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The Complexity of Clinical Huntington’s Disease: Developments in Molecular Genetics, Neuropathology and Neuroimaging Biomarkers

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Neurodegenerative Diseases

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 15))

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by extensive neuronal loss in the striatum and cerebral cortex, and a triad of clinical symptoms affecting motor, cognitive/behavioural and mood functioning. The mutation causing HD is an expansion of a CAG tract in exon 1 of the HTT gene. This chapter provides a multifaceted overview of the clinical complexity of HD. We explore recent directions in molecular genetics including the identification of loci that are genetic modifiers of HD that could potentially reveal therapeutic targets beyond the HTT gene transcript and protein. The variability of clinical symptomatology in HD is considered alongside recent findings of variability in cellular and neurochemical changes in the striatum and cerebral cortex in human brain. We review evidence from structural neuroimaging methods of progressive changes of striatum, cerebral cortex and white matter in pre-symptomatic and symptomatic HD, with a particular focus on the potential identification of neuroimaging biomarkers that could be used to test promising disease-specific and modifying treatments. Finally we provide an overview of completed clinical trials in HD and future therapeutic developments.

The original version of this chapter was revised. An erratum to this chapter can be found at DOI 10.1007/978-3-319-57193-5_21

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Abbreviations

AchE:

Acetylcholinesterase

CB:

Calbindin

CC:

Corpus callosum

CR:

Calretinin

DBS:

Deep brain stimulation

DTI:

Diffusion tensor imaging

FA:

Fractional anisotropy

GeM-HD:

Genetic Modifiers of Huntington’s disease

GP:

Globus pallidus

GPe:

Globus pallidus external segment

GPi:

Globus pallidus internal segment

HD:

Huntington’s disease

LAMP:

Limbic system-associated membrane protein

MD:

Mean diffusivity

MRI:

Magentic resonance imaging

MSNs:

Medium-sized spiny projection neurons

NOS:

Nitric oxide synthase

NPY:

Neuropeptide Y

preHD:

Pre-symptomatic HD

PV:

Parvalbumin

SNP:

Single nucleotide polymorphism

SNr:

Substantia nigra pars reticulata

VBM:

Voxel-based morphometry

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Authors and Affiliations

  1. Centre for Brain Research, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Lynette J. Tippett PhD, DipClinPsych, Henry J. Waldvogel PhD, Russell G. Snell PhD & Richard L. M. Faull MB, ChB, PhD, DSc

  2. School of Psychology, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Lynette J. Tippett PhD, DipClinPsych

  3. Department of Anatomy and Medical Imaging, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Henry J. Waldvogel PhD & Richard L. M. Faull MB, ChB, PhD, DSc

  4. School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Russell G. Snell PhD

  5. Department of Pathology, Presbyterian Hospital and Columbia University New York, New York, NY, 10032, USA

    Jean-Paul Vonsattel MD

  6. Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA

    Anne B. Young MD, PhD

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  1. Lynette J. Tippett PhD, DipClinPsych
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Correspondence to Lynette J. Tippett PhD, DipClinPsych .

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    Philip Beart

  2. Pediatrics and Pharmacology Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael Robinson

  3. School of Life Sciences Bradford School of Pharmacy, University of Bradford, Bradford, United Kingdom

    Marcus Rattray

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Nicholas J. Maragakis

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Tippett, L.J., Waldvogel, H.J., Snell, R.G., Vonsattel, JP., Young, A.B., Faull, R.L.M. (2017). The Complexity of Clinical Huntington’s Disease: Developments in Molecular Genetics, Neuropathology and Neuroimaging Biomarkers. In: Beart, P., Robinson, M., Rattray, M., Maragakis, N. (eds) Neurodegenerative Diseases. Advances in Neurobiology, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-57193-5_5

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