Hostname: page-component-797576ffbb-pxgks Total loading time: 0 Render date: 2023-12-03T18:45:58.264Z Has data issue: false Feature Flags: { "corePageComponentGetUserInfoFromSharedSession": true, "coreDisableEcommerce": false, "useRatesEcommerce": true } hasContentIssue false
  • English
  • Français

Intra-individual Variability in Prodromal Huntington Disease and Its Relationship to Genetic Burden

Published online by Cambridge University Press:  26 January 2015

Mandi Musso ,
Holly James Westervelt ,
Jeffrey D. Long ,
Erin Morgan ,
Steven Paul Woods ,
Megan M. Smith ,
Wenjing Lu ,
Jane S. Paulsen  and
the PREDICT-HD Investigators of the Huntington Study Group
Mandi Musso
Affiliation:
Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, Rhode Island
Holly James Westervelt
Affiliation:
Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, Rhode Island Department of Psychiatry, Rhode Island Hospital, Providence, Rhode Island
Jeffrey D. Long
Affiliation:
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa Department of Biostatistics, University of Iowa College of Public Health, Iowa City, Iowa
Erin Morgan
Affiliation:
Department of Psychiatry, University of California, San Diego, San Diego, California
Steven Paul Woods
Affiliation:
Department of Psychiatry, University of California, San Diego, San Diego, California
Megan M. Smith
Affiliation:
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa
Wenjing Lu
Affiliation:
Department of Biostatistics, University of Iowa College of Public Health, Iowa City, Iowa
Jane S. Paulsen*
Affiliation:
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa
*
Correspondence and reprint requests to: Jane S. Paulsen, 1-305 MEB, Carver College of Medicine, University of Iowa, Iowa City, IA 52242. E-mail: predict-publications@uiowa.edu.
Get access Rights & Permissions [Opens in a new window]

Abstract

The current study sought to examine the utility of intra-individual variability (IIV) in distinguishing participants with prodromal Huntington disease (HD) from nongene-expanded controls. IIV across 15 neuropsychological tasks and within-task IIV using a self-paced timing task were compared as a single measure of processing speed (Symbol Digit Modalities Test [SDMT]) in 693 gene-expanded and 191 nongene-expanded participants from the PREDICT-HD study. After adjusting for depressive symptoms and motor functioning, individuals estimated to be closest to HD diagnosis displayed higher levels of across- and within-task variability when compared to controls and those prodromal HD participants far from disease onset (FICV(3,877)=11.25; p<.0001; FPacedTiming(3,877)=22.89; p<.0001). When prodromal HD participants closest to HD diagnosis were compared to controls, Cohen’s d effect sizes were larger in magnitude for the within-task variability measure, paced timing (−1.01), and the SDMT (−0.79) and paced tapping coefficient of variation (CV) (−0.79) compared to the measures of across-task variability [CV (0.55); intra-individual standard deviation (0.26)]. Across-task variability may be a sensitive marker of cognitive decline in individuals with prodromal HD approaching disease onset. However, individual neuropsychological tasks, including a measure of within-task variability, produced larger effect sizes than an index of across-task IIV in this sample. (JINS, 2015, 21, 8–21)

Keywords

Huntington diseaseNeuropsychological testsExecutive functionAttentionAdultCognition disorders/diagnosisCognition disorders/geneticsProdromal symptomsIntra-individual variability
Type
Research Articles
Information
Journal of the International Neuropsychological Society , Volume 21 , Issue 1 , January 2015 , pp. 8 - 21
Copyright
Copyright © The International Neuropsychological Society 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Aylward, E.H., Liu, D., Nopoulos, P.C., Ross, C.A., Pierson, R.K., Mills, J.A., … the PREDICT-HD Inestigators and Coordinators of the Huntington Study Group (2012). Striatal volume contributes to the prediction of onset of Huntington disease in incident cases. Biological Psychiatry, 71, 822–828. doi:10.1016/j.biopsych.2011.07.030 Google Scholar
Ballard, C., O’Brien, J., Gray, A., Cormack, F., Ayre, G., Rowan, E., … Tovee, M. (2001). Attention and fluctuating attention in patients with dementia with Lewy bodies and Alzheimer disease. Archives of Neurology, 58(6), 977. doi:10.1001/archneur.58.6.977 Google Scholar
Beglinger, L.J., O’Rourke, J.J., Wang, C., Langbehn, D.R., Duff, K., Paulsen, J.S., & Huntington Study Group Investigators. (2010). Earliest functional declines in Huntington disease. Psychiatry Research, 178, 414–418. doi:10.1016/j.psychres.2010.04.030 Google Scholar
Bellgrove, M.A., Hester, R., & Garavan, H. (2004). The functional neuroanatomical correlates of response variability: Evidence from a response inhibition task. Neuropsychologia, 42, 1910–1916. doi:10.1016/j.neuropsychologia.2004.05.007 Google Scholar
Benton, A.L., Hamsher, K., Varney, N., & Spreen, O. (1983). Contributions to neuropsychological assessment: A clinical manual. New York: Oxford University Press.Google Scholar
Brandt, J., & Benedict, R.H.B. (2001). Hopkins verbal learning test-revised. Lutz: Psychological Assessment Resources.Google Scholar
Brandt, J., & Butters, N. (1986). The neuropsychology of Huntington's disease. Trends in Neurosciences, 9, 118–120. doi:10.1016/0166-2236(86)90039-1 Google Scholar
Bunce, D., Anstey, K.J., Christensen, H., Dear, K., Wen, W., & Sachdev, P. (2007). White matter hyperintensities and within-person variability in community-dwelling adults aged 60–64 years. Neuropsychologia, 45(9), 2009–2015. doi:10.1016/j.neuropsychologia.2007.02.006 Google Scholar
Castellanos, F.X., Sonuga-Barke, E.J., Scheres, A., Di Martino, A., Hyde, C., & Walters, J.R. (2005). Varieties of attention-deficit/hyperactivity disorder-related intra-individual variability. Biological Psychiatry, 57, 1416–1423. doi:10.1016/j.biopsych.2004.12.005 Google Scholar
Cherbuin, N., Sachdev, P., & Anstey, K. (2010). Neuropsychological predictors of transition from healthy cognitive aging to mild cognitive impairment: The PATH through life study. American Journal of Geriatric Psychiatry, 18, 723–733. doi:10.1097/JGP.0b013e3181cdecf1 Google Scholar
Christensen, H., Mackinnon, A.J., Korten, A.E., Jorm, A.F., Henderson, A.S., & Jacomb, P. (1999). Dispersion in cognitive abilities as a function of age: A longitudinal study of an elderly community sample. Aging, Neuropsychology, and Cognition, 6, 214–228. doi:10.1076/anec.6.3.214.779 Google Scholar
Cole, V.T., Weinberger, D.R., & Dickinson, D. (2011). Intra-individual variability across neuropsychological tasks in schizophrenia: A comparison of patients, siblings, and healthy controls. Schizophrenia Research, 129, 91–93. doi:10.1016/j.schres.2011.03.007 Google Scholar
Duchek, J.M., Balota, D.A., Tse, C.-S., Holtzman, D.M., Fagan, A.M., & Goate, A.M. (2009). The utility of intraindividual variability in selective attention tasks as an early marker for Alzheimer's Disease. Neuropsychology, 23, 746–758. doi:10.1037/a0016583 Google Scholar
Duff, K., Paulsen, J.S., Mills, J., Beglinger, L.J., Moser, D.J., Smith, M.M., … the PREDICT-HD Inestigators and Coordinators of the Huntington Study Group (2010). Mild cognitive impairment in prediagnosed Huntington disease. Neurology, 75, 500–507. doi:10.1212/WNL.0b013e3181eccfa2 Google Scholar
Ekman, P., & Friesen, W.V. (1976). Measuring facial movement. Environmental Psychology and Nonverbal Behavior, 1, 56–75. doi:10.1007/BF01115465 Google Scholar
Frazier-Wood, A.C., Bralten, J., Arias-Vasquez, A., Luman, M., Ooterlaan, J., Sergeant, J.,… Rommelse, N.N. (2011). Neuropsychological intra-individual variability explains unique genetic variance of ADHD and shows suggestive linkage to chromosomes 12, 13, and 17. American Journal of Medical Genetics Part B, 159B, 131–140. doi:10.1002/ajmg.b.32018 Google Scholar
Georgiou, N., Bradshaw, J.L., Phillips, J.G., Chiu, E., & Bradshaw, J.A. (1995). Reliance upon advance information and movement sequencing in Huntington’s disease. Movement Disorders, 10, 472–481. doi:10.1002/mds.870100412 Google Scholar
Harrington, D.L., Smith, M.M., Zhang, Y., Carlozzi, N.E., Paulsen, J.S., & the PREDICT-HD Inestigators and Coordinators of the Huntington Study Group. (2012). Cognitive domains that predict time to diagnosis in prodromal Huntington disease. Journal of Neurology, Neurosurgery, and Psychiatry, 83, 612–619. doi:10.1136/jnnp-2011-301732 Google Scholar
Hilborn, J.V., Strauss, E., Hultsch, D.F., & Hunter, M.A. (2009). Intraindividual variability across cognitive domains: Investigation of dispersion levels and performance profiles in older adults. Journal of Clinical and Experimental Neuropsychology, 31, 412–424. doi:10.1080/13803390802232659 Google Scholar
Hinton, S.C., Paulsen, J.S., Hoffmann, R.G., Reynolds, N.C., Zimbelman, J.L., Rao, S.M. (2007). Motor timing variability increases in preclinical Huntington’s disease patients as estimated onset of motor symptoms approaches. Journal of the International Neuropsychological Society, 13, 539–543. doi:10.1017/S1355617707070671 Google Scholar
Holtzer, R., Verghese, J., Wang, C., Hall, C., & Lipton, R.B. (2008). Within-person across-neuropsychological test variability and incident dementia. JAMA, 300, 823–830. doi:10.1001/jama.300.7.823 Google Scholar
Hultsch, D.F., MacDonald, S.W., Hunter, M.A., Levy-Bencheton, J., & Strauss, E. (2000). Intraindividual variability in cognitive performance in older adults: comparison of adults with mild dementia, adults with arthritis, and healthy adults. Neuropsychology, 14, 588–598.Google Scholar
Hultsch, D.F., MacDonald, S.W., & Dixon, R.A. (2002). Variability in reaction time performance of younger and older adults. The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, 57, P101–P115. doi:10.1093/geronb/57.2.P101 Google Scholar
Huntington Study Group. (1996). Unified Huntington’s Disease Rating Scale: Reliability and consistency. Movement Disorders, 11, 136–142. doi:10.1002/mds.870110204 Google Scholar
Johnson, S.A., Stout, J.C., Solomon, A.C., Langbehn, D.R., Aylward, E.H., Cruce, C.B., & Paulsen, J.S. (2007). Beyond disgust: Impaired recognition of negative emotions prior to diagnosis in Huntington's disease. Brain, 130, 1732–1744. doi:10.1093/brain/awm107 Google Scholar
Kaiser, S., Roth, A., Rentrop, M., Friederich, H.-C., Bender, S., & Weisbrod, M. (2008). Intra-individual reaction time variability in schizophrenia, depression, and borderline personality disorder. Brain and Cognition, 66, 73–82. doi:10.1016/j.bandc.2007.05.007 Google Scholar
Kieburtz, K., Penney, J.B., Como, P., Ranen, N., Shoulson, I., Feigin, A., … Kremer, B. (1996). Unified Huntington’s disease rating scale: Reliability and consistency. Movement Disorders, 11, 136–142. doi:10.1002/mds.870110204 Google Scholar
Kirkwood, S.C., Siemers, E., Stout, J.C., Hodes, M.E., Conneally, P.M., Christian, J.C., & Foroud, T. (1999). Longitudinal cognitive and motor changes among presymptomatic Huntington disease gene carriers. Archives of Neurology, 56, 563–568. doi:10.1001/archneur.56.5.563 Google Scholar
Klein, C., Wendling, K., Huettner, P., Ruder, H., & Peper, M. (2006). Intra-subject variability in attention-deficits hyperactivity disorder. Biological Psychiatry, 60, 1088–1097. doi:10.1016/j.biopsych.2006.04.003 Google Scholar
Lee, J.M., Ramos, E.M., Lee, J.H., Gillis, T., Mysore, J.S., Hayden, M.R., … Gusella, J.F. (2012). CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology, 78, 690–695. doi:10.1212/WNL.0b013e318249f683 Google Scholar
Long, J.D., Paulsen, J.S., Marder, K., Zhang, Y., Kim, J.-I., Mills, J.A., & the Researchers of the PREDICT-HD Huntington’s Study Group (2014). Tracking motor impairments in the progression of Huntington’s disease. Movement Disorders, 29, 311–319. doi:10.1002/mds.25657 Google Scholar
MacDonald, M.E., Ambrose, C.M., Duyao, M.P., Myers, R.H., Lin, C., Srinidhi, L., … Gusella, J.F. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 72, 971–983. doi:10.1016/0092-8674(93)90585-E Google Scholar
MacDonald, S.W., Backman, L., & Li, S.-C. (2009). Neural underpinnings of within-person variability in cognitive functioning. Psychology and Aging, 24, 792–808. doi:10.1037/a0017798 Google Scholar
Morgan, E.E., Woods, S.P., Grant, I., & The H.I.V. Neurobehavioral Research Program (HNRP) Group. (2012a). Intra-individual neurocognitive variability confers risk of dependence in activities of daily living among HIV-seropositive individuals without HIV-Assoicated Neurocogntive Disorders. Archives of Clinical Neuropsychology, 27, 293–303. doi:10.1093/arclin/acs003 Google Scholar
Morgan, E.E., Woods, S.P., Rooney, A., Perry, W., Grant, I., & Letendre, S.L., the Neurobehavioral Research Program (HNRP) Group. (2012b). Intra-Individual Variability across neurocognitive domains in chronic Hepatitis C infection: Elevated dispersion is associated with serostatus and unemployment risk. The Clinical Neuropsychologist, 26, 654–674. doi:10.1080/13854046.2012.680912 Google Scholar
Murtha, S., Cismaru, R., Waechter, R., & Chertkow, H. (2002). Increased variability accompanies frontal lobe damage in dementia. Journal of the International Neuropsychological Society, 8, 360–372. doi:10.1017.S1355617701020173 Google Scholar
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, 156–168. doi:10.1093/arclin/acs105 Google Scholar
Paulsen, J.S. (2001). PREDICT-HD: Markers indentifying individuals at risk for Huntington disease [Abstract]. Archives of Neurology, 58, 1317.Google Scholar
Paulsen, J.S., Langbehn, D.R., Stout, J.C., Aylward, E., Ross, C.A., Nance, M., … The PREDICT-HD Investigators and Coordinators of the Huntington Study Group (2008). Detection of Huntington's disease decades before diagnosis: The Predict-HD study. Journal of Neurology, Neurosurgery, and Psychiatry, 79, 874–880. doi:10.1136/jnnp.2007.128728 Google Scholar
Paulsen, J.S., Nopoulos, P.C., Aylward, E., Ross, C.A., Johnson, H., Magnotta, V.A., … PREDICT-HD Investigators and Coordinators of the Huntington Study Group (2010a). Striatal and white mater predictors of estimated diagnosis for Huntington disease. Brain Research Bulletin, 82, 201–207. doi:10.1016/j.brainresbull.2010.04.003 Google Scholar
Paulsen, J.S., Smith, M.M., Long, J.S., & the PREDICT HD investigators and coordinators of the Huntington Study Group. (2013). Cognitive decline in prodromal Huntington Disease: implications for clinical trials. Journal of Neurology, Neurosurgery, and Psychiatry, 84, 1233–1239. doi:10.1136/jnnp-2013-305114 Google Scholar
Paulsen, J.S., Wang, C., Duff, K., Barker, R., Nance, M., Beglinger, L., … van Kammen, D.P. (2010b). Challenges assessing clinical endpoints in early Huntington disease. Movement Disorders, 25, 2595–2603. doi:10.1002/mds.23337 Google Scholar
Paulsen, J.S., Zhao, H., Stout, J.C., Brinkman, R.R., Guttman, M., Ross, C.A., … The PREDICT-HD Investigators and Coordinators of the Huntington Study Group (2001). Clinical markers of early disease in persons near onset of Huntington's disease. Neurology, 57, 658–662. doi:10.1212/WNL.57.4.658 Google Scholar
Paulsen, J.S., Zimbelman, J.L., Hinton, S.C., Langbehn, D.R., Leveroni, C.L., Benjamin, M.L., & Rao, S.M. (2004). fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington's disease. AJNR American Journal of Neuroradiology, 25, 1715–1721.Google Scholar
Penney, J.B., Young, A.B., Shoulson, I., Starosta‐Rubenstein, S., Snodgrass, S.R., Sanchez‐Ramos, J., … Wexler, N.S. (1990). Huntington's disease in Venezuela: 7 years of follow‐up on symptomatic and asymptomatic individuals. Movement Disorders, 5, 93–99.Google Scholar
Pirogovsky, E., Gilbert, P.E., Jacobson, M., Peavy, G., Wetter, S., Goldstein, J., … Murphy, C. (2007). Impairments in source memory for olfactory and visual stimuli in preclinical and clinical stages of Huntington's disease. Journal of Clinical and Experimental Neuropsychology, 29, 395–404. doi:10.1080/13803390600726829 Google Scholar
Reitan, R.M. (1958). Validity of the Trail Making Test as an indicator of organic brain damage. Perceptual and Motor Skills, 8, 271–276. doi:10.2466/PMS.8.7.271-276 Google Scholar
Rentrop, M., Rodewald, K., Roth, A., Simon, J., Walther, S., Fiedler, P., … Kaiser, S. (2010). Intra-individual variability in high-functioning patients with schizophrenia. Psychiatry Research, 178, 27–32. doi:10.1016/j.psychres.2010.04.009 Google Scholar
Rowe, K.C., Paulsen, J.S., Langbehn, D.R., Duff, K., Beglinger, L.J., Wang, C., … Moser, D.J. (2010). Self-paced timing detects and tracks change in prodromal Huntington disease. Neuropsychology, 24, 435, doi:10.1037/a0018905 Google Scholar
Saint-Cyr, J.A., Taylor, A.E., & Lang, A.E. (1988). Procedural learning and neostriatal dysfunction in man. Brain, 111, 941–959. doi:10.1093/brain/111.4.941 Google Scholar
Scahill, R.I., Hobbs, N.Z., Say, M.J., Bechtel, N., Henley, S.M., Hyare, H., … The TRACK-HD Investigators (2013). Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy. Human Brain Mapping, 34, 519–529. doi:10.1002/hbm.21449 Google Scholar
Smith, A. (1991). Symbol Digit Modalities Test. Los Angeles: Western Psychological Services.Google Scholar
Smith, M.M., Mills, J.A., Epping, E.A., Westervelt, H.J., & Paulsen, J.S. (2012). Depressive symptom severity is related to poorer cognitive performance in prodromal Huntington disease. Neuropsychology, 26, 664–669. doi:10.1037/a0029218 Google Scholar
Stout, J.C., Jones, R., Labuschagne, I., O’Regan, A.M., Say, M.J., Dumas, E.M., … the PREDICT-HD Investigators and Coordinators of the Huntington Study Group (2012). Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington's disease. Journal of Neurology, Neurosurgery, and Psychiatry, 83, 687–694. doi:10.1136/jnnp-2011-301940 Google Scholar
Stout, J.C., Paulsen, J.S., Queller, S., Solomon, A.C., Whitlock, K.B., Campbell, J.C., … the PREDICT-HD Investigators and Coordinators of the Huntington Study Group (2011). Neurocognitive sings in prodromal Huntington disease. Neuropsychology, 25, 1–14. doi:10.1037/a0020937 Google Scholar
Stroop, J.R. (1935). Studies of interference in serial verbal reactions. Journal of Experimental Psychology: General, 18(6), 643–662. doi:10.1037/0096-3445.121.1.15 Google Scholar
Stuss, D.T., Murphy, K.J., & Binns, M.A. (1999). The frontal lobes and performance variability: Evidence from reaction time. Journal of the International Neuropsychological Society, 5, 123.Google Scholar
Stuss, D.T., Murphy, K.J., Binns, M.A., & Alexander, M.P. (2003). Staying on the job: The frontal lobes control individual performance variability. Brain, 126, 2363–2380. doi:10.1093/brain/awg237 Google Scholar
Stuss, D.T., Stethem, L.L., Hugenholtz, H., Picton, T., Pivik, J., & Richard, M.T. (1989). Reaction time after head injury: Fatigue, divided and focused attention, and consistency of performance. Journal of Neurology, Neurosurgery, and Psychiatry, 52, 742–748. doi:10.1136/jnnp.52.6.742 Google Scholar
Warner, J.P., Barron, L.H., & Brock, D.J. (1993). A new plymerase chain reaction (PCR) assay for trinucleotide repeat that is unstable and expanded on Huntington's disease chromosomes. Molecular and Cellular Probes, 7, 235–239. doi:10.1006/mcpr.1993.1034r Google Scholar
Willingham, D.B., Nissen, M.J., & Bullemer, P. (1989). On the development of procedural knowledge. Journal of Experimental Psychology . Learning, Memory, and Cognition, 15, 1047–1060. doi:10.1037/0278-7393.15.6.1047 Google Scholar
Wechsler, D. (1997). Wechsler Adult Intelligence Scale. 3rd ed. San Antonio: The Psychological Corporation.Google Scholar
Zakzanis, K.K. (1998). The Subcortical Dementia of Huntington’s Disease. Journal of Clinical and Experimental Neuropsychology, 20, 565–578. doi:10.1076/jcen.20.4.565.1468 Google Scholar
Zhang, Y., Long, J.D., Mills, J.A., Warner, J.H., Lu, W., Paulsen, J.S., … the 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, 156, 751–763. doi:10.1002/ajmg.b.31232 Google Scholar