Hostname: page-component-cd9895bd7-gvvz8 Total loading time: 0 Render date: 2024-12-23T12:58:09.008Z Has data issue: false 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: [email protected].
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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
Ekman, P., & Friesen, W.V. (1976). Measuring facial movement. Environmental Psychology and Nonverbal Behavior, 1, 56–75. doi:10.1007/BF01115465 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
Huntington Study Group. (1996). Unified Huntington’s Disease Rating Scale: Reliability and consistency. Movement Disorders, 11, 136–142. doi:10.1002/mds.870110204 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
Paulsen, J.S. (2001). PREDICT-HD: Markers indentifying individuals at risk for Huntington disease [Abstract]. Archives of Neurology, 58, 1317.CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle ScholarPubMed
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 CrossRefGoogle Scholar