Journal article
Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis
Nature medicine, Vol.31(3), pp.807-818
03/2025
DOI: 10.1038/s41591-024-03424-6
PMCID: PMC11922752
PMID: 39825149
Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with the age at which characteristic symptoms manifest strongly influenced by inherited HTT CAG length. Somatic CAG expansion occurs throughout life and understanding the impact of somatic expansion on neurodegeneration is key to developing therapeutic targets. In 57 HD gene expanded (HDGE) individuals, ~23 years before their predicted clinical motor diagnosis, no significant decline in clinical, cognitive or neuropsychiatric function was observed over 4.5 years compared with 46 controls (false discovery rate (FDR) > 0.3). However, cerebrospinal fluid (CSF) markers showed very early signs of neurodegeneration in HDGE with elevated neurofilament light (NfL) protein, an indicator of neuroaxonal damage (FDR = 3.2 × 10-12), and reduced proenkephalin (PENK), a surrogate marker for the state of striatal medium spiny neurons (FDR = 2.6 × 10-3), accompanied by brain atrophy, predominantly in the caudate (FDR = 5.5 × 10-10) and putamen (FDR = 1.2 × 10-9). Longitudinal increase in somatic CAG repeat expansion ratio (SER) in blood was a significant predictor of subsequent caudate (FDR = 0.072) and putamen (FDR = 0.148) atrophy. Atypical loss of interruption HTT repeat structures, known to predict earlier age at clinical motor diagnosis, was associated with substantially faster caudate and putamen atrophy. We provide evidence in living humans that the influence of CAG length on HD neuropathology is mediated by somatic CAG repeat expansion. These critical mechanistic insights into the earliest neurodegenerative changes will inform the design of preventative clinical trials aimed at modulating somatic expansion. ClinicalTrials.gov registration: NCT06391619 .Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with the age at which characteristic symptoms manifest strongly influenced by inherited HTT CAG length. Somatic CAG expansion occurs throughout life and understanding the impact of somatic expansion on neurodegeneration is key to developing therapeutic targets. In 57 HD gene expanded (HDGE) individuals, ~23 years before their predicted clinical motor diagnosis, no significant decline in clinical, cognitive or neuropsychiatric function was observed over 4.5 years compared with 46 controls (false discovery rate (FDR) > 0.3). However, cerebrospinal fluid (CSF) markers showed very early signs of neurodegeneration in HDGE with elevated neurofilament light (NfL) protein, an indicator of neuroaxonal damage (FDR = 3.2 × 10-12), and reduced proenkephalin (PENK), a surrogate marker for the state of striatal medium spiny neurons (FDR = 2.6 × 10-3), accompanied by brain atrophy, predominantly in the caudate (FDR = 5.5 × 10-10) and putamen (FDR = 1.2 × 10-9). Longitudinal increase in somatic CAG repeat expansion ratio (SER) in blood was a significant predictor of subsequent caudate (FDR = 0.072) and putamen (FDR = 0.148) atrophy. Atypical loss of interruption HTT repeat structures, known to predict earlier age at clinical motor diagnosis, was associated with substantially faster caudate and putamen atrophy. We provide evidence in living humans that the influence of CAG length on HD neuropathology is mediated by somatic CAG repeat expansion. These critical mechanistic insights into the earliest neurodegenerative changes will inform the design of preventative clinical trials aimed at modulating somatic expansion. ClinicalTrials.gov registration: NCT06391619 .
Details
- Title: Subtitle
- Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis
- Creators
- Rachael I Scahill - University College LondonMena Farag - University College LondonMichael J Murphy - University College LondonNicola Z Hobbs - University College LondonMichela Leocadi - University College LondonChristelle Langley - University of CambridgeHarry Knights - University College LondonMarc Ciosi - University of GlasgowKate Fayer - University College LondonMitsuko Nakajima - University College LondonOlivia Thackeray - University College LondonJohan Gobom - University of GothenburgJohn Rönnholm - University of GothenburgSophia Weiner - University of GothenburgYara R Hassan - University College LondonNehaa K P Ponraj - University of GlasgowCarlos Estevez-Fraga - University College LondonChristopher S Parker - University College LondonIan B Malone - University College LondonHarpreet Hyare - University College LondonJeffrey D Long - University of Iowa, PsychiatryAmanda Heslegrave - UK Dementia Research InstituteCristina Sampaio - CHDI FoundationHui Zhang - University College LondonTrevor W Robbins - University of CambridgeHenrik Zetterberg - University of GothenburgEdward J Wild - University College LondonGeraint Rees - University College LondonJames B Rowe - MRC Cognition and Brain Sciences UnitBarbara J Sahakian - University of CambridgeDarren G Monckton - University of GlasgowDouglas R Langbehn - University of IowaSarah J Tabrizi - University College London
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.31(3), pp.807-818
- DOI
- 10.1038/s41591-024-03424-6
- PMID
- 39825149
- PMCID
- PMC11922752
- NLM abbreviation
- Nat Med
- ISSN
- 1546-170X
- eISSN
- 1546-170X
- Publisher
- NATURE PORTFOLIO; BERLIN
- Grant note
- SciLifeLabBioMSWellcome Collaborative Award: 223082/Z/21/Z CHDI FoundationUK Dementia Research Institute (DRI; London, UK) through UK DRI - UK Medical Research CouncilUniversity College London Hospital/University College London (London, UK) - National Institute for Health and Care Research (NIHR) University College London Hospitals Biomedical Research CentreWellcome Trust: 220258 Medical Research Council: MC_UU_00030/14, MR/T033371/1 NIHR Cambridge Biomedical Research Centre: NIHR203312
We are grateful to all the study participants and their families who have so generously given their time to the HD Young Adult Study. We would also like to thank the staff at the Wellcome Centre for Human Neuroimaging (London, UK) and the Leonard Wolfson Experimental Neurology Centre (London, UK). LC-MS analysis was performed at the Proteomics Core Facility, Sahlgrenska Academy, Gothenburg University, with financial support from SciLifeLab and BioMS. We thank Annabelle Coleman and Alexiane Touze for their help with blood collection and processing, Siti Binte Mohd Ikhsan for help with collecting cognitive and neuropsychiatric data, Peter McColgan for assistance with the structural connectivity pipeline and Davina Hensman-Moss and Emily Gantman for helpful discussions on the paper. Funding for this study was provided by the following: Wellcome Collaborative Award (223082/Z/21/Z to S.J.T., R.I.S., M.F., M.J.M., N.Z.H., M.L., C.L., K.F., T.W.R., J.B.R., B.J.S., D.G.M. and D.R.L.); the CHDI Foundation (a not-for-profit organization dedicated to finding treatments for Huntington's disease) funded CSF collection; the UK Dementia Research Institute (DRI; London, UK) through UK DRI, principally funded by the UK Medical Research Council; University College London Hospital/University College London (London, UK), supported by the National Institute for Health and Care Research (NIHR) University College London Hospitals Biomedical Research Centre; Wellcome Trust (220258 to J.B.R.); Medical Research Council (MC_UU_00030/14 and MR/T033371/1 to J.B.R.) and NIHR Cambridge Biomedical Research Centre (NIHR203312 to J.B.R.). H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council.
- Language
- English
- Electronic publication date
- 01/17/2025
- Date published
- 03/2025
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute; Biostatistics
- Record Identifier
- 9984773419102771
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