Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis

Rachael I Scahill; Mena Farag; Michael J Murphy; Nicola Z Hobbs; Michela Leocadi; Christelle Langley; Harry Knights; Marc Ciosi; Kate Fayer; Mitsuko Nakajima; Olivia Thackeray; Johan Gobom; John Rönnholm; Sophia Weiner; Yara R Hassan; Nehaa K P Ponraj; Carlos Estevez-Fraga; Christopher S Parker; Ian B Malone; Harpreet Hyare; Jeffrey D Long; Amanda Heslegrave; Cristina Sampaio; Hui Zhang; Trevor W Robbins; Henrik Zetterberg; Edward J Wild; Geraint Rees; James B Rowe; Barbara J Sahakian; Darren G Monckton; Douglas R Langbehn; Sarah J Tabrizi

doi:10.1038/s41591-024-03424-6

Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis

Nat Med. 2025 Mar;31(3):807-818. doi: 10.1038/s41591-024-03424-6. Epub 2025 Jan 17.

Authors

Rachael I Scahill^#¹, Mena Farag^#¹, Michael J Murphy¹, Nicola Z Hobbs¹, Michela Leocadi¹, Christelle Langley², Harry Knights¹, Marc Ciosi³, Kate Fayer¹, Mitsuko Nakajima¹, Olivia Thackeray¹, Johan Gobom^{4

5}, John Rönnholm⁴, Sophia Weiner⁴, Yara R Hassan¹, Nehaa K P Ponraj³, Carlos Estevez-Fraga¹, Christopher S Parker⁶, Ian B Malone⁷, Harpreet Hyare⁸, Jeffrey D Long⁹, Amanda Heslegrave^{10

11}, Cristina Sampaio^{12

13}, Hui Zhang⁶, Trevor W Robbins¹⁴, Henrik Zetterberg^{4

5

11

15

16}, Edward J Wild¹, Geraint Rees¹⁷, James B Rowe^{18

19

20}, Barbara J Sahakian², Darren G Monckton³, Douglas R Langbehn⁹, Sarah J Tabrizi²¹

Affiliations

¹ Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
² Department of Psychiatry, University of Cambridge, Cambridge, UK.
³ School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
⁵ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁶ Department of Computer Science and Centre for Medical Image Computing, University College London, London, UK.
⁷ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁸ Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁹ Department of Psychiatry and Biostatistics, Carver College of Medicine and College of Public Health, University of Iowa, Iowa City, Iowa, USA.
¹⁰ Dementia Research Institute, University College London, London, UK.
¹¹ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹² Faculdade Medicina da Universidade de Lisboa (FMUL), Lisbon, Portugal.
¹³ CHDI Management, Inc. Advisors to CHDI Foundation, Princeton, NJ, USA.
¹⁴ Department of Psychology, University of Cambridge, Cambridge, UK.
¹⁵ Hong Kong Center for Neurodegeneassociated with substantially fasterrative Diseases, Clear Water Bay, Hong Kong, China.
¹⁶ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹⁷ UCL Institute of Cognitive Neuroscience, University College London, London, UK.
¹⁸ Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
¹⁹ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
²⁰ Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.
²¹ Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK. s.tabrizi@ucl.ac.uk.

^# Contributed equally.

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 .

Publication types

Observational Study

MeSH terms

Adult
Aged
Biomarkers / blood
Biomarkers / cerebrospinal fluid
Enkephalins / blood
Enkephalins / cerebrospinal fluid
Female
Humans
Huntingtin Protein* / genetics
Huntington Disease* / blood
Huntington Disease* / cerebrospinal fluid
Huntington Disease* / diagnosis
Huntington Disease* / genetics
Huntington Disease* / pathology
Male
Middle Aged
Neurofilament Proteins / blood
Neurofilament Proteins / cerebrospinal fluid
Protein Precursors / blood
Protein Precursors / cerebrospinal fluid
Trinucleotide Repeat Expansion* / genetics

Substances

Biomarkers
Enkephalins
HTT protein, human
Huntingtin Protein
neurofilament protein L
Neurofilament Proteins
Protein Precursors

Associated data

ClinicalTrials.gov/NCT06391619

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding