Huntington disease: natural history, biomarkers and prospects for therapeutics
Abstract
Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials.
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Currently, there are no successful drugs to cure Huntington's disease.
“Currently, there are no successful drugs to cure the disease68.”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [68]
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Cites
MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366 · see citing works
Cerebrospinal fluid and plasma biomarkers in Alzheimer disease
Blennow, K., Hampel, H., Weiner, M., & Zetterberg, H. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.4 · Cited by 1,863 · see citing works
Browne, S. E., Bowling, A. C., Macgarvey, U., Baik, M. J., Berger, S. C., Muquit, M. M. K., Bird, E. D., & Beal, M. F. (1997) · Annals of Neurology · doi:10.1002/ana.410410514 · Cited by 885 · see citing works
Huntington disease: Clinical care and evaluation
Shoulson, I., & Fahn, S. (1979) · Neurology · doi:10.1212/wnl.29.1.1 · Cited by 746 · see citing works
Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders
Jucker, M., & Walker, L. C. (2011) · Annals of Neurology · doi:10.1002/ana.22615 · Cited by 622 · see citing works
Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2′dG
Hersch, S. M., Gevorkian, S., Marder, K., Moskowitz, C., Feigin, A., Cox, M., Como, P., Zimmerman, C., Lin, M., Zhang, L., et al. (2006) · Neurology · doi:10.1212/01.wnl.0000194318.74946.b6 · Cited by 313 · see citing works
What is a disease?: Disease, disability and their definitions
Scully, J. L. (2004) · The EMBO Reports · doi:10.1038/sj.embor.7400195 · Cited by 195 · see citing works
Flagged first, then by citations
Research works printed but not linked: 5
- [16]Wexler, N. S. et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc. Natl Acad. Sci. USA 101 , 34983503 (2004).
- [17]Langbehn, D. R., Hayden, M. R. & Paulsen, J. S. CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B , 397-408 (2010).
- [49]Harper, S. Q. et al. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc. Natl Acad. Sci. USA 102 , 5820-5825 (2005).
- [121]Hu, Y. et al. Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse. Proc. Natl Acad. Sci. USA 108 , 1714117146 (2011).
- [129]Warner, J. H. & Hayden, M. A new model for age-at-onset in Huntington's Disease. Presented at CHDI Foundation Huntington's Disease Therapeutics Conference (Palm Springs, CA, USA, 2012).
Cited by
Sorted by citations
Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., Nance, M., Ross, C. A., Scahill, R. I., Wetzel, R., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.5 · Cited by 1,641 · see citing works
Self-citationIdentification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease
Lee, J.-M., Wheeler, V. C., Chao, M. J., Vonsattel, J. P. G., Pinto, R. M., Lucente, D., Abu-Elneel, K., Ramos, E. M., Mysore, J. S., Gillis, T., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.003 · Cited by 655 · see citing works
Self-citationIntegrated genomics and proteomics define huntingtin CAG length-dependent networks in mice
Langfelder, P., Cantle, J. P., Chatzopoulou, D., Wang, N., Gao, F., Al-Ramahi, I., Lu, X.-H., Ramos, E. M., El-Zein, K., Zhao, Y., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4256 · Cited by 385 · see citing works
An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration
Moreno-García, A., Kun, A., Calero, O., Medina, M., & Calero, M. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00464 · Cited by 372 · see citing works
Byrne, L. M., Rodrigues, F. B., Blennow, K., Durr, A., Leavitt, B. R., Roos, R. A. C., Scahill, R. I., Tabrizi, S. J., Zetterberg, H., Langbehn, D., et al. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30124-2 · Cited by 364 · see citing works
Self-citationGene therapy for neurological disorders: progress and prospects
Deverman, B. E., Ravina, B. M., Bankiewicz, K. S., Paul, S. M., & Sah, D. W. Y. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.110 · Cited by 306 · see citing works
Injured adult neurons regress to an embryonic transcriptional growth state
Poplawski, G. H. D., Kawaguchi, R., Van Niekerk, E., Lu, P., Mehta, N., Canete, P., Lie, R., Dragatsis, I., Meves, J. M., Zheng, B., et al. (2020) · Nature · doi:10.1038/s41586-020-2200-5 · Cited by 247 · see citing works
The HD iPSC Consortium, Lim, R. G., Salazar, L. L., Wilton, D. K., King, A. R., Stocksdale, J. T., Sharifabad, D., Lau, A. L., Stevens, B., Reidling, J. C., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4532 · Cited by 221 · see citing works
Self-citationDupont, A.-C., Largeau, B., Santiago Ribeiro, M., Guilloteau, D., Tronel, C., & Arlicot, N. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040785 · Cited by 182 · see citing works
Vercruysse, P., Vieau, D., Blum, D., Petersén, Å., & Dupuis, L. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00002 · Cited by 172 · see citing works
The Challenges and Opportunities of Small Effects: The New Normal in Academic Psychiatry
Paulus, M. P., & Thompson, W. K. (2019) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2018.4540 · Cited by 160 · see citing works
The P2X7 Receptor: Central Hub of Brain Diseases
Andrejew, R., Oliveira-Giacomelli, Á., Ribeiro, D. E., Glaser, T., Arnaud-Sampaio, V. F., Lameu, C., & Ulrich, H. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00124 · Cited by 162 · see citing works
Recent Advancements of Nanomedicine in Neurodegenerative Disorders Theranostics
Mukherjee, S., Madamsetty, V. S., Bhattacharya, D., Roy Chowdhury, S., Paul, M. K., & Mukherjee, A. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202003054 · Cited by 152 · see citing works
PET imaging of synaptic density: A new tool for investigation of neuropsychiatric diseases
Cai, Z., Li, S., Matuskey, D., Nabulsi, N., & Huang, Y. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2018.07.038 · Cited by 131 · see citing works
Intercellular Spread of Protein Aggregates in Neurodegenerative Disease
Davis, A. A., Leyns, C. E. G., & Holtzman, D. M. (2018) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100617-062636 · Cited by 131 · see citing works
Birba, A., García-Cordero, I., Kozono, G., Legaz, A., Ibáñez, A., Sedeño, L., & García, A. M. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.07.011 · Cited by 128 · see citing works
Riguet, N., Mahul-Mellier, A.-L., Maharjan, N., Burtscher, J., Croisier, M., Knott, G., Hastings, J., Patin, A., Reiterer, V., Farhan, H., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26684-z · Cited by 118 · see citing works
(2018) · Handbook of Clinical Neurology · doi:10.1016/b978-0-444-63233-3.00017-8 · Cited by 122 · see citing works
Self-citationGeisler, J. G. (2019) · Cells · doi:10.3390/cells8030280 · Cited by 104 · see citing works
Dar, G. H., Mendes, C. C., Kuan, W.-L., Speciale, A. A., Conceição, M., Görgens, A., Uliyakina, I., Lobo, M. J., Lim, W. F., EL Andaloussi, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27056-3 · Cited by 100 · see citing works
Oh, Y. M., Lee, S. W., Kim, W. K., Chen, S., Church, V. A., Cates, K., Li, T., Zhang, B., Dolle, R. E., Dahiya, S., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01185-4 · Cited by 100 · see citing works
Therapeutic reversal of Huntington’s disease by <i>in vivo</i> self-assembled siRNAs
Zhang, L., Wu, T., Shan, Y., Li, G., Ni, X., Chen, X., Hu, X., Lin, L., Li, Y., Guan, Y., et al. (2021) · Brain · doi:10.1093/brain/awab354 · Cited by 97 · see citing works
Tau or neurofilament light—Which is the more suitable biomarker for Huntington’s disease?
Niemelä, V., Landtblom, A.-M., Blennow, K., & Sundblom, J. (2017) · PLOS ONE · doi:10.1371/journal.pone.0172762 · Cited by 63 · see citing works
Relationships Among Apathy, Health-Related Quality of Life, and Function in Huntington’s Disease
Fritz, N. E., Boileau, N. R., Stout, J. C., Ready, R., Perlmutter, J. S., Paulsen, J. S., Quaid, K., Barton, S., McCormack, M. K., Perlman, S. L., et al. (2018) · The Journal of Neuropsychiatry and Clinical Neurosciences · doi:10.1176/appi.neuropsych.17080173 · Cited by 56 · see citing works
Self-citationThe pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases
Zhang, L., Zhang, W., & Tian, X. (2023) · International Journal of Neuroscience · doi:10.1080/00207454.2021.1924707 · Cited by 54 · see citing works
Microglia Activation in Basal Ganglia Is a Late Event in Huntington Disease Pathophysiology
Rocha, N. P., Charron, O., Latham, L. B., Colpo, G. D., Zanotti-Fregonara, P., Yu, M., Freeman, L., Furr Stimming, E., & Teixeira, A. L. (2021) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000984 · Cited by 52 · see citing works
Application of Novel Degraders Employing Autophagy for Expediting Medicinal Research
Li, X., Liu, Q., Xie, X., Peng, C., Pang, Q., Liu, B., & Han, B. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01712 · Cited by 46 · see citing works
Thorley, E. M., Iyer, R. G., Wicks, P., Curran, C., Gandhi, S. K., Abler, V., Anderson, K. E., & Carlozzi, N. E. (2018) · The Patient - Patient-Centered Outcomes Research · doi:10.1007/s40271-018-0312-x · Cited by 32 · see citing works
Marfil-Marin, E., Santamaría-Olmedo, M., PerezGrovas-Saltijeral, A., Valdes-Flores, M., Ochoa-Morales, A., Jara-Prado, A., Sevilla-Montoya, R., Camacho-Molina, A., & Hidalgo-Bravo, A. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02536-1 · Cited by 18 · see citing works
Vauleon, S., Schutz, K., Massonnet, B., Gruben, N., Manchester, M., Buehler, A., Schick, E., Boak, L., & Hawellek, D. J. (2023) · Scientific Reports · doi:10.1038/s41598-023-32630-4 · Cited by 14 · see citing works
Fisher, E. R., Rocha, N. P., Morales-Scheihing, D. A., Venna, V. R., Furr-Stimming, E. E., Teixeira, A. L., & Rossetti, M. A. (2021) · Journal of Huntington's disease · doi:10.3233/jhd-210467 · Cited by 8 · see citing works
Human iPSC Models in Drug Discovery: Opportunities and Challenges
Silva, M. C., Cross, A., Brandon, N. J., & Haggarty, S. J. (2017) · Comprehensive Medicinal Chemistry III · doi:10.1016/b978-0-12-409547-2.12284-x · Cited by 6 · see citing works
- Authors
- Ross, C. A., Aylward, E. H., Wild, E. J., Langbehn, D. R., Long, J. D., Warner, J. H., Scahill, R. I., Leavitt, B. R., Stout, J. C., Paulsen, J. S., Reilmann, R., Unschuld, P. G., Wexler, A., Margolis, R. L., & Tabrizi, S. J.
- Affiliations
- Johns Hopkins University (US)
- Seattle Children's Research Institute (US)
- University College London (GB)
- University of Iowa (US)
- CHDI Foundation (US)
- University of British Columbia (CA)
- Monash University (AU)
- George Huntington Institute (DE)
- University of Zurich (CH)
- University of California, Los Angeles (US)
- Corresponding author
- Ross, Christopher A.
- ORCID
- Venue
- Nature Reviews Neurology
- Published
- 2014-03-11
- Volume
- 10
- Issue
- 4
- Pages
- 204-216
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- OpenAlex
- W2020117714
- Cited by
- 1,016
- References
- 7
- Citations by year
- 2026: 63 · 2025: 72 · 2024: 70 · 2023: 88 · 2022: 79 · 2021: 90 · 2020: 111 · 2019: 90 · 2018: 91 · 2017: 97 · 2016: 74 · 2015: 61 · 2014: 29 · 2013: 1
- FWCI
- 9.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Institute for Health and Care Research (CL-2009-18-005)
- Academy of Medical Sciences (AMS-SGCL6-Wild)
- National Institute of Neurological Disorders and Stroke (R01NS040068)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- Huntington's disease, natural history (disease), biomarkers, neurodegeneration, brain atrophy, disease-modifying therapy, predictive genetic testing, motor impairment, cognitive impairment, emotional impairment, clinical trial endpoints, personalized prevention
- MeSH terms
- Brain, Humans, Huntington Disease, Magnetic Resonance Imaging, Radionuclide Imaging, Biomarkers, Neuroimaging
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