous in some patients with up to 115 total CMB in one patient (Table 1 ). There was no correlation between the degree of DN hypointensity and the extent of WMH (r = -0.30, p = 0.14) or CMBs (r = 0.23, p = 0.27). Table 1 A-T cohort included in this study, including patient demographics, A-T subtype, degree of white matter hyperintensities and dentate nuclei hypointensity evaluated using visual rating scores (Fazekas and Gupta respectively), and the number of cerebral microbleeds. Subject number Age (years) Sex (M/F) A-T subtype DN Visual rating score (Gupta) White matter hyperintensities rating score (Fazekas) Cerebral microbleeds (BOMBS criteria) 1 4.6 F Classic 0 0 0 2 6.6 F Classic 0 0 0 3 8.4 M Classic 0 0 0 4 11.1 F Variant 1 0 0 5 13.4 M Classic 0 0 3 6 13.8 M Classic 1 0 3 7 15.2 F Classic 1 0 1 8 15.2 F Classic 0 0 0 9 16.4 M Classic 1 0 4 10 17.6 F Classic 1 0 0 11 17.8 M Classic 1 0 25 12 18.5 M Variant 0 0 3 13 20.1 M Classic 0 0 0 14 20.2 F Classic 0 0 41 15 21.6 F Variant 0 0 0 16 21.8 M Classic 0 0 0 17 21.9 M Variant 0 0 0 18 22.1 F Classic 0 1 1 19 22.6 M Classic 0 0 115 20 25.4 M Classic 0 0 1 21 32.2 M Variant 0 1 0 22 36.1 F Variant 0 0 0 23 40.4 F Variant 1 0 0 24 48.4 F Variant 0 1 0 25 53.9 F Variant 0 1 0 26 55.7 F Variant 0 1 0 Key: M = male, F = female, BOMBS = Brain Observer MicroBleeds Scale Discussion We demonstrated significant differences in the degree of hypointensity of the DN in patients with adult A-T. Iron accumulation is part of normal ageing, demonstrated by increasing normalised SWI signal intensity ratio in the subcortical nuclei. This is particularly dynamic during childhood and young adulthood and acquiring hypointensity of the DN is normally expected by adulthood ( 15 ). The lack of DN hypointensity in the adult A-T cohort suggests local pathology, such as abnormal iron deposition ( 6 ). In Friedreich ataxia, DN atrophy is maximal in the early disease stage, whilst DN iron accumulation continues to progress during the disease course ( 4 ). The variable patterns of DN signal could assist in the differential diagnosis of genetic ataxias. Though a lack of DN hypointensity was previously reported in a classic A-T patient with extensive microbleeds, we have found no association between DN hypointensity and the degree of cerebral microbleeds or cerebral white matter changes in both classic and variant A-T subtypes ( 2 , 3 ). One of the limitations of our study is that we have excluded patients with marked movement disorders involving the head, neck and trunk which can lead to movement artefact and limit the interpretation of SWI imaging. MRI studies were excluded if there was incomplete imaging of the DN which is sometimes the case in clinical MRI studies. Our survey highlights the importance of the inclusion of complete cerebellar imaging, including SWI imaging to fully assess the DN in genetic ataxia patients. Conclusion Our study demonstrates that A-T patients lack DN hypointensity on MRI. DN visual rating scores of paediatric patients were higher than the adult cohort, which to our knowledge, has not been previously described. DN hypointensity is seen in normal adults due to iron deposition and normal ageing. Our observations suggest that the normal processes leading to the hypointensity of the DN are initiated in children with A-T. With progressive cerebellar degeneration in this neurodegenerative disease, DN hypointensity is lost in adulthood, which may be due to abnormal iron deposition. Future longitudinal studies into central nervous system iron deposition are required to evaluate the neurodegenerative processes in A-T and the association with clinical phenotype. Abbreviations A-T = Ataxia-Telangiectasia DN = dentate nuclei SWI = susceptibility-weighted imaging Declarations Acknowledgements We thank the patients and healthy controls for their participation in this study. Ethical Approval This study was ethically approved as part of the Genotype and Phenotype study (REC 13/YH/0310). Paediatric patients were scanned as part of the Childhood A-T Neuroimaging Assessment Project (CATNAP; UK National Research Ethics Service references 14/EM/1175 and 18/SW/0078). Competing Interests The authors have no competing interests. Authors’ Contributions M.Y.T was a rater for dentate nuclei hypointensity, drafted the manuscript, prepared table and figure and study design. D.J.S was a rater for dentate nuclei hypointensity, edited the manuscript, prepared figure and study design C.B was a rater for dentate nuclei hypointensity, prepared figure R.A.D was a rater for dentate nuclei hypointensity, edited the manuscript, prepared figure and study design R.H edited the manuscript, study concept and design, data interpretation A.E.H edited the manuscript, study design, data interpretation, clinical diagnosis of study participants All authors reviewed the manuscript Funding M.Y. Tiet is funded by Addenbrooke’s Charitable Trust G104114 and jointly by Action for AT, BrAshAT and AT society (grant TREAT-AT). The funders have no role in the study design, data collection and decision to submit this manuscript. R.Horvath. is a Wellcome Trust Investigator (109915/Z/15/Z), who received support from the Medical Research Council (UK) (MR/N025431/1 and MR/V009346/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation, Action for AT and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. RH is part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N°825575. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The CATNAP study was funded by research grants awarded jointly by A-T Children’s Project and Action for A-T [grant ref: ‘The CATNAP Study’], and jointly by Action for A-T and BraShA-T [grant ref: 17NOT03]. The funders had no role in the study design; the collection, analysis and interpretation of data; the writing of the report; and the decision to submit the article for publication. Availability of Data and Materials Interested persons can contact the corresponding author, Dr Anke Hensiek, regarding the study data and materials References Tiet MY, Horvath R, Hensiek AE. Ataxia telangiectasia: What the neurologist needs to know. Pract Neurol. 2020;20(5):404–14. Dineen RA, Blanchard C, Pszczolkowski S, Paine S, Prasad M, Chow G, et al. Accumulation of Brain Hypointense Foci on Susceptibility- Weighted Imaging in Childhood Ataxia Telangiectasia. AJNR Am J Neuroradiol. 2021;42(6):1144–50. Tiet MY, Nannoni S, Scoffings D, Schon K, Horvath R, Markus HS, et al. White Matter Hyperintensities and Cerebral Microbleeds in Ataxia-Telangiectasia. Neurol Genet. 2021;7(6). Ward PGD, Harding IH, Close TG, Corben LA, Delatycki MB, Storey E, et al. Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in friedreich ataxia. Mov Disord. 2019;34(3):335–43. Frismand S, Salem H, Panouilleres M, Pélisson D, Jacobs S, Vighetto A, et al. MRI findings in AOA2: Cerebellar atrophy and abnormal iron detection in dentate nucleus. NeuroImage Clin [Internet]. 2013;2(1):542–8. Available from: http://dx.doi.org/10.1016/j.nicl.2013.03.018 Ronsin S, Hannoun S, Thobois S, Petiot P, Vighetto A, Cotton F, et al. A new MRI marker of ataxia with oculomotor apraxia. Eur J Radiol [Internet]. 2019;110(October 2018):187–92. Available from: https://doi.org/10.1016/j.ejrad.2018.11.035 Liu HS, Chen YC, Chen CY. Cerebral microbleeds and iron depletion of dentate nuclei in ataxia-telangiectasia. Neurology. 2016;87(10):1062–3. Bond KM, Brinjikji W, Eckel LJ, Kallmes DF, McDonald RJ, Carr CM. Dentate update: Imaging features of entities that affect the dentate nucleus. Am J Neuroradiol. 2017;38(8):1467–74. Guell X, D’Mello AM, Hubbard NA, Romeo RR, Gabrieli JDE, Whitfield-Gabrieli S, et al. Functional Territories of Human Dentate Nucleus. Cereb Cortex. 2020;30(4):2401–17. Gupta D, Saini J, Kesavadas C, Sarma PS, Kishore A. Utility of susceptibility-weighted MRI in differentiating Parkinson’s disease and atypical parkinsonism. Neuroradiology. 2010;52(12):1087–94. Dineen RA, Raschke F, McGlashan HL, Pszczolkowski S, Hack L, Cooper AD, et al. Multiparametric cerebellar imaging and clinical phenotype in childhood ataxia telangiectasia. NeuroImage Clin [Internet]. 2020;25(August 2019):102110. Available from: https://doi.org/10.1016/j.nicl.2019.102110 Schon K, van Os NJH, Oscroft N, Baxendale H, Scoffings D, Ray J, et al. Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. Ann Neurol. 2019;85(2):170–80. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. Am J Neuroradiol. 1987;8(3):421–6. Cordonnier C, Potter GM, Jackson CA, Doubal F, Keir S, Sudlow CLM, et al. Improving interrater agreement about brain microbleeds: Development of the Brain Observer MicroBleed Scale (BOMBS). Stroke. 2009;40(1):94–9. Van Der Weijden MCM, Van Laar PJ, Lambrechts RA, Verbeek DS, Tijssen MAJ. Cortical pencil lining on SWI MRI in NBIA and healthy aging. BMC Neurol. 2019;19(1):1–8. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2842224","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":194453594,"identity":"6c18a752-b5f9-4cc1-82a3-6c370bf103cf","order_by":0,"name":"May Yung Tiet","email":"","orcid":"","institution":"University of Cambridge","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"May","middleName":"Yung","lastName":"Tiet","suffix":""},{"id":194453597,"identity":"5b584f9d-32e0-428d-9982-8e243467a282","order_by":1,"name":"Daniel J Scoffings","email":"","orcid":"","institution":"Addenbrooke's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"J","lastName":"Scoffings","suffix":""},{"id":194453598,"identity":"8e17f0b2-39a8-4a76-a2d2-88f776f34707","order_by":2,"name":"Caroline Blanchard","email":"","orcid":"","institution":"University of Nottingham","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"","lastName":"Blanchard","suffix":""},{"id":194453599,"identity":"e0652d6b-e8a5-4942-812b-7442e4edf809","order_by":3,"name":"Robert A Dineen","email":"","orcid":"","institution":"University of Nottingham","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Robert","middleName":"A","lastName":"Dineen","suffix":""},{"id":194453601,"identity":"247e37de-29f9-4335-b51d-5c56d56c054b","order_by":4,"name":"Rita Horvath","email":"","orcid":"","institution":"University of Cambridge","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rita","middleName":"","lastName":"Horvath","suffix":""},{"id":194453602,"identity":"cbc31fea-63ac-40a9-884c-b70156534451","order_by":5,"name":"Anke E Hensiek","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYDACCRBhwGDAz8BDqhbJBh4EnwgtQE0GB4jVwj+7+djDHwU2xsa3ew9/YNxhU0fYkjvH0o15DNLMzO6cS5NgPJNGhMNu5JhJMxgctjEDMhgY2w4T1iJ/I/+b5A+D/zbGM3KMPzC2/SesxeBGDpsEj8EBMwOJHAMJxrYDhLUY3kgzk+YxSDaWADpMIrEtWbKBkBa5G8nPJH/8sTPsBznsY5sdP0FbUEECiepHwSgYBaNgFOAAAPRTNt8LnGciAAAAAElFTkSuQmCC","orcid":"","institution":"Addenbrooke's Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Anke","middleName":"E","lastName":"Hensiek","suffix":""}],"badges":[],"createdAt":"2023-04-20 16:29:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2842224/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2842224/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":36344443,"identity":"c22a2fd6-37e0-4505-9252-e2fad8c5a66a","added_by":"auto","created_at":"2023-04-26 19:55:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":609214,"visible":true,"origin":"","legend":"\u003cp\u003eHypointensity of the dentate nuclei (arrows) according to increasing Gupta visual rating score in subjects with A-T (A-E) and controls (F-G). Grade 0 = hypointensity similar to cerebrospinal fluid and grade 3 as severe hypointensity (not observed in our cohort). (A-C) score 0, (D-E) score 1, (F-G) score 2. Ages (A) 4 years, (B) 15 years, (C) 25 years, (D) 11 years, (E) 16 years, (F) 17 years, (G) 15 years.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2842224/v1/46e8e7d4ef51a4a640f8bd6e.png"},{"id":41328038,"identity":"6e591505-3da4-42cc-a7fc-189a5d6ce19b","added_by":"auto","created_at":"2023-08-09 19:22:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":809797,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2842224/v1/d9b458f1-67ff-4d58-9f1b-ea8fcea1f376.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A novel biomarker for Ataxia-Telangiectasia: Evaluating the lack of hypointensity of the dentate nuclei","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAtaxia-Telangiectasia (A-T) is a very rare incurable autosomal recessive multisystemic disease. In the absence of ATM kinase function, classic A-T patients have a neurodegenerative phenotype with cerebellar ataxia, peripheral neuropathy and extrapyramidal symptoms (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Residual ATM kinase function leads to an often later-onset milder disease, variant A-T, without immunodeficiency but with disabling neurological symptoms. Cerebellar ataxia is a universal and incapacitating symptom in classic A-T; however, in variant A-T, the neurological presentation can be heterogeneous and extrapyramidal symptoms sometimes dominate. The clinical presentation of A-T can be clinically difficult to distinguish from other neurological disorders and delayed diagnosis is common. The susceptibility to malignancies in A-T means that a timely diagnosis is vital (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) and the characterization of typical MRI features of the disease is important. Furthermore, the current lack of A-T biomarkers, including imaging biomarkers, limits the development and evaluation of novel therapies.\u003c/p\u003e \u003cp\u003eWe have previously reported microbleeds in supratentorial regions in A-T (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Abnormal hypointensity of the DN has recently been reported in other genetic ataxias (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), including DNA repair disorder Ataxia with Oculomotor Apraxia (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Lack of hypointensity of the DN has been previously reported in a single case report of A-T with microbleeds (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The iron-rich DN is the largest of the deep cerebellar nuclei. Most efferents from the cerebellum synapse at the DN. Acquired pathology in the dentate nucleus is uncommon and leads to complex and non-specific symptoms which are difficult to localise (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) but recent studies demonstrate DN territories in default mode, attentional motor and visual networks (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The development of the Gupta visual rating scale enables objective grading of the variability of DN hypointensity (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). We assess the hypointensity of the DN from our UK National A-T centres as a potential diagnostic imaging signature for A-T.\u003c/p\u003e"},{"header":"Patients And Methods","content":"\u003cp\u003eOur cohort of 26 A-T patients are reviewed annually or biannually at the National Paediatric or Adult A-T clinics in Nottingham and Cambridge, UK. Uncontrasted MRI brain imaging was performed as part of routine clinical care for adult patients (Health Research Authority Integrated Research Application System 204229). Paediatric patients were scanned as part of the Childhood A-T Neuroimaging Assessment Project (CATNAP; UK National Research Ethics Service references 14/EM/1175 and 18/SW/0078) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), including age-matched healthy controls. The cohort included 16 classic A-T (age range 4.6\u0026ndash;25.4 years, mean 16.3 years, median 17.0 years), 10 variant A-T (age range 11.3\u0026ndash;55.7 years, mean 34.0 years, median 34.2 years) patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and 14 age- and sex-matched paediatric healthy controls (age range 5.5\u0026ndash;17.6 years, mean 13.6 years, median 14.6 years).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe classic A-T patients presented with a typical phenotype of early-onset cerebellar ataxia, axonal peripheral neuropathy and extrapyramidal symptoms. As previously published, our variant A-T cohort often had a milder and late-onset disease, and some patients had a predominant extrapyramidal phenotype (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDentate nuclei hypointensity\u003c/h2\u003e \u003cp\u003eThe MRI acquisition for the CATNAP study participants was performed on a 3T unit (Discovery MR750, GE Healthcare) and included susceptibility weighted acquisition using 3D multiecho gradient SWAN sequence with parameters of TR 39.3 ms, effective TE 24.68 ms, flip angle\u0026thinsp;=\u0026thinsp;15\u0026deg; section thickness 1 mm with 0.5 mm overlap, FOV 25.6 cm, matrix 256 \u0026times; 256. Adult patients were imaged at 3T (Skyra, Siemens) with SWI parameters of TR 34 ms, TE 15 ms, flip angle 15\u0026deg;, section thickness 1.2 mm, FOV 23 cm, matrix 320 x 294.\u003c/p\u003e \u003cp\u003eThe Gupta visual rating score for DN hypointensity is calculated by the region of interest graded as 0, 1, 2 or 3 relative to signal intensity (SI), with grade 0 as SI similar to cerebrospinal fluid and grade 3 as severe hypointensity (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In our cohort MRIs, evaluation of DN hypointensity using the Gupta visual rating scale was performed by two independent assessors at each study site who were blinded to the subject\u0026rsquo;s phenotype. Each site had an experienced neuroradiologist as a rater. The raters each had a minimum of 3 years of experience in reviewing MRIs in A-T patients. For discrepancies in rating, after discussions between the raters, a unified rating was decided. Where available, the presence or absence of DN hypointensity in FLAIR sequences were also assessed. White matter hyperintensities (WMH) and cerebral microbleeds (CMB) were evaluated using visual rating scales Fazekas (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) and Brain Observer MicroBleeds Scale (BOMBS) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Some of the adult AT cohort were previously described (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eStatistical analysis of the visual rating scores between patient groups and controls was performed using the Mann Whitney test or Spearman rank correlation using GraphPad Prism version 9.3.1.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe mean DN visual rating score for patients was 0.55 in paediatric subjects (N\u0026thinsp;=\u0026thinsp;11) and 0.64 in age- and sex-matched controls (N\u0026thinsp;=\u0026thinsp;14) compared to adult A-T subjects with an average score of 0.07 (N\u0026thinsp;=\u0026thinsp;15) (Fig.\u0026nbsp;2). Adult A-T patients had significantly lower visual rating scores than paediatric patients (p\u0026thinsp;=\u0026thinsp;0.01). The presence or absence of DN hypointensity in SWI imaging was confirmed with FLAIR sequences (data not shown).\u003c/p\u003e \u003cp\u003eWMH were absent in the paediatric cohort. The frequency of CMB was numerous in some patients with up to 115 total CMB in one patient (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There was no correlation between the degree of DN hypointensity and the extent of WMH (r = -0.30, p\u0026thinsp;=\u0026thinsp;0.14) or CMBs (r\u0026thinsp;=\u0026thinsp;0.23, p\u0026thinsp;=\u0026thinsp;0.27).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eA-T cohort included in this study, including patient demographics, A-T subtype, degree of white matter hyperintensities and dentate nuclei hypointensity evaluated using visual rating scores (Fazekas and Gupta respectively), and the number of cerebral microbleeds.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubject number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex (M/F)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA-T subtype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDN Visual rating score (Gupta)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eWhite matter hyperintensities rating score\u003c/p\u003e \u003cp\u003e(Fazekas)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCerebral microbleeds (BOMBS criteria)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e115\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eKey: M\u0026thinsp;=\u0026thinsp;male, F\u0026thinsp;=\u0026thinsp;female, BOMBS\u0026thinsp;=\u0026thinsp;Brain Observer MicroBleeds Scale\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe demonstrated significant differences in the degree of hypointensity of the DN in patients with adult A-T. Iron accumulation is part of normal ageing, demonstrated by increasing normalised SWI signal intensity ratio in the subcortical nuclei. This is particularly dynamic during childhood and young adulthood and acquiring hypointensity of the DN is normally expected by adulthood (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The lack of DN hypointensity in the adult A-T cohort suggests local pathology, such as abnormal iron deposition (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In Friedreich ataxia, DN atrophy is maximal in the early disease stage, whilst DN iron accumulation continues to progress during the disease course (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The variable patterns of DN signal could assist in the differential diagnosis of genetic ataxias. Though a lack of DN hypointensity was previously reported in a classic A-T patient with extensive microbleeds, we have found no association between DN hypointensity and the degree of cerebral microbleeds or cerebral white matter changes in both classic and variant A-T subtypes (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne of the limitations of our study is that we have excluded patients with marked movement disorders involving the head, neck and trunk which can lead to movement artefact and limit the interpretation of SWI imaging. MRI studies were excluded if there was incomplete imaging of the DN which is sometimes the case in clinical MRI studies. Our survey highlights the importance of the inclusion of complete cerebellar imaging, including SWI imaging to fully assess the DN in genetic ataxia patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study demonstrates that A-T patients lack DN hypointensity on MRI. DN visual rating scores of paediatric patients were higher than the adult cohort, which to our knowledge, has not been previously described. DN hypointensity is seen in normal adults due to iron deposition and normal ageing. Our observations suggest that the normal processes leading to the hypointensity of the DN are initiated in children with A-T. With progressive cerebellar degeneration in this neurodegenerative disease, DN hypointensity is lost in adulthood, which may be due to abnormal iron deposition. Future longitudinal studies into central nervous system iron deposition are required to evaluate the neurodegenerative processes in A-T and the association with clinical phenotype.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eA-T = Ataxia-Telangiectasia\u003c/p\u003e\n\u003cp\u003eDN = dentate nuclei\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSWI = susceptibility-weighted imaging\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patients and healthy controls for their participation in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was ethically approved as part of the Genotype and Phenotype study (REC 13/YH/0310). Paediatric patients were scanned as part of the Childhood A-T Neuroimaging Assessment Project (CATNAP; UK National Research Ethics Service references 14/EM/1175 and 18/SW/0078).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM.Y.T was a rater for dentate nuclei hypointensity, drafted the manuscript, prepared table and figure and study design.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eD.J.S was a rater for dentate nuclei hypointensity, edited the manuscript, prepared figure and study design\u003c/p\u003e\n\u003cp\u003eC.B was a rater for dentate nuclei hypointensity, prepared figure\u003c/p\u003e\n\u003cp\u003eR.A.D was a rater for dentate nuclei hypointensity, edited the manuscript, prepared figure and study design\u003c/p\u003e\n\u003cp\u003eR.H edited the manuscript, study concept and design, data interpretation\u003c/p\u003e\n\u003cp\u003eA.E.H edited the manuscript, study design, data interpretation, clinical diagnosis of study participants\u003c/p\u003e\n\u003cp\u003eAll authors reviewed the manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM.Y. Tiet is funded by Addenbrooke\u0026rsquo;s Charitable Trust G104114 and jointly by Action for AT, BrAshAT and AT society (grant TREAT-AT). The funders have no role in the study design, data collection and decision to submit this manuscript.\u003c/p\u003e\n\u003cp\u003eR.Horvath. is a Wellcome Trust Investigator (109915/Z/15/Z), who received support from the Medical Research Council (UK) (MR/N025431/1 and MR/V009346/1), the Addenbrookes Charitable Trust \u0026nbsp;(G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation, Action for AT and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. RH is part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N\u0026deg;825575. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). \u0026nbsp; The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.\u003c/p\u003e\n\u003cp\u003eThe CATNAP study was funded by research grants awarded jointly by A-T Children\u0026rsquo;s Project and Action for A-T [grant ref: \u0026lsquo;The CATNAP Study\u0026rsquo;], and jointly by Action for A-T and BraShA-T [grant ref: 17NOT03]. The funders had no role in the study design; the collection, analysis and interpretation of data; the writing of the report; and the decision to submit the article for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInterested persons can contact the corresponding author, Dr Anke Hensiek, regarding the study data and materials\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTiet MY, Horvath R, Hensiek AE. Ataxia telangiectasia: What the neurologist needs to know. Pract Neurol. 2020;20(5):404\u0026ndash;14. \u003c/li\u003e\n\u003cli\u003eDineen RA, Blanchard C, Pszczolkowski S, Paine S, Prasad M, Chow G, et al. Accumulation of Brain Hypointense Foci on Susceptibility- Weighted Imaging in Childhood Ataxia Telangiectasia. AJNR Am J Neuroradiol. 2021;42(6):1144\u0026ndash;50. \u003c/li\u003e\n\u003cli\u003eTiet MY, Nannoni S, Scoffings D, Schon K, Horvath R, Markus HS, et al. White Matter Hyperintensities and Cerebral Microbleeds in Ataxia-Telangiectasia. Neurol Genet. 2021;7(6). \u003c/li\u003e\n\u003cli\u003eWard PGD, Harding IH, Close TG, Corben LA, Delatycki MB, Storey E, et al. Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in friedreich ataxia. Mov Disord. 2019;34(3):335\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003eFrismand S, Salem H, Panouilleres M, P\u0026eacute;lisson D, Jacobs S, Vighetto A, et al. MRI findings in AOA2: Cerebellar atrophy and abnormal iron detection in dentate nucleus. NeuroImage Clin [Internet]. 2013;2(1):542\u0026ndash;8. Available from: http://dx.doi.org/10.1016/j.nicl.2013.03.018\u003c/li\u003e\n\u003cli\u003eRonsin S, Hannoun S, Thobois S, Petiot P, Vighetto A, Cotton F, et al. A new MRI marker of ataxia with oculomotor apraxia. Eur J Radiol [Internet]. 2019;110(October 2018):187\u0026ndash;92. Available from: https://doi.org/10.1016/j.ejrad.2018.11.035\u003c/li\u003e\n\u003cli\u003eLiu HS, Chen YC, Chen CY. Cerebral microbleeds and iron depletion of dentate nuclei in ataxia-telangiectasia. Neurology. 2016;87(10):1062\u0026ndash;3. \u003c/li\u003e\n\u003cli\u003eBond KM, Brinjikji W, Eckel LJ, Kallmes DF, McDonald RJ, Carr CM. Dentate update: Imaging features of entities that affect the dentate nucleus. Am J Neuroradiol. 2017;38(8):1467\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eGuell X, D\u0026rsquo;Mello AM, Hubbard NA, Romeo RR, Gabrieli JDE, Whitfield-Gabrieli S, et al. Functional Territories of Human Dentate Nucleus. Cereb Cortex. 2020;30(4):2401\u0026ndash;17. \u003c/li\u003e\n\u003cli\u003eGupta D, Saini J, Kesavadas C, Sarma PS, Kishore A. Utility of susceptibility-weighted MRI in differentiating Parkinson\u0026rsquo;s disease and atypical parkinsonism. Neuroradiology. 2010;52(12):1087\u0026ndash;94. \u003c/li\u003e\n\u003cli\u003eDineen RA, Raschke F, McGlashan HL, Pszczolkowski S, Hack L, Cooper AD, et al. Multiparametric cerebellar imaging and clinical phenotype in childhood ataxia telangiectasia. NeuroImage Clin [Internet]. 2020;25(August 2019):102110. Available from: https://doi.org/10.1016/j.nicl.2019.102110\u003c/li\u003e\n\u003cli\u003eSchon K, van Os NJH, Oscroft N, Baxendale H, Scoffings D, Ray J, et al. Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. Ann Neurol. 2019;85(2):170\u0026ndash;80. \u003c/li\u003e\n\u003cli\u003eFazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer\u0026rsquo;s dementia and normal aging. Am J Neuroradiol. 1987;8(3):421\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eCordonnier C, Potter GM, Jackson CA, Doubal F, Keir S, Sudlow CLM, et al. 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BMC Neurol. 2019;19(1):1\u0026ndash;8. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ataxia-Telangiectasia, Dentate nuclei, MRI ","lastPublishedDoi":"10.21203/rs.3.rs-2842224/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2842224/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAtaxia-Telangiectasia (A-T) is a very rare autosomal recessive disease characterised by cerebellar ataxia, extrapyramidal movements and cancer predisposition. Delayed diagnosis is common due to clinical heterogeneity. The development of clinical trials in A-T is limited by a lack of suitable biomarkers. Abnormal hypointensity of the dentate nuclei (DN) has been demonstrated in some genetic ataxias. We assess the degree of hypointensity of the DN in paediatric and adult A-T patients using the Gupta visual ranking score and report a novel observation of a lack of hypointensity of the DN in adults. Adult A-T patients had significantly lower visual rating scores than paediatric patients (0.07 versus 0.55 respectively). Our findings demonstrate that the normal process leading to hypointensity of the DN is initiated in children with A-T, but the physiological DN hypointensity is lost by adulthood.\u003c/p\u003e","manuscriptTitle":"A novel biomarker for Ataxia-Telangiectasia: Evaluating the lack of hypointensity of the dentate nuclei","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-04-26 19:55:05","doi":"10.21203/rs.3.rs-2842224/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a64c7481-ed7e-49ac-a8d6-c6115f0fb6c8","owner":[],"postedDate":"April 26th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-08-09T19:14:11+00:00","versionOfRecord":[],"versionCreatedAt":"2023-04-26 19:55:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2842224","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2842224","identity":"rs-2842224","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}