Skip to main content Accessibility help
×
Home

Cognitive Control, Learning, and Clinical Motor Ratings Are Most Highly Associated with Basal Ganglia Brain Volumes in the Premanifest Huntington’s Disease Phenotype

  • Maria B. Misiura (a1), Spencer Lourens (a2), Vince D. Calhoun (a3) (a4), Jeffrey Long (a2), Jeremy Bockholt (a2), Hans Johnson (a2), Ying Zhang (a2), Jane S. Paulsen (a2), Jessica A. Turner (a1), Jingyu Liu (a3), Betul Kara (a5), Elizabeth Fall (a1) and for the PREDICT-HD Investigators & Working Group...

Abstract

Objectives: Huntington’s disease (HD) is a debilitating genetic disorder characterized by motor, cognitive and psychiatric abnormalities associated with neuropathological decline. HD pathology is the result of an extended chain of CAG (cytosine, adenine, guanine) trinucleotide repetitions in the HTT gene. Clinical diagnosis of HD requires the presence of an otherwise unexplained extrapyramidal movement disorder in a participant at risk for HD. Over the past 15 years, evidence has shown that cognitive, psychiatric, and subtle motor dysfunction is evident decades before traditional motor diagnosis. This study examines the relationships among subcortical brain volumes and measures of emerging disease phenotype in prodromal HD, before clinical diagnosis. Methods: The dataset includes 34 cognitive, motor, psychiatric, and functional variables and five subcortical brain volumes from 984 prodromal HD individuals enrolled in the PREDICT HD study. Using cluster analyses, seven distinct clusters encompassing cognitive, motor, psychiatric, and functional domains were identified. Individual cluster scores were then regressed against the subcortical brain volumetric measurements. Results: Accounting for site and genetic burden (the interaction of age and CAG repeat length) smaller caudate and putamen volumes were related to clusters reflecting motor symptom severity, cognitive control, and verbal learning. Conclusions: Variable reduction of the HD phenotype using cluster analysis revealed biologically related domains of HD and are suitable for future research with this population. Our cognitive control cluster scores show sensitivity to changes in basal ganglia both within and outside the striatum that may not be captured by examining only motor scores. (JINS, 2017, 23, 159–170)

Copyright

Corresponding author

Correspondence and reprint requests to: Jane S. Paulsen,305 Medical Education Building, 200 Newton Road, Iowa City, IA 52242. E-mail:jane-paulsen@uiowa.edu

References

Hide All
Alexander, G.E., & Crutcher, M.D. (1990). Functional architecture of basal ganglia circuits: Neural substrates of parallel processing. Trends in Neurosciences, 13(7), 266271.
Aylward, E.H., Harrington, D.L., Mills, J.A., Nopoulos, P.C., Ross, C.A., Long, J.D., & the PREDICT-HD Investigators and Coordinators of the Huntington Study Group. (2013). Regional atrophy associated with cognitive and motor function in prodromal Huntington disease. Journal of Huntington’s Disease, 2(4), 477489. https://doi.org/10.3233/JHD-130076
Aylward, E.H., Liu, D., Nopoulos, P.C., Ross, C.A., Pierson, R.K., Mills, J.A., & Paulsen, J.S. (2011). Striatal volume contributes to the prediction of onset of Huntington disease in incident cases. Biological Psychiatry, 71(9), 822828. https://doi.org/10.1016/j.biopsych.2011.07.030
Aylward, E.H., Nopoulos, P.C., Ross, C.A., Langbehn, D.R., Pierson, R.K., … Mills, J.A., Coordinators of Huntington Study, G. (2011). Longitudinal change in regional brain volumes in prodromal Huntington disease. Journal of Neurology, Neurosurgery, and Psychiatry, 82(4), 405410. https://doi.org/10.1136/jnnp.2010.208264
Beglinger, L.J., Paulsen, J.S., Watson, D.B., Wang, M.C., Duff, K., Langbehn, D.R., … Stout, J.C. (2008). Obsessive and compulsive symptoms in prediagnosed Huntington’s disease. The Journal of Clinical Psychiatry, 69(11), 17581765.
Dalley, J.W., Everitt, B.J., & Robbins, T.W. (2011). Impulsivity, compulsivity, and top-down cognitive control. Neuron, 69(4), 680694. https://doi.org/http://dx.doi.org/10.1016/j.neuron.2011.01.020
Duff, K., Paulsen, J.S., Beglinger, L.J., Langbehn, D.R., Stout, J.C., & Predict-HD Investigators of the Huntington Study Group. (2007). Psychiatric symptoms in Huntington’s disease before diagnosis: The predict-HD study. Biological Psychiatry, 62(12), 13411346. https://doi.org/10.1016/j.biopsych.2006.11.034
Elliott, R. (2003). Executive functions and their disorders: Imaging in clinical neuroscience. British Medical Bulletin, 65(1), 4959. https://doi.org/10.1093/bmb/65.1.49
Epping, E.A., Kim, J.-I., Craufurd, D., Brashers-Krug, T.M., Anderson, K.E., McCusker, E., & Paulsen, J. (2015). Longitudinal psychiatric symptoms in prodromal Huntington’s disease: A decade of data. American Journal of Psychiatry, 173(2), 184192. https://doi.org/10.1176/appi.ajp.2015.14121551
Epping, E.A., Mills, J.A., Beglinger, L.J., Fiedorowicz, J.G., Craufurd, D., Smith, M.M., & Paulsen, J.S. (2013). Characterization of depression in prodromal Huntington disease in the neurobiological predictors of HD (PREDICT-HD) study. Journal of Psychiatric Research, 47(10), 14231431. https://doi.org/10.1016/j.jpsychires.2013.05.026
Evans, S.J., Douglas, I., Rawlins, M.D., Wexler, N.S., Tabrizi, S.J., & Smeeth, L. (2013). Prevalence of adult Huntington’s disease in the UK based on diagnoses recorded in general practice records. Journal of Neurology, Neurosurgery, & Psychiatry, 84(10), 11561160. https://doi.org/10.1136/jnnp-2012-304636
Fennema-Notestine, C., Gamst, A.C., Quinn, B.T., Pacheco, J., Jernigan, T.L., Thal, L., & Gollub, R.L. (2007). Feasibility of multi-site clinical structural neuroimaging studies of aging using legacy data. Neuroinformatics, 5(4), 235245. https://doi.org/10.1007/s12021-007-9003-9
Fisher, E.R., & Hayden, M.R. (2014). Multisource ascertainment of Huntington disease in Canada: Prevalence and population at risk. Movement Disorders, 29(1), 105114. https://doi.org/10.1002/mds.25717
Ghayoor, A., Vaidya, J.G., & Johnson, H.J. (2013). Development of a novel constellation based landmark detection algorithm. Proc SPIE, 8669, 86693F86693F–6.
Halliday, G.M., McRitchie, D.A., Macdonald, V., Double, K.L., Trent, R.J., & McCusker, E. (1998). Regional specificity of brain atrophy in Huntington’s disease. Experimental Neurology, 154(2), 663672. https://doi.org/10.1006/exnr.1998.6919
Harrington, D.L., Liu, D., Smith, M.M., Mills, J.A., Long, J.D., Aylward, E.H., &&Paulsen, J.S. (2014). Neuroanatomical correlates of cognitive functioning in prodromal Huntington disease. Brain and Behavior, 4(1), 2940. https://doi.org/10.1002/brb3.185
Harrington, D.L., Rubinov, M., Durgerian, S., Mourany, L., Reece, C., Koenig, K., & Rao, S.M. (2015). Network topology and functional connectivity disturbances precede the onset of Huntington’s disease. Brain, 138(8), 23322346. https://doi.org/10.1093/brain/awv145
Harrington, D.L., Smith, M.M., Zhang, Y., Carlozzi, N.E., Paulsen, J.S., & PREDICT-HD Investigators of the Huntington Study Group. (2012). Cognitive domains that predict time to diagnosis in prodromal Huntington disease. Journal of Neurology, Neurosurgery, & Psychiatry, 83(6), 612619. https://doi.org/10.1136/jnnp-2011-301732
Herben-Dekker, M., van Oostrom, J. C.H., Roos, R.A.C., Jurgens, C.K., Witjes-Ané, M.-N.W., Kremer, H.P.H., … Spikman, J.M. (2014). Striatal metabolism and psychomotor speed as predictors of motor onset in Huntington’s disease. Journal of Neurology, 261(7), 13871397.
Jech, R., Klempir, J., Vymazal, J., Zidovska, J., Klempirova, O., Ruzicka, E., && Roth, J. (2007). Variation of selective gray and white matter atrophy in Huntington’s disease. Movement Disorders, 22(12), 17831789. https://doi.org/10.1002/mds.21620
Joost, M.H., Raymund, C.H.V.O., Leenders, K.L., & Spikman, J.M. (2014). Striatal metabolism and psychomotor speed as predictors of motor onset in Huntington’s disease, 1387–1397. https://doi.org/10.1007/s00415-014-7350-7.
Jovicich, J., Czanner, S., Han, X., Salat, D., van der Kouwe, A., Quinn, B., & Fischl, B. (2009). MRI-derived measurements of human subcortical, ventricular and intracranial brain volumes: Reliability effects of scan sessions, acquisition sequences, data analyses, scanner upgrade, scanner vendors and field strengths. Neuroimage, 46(1), 177192. https://doi.org/10.1016/j.neuroimage.2009.02.010
Julien, C.L., Thompson, J.C., Wild, S., Yardumian, P., Snowden, J.S., Turner, G., &&Craufurd, D. (2007). Psychiatric disorders in preclinical Huntington’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 78(9), 939943. https://doi.org/10.1136/jnnp.2006.103309
Kim, E.Y., Magnotta, V.A., Liu, D., & Johnson, H.J. (2014). Stable Atlas-based Mapped Prior (STAMP) machine-learning segmentation for multicenter large-scale MRI data. Magnetic Resonance Imaging, 32(7), 832844. https://doi.org/http://dx.doi.org/10.1016/j.mri.2014.04.016
Kloppel, S., Chu, C., Tan, G.C., Draganski, B., Johnson, H., Paulsen, J.S., & PREDICT-HD Investigators of the Huntington Study Group. (2009). Automatic detection of preclinical neurodegeneration: Presymptomatic Huntington disease. Neurology, 72(5), 426431. https://doi.org/10.1212/01.wnl.0000341768.28646.b6
Klöppel, S., Stonnington, C.M., Petrovic, P., Mobbs, D., Tüscher, O., Craufurd, D., & Frackowiak, R.S. (2010). Irritability in pre-clinical Huntington’s disease. Neuropsychologia, 48(2), 549557. https://doi.org/10.1016/j.neuropsychologia.2009.10.016
Koenig, K.A., Lowe, M.J., Harrington, D.L., Lin, J., Durgerian, S., Mourany, L., & Rao, S.M. (2014). Functional connectivity of primary motor cortex is dependent on genetic burden in prodromal Huntington disease. Brain Connectivity, 4(7), 535546. https://doi.org/10.1089/brain.2014.0271
Leisman, G., Braun-Benjamin, O., & Melillo, R. (2014). Cognitive-motor interactions of the basal ganglia in development. Frontiers in Systems Neuroscience, 8, 16. https://doi.org/10.3389/fnsys.2014.00016
Levy, M.L., Cummings, J.L., Fairbanks, L.A., Masterman, D., Miller, B.L., Craig, A.H., & Litvan, I. (1998). Apathy is not depression. The Journal of Neuropsychiatry and Clinical Neurosciences, 10(3), 314319.
Litvan, I., Paulsen, J.S., Mega, M.S., & Cummings, J.L. (1998). Neuropsychiatric assessment of patients with hyperkinetic and hypokinetic movement disorders. Archives of Neurology, 55(10), 13131319. https://doi.org/10.1001/archneur.55.10.1313
Malejko, K., Weydt, P., Sussmuth, S.D., Gron, G., Landwehrmeyer, B.G., & Abler, B. (2014). Prodromal Huntington disease as a model for functional compensation of early neurodegeneration. PLoS One, 9(12), e114569. https://doi.org/10.1371/journal.pone.0114569
Marin, R.S. (1991). Apathy: A neuropsychiatric syndrome. The Journal of Neuropsychiatry and Clinical Neurosciences, 3(3), 243254.
Martinez-Horta, S., Perez-Perez, J., van Duijn, E., Fernandez-Bobadilla, R., Carceller, M., Pagonabarraga, J., & Kulisevsky, J. (2016). Neuropsychiatric symptoms are very common in premanifest and early stage Huntington’s Disease. Parkinsonism & Related Disorders, 25, 5864. https://doi.org/10.1016/j.parkreldis.2016.02.008
Meyer, A., Zimmermann, R., Gschwandtner, U., Hatz, F., Bousleiman, H., Schwarz, N., && Fuhr, P. (2014). Apathy in Parkinson’s disease is related to executive function, gender and age but not to depression. Frontiers in Aging Neuroscience, 6, 350. https://doi.org/10.3389/fnagi.2014.00350
Moorhead, T.W., Gountouna, V.E., Job, D.E., McIntosh, A.M., Romaniuk, L., Lymer, G.K., & Lawrie, S.M. (2009). Prospective multi-centre Voxel Based Morphometry study employing scanner specific segmentations: Procedure development using CaliBrain structural MRI data. BMC Medical Imaging, 9(1), 8. https://doi.org/10.1186/1471-2342-9-8
Naarding, P., Janzing, J.G.E., Eling, P., van der Werf, S., & Kremer, B. (2009). Apathy is not depression in Huntington’s disease. The Journal of Neuropsychiatry and Clinical Neurosciences, 21(3), 266270. https://doi.org/10.1176/appi.neuropsych.21.3.266
O’Rourke, J.J., Beglinger, L.J., Smith, M.M., Mills, J., Moser, D.J., Rowe, K.C., & the PREDICT-HD Investigators of the Huntington Study Group. (2011). The Trail Making Test in Prodromal Huntington Disease: Contributions of disease progression to test performance. Journal of Clinical and Experimental Neuropsychology, 33(5), 567579. https://doi.org/10.1080/13803395.2010.541228
Papp, K.V., Snyder, P.J., Mills, J.A., Duff, K., Westervelt, H.J., Long, J.D., & Paulsen, J.S. (2013). Measuring executive dysfunction longitudinally and in relation to genetic burden, brain volumetrics, and depression in prodromal Huntington disease. Archives of Clinical Neuropsychology, 28(2), 156168. https://doi.org/10.1093/arclin/acs105
Paulsen, J.S. (2010). Early detection of Huntington disease. Future Neurology, 5(1). 10.2217/fnl.09.78. https://doi.org/10.2217/fnl.09.78
Paulsen, J.S., Langbehn, D.R., Stout, J.C., Aylward, E., Ross, C.A., Nance, M., & Hayden, M. (2008). Detection of Huntington’s disease decades before diagnosis: The Predict-HD study. Journal of Neurology, Neurosurgery, and Psychiatry, 79(8), 874880. https://doi.org/10.1136/jnnp.2007.128728
Paulsen, J.S., Long, J.D., Johnson, H.J., Aylward, E.H., Ross, C.A., … Williams, J.K., PREDICT-HD Investigators and Coordinators of the Huntington Study Group. (2014). Clinical and biomarker changes in premanifest Huntington disease show trial feasibility: A decade of the PREDICT-HD study. Frontiers in Aging Neuroscience, 6, 78. https://doi.org/10.3389/fnagi.2014.00078
Paulsen, J.S., Long, J.D., Ross, C.A., Harrington, D.L., Erwin, C.J., Williams, J.K., & Barker, R.A. (2014). Prediction of manifest Huntington’s disease with clinical and imaging measures: A prospective observational study. The Lancet Neurology, 13(12), 11931201. https://doi.org/10.1016/s1474-4422(14)70238-8
Paulsen, J.S., Magnotta, V.A., Mikos, A.E., Paulson, H.L., Penziner, E., Andreasen, N.C., && Nopoulos, P.C. (2006). Brain structure in preclinical Huntington’s disease. Biological Psychiatry, 59(1), 5763. https://doi.org/10.1016/j.biopsych.2005.06.003
Paulsen, J.S., Nopoulos, P.C., Aylward, E., Ross, C.A., Johnson, H., Magnotta, V.A., & Nance, M. (2010). Striatal and white matter predictors of estimated diagnosis for Huntington disease. Brain Research Bulletin, 82(3-4), 201207. https://doi.org/10.1016/j.brainresbull.2010.04.003
Paulsen, J.S., Zhao, H., Stout, J.C., Brinkman, R.R., Guttman, M., Ross, C.A., & Shoulson, I. (2001). Clinical markers of early disease in persons near onset of Huntington’s disease. Neurology, 57(4), 658662.
Pla, P., Orvoen, S., Saudou, F., David, D.J., & Humbert, S. (2014). Mood disorders in Huntington’s disease: From behavior to cellular and molecular mechanisms. Frontiers in Behavioral Neuroscience, 8, 135. https://doi.org/10.3389/fnbeh.2014.00135
R: A language and environment for statistical computing . (2015). Vienna, Austria: R Foundation for Statistical Computing. Retrieved from http://www.R-project.org/
Reilmann, R., Leavitt, B.R., & Ross, C.A. (2014). Diagnostic criteria for Huntington’s disease based on natural history. Movement Disorders, 29(11), 13351341. https://doi.org/10.1002/mds.26011
Snowden, J.S., Craufurd, D., Thompson, J., & Neary, D. (2002). Psychomotor, executive, and memory function in preclinical Huntington’s disease. Journal of Clinical & Experimental Neuropsychology, 24(2), 133.
Stout, J.C., Paulsen, J.S., Queller, S., Solomon, A.C., Whitlock, K.B., Campbell, J.C., & Aylward, E.H. (2011). Neurocognitive signs in prodromal Huntington disease. Neuropsychology, 25(1), 114. https://doi.org/10.1037/a0020937
Tabrizi, S.J., Scahill, R.I., Durr, A., Roos, R.A.C., Leavitt, B.R., Jones, R., & Stout, J.C. (2011). Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: The 12-month longitudinal analysis. The Lancet Neurology, 10(1), 3142. https://doi.org/10.1016/s1474-4422(10)70276-3
Unschuld, P.G., Joel, S.E., Liu, X., Shanahan, M., Margolis, R.L., Biglan, K.M., & Ross, C.A. (2012). Impaired cortico-striatal functional connectivity in prodromal Huntington’s Disease. Neuroscience Letters, 514(2), 204209. https://doi.org/10.1016/j.neulet.2012.02.095
Vaccarino, A.L., Sills, T., Anderson, K.E., Bachoud-Levi, A.C., Borowsky, B., Craufurd, D., & Evans, K. (2011). Assessment of depression, anxiety and apathy in prodromal and early Huntington disease. PLoS Currents, 3, RRN1242. https://doi.org/10.1371/currents.RRN1242
van den Bogaard, S.J.A., Dumas, E.M., Acharya, T.P., Johnson, H., Langbehn, D.R., Scahill, R.I., & TRACK-HD Investigator Group. (2011). Early atrophy of pallidum and accumbens nucleus in Huntington’s disease. Journal of Neurology, 258(3), 412420. https://doi.org/10.1007/s00415-010-5768-0
Verbeke, G., & Molenberghs, G. (2000). Linear mixed models for longitudinal data. New York: Springer.
Walker, F.O. (20). Huntington’s disease. The Lancet, 369(9557), 218228. https://doi.org/10.1016/S0140-6736(07)60111-1
Ward, J.H. (1963). Hierarchical grouping to optimize an objective function. Journal of the American Statistical Association, 58(301), 236244.
Whalley, C.H., & Wardlaw, M.J. (2001). Accuracy and reproducibility of simple cross-sectional linear and area measurements of brain structures and their comparison with volume measurements. Neuroradiology, 43(4), 263271. https://doi.org/10.1007/s002340000437
Williams, J.K., Kim, J.-I., Downing, N., Farias, S., Harrington, D.L., Long, J.D., & Paulsen, J.S. (2015). Everyday cognition in prodromal Huntington disease. Neuropsychology, 29(2), 255267. https://doi.org/10.1037/neu0000102
Wolf, R.C., Thomann, P.A., Thomann, A.K., Vasic, N., Wolf, N.D., Landwehrmeyer, G.B., && Orth, M. (2013). Brain structure in preclinical Huntington’s disease: A multi-method approach. Neurodegenerative Diseases, 12(1), 1322.
Young Kim, E., & Johnson, H.J. (2013). Robust multi-site MR data processing: Iterative optimization of bias correction, tissue classification, and registration. Frontiers in Neuroinformatics, 7, 29. https://doi.org/10.3389/fninf.2013.00029
Zhang, Y., Long, J.D., Mills, J.A., Warner, J.H., Lu, W., & Paulsen, J.S., PREDICT-HD Investigators and Coordinators of the Huntington Study Group. (2011). Indexing disease progression at study entry with individuals at-risk for Huntington disease. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 156(7), 751763. https://doi.org/10.1002/ajmg.b.31232

Keywords

Type Description Title
WORD
Supplementary materials

Misiura supplementary material
Misiura supplementary material 1

 Word (24 KB)
24 KB

Metrics

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