Skip to main content
×
×
Home

Multimodal imaging biomarkers in premanifest and early Huntington's disease: 30-month IMAGE-HD data

  • Juan F. Domínguez (a1), Julie C. Stout (a1), Govinda Poudel (a2), Andrew Churchyard (a3), Phyllis Chua (a1), Gary F. Egan (a4) and Nellie Georgiou-Karistianis (a1)...
Abstract
Background

The discovery of potential disease-modifying therapies in a neurodegenerative condition like Huntington's disease depends on the availability of sensitive biomarkers that reflect decline across disease stages and that are functionally and clinically relevant.

Aims

To quantify macrostructural and microstructural changes in participants with premanifest and symptomatic Huntington's disease over 30 months, and to establish their functional and clinical relevance.

Method

Multimodal magnetic resonance imaging study measuring changes in macrostructural (volume) and microstructural (diffusivity) measures in 40 patients with premanifest Huntington's disease, 36 patients with symptomatic Huntington's disease and 36 healthy control participants over three testing sessions spanning 30 months.

Results

Relative to controls, there was greater longitudinal atrophy in participants with symptomatic Huntington's disease in whole brain, grey matter, caudate and putamen, as well as increased caudate fractional anisotropy; caudate volume loss was the only measure to differ between premanifest Huntington's disease and control groups. Changes in caudate volume and fractional anisotropy correlated with each other and neurocognitive decline; caudate volume loss also correlated with clinical and disease severity.

Conclusions

Caudate neurodegeneration, especially atrophy, may be the most suitable candidate surrogate biomarker for consideration in the development of upcoming clinical trials.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Multimodal imaging biomarkers in premanifest and early Huntington's disease: 30-month IMAGE-HD data
      Available formats
      ×
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Multimodal imaging biomarkers in premanifest and early Huntington's disease: 30-month IMAGE-HD data
      Available formats
      ×
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Multimodal imaging biomarkers in premanifest and early Huntington's disease: 30-month IMAGE-HD data
      Available formats
      ×
Copyright
Corresponding author
Nellie Georgiou-Karistianis, School of Psychological Sciences, Monash University, Clayton, Victoria 3800, Australia. Email: nellie.georgiou-karistianis@monash.edu
Footnotes
Hide All

Declaration of interest

J.C.S. reports grants from Prana Biotechnology, other from Teva Pharmaceuticals, personal fees from Roche, personal fees from University of Michigan, other from Omeros, personal fees from Stout Neuropsych Pty., personal fees from Huntington's Study Group (HSG), outside the submitted work. P.C. reports other from Prana Biotechnology, other from Teva Pharmaceuticals, outside the submitted work. G.F.E. reports grants from Siemens Healthcare Australia, outside the submitted work; he is a Principal Research Fellow with the National Health and Medical Research Council.

Footnotes
References
Hide All
1 Ross, CA, Tabrizi, SJ. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 2011; 10: 8398.
2 Kozauer, N, Katz, R. Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med 2013; 368: 1169–71.
3 Borsook, D, Becerra, L, Fava, M. Use of functional imaging across clinical phases in CNS drug development. Transl Psychiatry 2013; 3: e282.
4 Tabrizi, SJ, Scahill, RI, Durr, A, Roos, RA, Leavitt, BR, Jones, R, et al. Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 2011; 10: 3142.
5 Aylward, EH, Codori, AM, Rosenblatt, A, Sherr, M, Brandt, J, Stine, OC, et al. Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington's disease. Mov Disord 2000; 15: 552–60.
6 Aylward, EH, Nopoulos, PC, Ross, CA, Langbehn, DR, Pierson, RK, Mills, JA, et al. Longitudinal change in regional brain volumes in prodromal Huntington disease. J Neurol Neurosurg Psychiatry 2011; 82: 405–10.
7 Henley, SMD, Wild, EJ, Hobbs, NZ, Frost, C, MacManus, DG, Barker, RA, et al. Whole-brain atrophy as a measure of progression in premanifest and early Huntington's disease. Mov Disord 2009; 24: 932–6.
8 Hobbs, NZ, Henley, SMD, Wild, EJ, Leung, KK, Frost, C, Barker, RA, et al. Automated quantification of caudate atrophy by local registration of serial MRI: evaluation and application in Huntington's disease. NeuroImage 2009; 47: 1659–65.
9 Hobbs, NZ, Henley, SM, Ridgway, GR, Wild, EJ, Barker, RA, Scahill, RI, et al. The progression of regional atrophy in premanifest and early Huntington's disease: a longitudinal voxel-based morphometry study. J Neurol Neurosurg Psychiatry 2010; 81: 756–63.
10 Domínguez, D JF, Egan, GF, Gray, MA, Poudel, GR, Churchyard, A, Chua, P, et al. Multi-modal neuroimaging in premanifest and early Huntington's disease: 18 Month Longitudinal Data from the IMAGE-HD Study. PloS ONE 2013; 8: e74131.
11 Katz, R. Biomarkers and surrogate markers: an FDA perspective. NeuroRx 2004; 1: 189–95.
12 Nelson, HE, Willison, J. National Adult Reading Test (NART): Test Manual. NFER Nelson, 1991.
13 Huntington Study Group. Unified Huntington's disease rating scale: reliability and consistency. Mov Disord 1996; 11: 136–42.
14 Tabrizi, SJ, Langbehn, DR, Leavitt, BR, Roos, RA, Durr, A, Craufurd, D, et al. Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009; 8: 791801.
15 Stout, JC, Paulsen, JS, Queller, S, Solomon, AC, Whitlock, KB, Campbell, JC, et al. Neurocognitive signs in prodromal Huntington disease. Neuropsychology 2011; 25: 114.
16 Smith, A. Symbol Digit Modality Test (SDMT): Manual (Revised). Psychological Services, 1982.
17 Stroop, JR. Studies of interference in serial verbal reactions. J Exp Psychol 1935; 18: 643–62.
18 Georgiou-Karistianis, N, Poudel, GR, Domínguez, D JF, Langmaid, R, Gray, MA, Churchyard, A, et al. Functional and connectivity changes during working memory in Huntington's disease: 18 month longitudinal data from the IMAGE-HD study. Brain Cogn 2013; 83: 8091.
19 Georgiou-Karistianis, N, Stout, JC, Domínguez, D J, Carron, SP, Ando, A, Churchyard, A, et al. Functional magnetic resonance imaging of working memory in Huntington's disease: cross-sectional data from the IMAGE-HD study. Hum Brain Mapp 2014; 35: 1847–64.
20 Poudel, GR, Stout, JC, Gray, MA, Domínguez, D JF, Salmon, L, Churchyard, A, et al. Functional changes during working memory in Huntington's disease: 30 month longitudinal data from the IMAGE-HD study. Brain Struct Funct 2015; 220: 501–12.
21 Gray, MA, Egan, GF, Ando, A, Churchyard, A, Chua, P, Stout, JC, et al. Prefrontal activity in Huntington's disease reflects cognitive and neuropsychiatric disturbances: the IMAGE-HD study. Exp Neurol 2013; 239: 218–28.
22 Grace, J, Mallory, PF. Frontal Systems Behavior Scale: Professional Manual. Psychological Assessment Resources, 2001.
23 Watson, D, Wu, KD. Development and validation of the schedule of compulsions, obsessions, and pathological impulses (SCOPI). Assessment 2005; 12: 5065.
24 Georgiou-Karistianis, N, Gray, MA, Domínguez, D JF, Dymowski, AR, Bohanna, I, Johnston, LA, et al. Automated differentiation of pre-diagnosis Huntington's disease from healthy control individuals based on quadratic discriminant analysis of the basal ganglia: the IMAGE-HD study. Neurobiol Dis 2013; 51: 8292.
25 Zhang, Y, Brady, M, Smith, S. Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Trans Med Imaging 2001; 20: 4557.
26 Patenaude, B, Smith, S, Kennedy, D, Jenkinson, M. Bayesian statistical models of shape and appearance for subcortical brain segmentation. NeuroImage 2011; 56: 907–22.
27 Moncrieff, J, Leo, J. A systematic review of the effects of antipsychotic drugs on brain volume. Psychol Med 2010; 40: 1409–22.
28 Penney, JB, Vonsattel, J-P, Macdonald, ME, Gusella, JF, Myers, RH. CAG repeat number governs the development rate of pathology in Huntington's disease. Ann Neurol 1997; 41: 689–92.
29 StataCorp. Stata Statistical Software: Release 12. StataCorp LP, 2011.
30 Calamia, M, Markon, K, Tranel, D. Scoring higher the second time around: meta-analyses of practice effects in neuropsychological assessment. Clin Neuropsychol 2012; 26: 543–70.
31 Hobbs, NZ, Barnes, J, Frost, C, Henley, SMD, Wild, EJ, Macdonald, K, et al. Onset and progression of pathologic atrophy in Huntington disease: a longitudinal MR imaging study. Am J Neuroradiol 2010; 31: 1036–41.
32 Majid, DS, Aron, AR, Thompson, W, Sheldon, S, Hamza, S, Stoffers, D, et al. Basal ganglia atrophy in prodromal Huntington's disease is detectable over 1 year using automated segmentation. Mov Disord 2011; 26: 2544–51.
33 Tabrizi, SJ, Reilmann, R, Roos, RA, Durr, A, Leavitt, B, Owen, G, et al. Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol 2012; 11: 4253.
34 Tabrizi, SJ, Scahill, RI, Owen, G, Durr, A, Leavitt, BR, Roos, RA, et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol 2013; 12: 637–49.
35 Reuter, M, Schmansky, NJ, Rosas, HD, Fischl, B. Within-subject template estimation for unbiased longitudinal image analysis. NeuroImage 2012; 61: 1402–18.
36 Magnotta, VA, Harris, G, Andreasen, NC, O'Leary, DS, Yuh, WTC, Heckel, D. Structural MR image processing using the BRAINS2 toolbox. Comput Med Imag Grap 2002; 26: 251–64.
37 Freeborough, PA, Fox, NC, Kitney, RI. Interactive algorithms for the segmentation and quantitation of 3-D MRI brain scans. Comput Methods Programs Biomed 1997; 53: 1525.
38 Rosas, HD, Tuch, DS, Hevelone, ND, Zaleta, AK, Vangel, M, Hersch, SM, et al. Diffusion tensor imaging in presymptomatic and early Huntington's disease: selective white matter pathology and its relationship to clinical measures. Mov Disord 2006; 21: 1317–25.
39 Douaud, G, Behrens, TE, Poupon, C, Cointepas, Y, Jbabdi, S, Gaura, V, et al. In vivo evidence for the selective subcortical degeneration in Huntington's disease. NeuroImage 2009; 46: 958–66.
40 Sánchez-Castañeda, C, Cherubini, A, Elifani, F, Peran, P, Orobello, S, Capelli, G, et al. Seeking Huntington disease biomarkers by multimodal, cross-sectional basal ganglia imaging. Hum Brain Mapp 2013; 34: 1625–35.
41 Sritharan, A, Egan, GF, Johnston, L, Horne, M, Bradshaw, JL, Bohanna, I, et al. A longitudinal diffusion tensor imaging study in symptomatic Huntington's disease. J Neurol Neurosurg Psychiatry 2010; 81: 257–62.
42 Vandenberghe, W, Demaerel, P, Dom, R, Maes, F. Diffusion-weighted versus volumetric imaging of the striatum in early symptomatic Huntington disease. J Neurol 2009; 256: 109–14.
43 Myers, RH, Vonsattel, JP, Paskevich, PA, Kiely, DK, Stevens, TJ, Cupples, LA, et al. Decreased neuronal and increased oligodendroglial densities in Huntington's disease caudate nucleus. J Neuropathol Exp Neurol 1991; 50: 729–42.
44 Gómez-Tortosa, E, MacDonald, ME, Friend, JC, Taylor, SA, Weiler, LJ, Cupples, LA, et al. Quantitative neuropathological changes in presymptomatic Huntington's disease. Ann Neurol 2001; 49: 2934.
45 Mandelli, ML, Savoiardo, M, Minati, L, Mariotti, C, Aquino, D, Erbetta, A, et al. Decreased diffusivity in the caudate nucleus of presymptomatic Huntington disease gene carriers: which explanation? Am J Neuroradiol 2010; 31: 706–10.
46 Bartzokis, G, Lu, PH, Tishler, TA, Fong, SM, Oluwadara, B, Finn, JP, et al. Myelin breakdown and iron changes in Huntington's disease: pathogenesis and treatment implications. Neurochem Res 2007; 32: 1655–64.
47 Rosas, HD, Chen, YI, Doros, G, Salat, DH, Chen, NK, Kwong, KK, et al. Alterations in brain transition metals in Huntington disease: an evolving and intricate story. Arch Neurol 2012; 69: 887–93.
48 Tanis, KQ, Newton, SS, Duman, RS. Targeting neurotrophic/growth factor expression and signaling for antidepressant drug development. CNS Neurol Disord Drug Targets 2007; 6: 151–60.
49 Hua, X, Hibar, DP, Ching, CR, Boyle, CP, Rajagopalan, P, Gutman, BA, et al. Unbiased tensor-based morphometry: improved robustness and sample size estimates for Alzheimer's disease clinical trials. NeuroImage 2013; 66: 648–61.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
  • URL: /core/journals/the-british-journal-of-psychiatry
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×
Type Description Title
PDF
Supplementary materials

Domínguez et al. supplementary material
Supplementary Material

 PDF (804 KB)
804 KB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

Multimodal imaging biomarkers in premanifest and early Huntington's disease: 30-month IMAGE-HD data

  • Juan F. Domínguez (a1), Julie C. Stout (a1), Govinda Poudel (a2), Andrew Churchyard (a3), Phyllis Chua (a1), Gary F. Egan (a4) and Nellie Georgiou-Karistianis (a1)...
Submit a response

eLetters

No eLetters have been published for this article.

×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *