Review
Magnetic resonance imaging as an approach towards identifying neuropathological biomarkers for Huntington's disease

https://doi.org/10.1016/j.brainresrev.2008.04.001Get rights and content

Abstract

Magnetic Resonance Imaging (MRI), functional MRI (fMRI) and Diffusion Tensor Imaging (DTI) have been central to characterisation of abnormalities in brain structure and function in both clinical and preclinical Huntington's disease (HD). One current challenge in clinical HD research is the identification of sensitive and reliable biomarkers to detect progressive neurodegeneration and neural dysfunction, which could be used to assess the effect of therapeutic intervention on brain structure and function in a HD clinical trial. To this end, both established and novel neuroimaging approaches could potentially provide sensitive, reliable and non-invasive tools to assess long-term and dynamic effects of treatment on specific brain regions, including their microstructure and connectivity. This review examines contributions from structural MRI, fMRI and DTI studies to our current understanding of preclinical and clinical HD, and critically appraises MRI methods potentially suitable for both scientific characterisation and for use as biomarkers in HD clinical trials. A combined neuroimaging approach incorporating structural MRI, fMRI and DTI is yet to be realised in HD clinical trials, however if proven to be sensitive and reliable, these methods could potentially serve as biomarkers for use in future clinical drug trials in HD.

Introduction

Huntington's disease (HD), a dominantly inherited neurodegenerative disorder, is characterised by the gradual onset and progression of motor, cognitive and psychiatric symptoms. The prevalence of this debilitating disease is generally reported as between 5 and 10 in 100,000 individuals, however this varies greatly between geographical regions (Conneally, 1984). HD is caused by a mutation in the gene that codes for the protein huntingtin; HD individuals have an expansion of 39 or greater CAG repeats within this gene (The Huntington's Disease Collaborative Research Group, 1993). The HD mutation causes progressive neurodegeneration and death usually occurs within one to two decades after the first occurrence of symptoms (Gomez-Tortosa et al., 2001). At present there is no cure, nor any effective treatment to delay symptom onset or slow progression, and most current treatments aim to minimise symptoms.

Currently, motor manifestations, measured using the Unified Huntington's Disease Rating Scale (UHDRS) (Huntington Study Group, 1996), are the accepted basis for clinical diagnosis of HD. Despite this, recent and accumulating evidence demonstrate that both cognitive (Hodges et al., 1990, Hahn-Barma et al., 1998, Lawrence et al., 1996, Lawrence et al., 1998, Lemiere et al., 2004, Paulsen et al., 2001, Paulsen et al., 2006a) and psychiatric (Berrios et al., 2002, Brandt et al., 1989, Brandt et al., 1995, Kirkwood et al., 2002, Duff et al., 2007, Paulsen et al., 2006a) symptoms often precede the motor disorder in human HD mutation carriers. Findings of early deterioration before the onset of motor symptoms has prompted research into understanding the nature of early degeneration, in terms of both symptom manifestation and neuropathology.

Neuroimaging techniques have been central to the characterisation of neurobiological and neurophysiological change in clinical (i.e. diagnosed) HD, and are proving invaluable in similar investigations in preclinical HD mutation carriers. Magnetic Resonance Imaging (MRI) and functional MRI (fMRI) studies have improved understanding of striatal atrophy and cortical dysfunction, which appear to be characteristic abnormalities in HD, while Diffusion Tensor Imaging (DTI) has recently yielded significant insights into brain microstructure in both clinical and preclinical HD. Recently, using in vivo neuroimaging, abnormalities in brain structure and function have been detected in HD mutation carriers many years before the onset of symptoms.

Since the discovery of neurodegenerative changes prior to symptom manifestation, the HD neuropathological process has increasingly been conceptualised as a continuum from health to disease; with progression along this continuum there are notable changes in brain structure, brain function that eventually leads to symptom manifestation. One focus of HD research is to identify symptom-independent biomarkers of HD neuropathology and progression, against which therapeutic interventions can be tested. The Biomarkers Definitions Working Group (2001) defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”. Together MRI, fMRI and DTI provide a powerful set of complementary techniques to investigate dynamic and long-term aspects of brain structure, function and connectivity. Furthermore, it is likely that an integrative multi-modal neuroimaging approach may yield non-invasive, symptom-independent biomarkers of both neuropathology and progression that have potential use in therapeutic intervention studies. This review will examine MRI, fMRI and DTI studies in clinical and preclinical HD, examine advances in neuroimaging of potential benefit to HD research, and lastly, propose an integrative multi-modal neuroimaging approach toward identifying reliable and sensitive biomarkers in HD for use in future clinical trials.

Section snippets

Brain atrophy in HD detected by structural MRI

The hallmark of HD neuropathology is neurodegeneration in the caudate and putamen (Hersch and Ferrante, 1997). Considering this, structural MRI studies, shown in Table 1, have generally focused on examining striatal atrophy. Degeneration in HD begins in the dorsal caudate and proceed ventrally and laterally to encompass the putamen, primarily affecting the medium spiny neurons (Vonsattel et al., 1985, Margolis and Ross, 2001). Consistent with this, in clinical HD, significant atrophy has been

Neural dysfunction in HD detected using fMRI

Functional MRI offers the unique opportunity to measure brain function over time during rest, or more commonly, in association with a cognitive task or stimulus that engages relevant brain areas and networks. Blood Oxygen Level Dependent (BOLD) fMRI, the most common functional imaging method in HD, measures brain activity indirectly, relying on local alterations in blood flow associated with neuronal activity. Measures of activation intensity, activation extent and functional connectivity can

Microstructural abnormalities in HD detected by DTI

Diffusion imaging has recently been used to investigate microstructural changes in HD though few studies have been published in clinical HD (Seppi et al., 2006, Mascalchi et al., 2004, Reading et al., 2005) and only one study has addressed preclinical HD (Rosas et al., 2006). Diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI) enable characterisation of water diffusion, which in the brain is random (isotropic) unless the molecule encounters a barrier, causing diffusion to become

Accounting for phenotypic variability in HD using DTI

An important phenomenon observed in clinical HD that remains to be comprehensively addressed is that of phenotypic variability. There is strong anecdotal and clinical evidence in individuals who carry the HD mutation of phenotypic differences in terms of symptom development (i.e. which symptoms develops first), symptom prominence (i.e. motor, cognitive, psychiatric, or a combination), and rate of symptom progression. This variability represents a power-reducing confound that has subsequently

An integrative neuroimaging approach for identification of HD biomarkers

There is now unequivocal evidence that neurobiological and neurophysiological changes occur in HD mutation carriers before symptoms develop, beginning a decade or more before a clinical diagnosis is likely to be made. Considering this, it would be ideal to administer therapeutic interventions during the preclinical phase, with the aim of slowing neurodegeneration and thereby delaying the onset of physical, cognitive and emotional decline (Rosas et al., 2004, Paulsen et al., 2006a). In order to

Conclusion

Neuroimaging techniques have played a central role in characterising neurobiological and neurophysiological alterations during the preclinical phase of HD, and novel developments in DTI are likely to provide further insights into the underlying neuropathological processes in human HD. Since the discovery of neurobiological changes in HD mutation carriers long before symptoms manifest, the need for sensitive, reliable, non-invasive symptom-independent biomarkers for use in future preventative

References (102)

  • JerniganT.L. et al.

    Cerebral structure on MRI, Part II: Specific changes in Alzheimer's and Huntington's diseases

    Biol. Psychiatry

    (1991)
  • KarlsgodtK.H. et al.

    Diffusion tensor imaging of the superior longitudinal fasciculus and working memory in recent-onset schizophrenia

    Biol. Psychiatry

    (2008)
  • KimJ.S. et al.

    Functional MRI study of a serial reaction time task in Huntington's disease

    Psychiatry Res.

    (2004)
  • KircherT.T. et al.

    Cortical activation during cholinesterase-inhibitor treatment in Alzheimer disease: preliminary findings from a pharmaco-fMRI study

    Am. J. Geriatr. Psychiatry

    (2005)
  • LandauS.M. et al.

    Regional specificity and practice: dynamic changes in object and spatial working memory

    Brain Res.

    (2007)
  • LehS.E. et al.

    Fronto-striatal connections in the human brain: a probabilistic diffusion tractography study

    Neurosci. Lett.

    (2007)
  • MargolisR.L. et al.

    Expansion explosion: new clues to the pathogenesis of repeat expansion neurodegenerative diseases

    Trends Mol. Med.

    (2001)
  • PaulsenJ.S. et al.

    Brain structure in preclinical Huntington's disease

    Biol. Psychiatry

    (2006)
  • PeinemannA. et al.

    Executive dysfunction in early stages of Huntington's disease is associated with striatal and insular atrophy: a neuropsychological and voxel-based morphometric study

    J. Neurol. Sci.

    (2005)
  • ReadingS.A. et al.

    Regional white matter change in preclinical Huntington's disease: a diffusion tensor imaging study

    Psychiatry Res.

    (2005)
  • RogersB.P. et al.

    Assessing functional connectivity in the human brain by fMRI

    Magn. Reson. Imaging

    (2007)
  • RosasH.D. et al.

    Using advances in neuroimaging to detect, understand, and monitor disease progression in Huntington's disease

    NeuroRx

    (2004)
  • SarterM. et al.

    More attention must be paid: the neurobiology of attentional effort

    Brain Res. Rev.

    (2006)
  • ShanksM.F. et al.

    Regional brain activity after prolonged cholinergic enhancement in early Alzheimer's disease

    Magn. Reson. Imaging

    (2007)
  • SmithS.M. et al.

    Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data

    Neuroimage

    (2006)
  • SunF.T. et al.

    Measuring interregional functional connectivity using coherence and partial coherence analyses of fMRI data

    Neuroimage

    (2004)
  • TomasiD. et al.

    Practice-induced changes of brain function during visual attention: a parametric fMRI study at 4 Tesla

    Neuroimage

    (2004)
  • AlexanderG.E. et al.

    Parallel organization of functionally segregated circuits linking basal ganglia and cortex

    Annu. Rev. Neurosci.

    (1986)
  • AylwardE.H. et al.

    Reduced basal ganglia volume associated with the gene for Huntington's disease in asymptomatic at-risk persons

    Neurology.

    (1994)
  • AylwardE.H. et al.

    Basal ganglia volume and proximity to onset in preclinical Huntington disease

    Arch. Neurol.

    (1996)
  • AylwardE.H. et al.

    Longitudinal change in basal ganglia volume in patients with Huntington's disease

    Neurology.

    (1997)
  • AylwardE.H. et al.

    Frontal lobe volume in patients with Huntington's disease

    Neurology.

    (1998)
  • AylwardE.H. et al.

    Rate of caudate atrophy in preclinical and clinical stages of Huntington's disease

    Mov. Disord.

    (2000)
  • AylwardE.H. et al.

    Onset and rate of striatal atrophy in preclinical Huntington disease

    Neurology

    (2004)
  • BackmanL. et al.

    Cognitive deficits in Huntington's disease are predicted by dopaminergic PET markers and brain volumes

    Brain

    (1997)
  • BeaulieuC.

    The basis of anisotropic water diffusion in the nervous system — a technical review

    NMR Biomed.

    (2002)
  • BeglingerL.J. et al.

    White matter volume and cognitive dysfunction in early Huntington's disease

    Cogn. Behav. Neurol.

    (2005)
  • BehrensT.E. et al.

    Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging

    Nat. Neurosci.

    (2003)
  • BerriosG.E. et al.

    Psychiatric symptoms in neurologically clinical Huntington's disease gene carriers: a comparison with gene negative at risk subjects

    Acta Psychiatr. Scand.

    (2002)
  • Biomarkers Definitions Working Group

    Biomarkers and surrogate endpoints: preferred definitions and conceptual framework

    Clin. Pharmacol. Ther.

    (2001)
  • BrandtJ. et al.

    Preclinical DNA testing for Huntington's disease

    J. Neuropsychiatry Clin. Neurosci.

    (1989)
  • BrandtJ. et al.

    Impaired source memory in Huntington's disease and its relation to basal ganglia atrophy

    J. Clin. Exp. Neuropsychol.

    (1995)
  • CampodonicoJ.R. et al.

    When does Huntington's disease begin?

    J. Int. Neuropsychol. Soc.

    (1998)
  • CiarmielloA. et al.

    Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington's disease

    J. Nucl. Med.

    (2006)
  • ClarkV.P. et al.

    Altered functional MRI responses in Huntington's disease

    Neuroreport.

    (2002)
  • ConneallyP.M.

    Huntington disease: genetics and epidemiology

    Am. J. Hum. Genet.

    (1984)
  • DeckelA.W.

    Nitric oxide and nitric oxide synthase in Huntington's disease

    J. Neurosci. Res.

    (2001)
  • FeiginA. et al.

    Thalamic metabolism and symptom onset in preclinical Huntington's disease

    Brain

    (2007)
  • FristonK.J.

    Functional and effective connectivity in neuroimaging: a synthesis

    Hum. Brain Mapp.

    (1994)
  • Gomez-TortosaE. et al.

    Quantitative neuropathological changes in preclinical Huntington's disease

    Ann. Neurol.

    (2001)
  • Cited by (0)

    View full text