{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T16:10:23Z","timestamp":1741623023647,"version":"3.38.0"},"reference-count":28,"publisher":"SAGE Publications","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JHD"],"published-print":{"date-parts":[[2023,12,15]]},"abstract":"<jats:p>Background: Over one third of age of onset variation in Huntington\u2019s disease is unexplained by CAG repeat length. In Alzheimer\u2019s disease, frailty partly modulates the relationship between neuropathology and dementia. Objective: We investigated whether a multi-domain frailty index, reflecting non-genetic factors in Huntington\u2019s disease, similarly modulates the relationship between CAG repeat length and age of onset. Methods: We created a frailty index assessing comorbidities, substance abuse, polypharmacy, and education. We applied multiple linear regression models to 2,741 subjects with manifest Huntington\u2019s disease from the Enroll-HD cohort study, including 729 subjects with late-onset (post-60 years) disease, using frailty index or constituent item scores and CAG repeat length as independent variables. We used actual and \u201cresidual\u201d ages of onset (difference between actual and CAG-based predicted onset) as dependent variables, the latter offsetting the increased time available to accumulate comorbidities in older subjects. Results: Higher frailty index scores were associated with significantly lower residual ages of onset in the late-onset subgroup (p\u200a=\u200a0.03), though the effect was small (R2\u200a=\u200a0.27 with frailty as a predictor vs. 0.26 without). Number of comorbidities was also associated with significantly lower residual ages of onset in the late-onset subgroup (p\u200a=\u200a0.04). Drug abuse and smoking were associated with significantly earlier ages of onset in the whole cohort (p\u200a&lt;\u200a0.01, p\u200a=\u200a0.02) and late-onset subgroup (p\u200a&lt;\u200a0.01, p\u200a=\u200a0.03). Conclusions: The impact of non-genetic factors on age of onset, assessed using a frailty index or separately, in Huntington\u2019s disease is limited.<\/jats:p>","DOI":"10.3233\/jhd-230572","type":"journal-article","created":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T17:42:00Z","timestamp":1700847720000},"page":"355-361","source":"Crossref","is-referenced-by-count":0,"title":["Frailty and Associated Environmental Factors Only Have Small Effects on Age of Onset in Huntington\u2019s Disease"],"prefix":"10.1177","volume":"12","author":[{"given":"Niroshan","family":"Jeyakumar","sequence":"first","affiliation":[{"name":"School of Medicine, The University of Sydney, Sydney, Australia"}]},{"given":"Sarah N.","family":"Hilmer","sequence":"additional","affiliation":[{"name":"The Kolling Institute, The University of Sydney, Sydney, Australia"}]},{"given":"Armando","family":"Teixeira-Pinto","sequence":"additional","affiliation":[{"name":"School of Public Health, The University of Sydney, Sydney, Australia"}]},{"given":"Clement T.","family":"Loy","sequence":"additional","affiliation":[{"name":"Macquarie Medical School, Macquarie University, Sydney, Australia"}]}],"member":"179","reference":[{"key":"10.3233\/JHD-230572_ref1","doi-asserted-by":"crossref","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","article-title":"Huntington disease","volume":"1","author":"Bates","year":"2015","journal-title":"Nat Rev Dis Primers"},{"issue":"11","key":"10.3233\/JHD-230572_ref2","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1002\/mds.26011","article-title":"Diagnostic criteria for Huntington\u2019s disease based on natural history","volume":"29","author":"Reilmann","year":"2014","journal-title":"Mov Disord"},{"issue":"6","key":"10.3233\/JHD-230572_ref3","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes","volume":"72","author":"MacDonald","year":"1993","journal-title":"Cell"},{"issue":"4","key":"10.3233\/JHD-230572_ref4","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/ng0893-387","article-title":"Trinucleotide repeat length instability and age of onset in Huntington\u2019s disease","volume":"4","author":"Bonilla","year":"1993","journal-title":"Nat Genet"},{"issue":"10","key":"10.3233\/JHD-230572_ref5","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/hmg\/2.10.1547","article-title":"Correlation between the onset age of Huntington\u2019s disease and length of the trinucleotide repeat in IT-15","volume":"2","author":"Stine","year":"1993","journal-title":"Hum Mol Genet"},{"issue":"11","key":"10.3233\/JHD-230572_ref6","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1002\/mds.26001","article-title":"Genetic modifiers of Huntington\u2019s disease","volume":"29","author":"Gusella","year":"2014","journal-title":"Mov Disord"},{"issue":"12","key":"10.3233\/JHD-230572_ref7","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1136\/jmg.30.12.991","article-title":"Molecular analysis of late onset Huntington\u2019s disease","volume":"30","author":"Kremer","year":"1993","journal-title":"J Med Genet"},{"issue":"2","key":"10.3233\/JHD-230572_ref8","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S1474-4422(18)30371-5","article-title":"Investigation of frailty as a moderator of the relationship between neuropathology and dementia in Alzheimer\u2019s disease: A cross-sectional analysis of data from the Rush Memory and Aging Project","volume":"18","author":"Wallace","year":"2019","journal-title":"Lancet Neurol"},{"issue":"10","key":"10.3233\/JHD-230572_ref9","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1017\/S1041610220003932","article-title":"Frailty and neuropathology in relation to dementia status: The Cambridge City over-75s Cohort study","volume":"33","author":"Wallace","year":"2021","journal-title":"Int Psychogeriatr"},{"issue":"9868","key":"10.3233\/JHD-230572_ref10","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/S0140-6736(12)62167-9","article-title":"Frailty in elderly people","volume":"381","author":"Clegg","year":"2013","journal-title":"Lancet"},{"key":"10.3233\/JHD-230572_ref11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1471-2318-8-24","article-title":"A standard procedure for creating a frailty index","volume":"8","author":"Searle","year":"2008","journal-title":"BMC Geriatr"},{"key":"10.3233\/JHD-230572_ref12","unstructured":"CHDI Foundation. 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CAG repeat not polyglutamine length determines timing of Huntington\u2019s disease onset","volume":"178","author":"Genetic Modifiers of Huntington\u2019s Disease Consortium","year":"2019","journal-title":"Cell"},{"issue":"6","key":"10.3233\/JHD-230572_ref26","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.ajhg.2019.04.007","article-title":"Length of uninterrupted CAG, independent of polyglutamine size, results in increased somatic instability, hastening onset of Huntington disease","volume":"104","author":"Wright","year":"2019","journal-title":"Am J Hum Genet"},{"key":"10.3233\/JHD-230572_ref27","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.parkreldis.2021.01.010","article-title":"Estimating the causal effects of modifiable, non-genetic factors on Huntington disease progression using propensity score weighting","volume":"83","author":"Griffin","year":"2021","journal-title":"Parkinsonism Relat Disord"},{"issue":"8","key":"10.3233\/JHD-230572_ref28","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1136\/jnnp.2007.128728","article-title":"Detection of Huntington\u2019s disease decades before diagnosis: The Predict-HD study","volume":"79","author":"Paulsen","year":"2008","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"10.3233\/JHD-230572_ref29","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3389\/fnagi.2013.00012","article-title":"Refining the diagnosis of Huntington disease: The PREDICT-HD study","volume":"5","author":"Biglan","year":"2013","journal-title":"Front Aging Neurosci"}],"container-title":["Journal of Huntington's Disease"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JHD-230572","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T15:23:59Z","timestamp":1741620239000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JHD-230572"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,15]]},"references-count":28,"journal-issue":{"issue":"4"},"URL":"https:\/\/doi.org\/10.3233\/jhd-230572","relation":{},"ISSN":["1879-6397","1879-6400"],"issn-type":[{"type":"print","value":"1879-6397"},{"type":"electronic","value":"1879-6400"}],"subject":[],"published":{"date-parts":[[2023,12,15]]}}}