Unawareness of motor phenoconversion in Huntington disease

Unawareness of motor phenoconversion in Huntington disease Elizabeth A. McCusker, MBBS (Hons), FRACP, FAAN David G. Gunn, PhD Eric A. Epping, MD, PhD Clement T. Loy, MBBS, FRACP, MPH Kylie Radford, PhD Jane Griffith, RN James A. Mills, MS Jeffrey D. Long, PhD Jane S. Paulsen, PhD On behalf of the PREDICT-HD Investigators of the Huntington Study Group Correspondence to Dr. Paulsen: [email protected] ABSTRACT Objective: To determine whether Huntington disease (HD) mutation carriers have motor symptoms (complaints) when definite motor onset (motor phenoconversion) is diagnosed and document differences between the groups with and without unawareness of motor signs. Methods: We analyzed data from 550 HD mutation carriers participating in the multicenter PREDICT-HD Study followed through the HD prodrome. Data analysis included demographics, the Unified Huntington’s Disease Rating Scale (UHDRS) and the Participant HD History of symptoms, selfreport of progression, and cognitive, behavioral, and imaging measures. Unawareness was identified when no motor symptoms were self-reported but when definite motor HD was diagnosed. Results: Of 38 (6.91%) with onset of motor HD, almost half (18/38 5 47.36%) had no motor symptoms despite signs of disease on the UHDRS motor rating and consistent with unawareness. A group with motor symptoms and signs was similar on a range of measures to the unaware group. Those with unawareness of HD signs reported less depression. Patients with symptoms had more striatal atrophy on imaging measures. Conclusions: Only half of the patients with newly diagnosed motor HD had motor symptoms. Unaware patients were less likely to be depressed. Self-report of symptoms may be inaccurate in HD at the earliest stage. Neurologyâ 2013;81:1141–1147 GLOSSARY ANCOVA 5 analysis of covariance; BDI-II 5 Beck Depression Inventory–II; CAP 5 CAG-Age Product; DCL 5 diagnostic confidence level; FrSBe 5 Frontal Systems Behavior Scale; HD 5 Huntington disease; HDHX 5 Participant Huntington Disease History; UHDRS 5 Unified Huntington’s Disease Rating Scale. Patient unawareness of disease manifestations is documented in neurodegenerative diseases associated with cognitive impairment.1 Unawareness or anosognosia, the pathologic unawareness of a neurologic or functional deficit,2 is measured as “the discrepancy between the patient’s self-report and the report of a natural caregiver or the clinical rating of a health professional.”3 Clearly, affected patients may have no complaints (symptoms), deny difficulty, and display lack of concern (anosodiaphoria) and insight into disease impact and, importantly, the need for care.4,5 Evidence of unawareness in Huntington disease (HD) in the following studies focused mainly on individuals with a clinical diagnosis. Patients with HD have difficulty identifying their chorea, as contrasted with findings on an objective neurologic examination.6 Impaired self-awareness of the movement disorder is greater in HD than in Parkinson disease.7 Patients with HD have impaired awareness of their cognitive, emotional, and functional capacity compared with companion ratings and objective assessments.7,8 The PREDICT-HD Study is a longitudinal observational investigation of those with the HD mutation but who do not meet criteria for a diagnosis of HD at study entry.9 In an earlier study of a subset of the PREDICT-HD sample, mutation carriers had significantly more frontal behaviors than noncarriers and a greater discrepancy in reporting frontal behaviors from the companion report in those closest to phenoconversion, consistent with unawareness.10 Supplemental data at www.neurology.org From the Neurology Department (E.A.M., D.G.G., C.T.L., K.R., J.G.), Westmead Hospital, Sydney; Sydney Medical School (E.A.M., C.T.L.), University of Sydney, Australia; and Department of Psychiatry (E.A.E., J.A.M., J.D.L, J.S.P.), University of Iowa, Iowa City. PREDICT-HD coinvestigators are listed on the Neurology® Web site at www.neurology.org. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2013 American Academy of Neurology 1141 ª

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QSPIJCJUFE Unawareness could influence accuracy of information about disease course when there is reliance on self-report alone. We analyzed the PREDICT-HD data at the third annual study visit to: 1. Examine whether patients with HD have motor symptoms at the time the rater records a motor diagnosis (phenoconversion) based on the findings of unequivocal signs on motor examination. 2. Document differences between the groups with unawareness of motor phenoconversion and without. 3. Determine whether there is a group with increased vigilance for possible HD symptoms and signs. METHODS Standard protocol approvals, registrations, and patient consents. Five hundred fifty HD mutation carriers and 163 noncarriers (controls) from the PREDICT-HD Study (clinicaltrials.gov registry identifier NCT00051324) were included. All participants provided written informed consent as approved by their individual sites’ Institutional Review Boards. Participants. The participants did not know of this study hypothesis when they consented to join the PREDICT-HD Study. The study was not conceived at the time of data collection by motor raters. Observations at the third annual study visit provided a reasonable sample size for the grouping of interest. Demographics and data on a variety of domains were collected at each visit, including the Unified Huntington’s Disease Rating Scale (UHDRS) and the Participant HD History (HDHX). Table 1 shows the 4 groups (A–D) identified by responses to 1) the selfreport HDHX item 1 (“Since your last visit, have you noticed any symptoms that you feel are suggestive of HD?”), and 2) the motor examiner report UHDRS item 17 (“To what degree are you confident that this participant meets the operational definition of the unequivocal presence of an otherwise unexplained extrapyramidal movement disorder in a participant at risk for HD?”). Motor diagnosis is defined as a rating of 4 ($99% rater confidence) on UHDRS item 17, known as the diagnostic confidence level (DCL). Those diagnosed at baseline or visit 2 were excluded, and because UHDRS item 17 refers to motor signs, participants reporting symptoms other than “Motor,” “Oculomotor,” or “Mixed” on HDHX item 3 (“Describe the symptom[s] that Table 1 Definition of 4 awareness groups (A–D) for participants with HD mutation HDHX item 1: Since your last visit, have you noticed any symptoms that you feel are suggestive of HD? UHDRS item 17 No symptoms Symptoms No Dx (rating of 0–3) A (n 5 427) B (n 5 85) Dx (rating of 4) C (n 5 18) D (n 5 20) DCL Abbreviations: DCL 5 diagnostic confidence level; Dx 5 diagnosis; HD 5 Huntington disease; HDHX 5 Participant HD History; UHDRS 5 Unified Huntington’s Disease Rating Scale. 1142 Neurology 81 you noticed since your last visit: Motor, Cognitive, Psychiatric, Oculomotor, Other, Mixed”) were also excluded. Unawareness was identified when no motor symptoms were self-reported but when a diagnosis of definite motor HD was made. As seen in table 1, group A reported no symptoms and did not have a motor diagnosis. Group B reported symptoms but did not have a motor diagnosis. Group C reported no symptoms but had a motor diagnosis. Finally, group D reported symptoms and had a motor diagnosis. Measures. Clinical. Trained examiners administered the UHDRS motor examination,11 consisting of 15 primary items. The examiner rates the DCL based on the UHDRS motor examination that conveys the degree of likelihood that the participant has manifest HD ranging from 0 5 no abnormalities to 4 5 motor abnormalities that are unequivocal signs of HD ($99% confidence). The UHDRS also includes the Total Functional Capacity score and a participant assessment of HD progression (UHDRS item 79: “Since your last assessment, do you feel improved, worsened, or about the same?”). At the first study visit, examiners record whether they are blinded to the participant’s HD mutation status. For this sample, data were available for all participants except for one mutation carrier. Motor raters knew the gene status for 74% of the HD mutation carriers, and 71% of the noncarriers. Self-report questionnaires. Frontal/executive dysfunction was rated using an adaptation of the Frontal Systems Behavior Scale (FrSBe),12 a 24-item scale on which both participants and their companions (informants) rate the participant’s severity and level of distress on a number of frontal/dysexecutive behaviors. Mood was assessed with the Beck Depression Inventory–II (BDI-II).13 Cognitive measures. Because they are robust clinical indicators of the disease process,14 motor speed was assessed using the Speeded Tapping Test15 and verbal memory using the Delayed Trial of the Hopkins Verbal Learning Test–Revised.16 Measures of executive functioning included a computerized tower task to assess planning and reasoning (similar to that used by Saint-Cyr et al.17) and the Interference task from the Stroop Interference Test.18 Imaging measures. MRI scans were obtained at the same visit as the clinical measures and acquired and analyzed using a standard protocol described in previous PREDICT-HD studies.19–24 Data analysis. Two main methods of analysis were used: the x2 test of association for contingency tables, and analysis of covariance (ANCOVA) for comparisons between the groups. A x2 test of association was used to examine awareness group (groups A–D) responses to UHDRS item 79 (see above). For a comparison of symptoms reported by participant group (groups B and D), a x2 test was used. Analysis groups were compared on clinical, selfreport, cognitive, and imaging measures by ANCOVA models, adjusting for age, sex, and education. Pairwise group comparisons were made with follow-up t tests. RESULTS Table 2 presents demographic variables for the groups. The groups did not differ for female preponderance or education levels. Age difference was not statistically significant between the mutation carrier groups (groups A–D). Baseline progression was indexed by the CAG-Age Product or CAP score,25 which is computed as CAP 5 (Age at entry) 3 (CAG 2 33.66). CAP scores can be converted to a scaled CAP score (CAPS) based on a 5-year probability of diagnosis from study entry.25 While group D’s CAP score was September 24, 2013 ª

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QSPIJCJUFE Table 2 Demographics Group A (no Sym, no Dx) B (Sym, no Dx) C (no Sym, Dx) D (Sym, Dx) E (control) No. 427 85 18 20 163 Sex, % female 62.30 65.88 72.22 70.00 65.64 Age, y, mean (SD) 42.87 (10.01) 44.79 (9.43) 44.83 (11.28) 43.99 (8.05) 46.69 (10.98) Education, y, mean (SD) 14.48 (2.73) 14.69 (2.78) 13.89 (2.81) 13.75 (2.00) 14.73 (2.61) 337.98 (75.51) 349.66 (78.94) 387.99 (66.66) 460.30 (114.50) NA a CAP, mean (SD) Abbreviations: CAP 5 CAG-Age Product; Dx 5 diagnosis; NA 5 not applicable; Sym 5 symptoms. a CAP 5 (Age at entry) 3 (CAG 2 33.66). significantly higher than that in other groups, the CAP score for the other diagnosed group (group C) was significantly higher than for groups A and B, indicating that these undiagnosed groups were further from estimated diagnosis. Table 3 shows the frequency and percentage of responses to UHDRS item 79 by awareness groups. There was a statistically significant group effect, x2 (6) 5 155.52, p , 0.0001, with a greater frequency of group D (symptoms, diagnosis) participants reporting decline than participants from other groups (63.2% vs 43.4% for group B, 11.8% for group C, and 3.6% for group A). The comparison between groups B and D was not statistically significant, x2 (1) 5 1.03, p 5 0.3098, indicating no evidence of a difference of symptom perception among the groups. Table 4 shows the frequency and percentage of HDHX item 3 for the subcomparison of the symptomatic groups B and D. More than half of the participants in each group reported a decline of motor functioning relative to their previous visit. Table 5 presents results for clinical, self-report, cognitive, and imaging variables. Analysis group means and SDs are displayed along with ANCOVA model results. Pairwise group comparisons are shown in the last column. The ANCOVA results column indicates a statistically significant group effect for all variables. The group Table 3 comparison column shows the details of the inequalities. For every outcome, the control group had the best performance (e.g., smallest mean total motor score). Group C or D (i.e., manifest HD) or both had the worst performance or most negative mean score on most of the outcomes. However, groups reporting HD symptoms, group B (no diagnosis) along with D (diagnosis), had the most negative mean score on the BDI-II and the FrSBe. For most variables, group A (no symptoms, no diagnosis) had the second-best performance/positive mean score after the control group. Comparison of groups C and D. Table 5 shows the group means and differences on the clinical, questionnaire, cognitive, and imaging measures between the 2 groups with a diagnosis, one group of patients with impaired awareness of motor symptoms (group C) and another without (group D). These 2 groups did not differ on their total motor score on the UHDRS or any cognitive measures, although they performed worse on these measures than the 2 other patient groups and the control group. Group C had significantly (albeit slightly) better functional capacity, less depressive symptoms, performed faster on a motor speed task, and had greater striatal and white matter volumes. Companions in group C reported significantly lower levels of dysexecutive behaviors on the FrSBe compared with group D; there was no statistically significant Participant self-ratings of HD progression (UHDRS item 79) Group HD progression A (no Sym, no Dx) B (Sym, no Dx) C (no Sym, Dx) D (Sym, Dx) Total Worsened 15 (3.6) 36 (43.4) 2 (11.8) 12 (63.2) 65 About the same 347 (82.2) 39 (47.0) 14 (82.4) 4 (21.1) 404 Improved 60 (14.2) 8 (9.6) 1 (5.9) 3 (15.8) 72 Total 422 83 17 19 541 Abbreviations: Dx 5 diagnosis; HD 5 Huntington disease; Sym 5 symptoms; UHDRS 5 Unified Huntington’s Disease Rating Scale. Data are n (%) by awareness group (p , 0.0001). Neurology 81 September 24, 2013 1143 ª

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QSPIJCJUFE Table 4 Frequency (%) of symptoms reported (HDHX item 3) by group (B and D) Group Symptom type B (Sym, no Dx) D (Sym, Dx) Total Motor only 57 (67) 11 (55) 68 Mixed motor 28 (33) 9 (45) 37 Total 85 20 105 Abbreviations: Dx 5 diagnosis; Sym 5 symptoms; HDHX 5 Participant Huntington Disease History. difference in FrSBe participant ratings between these groups. Comparison of groups A and B. Table 5 also shows the group means and differences on the clinical, questionnaire, cognitive, and imaging measures between the 2 groups that did not have a diagnosis, one reporting symptoms (group B) and one without symptoms (group A). Group B participants returned a significantly higher motor score on the UHDRS, reported less functional capacity, had a higher level of depressive symptoms Table 5 (similar to group D), and were slower on the speeded tapping task. Participants and companions of group B reported greater dysexecutive behaviors compared with group A. These 2 prodromal groups did not differ on any of the cognitive or imaging measures. However, compared with the control group, both performed significantly worse on Verbal Memory and Stroop Interference and had smaller magnetic resonance volumes. Post hoc correlation analyses. Examination of the results in table 5 suggested a relationship between dysexecutive behaviors (FrSBe) and depressive symptoms (BDI-II). To explore this possibility, correlations between these 2 measures for each of the groups were analyzed (table e1 on the Neurology® Web site at www.neurology.org). In all groups, participants with increasing BDI-II scores also had significantly higher FrSBe scores. Similar significant results in the same direction were observed for companion ratings in groups A, B, C, and the controls. Companions had no significant correlation in group D. DISCUSSION The main findings in this study were that half of the patients with newly diagnosed motor Mean (SD) for analysis groups Group Measure A (no Sym, no Dx) B (Sym, no Dx) C (no Sym, Dx) D (Sym, Dx) Control ANCOVA result Group comparisona UHDRS motor score 4.70 (5.2) 9.02 (6.6) 20.89 (6.9) 23.20 (11.1) 2.66 (2.8) F4,705 5 117.46; p , 0.0001 C, D . B . A . Cont UHDRS TFC 12.85 (0.7) 12.27 (1.2) 12.00 (1.9) 11.20 (2.0) 12.98 (0.2) F4,705 5 34.57; p , 0.0001 D , B, C , A, Cont FrSBe total-participantb 55.6 (16.4) 66.7 (23.7) 59.3 (24.2) 68.8 (25.6) 54.3 (14.8) F4,691 5 10.47; p , 0.0001 B, D . A, Cont FrSBe total-companionb 53.1 (17.9) 62.1 (23.0) 60.7 (22.0) 73.7 (29.4) 47.1 (13.0) F4,619 5 15.19; p , 0.0001 D . B . A . Cont; D . C . Cont BDI-II 5.71 (7.0) 12.86 (11.7) 7.39 (11.4) 14.55 (12.3) 4.40 (5.8) F4,703 5 23.51; p , 0.0001 B, D . A, C, Cont Speeded Tapping–nondominant index 253.1 (48.8) 274.9 (63.5) 308.9 (70.1) 380.3 (122.7) 232.9 (28.9) F4,684 5 45.70; p , 0.0001 D . C . B . A . Cont HVLT delayed recall 9.80 (2.1) 9.81 (1.8) 8.13 (2.3) 7.40 (3.4) 10.61 (1.7) F4,628 5 14.39; p , 0.0001 C, D , A, B , Cont Tower task 25.37 (6.5) 24.82 (6.0) 30.05 (8.6) 29.61 (7.3) 24.84 (5.5) F4,603 5 3.94; p 5 0.0036 C, D . A, B, Cont Stroop Interference 47.00 (10.6) 44.72 (9.8) 36.18 (8.7) 32.25 (9.1) 48.43 (9.4) F4,695 5 18.01; p , 0.0001 C, D , A, B , Cont Striatum/ICV ratio 0.010 (0.002) 0.010 (0.001) 0.009 (0.001) 0.006 (0.001) 0.011 (0.001) F4,348 5 31.62; p , 0.0001 D , A, B, C , Cont White matter/ICV ratio 0.28 (0.03) 0.28 (0.03) D , A , Cont; B , Cont; D ,C 0.29 (0.03) 0.27 (0.03) 0.30 (0.03) F4,348 5 8.30; p , 0.0001 Abbreviations: ANCOVA 5 analysis of covariance; BDI 5 Beck Depression Inventory–II; Cont 5 control; Dx 5 diagnosis; FrSBe 5 Frontal Systems Behavior Scale; HVLT 5 Hopkins Verbal Learning Test; ICV 5 intracranial volume; Sym 5 symptoms; TFC 5 Total Functional Capacity; UHDRS 5 Unified Huntington’s Disease Rating Scale. The less than (,) and greater than (.) symbols indicate a statistically significant group difference in the stated direction. A group that is not statistically different from any of the others is not listed. For example, on the FrSBe participant measure, groups B and D are not statistically different from each other but they are higher than group A and control, while group C is omitted because it is not statistically different from any other group. a Results of ANCOVA adjusting for age, sex, and education. b The FrSBe total score is calculated by summing the products of the frequency and distress scores for items 1–18. 1144 Neurology 81 September 24, 2013 ª

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QSPIJCJUFE HD had unawareness and were without motor symptoms. These unaware patients were less likely to be depressed or to report progression. However, paradoxically aware patients had more striatal atrophy. The unaware group (group C) was similar on a range of measures—memory and executive functioning and motor score—to the group who reported symptoms and had a motor diagnosis (group D). Group B reported motor symptoms but had no motor diagnosis. An unexpected finding was that groups C and D differed significantly on FrSBe companion scores (D . C; see table 5). This questionnaire may not be an accurate measure of frontal dysfunction associated with unawareness and may reflect a degree of depressive symptomatology. A relationship between depressive symptoms and reporting of dysexecutive behaviors on the FrSBe is shown in the supplementary material. The reliability of these subjective reports of frontal dysfunction is also questionable in the group with unawareness. In other studies, impairment on the Wisconsin Card Sorting Test correlated better with lack of awareness.8 Group C had significantly lower scores on the BDIII than group D. The other symptomatic group, group B, also had a higher depression rating. Depression is unlikely to account for the motor symptoms in groups B and D. Depression may be reactive and related to awareness of onset of motor dysfunction. Greater insight and awareness would be expected to be associated with more depression.26 The finding of less depression in group C suggests lack of insight in this asymptomatic group. In a recent review of suicide in dementia, preserved insight was a putative risk factor.27 Participants in the PREDICT-HD Study are not informed of the HD diagnosis/phenoconversion by the research team, but some with more symptoms may have been given a formal diagnosis of HD onset by their treating HD specialist. Because group D had slightly more progression of HD, more symptoms would be expected, but group B although undiagnosed was symptomatic as well. In group B, there were more motor signs recorded on the UHDRS compared with group A. Group A participants (without a diagnosis or symptoms) had very subtle motor signs, were younger, and had a lower CAP score, being furthest from predicted onset. Symptoms reported in group B, although undiagnosed and with a lower motor rating than groups C and D, may represent hypervigilance but some may have had activities that required fine motor skills that are more sensitive to changes. Considering the range of overlap between the motor scores for groups B (9.02 6 6.6) and C (20.89 6 6.9), earlier diagnosis could have been given to some in group B but the DCL rating of 4 is a conservative assessment that there can be no doubt about the diagnosis. Group C differed in other ways from the groups with symptoms (groups B and D). Group C was more likely to report no change or improvement since the visit the year before, again consistent with unawareness with 88% feeling the same or better and only 12% reporting decline. The participants in the symptomatic groups D and B were much more likely to report that they were the same or worse. There are other possible reasons for unawareness. With a very gradual change over many years, onset might not be noticed. Better knowledge of the disease including seeing an affected relative could influence symptom report. Some motor signs may not be associated with symptoms, i.e., eye-movement impairment. However, the UHDRS mean score in these groups is such that some signs would be expected to produce symptoms. If these individuals whose symptom report is at variance with findings on examination are included in a clinical trial, efficacy measures, based on self-report for an intervention, could be inaccurate. For participants classified as still prodromal, those with motor symptoms of HD (group B) had similar cognitive functioning on most measures to the asymptomatic, undiagnosed younger group A participants. Group B participants had significantly higher ratings of depression and more frontal/executive dysfunction compared with those who were “symptom-free” (group A). Interestingly, group B had similar ratings on some measures to the groups with an HD diagnosis (C and D) despite fewer signs of disease. Earlier care or intervention could be offered to a group of individuals identified with apparently heightened awareness in the prodromal stages. There is clearly a group unaware of manifestations (group C). In addition, there is a group whose participants were more aware of motor symptoms (group B) even before a definitive diagnosis. Looking at the groups identified in this analysis, it appears that there is the expected progression of motor signs in the prodrome leading up to HD diagnosis but not a parallel progression of symptoms. There were no significant differences in striatal volumes between the groups other than group D, who had a significant reduction of striatal volumes. In previous studies, patient self-reported ratings of “frontal” behaviors have not correlated with measures of striatal atrophy.10 Striatal and white matter volumes may be irrelevant in the study of unawareness but correlate better with motor manifestations and other measures of cognitive function. Imaging studies that target the likely area of pathology in unawareness have not been reported in HD. In other neurodegenerations, including Alzheimer disease, using a range of imaging modalities, the predominant changes were in the right dorsolateral prefrontal region.4,28–31 Orbitofrontal-limbic pathology is suggested as the likely trigger Neurology 81 September 24, 2013 1145 ª

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QSPIJCJUFE for anosognosia/anosodiaphoria in HD.7 Neuroimaging in extrastriatal areas may be more informative. This study addressed only the motor phenoconverters. There is increased recognition of cognitive/behavioral phenotypes.32–36 A more comprehensive study would include these other HD manifestations. There is approximately 20% uptake of predictive testing.37,38 The PREDICT-HD participants are a select group of volunteers. Because pretest and posttest counseling programs are a requirement of predictive genetic testing, greater awareness of HD symptoms and signs would be expected in these tested participants. Unawareness in this group and unreliable symptom report could be more marked in the general population of those at risk. Unawareness has major implications for better defining the disease process, time of presentation for diagnosis and assistance, measures of progression, the impact of impaired function in daily activities including driving and in the workplace, as well as perception of possible discrimination and caregiver burden. Treatment, when available or for symptomatic disease features, could be delayed if the person fails to notice the changes taking place and to present for care. Methods of measurement and documentation of unawareness in this earliest disease stage need further study. Possible measures in established HD and in frontotemporal dementia and Alzheimer disease are reported that include an anosognosia rating scale39 as well as several neuropsychological measures of impairment in the anosognosia group, the Wisconsin Card Sorting Test and tests of visual-spatial ability on the Wechsler Adult Intelligence Scale–revised. Patients with HD studied using the Dysexecutive Questionnaire40 rated their carer accurately but underrated their own executive dysfunction. Patients with HD self-reported higher ratings on a competency rating scale than their collateral’s rating and disease severity correlated with measures of executive function.8 In particular, the collateral’s rating of the patient’s behavioral and functional competency correlated with the patient’s number of Wisconsin Card Sorting Test perseverative responses and scores on the Dementia Rating Scale Initiation and Perseveration subscales and the Symbol Digit Modalities Test. Although the numbers in this study are small, these results suggest that unawareness of HD motor changes occurs in a significant number of participants converting from the prodromal to the early stages of HD and that self-report of symptoms can be unreliable. Another group may overreport symptoms, or rater scores for diagnosis including use of the DCL rating are too conservative or not sufficiently accurate and objective to reflect subtle but definite HD signs. These findings in this unique group of participants in the PREDICT-HD Study evolving to very early HD have implications for other neurodegenerations. 1146 Neurology 81 AUTHOR CONTRIBUTIONS Elizabeth McCusker: concept and design, data acquisition, analysis and interpretation, and critical revisions. David Gunn and Eric Epping: data acquisition, analysis and interpretation, and critical revisions. Clement Loy and Kylie Radford: concept and design, data acquisition, analysis and interpretation, and critical revisions. Jane Griffith: data acquisition and critical revisions. James Mills: analysis and interpretation. Jeffery Long: analysis and interpretation and critical revisions. Jane Paulsen: funding, analysis and interpretation, and critical revisions. ACKNOWLEDGMENT The authors thank the PREDICT-HD sites, the study participants, the National Research Roster for Huntington Disease Patients and Families, the Huntington’s Disease Society of America, and the Huntington Study Group. STUDY FUNDING Supported by the NIH, National Institute of Neurological Disorders and Stroke (NS040068), CHDI Foundation, Inc. (A3917), Cognitive and Functional Brain Changes in Preclinical Huntington’s Disease (5R01NS054893), 4D Shape Analysis for Modeling Spatiotemporal Change Trajectories in Huntington’s (1U01NS082086), Functional Connectivity in Premanifest Huntington’s Disease (1U01NS082083), and Basal Ganglia Shape Analysis and Circuitry in Huntington’s Disease (1U01NS082085). This publication was supported by the National Center for Advancing Translational Sciences, and the NIH, through grant 2 UL1 TR000442-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. DISCLOSURE E. McCusker and D. Gunn report no disclosures. E. Epping served on the advisory board for Lundbeck, Inc. in 2012 and receives funding from NARSAD and Nellie Ball Trust. C. Loy receives funding from the NIH, Australian Huntington’s Disease Association, Brain Foundation, NHMRC, CHDI, Mason Foundation, University of Sydney, China Study Centre, Prana Biotechnology, and Wesmead Charitable Trust Capital Equipment Grant. K. Radford, J. Griffith, J. Mills, and J. Long report no disclosures. J. Paulsen receives funding through the NIH for the PREDICT-HD Study. Go to Neurology.org for full disclosures. Received December 28, 2012. Accepted in final form June 24, 2013. REFERENCES 1. McGlynn SM, Schacter DL. The neuropsychology of insight: impaired awareness of deficits in a psychiatric context. Psychiatr Ann 1997;27:806–811. 2. Flashman LA. Disorders of awareness in neuropsychiatric syndromes: an update. Curr Psychiatry Rep 2002;4: 346–353. 3. Antoine C, Antoine P, Guermonprez P, Frigard B. Awareness of deficits and anosognosia in Alzheimer’s disease [in French]. Encephale 2004;30:570–577. 4. Mendez MF, Shapira JS. Loss of insight and functional neuroimaging in frontotemporal dementia. J Neuropsychiatry Clin Neurosci 2005;17:413–416. 5. Sitek EJ, Slawek J, Wieczorek D. Self-awareness of deficits in Huntington’s and Parkinson’s disease. Psychiatr Pol 2008;42:393–403. 6. Snowden JS, Craufurd D, Griffiths HL, Neary D. Awareness of involuntary movements in Huntington disease. Arch Neurol 1998;55:801–805. 7. Sitek EJ, Soltan W, Wieczorek D, et al. Self-awareness of motor dysfunction in patients with Huntington’s disease in comparison to Parkinson’s disease and cervical dystonia. J Int Neuropsychol Soc 2011;17:788–795. 8. Hoth KF, Paulsen JS, Moser DJ, Tranel D, Clark LA, Bechara A. Patients with Huntington’s disease have impaired awareness of cognitive, emotional, and functional abilities. J Clin Exp Neuropsychol 2007;29:365–376. September 24, 2013 ª

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QSPIJCJUFE 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Paulsen JS, Langbehn DR, Stout JC, et al. Detection of Huntington’s disease decades before diagnosis: the PREDICT-HD Study. J Neurol Neurosurg Psychiatry 2008;79:874–880. Duff K, Paulsen JS, Beglinger LJ, et al. “Frontal” behaviors before the diagnosis of Huntington’s disease and their relationship to markers of disease progression: evidence of early lack of awareness. J Neuropsychiatry Clin Neurosci 2010;22:196–207. Siesling S, van Vugt JP, Zwinderman KA, Kieburtz K, Roos RA. Unified Huntington’s Disease Rating Scale: a follow up. Mov Disord 1998;13:915–919. Grace J, Malloy PF. Frontal Systems Behavior Scale (FrSBE): Professional Manual. Lutz, FL: Psychological Assessment Resources; 2001. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory-II. San Antonio: Psychological Corporation; 1996. Stout JC, Paulsen JS, Queller S, et al. Neurocognitive signs in prodromal Huntington disease. Neuropsychology 2011; 25:1–14. Reitan RM. Manual for Administration and Scoring of the Halstead-Reitan of Neuropsychological Test Battery for Adults and Children. Tucson: Neuropsychology Press; 1979. Brandt J. The Hopkins Verbal Learning Test: development of a new memory test with six equivalent forms. Clin Neuropsychol 1991;25:125–142. Saint-Cyr JA, Taylor AE, Lang AE. Procedural learning and neostriatal dysfunction in man. Brain 1988;111(pt 4):941–959. Unified Huntington’s Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Disord 1996; 11:136–142. Pierson R, Johnson H, Harris G, et al. Fully automated analysis using BRAINS: AutoWorkup. Neuroimage 2011; 54:328–336. Magnotta VA, Harris G, Andreasen NC, O’Leary DS, Yuh WT, Heckel D. Structural MR image processing using the BRAINS2 toolbox. Comput Med Imaging Graph 2002;26:251–264. Powell S, Magnotta VA, Johnson H, Jammalamadaka VK, Pierson R, Andreasen NC. Registration and machine learningbased automated segmentation of subcortical and cerebellar brain structures. Neuroimage 2008;39:238–247. Magnotta VA, Heckel D, Andreasen NC, et al. Measurement of brain structures with artificial neural networks: two- and three-dimensional applications. Radiology 1999;211:781–790. Paulsen JS, Nopoulos PC, Aylward E, et al. Striatal and white matter predictors of estimated diagnosis for Huntington disease. Brain Res Bull 2010;82:201–207. Aylward EH, Nopoulos PC, Ross CA, et al. Longitudinal change in regional brain volumes in prodromal Huntington disease. J Neurol Neurosurg Psychiatry 2011;82:405–410. Zhang Y, Long JD, Mills JA, Warner JH, Lu W, Paulsen JS. Indexing disease progression at study entry with individuals 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. at-risk for Huntington disease. Am J Med Genet B Neuropsychiatr Genet 2011;156B:751–763. Paulsen JS, Nehl C, Hoth KF, et al. Depression and stages of Huntington’s disease. J Neuropsychiatry Clin Neurosci 2005;17:496–502. Haw C, Harwood D, Hawton K. Dementia and suicidal behavior: a review of the literature. Int Psychogeriatr 2009; 21:440–453. Hanyu H, Sato T, Akai T, et al. Neuroanatomical correlates of unawareness of memory deficits in early Alzheimer’s disease. Dement Geriatr Cogn Disord 2008;25:347–353. Reed BR, Jagust WJ, Coulter L. Anosognosia in Alzheimer’s disease: relationships to depression, cognitive function, and cerebral perfusion. J Clin Exp Neuropsychol 1993;15:231–244. Derouesne C, Thibault S, Lagha-Pierucci S, BaudouinMadec V, Ancri D, Lacomblez L. Decreased awareness of cognitive deficits in patients with mild dementia of the Alzheimer type. Int J Geriatr Psychiatry 1999;14:1019–1030. Starkstein SE, Jorge R, Mizrahi R, Robinson RG. A diagnostic formulation for anosognosia in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2006;77:719–725. Craufurd D, Thompson JC, Snowden JS. Behavioral changes in Huntington disease. Neuropsychiatry Neuropsychol Behav Neurol 2001;14:219–226. Kingma EM, van Duijn E, Timman R, van der Mast RC, Roos RA. Behavioural problems in Huntington’s disease using the Problem Behaviours Assessment. Gen Hosp Psychiatry 2008;30:155–161. Rickards H, De Souza J, van Walsem M, et al. Factor analysis of behavioural symptoms in Huntington’s disease. J Neurol Neurosurg Psychiatry 2011;82:411–412. Thompson JC, Snowden JS, Craufurd D, Neary D. Behavior in Huntington’s disease: dissociating cognitionbased and mood-based changes. J Neuropsychiatry Clin Neurosci 2002;14:37–43. Marder K, Zhao H, Myers RH, et al; Huntington Study Group. Rate of functional decline in Huntington’s disease. Neurology 2000;54:452–458. Harper PS, Lim C, Craufurd D. Ten years of presymptomatic testing for Huntington’s disease: the experience of the UK Huntington’s Disease Prediction Consortium. J Med Genet 2000;37:567–571. Creighton S, Almqvist EW, MacGregor D, et al. Predictive, pre-natal and diagnostic genetic testing for Huntington’s disease: the experience in Canada from 1987 to 2000. Clin Genet 2003;63:462–475. Deckel AW, Morrison D. Evidence of a neurologically based “denial of illness” in patients with Huntington’s disease. Arch Clin Neuropsychol 1996;11:295–302. Ho AK, Robbins AOG, Barker RA. Huntington’s disease patients have selective problems with insight. Mov Disord 2006;21:385–389. Neurology 81 September 24, 2013 1147 ª

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