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Current Medical Imaging


ISSN (Print): 1573-4056
ISSN (Online): 1875-6603

Review Article

Diffusion Tensor Imaging in Preclinical and Human Studies of Huntington’s Disease: What Have we Learned so Far?

Author(s): Rodolfo Gabriel Gatto* and Carina Weissmann

Volume 15, Issue 6, 2019

Page: [521 - 542] Pages: 22

DOI: 10.2174/1573405614666181115113400

Price: $65


Background: Huntington’s Disease is an irreversible neurodegenerative disease characterized by the progressive deterioration of specific brain nerve cells. The current evaluation of cellular and physiological events in patients with HD relies on the development of transgenic animal models. To explore such events in vivo, diffusion tensor imaging has been developed to examine the early macro and microstructural changes in brain tissue. However, the gap in diffusion tensor imaging findings between animal models and clinical studies and the lack of microstructural confirmation by histological methods has questioned the validity of this method.

Objective: This review explores white and grey matter ultrastructural changes associated to diffusion tensor imaging, as well as similarities and differences between preclinical and clinical Huntington’s Disease studies.

Methods: A comprehensive review of the literature using online-resources was performed (Pub- Med search).

Results: Similar changes in fractional anisotropy as well as axial, radial and mean diffusivities were observed in white matter tracts across clinical and animal studies. However, comparative diffusion alterations in different grey matter structures were inconsistent between clinical and animal studies.

Conclusion: Diffusion tensor imaging can be related to specific structural anomalies in specific cellular populations. However, some differences between animal and clinical studies could derive from the contrasting neuroanatomy or connectivity across species. Such differences should be considered before generalizing preclinical results into the clinical practice. Moreover, current limitations of this technique to accurately represent complex multicellular events at the single micro scale are real. Future work applying complex diffusion models should be considered.

Keywords: Animal models, axonal degeneration, clinical studies, diffusion tensor imaging, Huntington’s disease, magnetic resonance imaging.

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Barbeau A. Huntington’s chorea: 1872-1972. Union Med Can 1972; 101(7): 1377-9.
Ghosh R, Tabrizi SJ. Clinical features of Huntington’s disease. Adv Exp Med Biol 2018; 1049: 1-28.
Nance MA, Myers RH. Juvenile onset Huntington’s disease--clinical and research perspectives. Ment Retard Dev Disabil Res Rev 2001; 7(3): 153-7.
Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N. The incidence and prevalence of Huntington’s disease: A systematic review and meta-analysis. Mov Disord 2012; 27(9): 1083-91.
Quarrell O, O'Donovan KL, Bandmann O, Strong M. The prevalence of juvenile Huntington’s disease: A review of the literature and meta-analysis PLoS Currents 2012; 4: e4f8606b742ef3.
Walker FO. Huntington’s disease. Lancet 2007; 369(9557): 218-28.
Brinkman RR, Mezei MM, Theilmann J, Almqvist E, Hayden MR. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet 1997; 60(5): 1202-10.
Squitieri F. Neurodegenerative disease: ‘Fifty shades of grey’ in the Huntington disease gene. Nat Rev Neurol 2013; 9(8): 421-2.
Cisbani G, Cicchetti F. An in vitro perspective on the molecular mechanisms underlying mutant huntingtin protein toxicity. Cell Death Dis 2012; 3e382
Saudou F, Humbert S. The biology of Huntingtin. Neuron 2016; 89(5): 910-26.
Bates G. Huntingtin aggregation and toxicity in Huntington’s disease. Lancet 2003; 361(9369): 1642-4.
DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997; 277(5334): 1990-3.
Labbadia J, Morimoto RI. Huntington’s disease: Underlying molecular mechanisms and emerging concepts. Trends Biochem Sci 2013; 38(8): 378-85.
Li SH, Li XJ. Aggregation of N-terminal huntingtin is dependent on the length of its glutamine repeats. Hum Mol Genet 1998; 7(5): 777-82.
Li H, Li SH, Yu ZX, Shelbourne P, Li XJ. Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington’s disease mice. J Neurosci 2001; 21(21): 8473-81.
Damiano M, Galvan L, Déglon N, Brouillet E. Mitochondria in Huntington’s disease. Biochim Biophys Acta 2010; 1802(1): 52-61.
Huang B, Wei W, Wang G, et al. Mutant huntingtin downregulates myelin regulatory factor-mediated myelin gene expression and affects mature oligodendrocytes. Neuron 2015; 85(6): 1212-26.
Bartzokis G, Lu PH, Tishler TA, et al. Myelin breakdown and iron changes in Huntington’s disease: Pathogenesis and treatment implications. Neurochem Res 2007; 32(10): 1655-64.
Li X, Standley C, Sapp E, et al. Mutant huntingtin impairs vesicle formation from recycling endosomes by interfering with Rab11 activity. Mol Cell Biol 2009; 29(22): 6106-16.
Ortega Z, Lucas JJ. Ubiquitin-proteasome system involvement in Huntington’s disease. Front Mol Neurosci 2014; 7: 77.
Gunawardena S, Her LS, Brusch RG, et al. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 2003; 40(1): 25-40.
Smith R, Brundin P, Li JY. Synaptic dysfunction in Huntington’s disease: A new perspective. Cell Mol Life Sci 2005; 62(17): 1901-12.
Kumar A, Vaish M, Ratan RR. Transcriptional dysregulation in Huntington’s disease: A failure of adaptive transcriptional homeostasis. Drug Discov Today 2014; 19(7): 956-62.
Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr. Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 1985; 44(6): 559-77.
Sotrel A, Paskevich PA, Kiely DK, Bird ED, Williams RS, Myers RH. Morphometric analysis of the prefrontal cortex in Huntington’s disease. Neurology 1991; 41(7): 1117-23.
Jackson M, Gentleman S, Lennox G, et al. The cortical neuritic pathology of Huntington’s disease. Neuropathol Appl Neurobiol 1995; 21(1): 18-26.
Gómez-Tortosa E, MacDonald ME, Friend JC, et al. Quantitative neuropathological changes in presymptomatic Huntington’s disease. Ann Neurol 2001; 49(1): 29-34.
Li H, Li SH, Johnston H, Shelbourne PF, Li XJ. Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat Genet 2000; 25(4): 385-9.
Cowan CM, Raymond LA. Selective neuronal degeneration in Huntington’s disease. Curr Top Dev Biol 2006; 75: 25-71.
Pérez-Navarro E, Canals JM, Ginés S, Alberch J. Cellular and molecular mechanisms involved in the selective vulnerability of striatal projection neurons in Huntington’s disease. Histol Histopathol 2006; 21(11): 1217-32.
Sieradzan KA, Mann DM. The selective vulnerability of nerve cells in Huntington’s disease. Neuropathol Appl Neurobiol 2001; 27(1): 1-21.
Reiner A, Deng YP. Disrupted striatal neuron inputs and outputs in Huntington’s disease. CNS Neurosci Ther 2018; 24(4): 250-80.
Mori S, Zhang J. Principles of diffusion tensor imaging and its applications to basic neuroscience research. Neuron 2006; 51(5): 527-39.
Gatto RG, Li W, Gao J, Magin RL. In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis. NMR Biomed 2018; 31(8)e3954
Gatto RG, Amin MY, Deyoung D, Hey M, Mareci TH, Magin RL. Ultra-high field diffusion mri reveals early axonal pathology in spinal cord of ALS mice. Transl Neurodegener 2018; 7: 20.
Koerte KI, Muehlmann M. Diffusion Tensor Imaging. In: MRI in Psychiatry. Springer: Berlin, Heidelberg 2014; pp. 77-86.
Basser PJ, Pierpaoli C. Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B 1996; 111(3): 209-19.
Alexander AL, Hurley SA, Samsonov AA, et al. Characterization of cerebral white matter properties using quantitative magnetic resonance imaging stains. Brain Connect 2011; 1(6): 423-46.
Alexander AL, Lee JE, Lazar M, Field AS. Diffusion tensor imaging of the brain. Neurotherapeutics 2007; 4(3): 316-29.
Beaulieu C, Allen PS. Determinants of anisotropic water diffusion in nerves. Magn Reson Med 1994; 31(4): 394-400.
Beaulieu C, Allen PS. Water diffusion in the giant axon of the squid: Implications for diffusion-weighted MRI of the nervous system. Magn Reson Med 1994; 32(5): 579-83.
Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH. Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 2003; 20(3): 1714-22.
Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH. Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 2002; 17(3): 1429-36.
Song SK, Yoshino J, Le TQ, et al. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage 2005; 26(1): 132-40.
Basser PJ, Pajevic S, Pierpaoli C, Duda J, Aldroubi A. In vivo fiber tractography using DT-MRI data. Magn Reson Med 2000; 44(4): 625-32.
Mori S, Crain BJ, Chacko VP, van Zijl PC. Three-dimensional tracking of axonal projections in the brain by magnetic resonance imaging. Ann Neurol 1999; 45(2): 265-9.
Phillips O, Sanchez-Castaneda C, Elifani F, et al. Tractography of the corpus callosum in Huntington’s disease. PLoS One 2013; 8(9)e73280
Daducci A, Dal Palú A, Descoteaux M, Thiran JP. Microstructure Informed Tractography: Pitfalls and Open Challenges. Front Neurosci 2016; 10: 247.
Campbell JS, Pike GB. Potential and limitations of diffusion MRI tractography for the study of language. Brain Lang 2014; 131: 65-73.
Thomas C, Ye FQ, Irfanoglu MO, et al. Anatomical accuracy of brain connections derived from diffusion MRI tractography is inherently limited. Proc Natl Acad Sci USA 2014; 111(46): 16574-9.
Lunkes A, Mandel JL. A cellular model that recapitulates major pathogenic steps of Huntington’s disease. Hum Mol Genet 1998; 7(9): 1355-61.
Li Z, Karlovich CA, Fish MP, Scott MP, Myers RM. A putative Drosophila homolog of the Huntington’s disease gene. Hum Mol Genet 1999; 8(9): 1807-15.
Zhang S, Feany MB, Saraswati S, Littleton JT, Perrimon N. Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington’s disease model. Dis Model Mech 2009; 2(5-6): 247-66.
Marsh JL, Pallos J, Thompson LM. Fly models of Huntington’s disease. Hum Mol Genet 2003; 12(Spec No 2): R187-93.
Voisine C, Varma H, Walker N, Bates EA, Stockwell BR, Hart AC. Identification of potential therapeutic drugs for Huntington’s disease using Caenorhabditis elegans. PLoS One 2007; 2(6)e504
Best JD, Alderton WK. Zebrafish: An in vivo model for the study of neurological diseases. Neuropsychiatr Dis Treat 2008; 4(3): 567-76.
Xi Y, Noble S, Ekker M. Modeling neurodegeneration in zebrafish. Curr Neurol Neurosci Rep 2011; 11(3): 274-82.
Das S, Rajanikant GK. Huntington disease: Can a zebrafish trail leave more than a ripple? Neurosci Biobehav Rev 2014; 45: 258-61.
Bates GP, Mangiarini L, Mahal A, Davies SW. Transgenic models of Huntington’s disease. Hum Mol Genet 1997; 6(10): 1633-7.
Ramaswamy S, McBride JL, Kordower JH. Animal models of Huntington’s disease. ILAR J 2007; 48(4): 356-73.
Johnson CD, Davidson BL. Huntington’s disease: Progress toward effective disease-modifying treatments and a cure. Hum Mol Genet 2010; 19(R1): R98-R102.
Qin ZH, Wang J, Gu ZL. Development of novel therapies for Huntington’s disease: Hope and challenge. Acta Pharmacol Sin 2005; 26(2): 129-42.
Heng MY, Detloff PJ, Albin RL. Rodent genetic models of Huntington disease. Neurobiol Dis 2008; 32(1): 1-9.
Gil JM, Rego AC. The R6 lines of transgenic mice: A model for screening new therapies for Huntington’s disease. Brain Res Brain Res Rev 2009; 59(2): 410-31.
Mangiarini L, Sathasivam K, Seller M, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 1996; 87(3): 493-506.
Sathasivam K, Hobbs C, Turmaine M, et al. Formation of polyglutamine inclusions in non-CNS tissue. Hum Mol Genet 1999; 8(5): 813-22.
Naver B, Stub C, Møller M, et al. Molecular and behavioral analysis of the R6/1 Huntington’s disease transgenic mouse. Neuroscience 2003; 122(4): 1049-57.
García-Lara LM-M, Angeles-López QD, Pérez-Neri I, Rodríguez-Balderas CA, Pérez-Severiano F. Establishment and maintenance of an R6/1 transgenic mouse colony and validation of its progressive neurological pheno-type to study Huntington’s disease. Veterinaria 2018; 5(1)
Pérez-Severiano F, Ríos C, Segovia J. Striatal oxidative damage parallels the expression of a neurological phenotype in mice transgenic for the mutation of Huntington’s disease. Brain Res 2000; 862(1-2): 234-7.
Carter RJ, Lione LA, Humby T, et al. Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. J Neurosci 1999; 19(8): 3248-57.
Xiang Z, Valenza M, Cui L, et al. Peroxisome-proliferator-activated receptor gamma coactivator 1 α contributes to dysmyelination in experimental models of Huntington’s disease. J Neurosci 2011; 31(26): 9544-53.
Gatto RG, Chu Y, Ye AQ, et al. Analysis of YFP(J16)-R6/2 reporter mice and postmortem brains reveals early pathology and increased vulnerability of callosal axons in Huntington’s disease. Hum Mol Genet 2015; 24(18): 5285-98.
Gatto RG, Ye AQ, Colon-Perez L, et al. Detection of axonal degeneration in a mouse model of Huntington’s disease: Comparison between diffusion tensor imaging and anomalous diffusion metrics. Magn Reson Mater Phy 2019; pp. 1-11.
Slow EJ, van Raamsdonk J, Rogers D, et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 2003; 12(13): 1555-67.
Gray M, Shirasaki DI, Cepeda C, et al. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 2008; 28(24): 6182-95.
Menalled LB. Knock-in mouse models of Huntington’s disease. NeuroRx 2005; 2(3): 465-70.
Ehrnhoefer DE, Butland SL, Pouladi MA, Hayden MR. Mouse models of Huntington disease: Variations on a theme. Dis Model Mech 2009; 2(3-4): 123-9.
Bates GP, Hockly E. Experimental therapeutics in Huntington’s disease: Are models useful for therapeutic trials? Curr Opin Neurol 2003; 16(4): 465-70.
Steventon JJ, Trueman RC, Ma D, et al. Longitudinal in vivo MRI in a Huntington’s disease mouse model: Global atrophy in the absence of white matter microstructural damage. Sci Rep 2016; 6: 32423.
Smith GA, Rocha EM, McLean JR, et al. Progressive axonal transport and synaptic protein changes correlate with behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse model of Huntington’s disease. Hum Mol Genet 2014; 23(17): 4510-27.
Peng Q, Wu B, Jiang M, et al. Characterization of behavioral, neuropathological, brain metabolic and key molecular changes in zQ175 knock-in mouse model of Huntington’s disease. PLoS One 2016; 11(2)e0148839
Menalled LB, Kudwa AE, Miller S, et al. Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington’s disease: zQ175. PLoS One 2012; 7(12)e49838
Heikkinen T, Lehtimäki K, Vartiainen N, et al. Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington’s disease. PLoS One 2012; 7(12)e50717
Bordelon YM, Chesselet MF, Nelson D, Welsh F, Erecińska M. Energetic dysfunction in quinolinic acid-lesioned rat striatum. J Neurochem 1997; 69(4): 1629-39.
Van Camp N, Blockx I, Camón L, et al. A complementary diffusion tensor imaging (DTI)-histological study in a model of Huntington’s disease. Neurobiol Aging 2012; 33(5): 945-59.
von Hörsten S, Schmitt I, Nguyen HP, et al. Transgenic rat model of Huntington’s disease. Hum Mol Genet 2003; 12(6): 617-24.
Blockx I, Van Camp N, Verhoye M, et al. Genotype specific age related changes in a transgenic rat model of Huntington’s disease. Neuroimage 2011; 58(4): 1006-16.
Antonsen BT, Jiang Y, Veraart J, et al. Altered diffusion tensor imaging measurements in aged transgenic Huntington disease rats. Brain Struct Funct 2013; 218(3): 767-78.
Yu-Taeger L, Petrasch-Parwez E, Osmand AP, et al. A novel BACHD transgenic rat exhibits characteristic neuropathological features of Huntington disease. J Neurosci 2012; 32(44): 15426-38.
Abada YS, Nguyen HP, Schreiber R, Ellenbroek B. Assessment of motor function, sensory motor gating and recognition memory in a novel BACHD transgenic rat model for Huntington disease. PLoS One 2013; 8(7)e68584
Clemensson EK, Clemensson LE, Riess O, Nguyen HP. The BACHD rat model of Huntington disease shows signs of fronto-striatal dysfunction in two operant conditioning tests of short-term memory. PLoS One 2017; 12(1)e0169051
Manfré G, Doyère V, Bossi S, Riess O, Nguyen HP, El Massioui N. Impulsivity trait in the early symptomatic BACHD transgenic rat model of Huntington disease. Behav Brain Res 2016; 299: 6-10.
Adjeroud N, Yagüe S, Yu-Taeger L, et al. Reduced impact of emotion on choice behavior in presymptomatic BACHD rats, a transgenic rodent model for Huntington Disease. Neurobiol Learn Mem 2015; 125: 249-57.
Manfré G, Novati A, Faccini I, et al. BACHD rats expressing full-length mutant huntingtin exhibit differences in social behavior compared to wild-type littermates. PLoS One 2018; 13(2)e0192289
Manfré G, Clemensson EKH, Kyriakou EI, et al. The BACHD rat model of Huntington disease shows specific deficits in a test battery of motor function. Front Behav Neurosci 2017; 11: 218.
Teo RT, Hong X, Yu-Taeger L, et al. Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease. Hum Mol Genet 2016; 25(13): 2621-32.
Menalled L, El-Khodor BF, Patry M, et al. Systematic behavioral evaluation of Huntington’s disease transgenic and knock-in mouse models. Neurobiol Dis 2009; 35(3): 319-36.
Li JY, Popovic N, Brundin P. The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies. NeuroRx 2005; 2(3): 447-64.
Stack EC, Kubilus JK, Smith K, et al. Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington’s disease transgenic mice. J Comp Neurol 2005; 490(4): 354-70.
Schilling G, Becher MW, Sharp AH, et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 1999; 8(3): 397-407.
Carreira JC, Jahanshahi A, Zeef D, et al. Transgenic rat models of Huntington’s disease. Curr Top Behav Neurosci 2015; 22: 135-47.
Abada YS, Nguyen HP, Ellenbroek B, Schreiber R. Reversal learning and associative memory impairments in a BACHD rat model for Huntington disease. PLoS One 2013; 8(11)e71633
Petrella LI, Castelhano JM, Ribeiro M, et al. A whole brain longitudinal study in the YAC128 mouse model of Huntington’s disease shows distinct trajectories of neurochemical, structural connectivity and volumetric changes. Hum Mol Genet 2018; 27(12): 2125-37.
Garcia-Miralles M, Hong X, Tan LJ, et al. Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease. Sci Rep 2016; 6: 31652.
Wang LH, Qin ZH. Animal models of Huntington’s disease: Implications in uncovering pathogenic mechanisms and developing therapies. Acta Pharmacol Sin 2006; 27(10): 1287-302.
Li XJ, Li S. Large animal models of Huntington’s disease. Curr Top Behav Neurosci 2015; 22: 149-60.
Jacobsen JC, Bawden CS, Rudiger SR, et al. An ovine transgenic Huntington’s disease model. Hum Mol Genet 2010; 19(10): 1873-82.
Handley RR, Reid SJ, Patassini S, et al. Metabolic disruption identified in the Huntington’s disease transgenic sheep model. Sci Rep 2016; 6: 20681.
Reid SJ, Patassini S, Handley RR, et al. Further molecular characterisation of the OVT73 transgenic sheep model of Huntington’s disease identifies cortical aggregates. J Huntingtons Dis 2013; 2(3): 279-95.
Handley RR, Reid SJ, Brauning R, et al. Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases. Proc Natl Acad Sci USA 2017; 114(52): E11293-302.
Matsuyama N, Hadano S, Onoe K, et al. Identification and characterization of the miniature pig Huntington’s disease gene homolog: evidence for conservation and polymorphism in the CAG triplet repeat. Genomics 2000; 69(1): 72-85.
Uchida M, Shimatsu Y, Onoe K, et al. Production of transgenic miniature pigs by pronuclear microinjection. Transgenic Res 2001; 10(6): 577-82.
Baxa M, Hruska-Plochan M, Juhas S, et al. A transgenic minipig model of Huntington’s disease. J Huntingtons Dis 2013; 2(1): 47-68.
Schramke RSR, Frank F, Wirsig M, et al. The libechov minipig as a large animal model for preclinical research in Huntington’s disease – thoughts and perspectives. Cesk Slov Neurol N 2015; 78(11): 55-60.
Yan S, Tu Z, Liu Z, et al. A Huntingtin knockin pig model recapitulates features of selective neurodegeneration in Huntington’s disease. Cell 2018; 173: 989-1002.
Krizova J, Stufkova H, Rodinova M, et al. Mitochondrial metabolism in a large-animal model of huntington disease: The hunt for biomarkers in the spermatozoa of presymptomatic minipigs. Neurodegener Dis 2017; 17(4-5): 213-26.
Macakova M, Bohuslavova B, Vochozkova P, et al. Mutated Huntingtin causes testicular pathology in transgenic minipig boars. Neurodegener Dis 2016; 16(3-4): 245-59.
Vidinská D, Vochozková P, Šmatlíková P, et al. Gradual phenotype development in huntington disease transgenic minipig model at 24 months of Age. Neurodegener Dis 2018; 18(2-3): 107-19.
Schuldenzucker V, Schubert R, Muratori LM, et al. Behavioral assessment of stress compensation in minipigs transgenic for the Huntington gene using cortisol levels: A proof-of-concept study. J Huntingtons Dis 2018; 7(2): 151-61.
Schuldenzucker V, Schubert R, Muratori LM, et al. Behavioral testing of minipigs transgenic for the Huntington gene-A three-year observational study. PLoS One 2017; 12(10)e0185970
Schramke S, Schuldenzucker V, Schubert R, et al. Behavioral phenotyping of minipigs transgenic for the Huntington gene. J Neurosci Methods 2016; 265: 34-45.
Valekova I, Jarkovska K, Kotrcova E, et al. Revelation of the IFNα, IL-10, IL-8 and IL-1β as promising biomarkers reflecting immuno-pathological mechanisms in porcine Huntington’s disease model. J Neuroimmunol 2016; 293: 71-81.
Yang D, Wang CE, Zhao B, et al. Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum Mol Genet 2010; 19(20): 3983-94.
Jozefovicova M, Herynek V, Jiru F, et al. Minipig model of Huntington’s disease: 1H magnetic resonance spectroscopy of the brain. Physiol Res 2016; 65(1): 155-63.
Schubert R, Frank F, Nagelmann N, et al. Neuroimaging of a minipig model of Huntington’s disease: Feasibility of volumetric, diffusion-weighted and spectroscopic assessments. J Neurosci Methods 2016; 265: 46-55.
Ferrante RJ, Kowall NW, Cipolloni PB, Storey E, Beal MF. Excitotoxin lesions in primates as a model for Huntington’s disease: Histopathologic and neurochemical characterization. Exp Neurol 1993; 119(1): 46-71.
Hantraye P, Riche D, Maziere M, Isacson O. A primate model of Huntington’s disease: Behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon. Exp Neurol 1990; 108(2): 91-104.
Roitberg BZ, Emborg ME, Sramek JG, Palfi S, Kordower JH. Behavioral and morphological comparison of two nonhuman primate models of Huntington’s disease. Neurosurgery 2002; 50(1): 137-45.
Burns LH, Pakzaban P, Deacon TW, et al. Selective putaminal excitotoxic lesions in non-human primates model the movement disorder of Huntington disease. Neuroscience 1995; 64(4): 1007-17.
McBride JL, Pitzer MR, Boudreau RL, et al. Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Mol Ther 2011; 19(12): 2152-62.
Grondin R, Kaytor MD, Ai Y, et al. Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain 2012; 135(Pt 4): 1197-209.
Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of Huntingtin Synthesis. Neuron 2012; 74(6): 1031-44.
Li XJ, Li S. Influence of species differences on the neuropathology of transgenic Huntington’s disease animal models. J Genet Genomics 2012; 39(6): 239-45.
Hunter CE, Pongos AL, Chi TY, Payne C, Stroud FC, Chan AWS. Longitudinal Anthropometric Assessment of Rhesus Macaque (Macaca mulatta) Model of Huntington Disease. Comp Med 2018; 68(2): 163-7.
Snyder BR, Chan AWS. Progress in developing transgenic monkey model for Huntington’s disease. J Neural Transm (Vienna) 2018; 125(3): 401-17.
Chan AW, Jiang J, Chen Y, et al. Progressive cognitive deficit, motor impairment and striatal pathology in a transgenic Huntington disease monkey model from infancy to adulthood. PLoS One 2015; 10(5)e0122335
Raper J, Bosinger S, Johnson Z, Tharp G, Moran SP, Chan AWS. Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys. Brain Behav Immun 2016; 58: 181-90.
Politis M, Lahiri N, Niccolini F, et al. Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington’s disease gene carriers. Neurobiol Dis 2015; 83: 115-21.
Meng Y, Jiang J, Bachevalier J, Zhang X, Chan AW. Developmental whole brain white matter alterations in transgenic Huntington’s disease monkey. Sci Rep 2017; 7(1): 379.
Rosas HD, Koroshetz WJ, Chen YI, et al. Evidence for more widespread cerebral pathology in early HD: An MRI-based morphometric analysis. Neurology 2003; 60(10): 1615-20.
Reading SA, Yassa MA, Bakker A, et al. Regional white matter change in pre-symptomatic Huntington’s disease: A diffusion tensor imaging study. Psychiatry Res 2005; 140(1): 55-62.
Rosas HD, Tuch DS, Hevelone ND, 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(9): 1317-25.
Bohanna I, Georgiou-Karistianis N, Hannan AJ, Egan GF. Magnetic resonance imaging as an approach towards identifying neuropathological biomarkers for Huntington’s disease. Brain Res Brain Res Rev 2008; 58(1): 209-25.
Klöppel S, Draganski B, Golding CV, et al. White matter connections reflect changes in voluntary-guided saccades in pre-symptomatic Huntington’s disease. Brain 2008; 131(Pt 1): 196-204.
Weaver KE, Richards TL, Liang O, Laurino MY, Samii A, Aylward EH. Longitudinal diffusion tensor imaging in Huntington’s disease. Exp Neurol 2009; 216(2): 525-9.
Douaud G, Behrens TE, Poupon C, et al. In vivo evidence for the selective subcortical degeneration in Huntington’s disease. Neuroimage 2009; 46(4): 958-66.
Rosas HD, Lee SY, Bender AC, et al. Altered white matter microstructure in the corpus callosum in Huntington’s disease: Implications for cortical “disconnection”. Neuroimage 2010; 49(4): 2995-3004.
Bohanna I, Georgiou-Karistianis N, Sritharan A, et al. Diffusion tensor imaging in Huntington’s disease reveals distinct patterns of white matter degeneration associated with motor and cognitive deficits. Brain Imaging Behav 2011; 5(3): 171-80.
Di Paola M, Luders E, Cherubini A, et al. Multimodal MRI analysis of the corpus callosum reveals white matter differences in presymptomatic and early Huntington’s disease. In: Cerebral cortex . (New York, NY: 1991) 2012; 22: pp. 2858-66.
Dumas EM, van den Bogaard SJ, Ruber ME, et al. Early changes in white matter pathways of the sensorimotor cortex in premanifest Huntington’s disease. Hum Brain Mapp 2012; 33(1): 203-12.
Sritharan A, Egan GF, Johnston L, et al. A longitudinal diffusion tensor imaging study in symptomatic Huntington’s disease. J Neurol Neurosurg Psychiatry 2010; 81(3): 257-62.
Singh S, Mehta H, Fekete R. Altered fractional anisotropy in early Huntington’s disease. Case Rep Neurol 2013; 5(1): 26-30.
Mandelli ML, Savoiardo M, Minati L, et al. Decreased diffusivity in the caudate nucleus of presymptomatic huntington disease gene carriers: Which explanation? AJNR Am J Neuroradiol 2010; 31(4): 706-10.
Müller HP, Grön G, Sprengelmeyer R, et al. Evaluating multicenter DTI data in Huntington’s disease on site specific effects: An ex post facto approach. Neuroimage Clin 2013; 2: 161-7.
Hobbs NZ, Cole JH, Farmer RE, et al. Evaluation of multi-modal, multi-site neuroimaging measures in Huntington’s disease: Baseline results from the PADDINGTON study. Neuroimage Clin 2012; 2: 204-11.
Sánchez-Castañeda C, Cherubini A, Elifani F, et al. Seeking Huntington disease biomarkers by multimodal, cross-sectional basal ganglia imaging. Hum Brain Mapp 2013; 34(7): 1625-35.
Georgiou-Karistianis N, Gray MA, Domínguez DJF, 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: 82-92.
Domínguez DJF, Egan GF, Gray MA, 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(9)e74131
D JF, Stout JC, Poudel G, et al. Multimodal imaging biomarkers in premanifest and early Huntington’s disease: 30-month IMAGE-HD data. Br J Psychiatry 2016; 208(6): 571-8.
Gregory S, Scahill RI, Seunarine KK, et al. Neuropsychiatry and white matter microstructure in Huntington’s disease. J Huntingtons Dis 2015; 4(3): 239-49.
Gregory S, Cole JH, Farmer RE, et al. Longitudinal diffusion tensor imaging shows progressive changes in white matter in Huntington’s disease. J Huntingtons Dis 2015; 4(4): 333-46.
Odish OF, Leemans A, Reijntjes RH, et al. Microstructural brain abnormalities in Huntington’s disease: A two-year follow-up. Hum Brain Mapp 2015; 36(6): 2061-74.
Phillips OR, Joshi SH, Squitieri F, et al. Major superficial white matter abnormalities in Huntington’s disease. Front Neurosci 2016; 10: 197.
Phillips O, Squitieri F, Sanchez-Castaneda C, et al. Deep white matter in Huntington’s disease. PLoS One 2014; 9(10)e109676
Delmaire C, Dumas EM, Sharman MA, et al. The structural correlates of functional deficits in early Huntington’s disease. Hum Brain Mapp 2013; 34(9): 2141-53.
Odish OFF, Reijntjes RHAM, van den Bogaard SJA, Roos RAC, Leemans A. Progressive microstructural changes of the occipital cortex in Huntington’s disease. Brain Imaging Behav 2018; 12(6): 1786-94.
Shaffer JJ, Ghayoor A, Long JD, et al. Longitudinal diffusion changes in prodromal and early HD: Evidence of white-matter tract deterioration. Hum Brain Mapp 2017; 38(3): 1460-77.
Wu D, Faria AV, Younes L, et al. Mapping the order and pattern of brain structural MRI changes using change-point analysis in premanifest Huntington’s disease. Hum Brain Mapp 2017; 38(10): 5035-50.
Garcia-Gorro C, de Diego-Balaguer R, Martínez-Horta S, et al. Reduced striato-cortical and inhibitory transcallosal connectivity in the motor circuit of Huntington’s disease patients. Hum Brain Mapp 2018; 39(1): 54-71.
Paulsen JS. Early Detection of Huntington Disease. Future Neurol 2010; 5(1): 1-8.
Gorges M, Müller HP, Mayer IM, et al. Intact sensory-motor network structure and function in far from onset premanifest Huntington’s disease. Sci Rep 2017; 7: 43841.
Matsui JT, Vaidya JG, Johnson HJ, et al. Diffusion weighted imaging of prefrontal cortex in prodromal Huntington’s disease. Hum Brain Mapp 2014; 35(4): 1562-73.
Matsui JT, Vaidya JG, Wassermann D, et al. Prefrontal cortex white matter tracts in prodromal Huntington disease. Hum Brain Mapp 2015; 36(10): 3717-32.
Novak MJ, Seunarine KK, Gibbard CR, et al. White matter integrity in premanifest and early Huntington’s disease is related to caudate loss and disease progression. Cortex 2014; 52: 98-112.
Sprengelmeyer R, Young AW, Baldas EM, et al. The neuropsychology of first impressions: Evidence from Huntington’s disease. Cortex 2016; 85: 100-15.
Faria AV, Ratnanather JT, Tward DJ, et al. Linking white matter and deep gray matter alterations in premanifest Huntington disease. Neuroimage Clin 2016; 11: 450-60.
Rosas HDWP, Salat DH, Mercaldo ND, Vangel M, Yendikic AY, Hersch SM. Complex spatial and temporally defined myelin and axonal degeneration in Huntington disease. Neuroimage Clin 2018.
Liu W, Yang J, Burgunder J, Cheng B, Shang H. Diffusion imaging studies of Huntington’s disease: A Meta-analysis. Parkinsonism Relat Disord 2016; 32: 94-101.
Steventon JJ, Trueman RC, Rosser AE, Jones DK. Robust MR-based approaches to quantifying white matter structure and structure/function alterations in Huntington’s disease. J Neurosci Methods 2016; 265: 2-12.
Müller HP, Gorges M, Grön G, et al. Motor network structure and function are associated with motor performance in Huntington’s disease. J Neurol 2016; 263(3): 539-49.
Syka M, Keller J, Klempíř J, et al. Correlation between relaxometry and diffusion tensor imaging in the globus pallidus of Huntington’s disease patients. PLoS One 2015; 10(3)e0118907
Poudel GR, Stout JC, Domínguez DJF, et al. Longitudinal change in white matter microstructure in Huntington’s disease: The IMAGE-HD study. Neurobiol Dis 2015; 74: 406-12.
Müller HP, Kassubek J, Grön G, et al. Impact of the control for corrupted diffusion tensor imaging data in comparisons at the group level: An application in Huntington disease. Biomed Eng Online 2014; 13: 128.
Della Nave R, Ginestroni A, Tessa C, et al. Regional distribution and clinical correlates of white matter structural damage in Huntington disease: A tract-based spatial statistics study. AJNR Am J Neuroradiol 2010; 31(9): 1675-81.
Cummings DM, Alaghband Y, Hickey MA, et al. A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington’s disease. J Neurophysiol 2012; 107(2): 677-91.
Cowin RM, Bui N, Graham D, et al. Onset and progression of behavioral and molecular phenotypes in a novel congenic R6/2 line exhibiting intergenerational CAG repeat stability. PLoS One 2011; 6(12)e28409
Skillings EA, Wood NI, Morton AJ. Beneficial effects of environmental enrichment and food entrainment in the R6/2 mouse model of Huntington’s disease. Brain Behav 2014; 4(5): 675-86.
Menalled LB, Sison JD, Wu Y, et al. Early motor dysfunction and striosomal distribution of huntingtin microaggregates in Huntington’s disease knock-in mice. J Neurosci 2002; 22(18): 8266-76.
Chang R, Liu X, Li S, Li XJ. Transgenic animal models for study of the pathogenesis of Huntington’s disease and therapy. Drug Des Devel Ther 2015; 9: 2179-88.
Soares JM, Marques P, Alves V, Sousa N. A hitchhiker’s guide to diffusion tensor imaging. Front Neurosci 2013; 7: 31.
Gatto R, Chauhan M, Chauhan N. Anti-edema effects of rhEpo in experimental traumatic brain injury. Restor Neurol Neurosci 2015; 33(6): 927-41.
Gatto RG. Diffusion tensor imaging as a tool to detect presymptomatic axonal degeneration in a preclinical spinal cord model of amyotrophic lateral sclerosis. Neural Regen Res 2018; 13(3): 425-6.
Gatto RG, Li W, Magin RL. Diffusion tensor imaging identifies presymptomatic axonal degeneration in the spinal cord of ALS mice. Brain Res 2018; 1679: 45-52.
Inglese M, Bester M. Diffusion imaging in multiple sclerosis: Research and clinical implications. NMR Biomed 2010; 23(7): 865-72.
Stebbins GT, Murphy CM. Diffusion tensor imaging in Alzheimer’s disease and mild cognitive impairment. Behav Neurol 2009; 21(1): 39-49.
Garaci F, Toschi N, Lanzafame S, et al. Diffusion tensor imaging in SPG11- and SPG4-linked hereditary spastic paraplegia. Int J Neurosci 2014; 124(4): 261-70.
Jones DK, Knösche TR, Turner R. White matter integrity, fiber count, and other fallacies: The do’s and don’ts of diffusion MRI. Neuroimage 2013; 73: 239-54.
Crook ZR, Housman D. Huntington’s disease: Can mice lead the way to treatment? Neuron 2011; 69(3): 423-35.
Rajkowska G, Selemon LD, Goldman-Rakic PS. Neuronal and glial somal size in the prefrontal cortex: A postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 1998; 55(3): 215-24.
Luebke JI, Weaver CM, Rocher AB, et al. Dendritic vulnerability in neurodegenerative disease: Insights from analyses of cortical pyramidal neurons in transgenic mouse models. Brain Struct Funct 2010; 214(2-3): 181-99.
Barnat M, Le Friec J, Benstaali C, Humbert S. Huntingtin-mediated multipolar-bipolar transition of newborn cortical neurons is critical for their postnatal neuronal morphology. Neuron 2017; 93(1): 99-114.
Guidetti P, Charles V, Chen EY, et al. Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production. Exp Neurol 2001; 169(2): 340-50.
Jurgens CK, van de Wiel L, van Es AC, et al. Basal ganglia volume and clinical correlates in ‘preclinical’ Huntington’s disease. J Neurol 2008; 255(11): 1785-91.
van den Bogaard SJ, Dumas EM, Acharya TP, et al. Early atrophy of pallidum and accumbens nucleus in Huntington’s disease. J Neurol 2011; 258(3): 412-20.
Singer E, Walter C, Weber JJ, et al. Reduced cell size, chromosomal aberration and altered proliferation rates are characteristics and confounding factors in the STHdh cell model of Huntington disease. Sci Rep 2017; 7(1): 16880.
Akopian G, Barry J, Cepeda C, Levine MS. Altered membrane properties and firing patterns of external globus pallidus neurons in the R6/2 mouse model of Huntington’s disease. J Neurosci Res 2016; 94(12): 1400-10.
Chen J, Marks E, Lai B, et al. Iron accumulates in Huntington’s disease neurons: Protection by deferoxamine. PLoS One 2013; 8(10)e77023
Niu L, Ye C, Sun Y, et al. Mutant huntingtin induces iron overload via up-regulating IRP1 in Huntington’s disease. Cell Biosci 2018; 8: 41.
Domínguez JF, Ng AC, Poudel G, et al. Iron accumulation in the basal ganglia in Huntington’s disease: Cross-sectional data from the IMAGE-HD study. J Neurol Neurosurg Psychiatry 2016; 87(5): 545-9.
Rosas HD, Chen YI, Doros G, et al. Alterations in brain transition metals in Huntington disease: An evolving and intricate story. Arch Neurol 2012; 69(7): 887-93.
Dumas EM, Versluis MJ, van den Bogaard SJ, et al. Elevated brain iron is independent from atrophy in Huntington’s disease. Neuroimage 2012; 61(3): 558-64.
van den Bogaard SJ, Dumas EM, Roos RA. The role of iron imaging in Huntington’s disease. Int Rev Neurobiol 2013; 110: 241-50.
Jurgens CK, Jasinschi R, Ekin A, et al. MRI T2 Hypointensities in basal ganglia of premanifest Huntington’s disease. PLoS Curr 2010; 2: 2.
Di Paola M, Phillips OR, Sanchez-Castaneda C, et al. MRI measures of corpus callosum iron and myelin in early Huntington’s disease. Hum Brain Mapp 2014; 35(7): 3143-51.
Pattison LR, Kotter MR, Fraga D, Bonelli RM. Apoptotic cascades as possible targets for inhibiting cell death in Huntington’s disease. J Neurol 2006; 253(9): 1137-42.
Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 2011; 14(3): 285-93.
Aung WY, Mar S, Benzinger TL. Diffusion tensor MRI as a biomarker in axonal and myelin damage. Imaging Med 2013; 5(5): 427-40.
Müller HP, Kassubek J, Vernikouskaya I, Ludolph AC, Stiller D, Rasche V. Diffusion tensor magnetic resonance imaging of the brain in APP transgenic mice: A cohort study. PLoS One 2013; 8(6)e67630
Hofling AA, Kim JH, Fantz CR, Sands MS, Song SK. Diffusion tensor imaging detects axonal injury and demyelination in the spinal cord and cranial nerves of a murine model of globoid cell leukodystrophy. NMR Biomed 2009; 22(10): 1100-6.
Cong L, Muir ER, Chen C, et al. Multimodal MRI Evaluation of the MitoPark Mouse Model of Parkinson’s Disease. PLoS One 2016; 11(3)e0151884
Schilling K, Janve V, Gao Y, Stepniewska I, Landman BA, Anderson AW. Comparison of 3D orientation distribution functions measured with confocal microscopy and diffusion MRI. Neuroimage 2016; 129: 185-97.
Kamagata K, Kerever A, Yokosawa S, et al. Quantitative histological validation of diffusion tensor mri with two-photon microscopy of cleared mouse Brain. Magn Reson Med Sci 2016; 15(4): 416-21.
Cardenas AM, Sarlls JE, Kwan JY, et al. Pathology of callosal damage in ALS: An ex-vivo, 7 T diffusion tensor MRI study. Neuroimage Clin 2017; 15: 200-8.
Gatto RGM, Mustafi SM, Amin MY, Mareci TH, Wu YC, Magin RL. Neurite orientation dispersion and density imaging can detect presymptomatic axonal degeneration in the spinal cord of ALS mice. Funct Neurol 2018; 33(3): 155-63.
Zhang J, Gregory S, Scahill RI, et al. In vivo characterization of white matter pathology in premanifest huntington’s disease. Ann Neurol 2018; 84(4): 497-504.
Wheeler-Kingshott CA, Cercignani M. About “axial” and “radial” diffusivities. Magn Reson Med 2009; 61(5): 1255-60.
Magin RL, Ingo C, Colon-Perez L, Triplett W, Mareci TH. Characterization of anomalous diffusion in porous biological tissues using fractional order derivatives and entropy. Microporous Mesoporous Mater 2013; 178: 39-43.
Magin RL, Akpa BS, Neuberger T, Webb AG. Fractional order analysis of sephadex gel structures: NMR measurements reflecting anomalous diffusion. Commun Nonlinear Sci Numer Simul 2011; 16(12): 4581-7.
Ingo C, Magin RL, Colon-Perez L, Triplett W, Mareci TH. On random walks and entropy in diffusion-weighted magnetic resonance imaging studies of neural tissue. Magn Reson Med 2014; 71(2): 617-27.

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