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Original Contribution |

Longitudinal Cognitive and Motor Changes Among Presymptomatic Huntington Disease Gene Carriers FREE

Sandra Close Kirkwood, MS; Eric Siemers, MD; Julie C. Stout, PhD; M. E. Hodes, MD, PhD; P. Michael Conneally, PhD; Joe C. Christian, MD, PhD; Tatiana Foroud, PhD
[+] Author Affiliations

From the Departments of Medical and Molecular Genetics (Ms Kirkwood and Drs Hodes, Conneally, Christian, and Foroud) and Neurology (Drs Siemers and Conneally), Indiana University School of Medicine, Indianapolis; and the Department of Psychology, Indiana University, Bloomington (Dr Stout).


Arch Neurol. 1999;56(5):563-568. doi:10.1001/archneur.56.5.563.
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Published online

Objective  To determine whether longitudinal changes in cognitive and motor function can be detected among clinically presymptomatic individuals carrying the Huntington disease (HD) allele.

Design  A longitudinal, case-control, double-blind study comparing presymptomatic gene carriers and non–gene carriers at risk for HD examined an average of 3.7 years apart.

Setting  The Department of Medical and Molecular Genetics at a general clinic research center in Indianapolis, Ind.

Participants  A sample of 43 at-risk individuals consisting of presymptomatic gene carriers (n=12) and non–gene carriers (n=31).

Measures  Huntington disease gene status was determined by molecular testing of the HD gene. Subscales from the Wechsler Adult Intelligence Scale–Revised and a quantified neurologic rating scale were administered.

Results  Scores on the digit symbol subscale of the Wechsler Adult Intelligence Scale–Revised (P<.05) and 2 neurologic variables—optokinetic nystagmus (P<.01) and rapid alternating movements (P<.005)—declined more rapidly among presymptomatic gene carriers than among non–gene carriers. At follow-up examination, compared with non–gene carriers, presymptomatic gene carriers had significantly lower scores on the digit symbol subscale (P=.02) and for 4 neurologic variables—rapid alternating movements (P<.005), optokinetic nystagmus (P<.001), overall ocular movements (P<.02), and chorea of the trunk (P<.02).

Conclusions  Psychomotor speed, optokinetic nystagmus, and rapid alternating movements demonstrated significant decline early in the pathological process of HD. These results suggest that subtle worsening of psychomotor, oculomotor, and motor functions occurs before the onset of signs sufficient to make a clinical diagnosis in individuals who have inherited the HD allele.

HUNTINGTON disease (HD) is an autosomal-dominant, neurodegenerative disorder characterized neuropathologically by the loss of medium-sized spiny neurons in the neostriatum and clinically by a triad of progressive motor, cognitive, and emotional symptoms. The HD phenotype is caused by an increased number of triplet (CAG) repeats in the 5‘-translated region of the HD gene on chromosome 4.1 Typically, individuals with HD have 38 or more CAG repeats. A negative correlation between the number of CAG repeats and age at onset of HD has been found, with individuals with juvenile HD having the largest number of repeats (>55).1,2 The clinical implication of an allele with 32 to 37 repeats is ambiguous. These repeat sizes are often considered intermediate alleles with variable penetrance.

Great variation is seen in the age at onset of clinical symptoms, the initial symptom presentation, the clinical course of HD, and the duration of illness.35 The development of manifest HD occurs as early as childhood and as late as 80 years of age. The average age at onset is late in the fourth decade,6,7 and, as a result, the individual who has a parent with HD has many years of at-risk status.

Results of previous studies8,9 show that motor changes, including extraocular movements, mild chorea, brisk muscle stretch reflexes, and diminished rapid alternating movements, are the most consistent early findings of manifest HD. Cognitive decline, with progression from early changes in information processing, cognitive inflexibility, and memory retrieval to more severe and widespread abnormalities later in the disease course, has been demonstrated as part of the HD phenotype.10 Early changes in executive functions,1113 visuospatial abilities,14,15 cognitive speed or efficiency,16,17 sensorimotor function,16,18 and olfactory functioning19 and recognition20 have been reported.

Determination of the exact age at symptom onset is frequently difficult, and the categorization of an individual as affected or unaffected can be equivocal. Although the actual sequence of symptom appearance can be variable, the diagnosis of HD in at-risk individuals is usually made after the onset of involuntary, choreiform movements.6,21 Conflicting results have been found regarding neuropsychologic impairment and cognitive decline in otherwise asymptomatic individuals. Deficits reported in presymptomatic individuals at risk for HD include attentional learning and planning functions,22 memory,23,24 visuospatial tasks,23,25,26 performance of visuomotor skills,27 language tasks,28 tactile-motor coordination,29 and stimulus perception and encoding.30,31 Others have reported no difference between presymptomatic gene carriers (PSGCs) and non–gene carriers (NGCs) for sustained attention and mental processing speed,32,33 verbal memory and learning,23,32,34 visuospatial and motor task performance,32,33,35 and intelligence subtest patterns.32,3638

In previous studies,39 cross-sectional differences in cognitive function for PSGCs as measured by the Wechsler Adult Intelligence Scale–Revised (WAIS-R) were observed. Participants who were PSGCs showed a tendency to score lower on all subscales of the WAIS-R test, with the digit symbol and picture arrangement subscales reaching statistical significance. In addition, PSGCs also had abnormal neurologic findings for saccades velocity and muscle stretch reflexes.40 In contrast, PSGCs did not have significantly more chorea than NGCs, confirming that this sample was indeed clinically presymptomatic. The objective of the present study was to reexamine a subset of the original study population to determine whether longitudinal decline in cognitive or motor function could be detected among a sample of PSGCs who maintained presymptomatic status throughout follow-up and to estimate whether longer follow-up using the entire sample would be useful.

PARTICIPANTS

In the original study, a sample of individuals at risk for HD was recruited through the National Huntington Disease Research Roster for Patients and Families at the Indiana University School of Medicine, Indianapolis. At-risk individuals reporting themselves as asymptomatic and without previous diagnosis of HD were invited to participate. Details regarding patient recruitment can be found in the study by Foroud et al.39 A total of 45 participants from this original study, regardless of HD status, agreed to participate and were examined an average of 3.7 years after their initial study visit. Participants were informed of the risks and benefits involved in the study, and informed consent was obtained.

Two of the 45 participants were eliminated before data analysis. One of these participants exhibited sufficient neurologic symptoms at the follow-up examination to warrant a clinical diagnosis of HD. Therefore, this individual could not be considered clinically presymptomatic and was removed from further data analysis. A second participant was eliminated from the analysis because his DNA did not amplify properly, thus preventing gene status determination. Demographic information from the 43 remaining study participants is summarized in Table 1. No significant differences between PSGCs and NGCs were found except for the expected expanded allele size among PSGCs (P<.001).

Table Graphic Jump LocationTable 1. Demographic Data for the 43 Study Participants With DNA Results*
DNA ANALYSIS

DNA samples were analyzed with a polymerase chain reaction–based diagnostic screen as previously described.39 Briefly, the CAG repeat implicated in the disease phenotype was amplified, and the resulting alleles were compared with previously sequenced cosmids having 18 and 48 CAG repeats. Each gel was interpreted independently by 2 individuals who were unaware of the participants' neurologic and neuropsychologic test results.

There is uncertainty regarding disease outcome for allele sizes occurring in the intermediate size range. However, we chose a conservative allele classification scheme, with individuals with 2 alleles having less than 32 CAG repeats classified as NGCs (n=31) and those with 1 allele having 38 or more CAG repeats categorized as HD gene carriers (n=12). There were no participants with an allele in the range between 32 and 37 CAG repeats. Gene testing was performed anonymously, and the results were not provided to the participants.

EXAMINATIONS
Cognitive Examination

To measure cognitive function, each participant was examined by standard administration procedures on several verbal and performance subscales of the WAIS-R. Verbal subscales included digit span, vocabulary, and arithmetic. Performance subscales included picture arrangement, block design, and digit symbol.

Quantified Neurologic Examination

A quantified neurologic examination adapted from previously described protocols6,37 was administered by a board-certified neurologist with specialization in movement disorders (E.S.). These tests measured extraocular movements, gait and stability, chorea, dystonia, parkinsonism, tremor, muscle stretch reflexes, and cerebellar function. Ratings were assigned as 0 (normal), 1 (possibly abnormal), or 2 (abnormal) for 29 neurologic tests.40 Consistent with findings of previous studies,39,40 participants were classified as having manifest HD using criteria designed to approximate those used in clinical practice. Individuals with definite chorea, in the absence of other possible causes (eg, hyperthyroidism), were classified as having manifest HD. Individuals with an expanded CAG repeat (>37), without sufficient abnormalities to be considered manifest HD, were termed PSGCs. The neurologic examination was designed to detect early motor features of HD; thus, an attempt was made to maximize the sensitivity of the ratings, even at the expense of some specificity.40 Because neuropsychologic testing was performed separately, the neurologist did not ascertain specific information for evaluation of the cognitive or emotional status of the participant. In addition, the neurologist was unaware of the previous and current neuropsychologic and gene testing results.

STATISTICAL ANALYSES

One-way repeated-measures analysis of variance was used to test for differences between PSGCs and NGCs in longitudinal cognitive measures (repeated measures) evaluated at the initial and follow-up examinations. Raw scores for the WAIS-R subscales were used in this analysis to prevent the possible loss of sensitivity that may result from decade-related adjustments in published tables.

Although data for 29 variables were collected as part of the quantified neurologic examination, only those variables for which at least 1 PSGC had a score greater than 0 at the follow-up examination were included in the statistical analysis (17 of 29 variables). No PSGC had abnormalities in any of the following variables: extraocular range, saccades performance and latency, eye closure motor impersistence, dystonia of the trunk, bradykinesia of the body, gait and station stability, plantar reflex, resting tremor of the head and neck, and resting tremor of the extremities bilaterally and unilaterally. For the remaining 17 quantified neurologic variables, the Fisher exact test was used to compare PSGC and NGC groups for the longitudinal measures.

Confirmatory factor analysis, using the principle components method, was used separately in the PSGC and NGC samples to reduce the number of relevant items to a subset of factors. Factor analysis was used to test for evidence of a single underlying determinant associated with HD resulting in the observed longitudinal changes. The psychomotor, oculomotor, and motor function measures sensitive to progression were loaded into the factor analysis. To establish which factors were significant, only those with eigenvalues greater than 1.00 were considered.

In addition to the longitudinal analyses, the follow-up examination data were evaluated cross sectionally. For this analysis, the individual raw scores on each of the subscales of the WAIS-R were adjusted for age from published tables.41 One-tailed Student t tests were performed on the neuropsychologic scales to determine whether the PSGC group demonstrated significantly greater abnormality than the NGC group at the follow-up examination. The Fisher exact test was used to compare quantified neurologic variables between the 2 groups.

LONGITUDINAL ANALYSIS

In a previous comparison of individuals at risk for HD, significant differences in psychomotor, oculomotor, and functional motor performance were found between PSGCs and NGCs. When a local subset of the original sample (12 PSGCs and 31 NGCs) was compared longitudinally, significantly more rapid longitudinal decline among PSGCs was found in psychomotor speed (digit symbol subscale, P<.05) (Table 2), oculomotor function (optokinetic nystagmus, P<.01) (Table 3), and cerebellar motor function (rapid alternating movements, P<.005) (Table 3) than for NGCs. In addition to the significant decline in digit symbol subscale performance, longitudinal change in the arithmetic subscale (P<.10) tended to be greater in PSGCs than in NGCs.

Table Graphic Jump LocationTable 2. WAIS-R Initial and Follow-up Examination Means and Longitudinal Change*
Table Graphic Jump LocationTable 3. Possible or Definite Abnormal Findings of Initial and Follow-up Examinations and Longitudinal Change*

In a secondary set of analyses, confirmatory factor analysis was used to test for evidence of a single underlying factor that resulted in the significant longitudinal differences in the 3 measures sensitive to progression: the digit symbol subscale of the WAIS-R and the 2 neurologic variables—optokinetic nystagmus and rapid alternating movements. If these observed longitudinal changes are caused by 1 process associated with HD, they would be expected to contribute to 1 factor for PSGCs and have a different pattern in NGCs. To test this hypothesis, factor analysis was run separately for PSGCs and NGCs. One factor (eigenvalue=1.79) was extracted for PSGCs. This supported the idea that 1 process is responsible for the longitudinal change in PSGCs. All 3 measures sensitive to progression—the digit symbol subscale, optokinetic nystagmus, and rapid alternating movements—contributed to this factor (Table 4). The NGCs had 2 factors with eigenvalues greater than 1.00 (eigenvalues=1.17 and 1.06). This supported the hypothesis that different processes are responsible for their longitudinal changes. For NGCs, the first factor is composed of similar loadings of optokinetic nystagmus and rapid alternating movements, whereas the digit symbol subscale was weighted in the opposite direction. In the second factor, rapid alternating movements loads strongly, whereas optokinetic nystagmus loads in the opposite direction (Table 4).

FOLLOW-UP EXAMINATION

Similar to their first evaluation 3.7 years earlier, PSGCs demonstrated significantly worse performance on the digit symbol subscale than NGCs (P<.05) (Table 2). Of the 17 neurologic variables used in the analysis, PSGCs demonstrated a significantly higher rate of possible or definite abnormalities than did NGCs for 4 of the neurologic tests: optokinetic nystagmus (P<.001), rapid alternating movements (P<.005), overall ocular saccades (P<.05), and chorea of the trunk (P<.05) (Table 3).

This study, currently the largest published longitudinal study of clinically presymptomatic individuals at risk for HD, to our knowledge,32,37 provides significant evidence for longitudinal decline in psychomotor, oculomotor, and motor function before the onset of manifest HD. The PSGC group demonstrated greater decline in psychomotor speed, optokinetic nystagmus, and rapid alternating movements an average of 3.7 years after their first evaluation. Although PSGCs demonstrated a tendency toward a higher rate of abnormalities than did NGCs, after elimination of the 1 patient noted previously, none of the gene carriers included in this study exhibited sufficient neurologic symptoms at the follow-up examination to warrant a clinical diagnosis of HD. Our studies, and those of others, reveal subtle motor, cognitive, and behavioral changes before the onset of unequivocal chorea, suggesting that decline occurs earlier than the first clinical diagnosis.

Results of the factor analysis support the hypothesis that a single underlying mechanism may be responsible for the decline in the psychomotor speed, optokinetic nystagmus, and rapid alternating movements seen in PSGCs. For PSGCs, all 3 variables contributed with similar weights into 1 factor. Conversely, this same relationship was not observed for NGCs. Two factors are needed to explain the variance in these measures in NGCs, suggesting that different mechanisms may be responsible for the longitudinal change in these variables among NGCs compared with PSGCs.

Cross-sectional analyses of the follow-up data for at-risk individuals confirmed the results of a previous study,39,40 which suggested that individuals who inherited the HD gene have oculomotor, functional motor, and psychomotor deficits that precede the onset of definite abnormal neurologic functioning. Results of other studies demonstrate that these changes are the earliest features of manifest HD. These include changes in extraocular movements,8,9 motor function (including diminished rapid alternating movements, mild chorea, and brisk muscle stretch reflexes),8,9 and psychomotor speed.42,43 Our results are consistent with those previously reported, indicating that gene carriers who can be considered presymptomatic on clinical examination demonstrate greater abnormality for the oculomotor variables of optokinetic nystagmus and overall ocular movements and for the motor function variables of rapid alternating movement and chorea of the trunk. Although the changes we found in PSGCs represent a statistical increase in possible abnormalities on examination compared with NGCs, no PSGC had sufficient abnormalities to be classified as having manifest HD. Chorea of the extremities would be expected to be an earlier sign of HD than chorea of the trunk; however, chorea of the extremities was not significantly different between PSGCs and NGCs. In our study, a large proportion of PSGCs (42%) and NGCs (23%) were rated as having possible chorea of the extremities, thus limiting the power to discriminate between them. This was most likely the result of the neurologist's attempt to maximize the sensitivity of the ratings to avoid classifying symptomatic individuals as presymptomatic.

We show further that longitudinal changes are greater in the digit symbol subscale than in other measures of the WAIS-R. This suggests that presymptomatic individuals carrying the HD allele may have the greatest difficulties with the ability to learn new tasks, visual motor dexterity, and rapidity of task completion44 early in disease progression. Asymptomatic HD gene carriers have been shown to have changes in caudate metabolism45 and volume.46 In addition, animals and humans have demonstrated cognitive impairment after caudate lesions.47 Therefore, it is likely that the observed early cognitive changes in HD are related to changes in caudate function.

Our study avoided some of the difficulties that have plagued other studies of at-risk individuals. The psychosocial issues related to at-risk status that may affect cognitive performance, even among NGCs, have been experienced by all participants in our sample because we examined only individuals at risk for HD by virtue of having an affected parent. Therefore, the at-risk NGCs are an excellent control sample. Our gene carriers were all clinically presymptomatic at the time of examination, with an average age of 43.1 years, near the typical age at onset. Assuming that the rate of presymptomatic, longitudinal change is likely to be greatest just before onset of clinically manifest HD, the power to detect change in this sample of PSGCs should be improved compared with that in a younger sample of PSGCs. Furthermore, because all individuals participating in the initial study were adult, presymptomatic individuals, we would not have expected, and we did not have, any participants with a very large number of CAG repeats (>50). Rather, our restricted range of expanded CAG repeats (38-48) suggests that this is a representative sample of patients with adult-onset HD, and the longitudinal decline that we detected before disease onset may be the typical HD prodrome.

In this study, criteria for manifest HD were used that would approximate those used in clinical practice. Using these criteria, subtle changes have been found among at-risk individuals who do not fulfill clinical criteria for manifest HD. The present study expands on these findings and suggests that these abnormalities progress before a clinical diagnosis of HD can be established. These results demonstrate the importance of including neuropsychologic tests in the study of therapies designed to prevent or slow the clinical progression of disease. Given the subtlety of the neuropsychologic and motor findings, a longitudinal design using serial assessment of a large, well-characterized sample of at-risk individuals, such as ours, will be necessary to provide important data regarding neuropsychologic and motor symptom variability and progression. Further longitudinal analyses and follow-up of a larger subset of our original at-risk sample will allow us to evaluate the course of the longitudinal changes reported herein. A more complete understanding of the physiologic and cognitive changes that occur early in the course of HD will help better define the disease process and will be important for future diagnostic and therapeutic strategies. Such an understanding will assist in assessing the value of motor and cognitive assessments as relevant outcome measures in controlled clinical trials aimed at slowing the underlying neurodegenerative changes in HD.

Accepted for publication August 25, 1998.

This study was supported in part by grants R01-AG-08918, M01-RR-750, and PHS N01-NS-2326 from the Public Health Service, Washington, DC, and by Medical Genetics Training Grant Fellowship NICHD-T3HD07373 from the National Institute of Child Health and Human Development, Bethesda, Md (Ms Kirkwood).

We thank all participants and members of the National Huntington Disease Research Roster for Patients and Families for their efforts, and Dawn Kleindorfer and Jacqueline Gray for their assistance, Indiana University School of Medicine, Indianapolis.

Reprints: Tatiana Foroud, PhD, Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 W Walnut St, Indianapolis, IN 46202 (e-mail: tforoud@medgen.iupui.edu).

Huntington's Disease Collaborative Research Group, A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993;72971- 983
Link to Article
Andrew  SEGoldberg  YPKremer  B  et al.  The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993;4398- 403
Link to Article
Siesling  SZwinderman  AHvan Vugt  JPKieburtz  KRoos  RA A shortened version of the motor section of the Unified Huntington's Disease Rating Scale. Mov Disord. 1997;12229- 234
Link to Article
Roos  RACHermans  JVegter-van der Vlis  Mvan Ommen  GJBBruyn  GW Duration of illness in HD is not related to age at onset. J Neurol. 1993;5698- 100
Van Dijk  JGvan der Velde  EARoos  RACBruyn  GW Juvenile HD. Hum Genet. 1986;73235- 239
Link to Article
Folstein  SE Historical perspective and overview. InHuntington's Disease: A Disorder of Families. Baltimore, Md Johns Hopkins University Press1989;1- 10
Farrer  LAConneally  PM A genetic model for age at onset in Huntington disease. Am J Hum Genet. 1985;37350- 357
Penny  JBYoung  BMShoulson  I  et al.  Huntington's disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals. Mov Disord. 1990;593- 99
Link to Article
Young  ABShoulson  IPenny  JB  et al.  Huntington's disease in Venezuela: neurologic features and functional decline. Neurology. 1986;36244- 249
Link to Article
Lawrence  ADSahakian  BJHodges  JRRosser  AELange  KWRobbins  TW Executive and mnemonic functions in early HD. Brain. 1996;1191633- 1645
Link to Article
Paulsen  JSSalmon  DPMonsch  AUButters  NSwenson  MRBondi  MW Discrimination of cortical from subcortical dementias on the basis of memory and problem-solving tests. J Clin Psychol. 1995;5148- 58
Link to Article
Bamford  KACaine  EDKido  DKPlassche  WMShoulson  I Clinical-pathologic correlation in Huntington's disease: a neuropsychological and computed tomography study. Neurology. 1989;39796- 801
Link to Article
Butters  NWolfe  JMartone  MGranholm  ECermak  LS Memory disorders associated with Huntington's disease: verbal recall, verbal recognition and procedural memory. Neuropsychology. 1985;23729- 743
Link to Article
Bamford  KACaine  EDKido  DKCox  CShoulson  I A prospective evaluation of cognitive decline in early Huntington's disease: functional and radiographic correlates. Neurology. 1995;451867- 1873
Link to Article
Moses  JAGolden  CJBerger  PAWisniewski  AM Neuropsychological deficits in early, middle, and late stage Huntington's disease as measured by the Luria-Nebraska Neuropsychological Battery. Int J Neurosci. 1981;1495- 100
Link to Article
Lundervold  AJReinvang  I Neuropsychological findings and depressive symptoms in patients with Huntington's disease. Scand J Psychol. 1991;32275- 283
Link to Article
Huber  SJPaulsen  GW Memory impairment associated with progression of Huntington's disease. Cortex. 1987;23275- 283
Link to Article
Swerdlow  NRPaulsen  JBraff  DLButters  NGeyer  MASwenson  MR Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington's disease. J Neurol Neurosurg Psychiatry. 1995;58192- 200
Link to Article
Nordin  SPaulsen  JSMurphy  C Sensory- and memory-mediated olfactory dysfunction in Huntington's disease. J Int Neuropsychol Soc. 1995;1281- 290
Link to Article
Moberg  PJPearlson  GDSpeedie  LJLipsey  JRStrauss  MEFolstein  SE Olfactory recognition: different impairments in early and late Huntington's and Alzheimer's diseases. J Clin Exp Neuropsychol. 1987;9650- 664
Link to Article
Snell  RGMacMillan  JCCheadle  JP  et al.  Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet. 1993;4393- 397
Link to Article
Rosenberg  NKSorensen  SAChristensen  AL Neuropsychological characteristics of Huntington's disease carriers: a double blind study. J Med Genet. 1995;32600- 604
Link to Article
Rothlind  JCBylsma  FWPeyser  CFolstein  SEBrandt  J Cognitive and motor correlates of everyday functioning in early Huntington's disease. J Nerv Ment Dis. 1993;181194- 199
Link to Article
Lanto  ABRiege  WHMazziotta  JCPahl  JJPhelps  ME Increased false alarms in a subset of persons at-risk for Huntington's disease. Arch Clin Neuropsychol. 1990;5393- 404
Link to Article
Mohr  EBrouwers  PClaus  JJMann  UMFedio  PChase  TN Visuospatial cognition in Huntington's disease. Mov Disord. 1991;6127- 132
Link to Article
Hodges  JRSlanom  DPButters  N Differential impairment of semantic and episodic memory in Alzheimer's and Huntington's diseases: a controlled prospective study. J Neurol Neurosurg Psychiatry. 1990;531089- 1095
Link to Article
Oepen  GMohr  UWillmes  K  et al.  Huntington's disease: visuomotor disturbance in patients and offspring. J Neurol Neurosurg Psychiatry. 1985;48426- 433
Link to Article
Josiassen  RCCurry  LMMancall  EL Development of neuropsychological deficits in Huntington's disease. Arch Neurol. 1983;40791- 796
Link to Article
Baro  F A neuropsychological approach to early detection of Huntington's chorea. Adv Neurol. 1973;1329- 338
Hayward  LZubrick  SRHall  W Early sensory-perceptual changes in Huntington's disease. Aust N Z J Psychiatry. 1985;19384- 389
Link to Article
Wexler  NS Perceptual-motor, cognitive, and emotional characteristics of persons at risk for Huntington's disease. Adv Neurol. 1979;23257- 271
Campodonico  JRCodori  AMBrandt  J Neuropsychological stability over two years in asymptomatic carriers of the Huntington's disease mutation. J Neurol Neurosurg Psychiatry. 1996;61621- 624
Link to Article
Blackmore  LSimpson  SACrawford  JR Cognitive performance in UK sample of presymptomatic people carrying the gene for Huntington's disease. J Med Genet. 1995;32358- 362
Link to Article
Johnson  CTMcSorley  PBrandt  J  et al.  Memory test performance as a preclinical indicator of Huntington's disease in at-risk persons [abstract]? J Clin Exp Neuropsychol. 1987;951
Gomez-Tortosa  Edel Barrio  ABarroso  TGarcia Ruiz  PJ Visual processing disorders in patients with HD and asymptomatic carriers. J Neurol. 1996;243286- 292
Link to Article
de Boo  GTibben  ALanser  JB  et al.  Intelligence indices in people with a high/low risk for developing Huntington's disease. J Med Genet. 1997;34564- 568
Link to Article
Giordani  BBerent  SBoivin  MJ  et al.  Longitudinal neuropsychological and genetic linkage analysis of persons at risk for Huntington's disease. Arch Neurol. 1995;5259- 64
Link to Article
Strauss  MEBrandt  J Are there neuropsychologic manifestations of the gene for Huntington's disease in asymptomatic, at-risk individuals? Arch Neurol. 1990;47905- 908
Link to Article
Foroud  TSiemers  EKleindorfer  D  et al.  Cognitive scores in carriers of Huntington's disease gene compared to noncarriers. Ann Neurol. 1995;37657- 664
Link to Article
Siemers  EForoud  TBill  D  et al.  Motor changes in presymptomatic Huntington disease gene carriers. Arch Neurol. 1996;53487- 492
Link to Article
Wechsler  D Wechsler Adult Intelligence Scale–Revised.  New York, NY Psychological Corp1981;
Diamond  RWhite  RFMyers  RH  et al.  Evidence of presymptomatic cognitive decline in Huntington's disease. J Clin Exp Neuropsychol. 1992;14961- 975
Link to Article
Fedio  PCox  CSNeophytides  A  et al.  Neuropsychological profiles in Huntington's disease: patients and those at risk. Adv Neurol. 1979;23239- 255
Lezak  MD Neurological Assessment. 3rd ed. New York, NY Oxford University Press1995;377
Hayden  MRHewitt  JStoessi  AJ  et al.  The combined use of positron emission tomography and DNA polymorphisms for preclinical detection of Huntington disease. Neurology. 1987;371441- 1447
Link to Article
Aylward  EHBrandt  JCodori  AM  et al.  Reduced basal ganglia volume associated with the gene for Huntington's disease in asymptomatic at-risk persons. Neurology. 1994;44823- 828
Link to Article
Mendez  MFAdams  NLLewandowski  KL Neurobehavioral changes associated with caudate lesions. Neurology. 1989;39349- 354
Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Demographic Data for the 43 Study Participants With DNA Results*
Table Graphic Jump LocationTable 2. WAIS-R Initial and Follow-up Examination Means and Longitudinal Change*
Table Graphic Jump LocationTable 3. Possible or Definite Abnormal Findings of Initial and Follow-up Examinations and Longitudinal Change*

References

Huntington's Disease Collaborative Research Group, A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993;72971- 983
Link to Article
Andrew  SEGoldberg  YPKremer  B  et al.  The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993;4398- 403
Link to Article
Siesling  SZwinderman  AHvan Vugt  JPKieburtz  KRoos  RA A shortened version of the motor section of the Unified Huntington's Disease Rating Scale. Mov Disord. 1997;12229- 234
Link to Article
Roos  RACHermans  JVegter-van der Vlis  Mvan Ommen  GJBBruyn  GW Duration of illness in HD is not related to age at onset. J Neurol. 1993;5698- 100
Van Dijk  JGvan der Velde  EARoos  RACBruyn  GW Juvenile HD. Hum Genet. 1986;73235- 239
Link to Article
Folstein  SE Historical perspective and overview. InHuntington's Disease: A Disorder of Families. Baltimore, Md Johns Hopkins University Press1989;1- 10
Farrer  LAConneally  PM A genetic model for age at onset in Huntington disease. Am J Hum Genet. 1985;37350- 357
Penny  JBYoung  BMShoulson  I  et al.  Huntington's disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals. Mov Disord. 1990;593- 99
Link to Article
Young  ABShoulson  IPenny  JB  et al.  Huntington's disease in Venezuela: neurologic features and functional decline. Neurology. 1986;36244- 249
Link to Article
Lawrence  ADSahakian  BJHodges  JRRosser  AELange  KWRobbins  TW Executive and mnemonic functions in early HD. Brain. 1996;1191633- 1645
Link to Article
Paulsen  JSSalmon  DPMonsch  AUButters  NSwenson  MRBondi  MW Discrimination of cortical from subcortical dementias on the basis of memory and problem-solving tests. J Clin Psychol. 1995;5148- 58
Link to Article
Bamford  KACaine  EDKido  DKPlassche  WMShoulson  I Clinical-pathologic correlation in Huntington's disease: a neuropsychological and computed tomography study. Neurology. 1989;39796- 801
Link to Article
Butters  NWolfe  JMartone  MGranholm  ECermak  LS Memory disorders associated with Huntington's disease: verbal recall, verbal recognition and procedural memory. Neuropsychology. 1985;23729- 743
Link to Article
Bamford  KACaine  EDKido  DKCox  CShoulson  I A prospective evaluation of cognitive decline in early Huntington's disease: functional and radiographic correlates. Neurology. 1995;451867- 1873
Link to Article
Moses  JAGolden  CJBerger  PAWisniewski  AM Neuropsychological deficits in early, middle, and late stage Huntington's disease as measured by the Luria-Nebraska Neuropsychological Battery. Int J Neurosci. 1981;1495- 100
Link to Article
Lundervold  AJReinvang  I Neuropsychological findings and depressive symptoms in patients with Huntington's disease. Scand J Psychol. 1991;32275- 283
Link to Article
Huber  SJPaulsen  GW Memory impairment associated with progression of Huntington's disease. Cortex. 1987;23275- 283
Link to Article
Swerdlow  NRPaulsen  JBraff  DLButters  NGeyer  MASwenson  MR Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington's disease. J Neurol Neurosurg Psychiatry. 1995;58192- 200
Link to Article
Nordin  SPaulsen  JSMurphy  C Sensory- and memory-mediated olfactory dysfunction in Huntington's disease. J Int Neuropsychol Soc. 1995;1281- 290
Link to Article
Moberg  PJPearlson  GDSpeedie  LJLipsey  JRStrauss  MEFolstein  SE Olfactory recognition: different impairments in early and late Huntington's and Alzheimer's diseases. J Clin Exp Neuropsychol. 1987;9650- 664
Link to Article
Snell  RGMacMillan  JCCheadle  JP  et al.  Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet. 1993;4393- 397
Link to Article
Rosenberg  NKSorensen  SAChristensen  AL Neuropsychological characteristics of Huntington's disease carriers: a double blind study. J Med Genet. 1995;32600- 604
Link to Article
Rothlind  JCBylsma  FWPeyser  CFolstein  SEBrandt  J Cognitive and motor correlates of everyday functioning in early Huntington's disease. J Nerv Ment Dis. 1993;181194- 199
Link to Article
Lanto  ABRiege  WHMazziotta  JCPahl  JJPhelps  ME Increased false alarms in a subset of persons at-risk for Huntington's disease. Arch Clin Neuropsychol. 1990;5393- 404
Link to Article
Mohr  EBrouwers  PClaus  JJMann  UMFedio  PChase  TN Visuospatial cognition in Huntington's disease. Mov Disord. 1991;6127- 132
Link to Article
Hodges  JRSlanom  DPButters  N Differential impairment of semantic and episodic memory in Alzheimer's and Huntington's diseases: a controlled prospective study. J Neurol Neurosurg Psychiatry. 1990;531089- 1095
Link to Article
Oepen  GMohr  UWillmes  K  et al.  Huntington's disease: visuomotor disturbance in patients and offspring. J Neurol Neurosurg Psychiatry. 1985;48426- 433
Link to Article
Josiassen  RCCurry  LMMancall  EL Development of neuropsychological deficits in Huntington's disease. Arch Neurol. 1983;40791- 796
Link to Article
Baro  F A neuropsychological approach to early detection of Huntington's chorea. Adv Neurol. 1973;1329- 338
Hayward  LZubrick  SRHall  W Early sensory-perceptual changes in Huntington's disease. Aust N Z J Psychiatry. 1985;19384- 389
Link to Article
Wexler  NS Perceptual-motor, cognitive, and emotional characteristics of persons at risk for Huntington's disease. Adv Neurol. 1979;23257- 271
Campodonico  JRCodori  AMBrandt  J Neuropsychological stability over two years in asymptomatic carriers of the Huntington's disease mutation. J Neurol Neurosurg Psychiatry. 1996;61621- 624
Link to Article
Blackmore  LSimpson  SACrawford  JR Cognitive performance in UK sample of presymptomatic people carrying the gene for Huntington's disease. J Med Genet. 1995;32358- 362
Link to Article
Johnson  CTMcSorley  PBrandt  J  et al.  Memory test performance as a preclinical indicator of Huntington's disease in at-risk persons [abstract]? J Clin Exp Neuropsychol. 1987;951
Gomez-Tortosa  Edel Barrio  ABarroso  TGarcia Ruiz  PJ Visual processing disorders in patients with HD and asymptomatic carriers. J Neurol. 1996;243286- 292
Link to Article
de Boo  GTibben  ALanser  JB  et al.  Intelligence indices in people with a high/low risk for developing Huntington's disease. J Med Genet. 1997;34564- 568
Link to Article
Giordani  BBerent  SBoivin  MJ  et al.  Longitudinal neuropsychological and genetic linkage analysis of persons at risk for Huntington's disease. Arch Neurol. 1995;5259- 64
Link to Article
Strauss  MEBrandt  J Are there neuropsychologic manifestations of the gene for Huntington's disease in asymptomatic, at-risk individuals? Arch Neurol. 1990;47905- 908
Link to Article
Foroud  TSiemers  EKleindorfer  D  et al.  Cognitive scores in carriers of Huntington's disease gene compared to noncarriers. Ann Neurol. 1995;37657- 664
Link to Article
Siemers  EForoud  TBill  D  et al.  Motor changes in presymptomatic Huntington disease gene carriers. Arch Neurol. 1996;53487- 492
Link to Article
Wechsler  D Wechsler Adult Intelligence Scale–Revised.  New York, NY Psychological Corp1981;
Diamond  RWhite  RFMyers  RH  et al.  Evidence of presymptomatic cognitive decline in Huntington's disease. J Clin Exp Neuropsychol. 1992;14961- 975
Link to Article
Fedio  PCox  CSNeophytides  A  et al.  Neuropsychological profiles in Huntington's disease: patients and those at risk. Adv Neurol. 1979;23239- 255
Lezak  MD Neurological Assessment. 3rd ed. New York, NY Oxford University Press1995;377
Hayden  MRHewitt  JStoessi  AJ  et al.  The combined use of positron emission tomography and DNA polymorphisms for preclinical detection of Huntington disease. Neurology. 1987;371441- 1447
Link to Article
Aylward  EHBrandt  JCodori  AM  et al.  Reduced basal ganglia volume associated with the gene for Huntington's disease in asymptomatic at-risk persons. Neurology. 1994;44823- 828
Link to Article
Mendez  MFAdams  NLLewandowski  KL Neurobehavioral changes associated with caudate lesions. Neurology. 1989;39349- 354
Link to Article

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