Movement Disorders Vol. 6, No. 2, 1991, pp. 127-132 0 1991 Movement Disorder Society
Visuospatial Cognition in Huntington’s Disease Erich Mohr, *Pim Brouwers, ?Jules J. Claus, TUlrike M. Mann, Paul Fedio, and ?Thomas N. Chase Medical Neurology Branch, NINDS, *Pediatric Branch, NCI, and ?Experimental Therapeutics Branch, NINDS, National Institutes of Health, Berhesda, Maryland, U.S.A.
Summary: The notion of specificity of visuospatial dysfunction in Huntington’s disease (HD) was evaluated in a sample of afflicted patients as a function of symptom duration, age at onset, and overall dementia severity. Factor analytic procedures indicated that overall visuospatial processing capacity (factor 1) as well as the ability for spatial manipulation (factor 3) was markedly affected in HD patients. In contrast, consistency of spatial judgment (factor 2) appeared to remain relatively intact in these patients. Age at onset seemed to have no relationship with any of these variables, whereas dementia severity demonstrated a significant relationship with overall visuospatial processing capacity. Most importantly, duration of symptoms was significantly associated with the declining ability to mentally perform spatial manipulations. The observation of circumscribed visuospatial impairment in HD patients may have important consequences for the further understanding of the neurobehavioral consequences of this disorder. Key Words: Huntington’s disease.
paired performance on visuoconstructive tasks (11). Recent observations suggest that specific visuospatial deficits can be detected in asymptomatic individuals who are known to carry the HD gene (12). Furthermore, in addition to general dysfunction on complex psychomotor tasks, visuospatial function has been shown to clearly discriminate between early and further progressed patients with HD (13). To further explore the relationship between visuospatial dysfunction in HD and duration of symptoms, age at onset, and other relevant demographic variables, and to determine possible patterns of impairment in visuospatial cognition in this disorder, we examined a wide range of these cognitive tasks in a sample of patients in various stages of this illness.
Huntington’s disease (HD), an autosomal dominant genetic disorder, is characterized clinically by progressive chorea and dementia (1). Neuropathological studies reveal marked degenerative changes in the caudate and putamen with less consistent involvement of cerebral cortex, or other brain areas (2). Similarly, regional glucose metabolic profiles show marked striatal hypometabolism (3,4) in contrast to normal glucose utilization throughout the rest of the brain, regardless of motor or cognitive symptom severity (3). Intellectual deficits described in Huntington’s disease range widely (e.g., refs. 5-9) and include specific impairments in visuospatial function (1012). Patients with HD reportedly show consistent deficits on tasks of visuoperceptual and constructive abilities when manipulation of personal space is required, while demonstrating relatively less im-
METHODS Twenty patients with HD (11 men and nine women; age (mean k SEM), 45 +- 2.8 years; range, 25-75 years), diagnosed on the basis of typical motor and cognitive signs, a positive family history,
Address correspondence and reprint requests to Dr. E. Mohr at Neuropsychology Service, Royal Ottawa Hospital, 1145 Carling Ave., Ottawa, Ontario, K1Z 7K4, Canada.
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and computed tomography (CT) scan evidence of caudate atrophy (duration of symptoms: mean, 6 f 0.5 years, range, 3-16 years), with a mean education of 14 f 0.7 (range, 6-20) years, consented to participate in this study after full disclosure of potential benefits and risks. None had received any centrally active medication for at least 2 months prior to study onset. Nineteen neurologically normal subjects, matched for gender, age, and education (gender: 10 males, nine females; age: mean, 43 t 2.8 years, range 20-65 years; education: mean, 15 ? 0.7 years, range, 7-20 years) served as controls. Intellectual and memory function was assessed with the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (14) and the Wechsler Memory Scale (15). Dementing symptoms were evaluated with the Mattis Dementia Rating Scale (16). Visuospatially mediated subtests of the WAIS-R (Performance tests) were included in order to examine their potential association with distinct visuospatial domains. In addition, the following neuropsychological tests were administered to examine visuospatial function. Embedded Figures Test. Patients are asked to recognize a simple geometric design in one of four complex patterns (17). Rod and Frame Test. A rod within a tilted frame has to be adjusted to the upright from a 20" left or right tilt without other reference points (18). Mental Rotation Test. Complex three-dimensional geometric designs have to be rotated to compare with a target design (19,20). Street Map Test. Right and left turns in a direction away and towards the subject on a simulated map of a small town have to be identified (21). Mental Reorientation Test. Subject has to name which hand of a figure, rotated in the fronthack, lefthight and up/down planes is black (22). Extended In-Front Test. Subjects have to identify the locations (a) in front, (b) behind, and (c) next to an object or person(s), which are placed in the center of a 3 X 3 grid and systematically vary in their orientation (23).
Performance ratings for these neuropsychological tasks did not rely on speed or motor accuracy.
Movement Disorders, Vol. 6 , No. 2 , 1991
Data were analyzed with standard analysis of variance procedures (BMDP P7D) (24) for overall differences between HD patients and controls. Factor analysis was employed to investigate the possible presence of several independent domains of visuospatial function (BMDP P4M) (24). On the basis of significant intertest correlations (r > 0.6, p < 0.01), measures within individual tests were pooled as averages, and a total of 16 variables (Table 1) were entered into a principal components factor analysis. This was first applied to the HD group alone, to highlight constellations specific to the disease; subsequently, the HD and control data were combined and analyzed to contrast patterns distinguishing HD patients from healthy subjects. Correlational measures were used to examine the extent of the relationship between the two factor solutions (patients alone and patients plus controls) and to determine their association with demographic variables (age, age at onset, symptom duration) and dementia severity (Mattis Dementia Rating Scale). TABLE 1. Test scores used in factor solutions (mean & SEM and range) HD patients (n = 20) WAIS-R Picture 8 f 0.6 (414)" Completion WAIS-R Block Design 8 f 0.6 (2-12)" WAIS-R Picture Arrangement 8 2 0.6 (3-15)" 6 0.5 (2-11)O WAIS-R Digit Symbol WAIS-R Object Assembly 6 f 0.7 (1-11)" Mental Rotation Test 8 f 1.3 (0-18)" Street Map Test Overall correct 1 1 2 0.8 (0.5-l5)O Difference between away from self 2 0.7 (-3-8)b and toward self In-Front-Of Test Consistency Orientation to front 3 I- 0.2 ( 1 4 ) Orientation to person 3 2 0.2 (1-4) Orientation to person and group 1 2 0.1 (0-2) Overall consistency 2 f 0.5 (O-6)b Rod and Frame Test Frame orientation 5 t 0.8 (1-13)" left Frame orientation right 4 0.7 (1-13)" Mental Reorientation Test 5 2 0.4 (3-8)" 14 f 0.9 (5-19)" Embedded Figures Test
*
*
*
Normal controls (n = 19) I 1 t 0.4 (8-14) 12 t 0.7 (7-18)
*
12 0.5 (8-16) 12 I- 0.6 (6-16) 12 t 0.6 (7-16) 23 2 2.9 (4-40) 15
&
0.2 (12-16)
1 t 0.3 (-1-5)
3 f 0.2 (1-4) 3 0.2 (1-4)
*
1 2 0.2 (0-2) 0 2 0.0 (0-1) 2
f 0.2 (1-3)
1 2 0.2 (1-3)
8 f 0.1 (7-8) 18 f 0.3 (14-20)
a HD patients significantly different from controls at p < 0.001. HD patients significantly different from controls at p < 0.05.
VISUOSPATIAL FUNCTION IN H D
RESULTS Overall intellectual function was significantly compromised in the HD patients compared to control subjects. This was reflected in substantially lower scores on all three WAIS-R global scores (full scale IQ, Verbal and Performance IQ; p < 0.001) (Table 2). Examination of memory function (Memory Quotient, Wechsler Memory Scale) revealed the same pattern. HD patients evidenced markedly lower Memory Quotients than controls (P < 0.001) (Table 2). The Mattis Dementia Rating Scale classified all but two of the 20 HD patients, but none of the 19 controls, as demented (Table 2). Factor Analysis HD Patients Only Visuospatial function in HD patients (Table 1) was classifable into three major independent factors, accounting together for 67% of the observed variance (Table 3). Factor 1, with 29% of the variance (varimax rotation), loaded on all five performance subtests of the WAIS-R, the Embedded Figures Test, and the Mental Reorientation Test (Table 3). Factor 2, with 24% of the variance, consisted of performance on the Rod and Frame Test, orientational consistency (fronthack) on the In-Front-Of Test, and the difference score between orientation towards and away from self on the Street Map Test (Table 3). Factor 3 , with 14% of the variance, loaded on Mental Rotation, the Mental Reorientation Test, orientational consistency (all orientations) on the In-Front-Of Test and correct right/left choices on the Street Map (Table 3). Correlation of these factor scores with demographic data (age, age at onset, education, duration of symptoms) and dementia severity (Mattis DeTABLE 2. Intellectual and memory profiles in HD and control subjects (mean k SEM and range) HD patients WAIS-R Verbal IQ WAIS-R Performance IQ WAIS-R Full Scale IQ Wechsler Memory Scale Mattis Dementia Rating Scale a
Normal controls
88 4 2.8 (67-111)" I16
+.
3.4 (86146)
81 4 3.5 (5S120)" 1 1 1
?
2.7 (86-133)
84
?
3.0 (5Sl11)" 115 2 3.1 (87-142)
82 f 3.9 (61-119)" 120 5 4.0 (81-143)
125 f 2.9 (93-143)" 142
5
0.4 (139-144)
HD patients significantly different from controls at p
0.2) (Table 6). TABLE 5. Contrast of HD versus control subjects (Combined factor solution) HD -0.702 -0.031 0.364
2 2
*
Controls 0.185" 0.286 0.245'
0.739 2 0.118 0.032 f 0.142 - 0.383 & 0.169
HD patients significantly different from controls at p < 0.001.
HD patients significantly different from controls at p < 0.05.
Movement Disorders, Val. 6 , No. 2, 1991
Factor 1
any consistent association with demographic data or dementia. Contrasting factor scores for HD patients and their controls on this factor solution (patients and controls combined) indicated highly significant performance differences between groups on factors 1 and 3 (p < 0.001, p < 0.05, respectively), but failed to yield any differences on factor 2 (Table 5).
Factor 1 Factor 2 Factor 3
HD patients only
Factor loadings
Factors
HD patients and normal controls
Factor 1 Factor 2 Factor 3
Factor 2
Factor 3
0.8812" 0.9436" -0.2179
Correlation significant at p < 0.001.
COMMENT Overall intellectual and memory function was substantially impaired in patients with HD, as has been consistently observed previously (10,11,25). In addition to global decrements in visuospatially mediated intellectual ability, specific patterns of impairments in visuospatial function emerged in these HD patients. Visuospatial cognition was classifiable into three major domains in this patient group. Factor 1, principally associated with the performance subscales of the WAIS-R, the disembedding of simple figures from complex ones (Embedded Figures) and right/ left spatial judgment (Mental Reorientation), could best be conceptualized as a factor representing overall visuospatial processing capacity. The significant association between this factor and nonspecific overall dementia severity (Mattis Dementia Rating Scale) supports the contention that this is indeed a factor capturing overall ability levels of visuospatially mediated function. Factor 2, a consistency of spatial judgment factor (loading predominantly on judgment of upright orientation on the Rod and Frame Test, consistency of judgment of orientation of a figure, object or group on the InFront-Of-Test on a simple fronthack axis and consistency of rightheft judgment regardless of personal orientation on the Street Map), was not associated with any variables reflecting duration of illness, dementia severity or age at onset. It would, therefore, appear that this factor as a whole captures a domain not specifically affected by HD, in spite of the fact that several of its components showed significant decrements in the patient group. Factor 3, on the other hand, involving spatial manipulation [the ability to match a complex threedimensional figure, rotated in space, to an unrotated original (Mental Rotation), consistency of judgment of orientation on the In-Front-Of-Test, involving all complex orientations, and the overall ability level of right/left judgment on the Street
VISUOSPATIAL FUNCTION IN HD Map], appeared to be affected significantly by HD, evidenced by the negative correlation with duration of illness. The introduction of the normal control group in the second factor solution (patients and controls combined) further clarified these contentions. Factors 1 and 2 of both solutions (patients alone and patients and controls combined) were highly similar and stable (Table 4), suggesting that neither of these factors was specifically altered by HD. Factor 3 , on the other hand, which was associated with duration of illness in the factor solution with HD patients only, was not recovered when normal controls were added, suggesting that this factor captures a domain of functioning which is increasingly affected as HD progresses. The contrast between HD patients and their controls on the combined solution further highlighted the view that decrements in visuospatial function have certain circumscribed features in Huntington’s disease. Factor 1, conceptualized as a factor of overall visuospatial processing capacity, classified patients and controls as substantially different from each other. Factor 2, consistency of spatial judgment, was essentially identical for both groups, indicating that this particular function as a whole is not affected by the disease. Factor 3, in turn, showed significant differences between patients and controls, reflecting impaired function in this domain in HD patients. Earlier neuroanatomical findings, glucose metabolic profiles and regional cerebral blood flow studies may help explain some of these observations (2,3,8,26,27). Atrophy of cerebral cortex is apparently evident early on in HD and may not be directly linked to subsequent disease progression (2). Gross reduction in overall visuospatial ability levels-which are probably reflected in factor 1, overall visuospatial processing capacity (either solution)-may well be the functional representation of this global atrophic process. Neostriatal degeneration, closely linked to disease progression (2), might on the other hand be reflected in factor 3, spatial manipulation (solution with Huntington’s patients only). This factor’s negative correlation with symptom duration would support this hypothesis. The observation of a significant correlation between caudate atrophy and cortical regional cerebral blood flow (the larger the degree of caudate atrophy, the greater the cortical rCBF) during the performance of “frontal” neuropsychological tasks in HD patients (8) might have some parallel features
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to present results. Spatial manipulation (factor 3, HD patients only) may also be associated with functional integrity of the prefrontal cortex. The longer the duration of the disease, the greater perhaps the caudate atrophy and the greater the degree of functional uncoupling between neostriatum and cortex. Although appealing, it remains to be seen whether this hypothesis will hold. Recent neuropathological evidence suggested that duration of illness might be a poor indicator of degree of neuropathological involvement (28). Rather, age at onset was reported to be a better indicator of neuropathologic grade, suggesting that patients with different ages of onset could have dissimilar neostriatal degeneration at equivalent disease duration points (28). Nevertheless, the present study failed to reveal any cognitive association with age at onset, while demonstrating a significant relationship between duration of symptoms and spatial manipulation abilities. Cognitive impairment in HD thus appears to have, in addition to the more undifferentiated global decline, domain-specific components. Current findings suggest that the ability to successfully perform spatial manipulation may well be a sensitive indicator of disease progression in HD patients. Further studies with structural correlates of this disorder will need to confirm this putative relationship.
REFERENCES 1 . Hayden MR. Huntington’s chorea. New York: Springer Verlag, 1981. 2. De La Monte SM, Vonsattel JP, Richardson EP. Morphometric demonstration of atrophic changes in cerebral cortex, white matter, and neostriatum in Huntington’s disease. J Neuropathol Exp Neurol 1988;47:516-25. 3. Kuhl DE, Metter EJ, Riege WH, Markham CH. Patterns in cerebral glucose utilization in Parkinson’s disease and Huntington’s disease. Ann Neurol 1984;15(suppl):S11%25. 4. Young AB, Penny JB, Starosta-Rubinstein S, et al. PET scan investigations of Huntington’s disease: cerebral metabolic correlates of neurological features and functional decline. Ann Neurol 1986;20:296303. 5 . Granholm E,Butters N . Associate encoding and retrieval in Alzheimer’s and Huntington’s disease. Brain Cogn 1988;7: 355-47. 6. Starkstein SE, Brandt J, Folstein S, et al. Neuropsychological and neuroradiological correlates in Huntington’s disease. J Neurol Neurosurgery Psychiatry 1988;51:1259-43. 7. Saint-CyrJA, Taylor AE, Lang AE. Procedural learning and neostriatal dysfunction in man. Brain 1988;11:941-59. 8. Weinberger DR, Berrnan KF, Iadarola M, Driesen N , Zec RF. Prefrontal cortical blood flow and cognitive function in Huntington’s disease. J Neurol Neurosurgery Psychiatry 1988;51:94-104. 9. Goldberg TE, Berman KF, Mohr E, Weinberger DR. Regional cerebral blood flow and cognitive function in Huntington’s disease and schizophrenia: a comparison of patients matched for performance on a prefrontal-type task. Arch Neurol 1990;47:418-22.
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10. Fedio P, Cox CS, Neophytides A , Canal-Frederick G, Chase TN. Neuropsychological profile of Huntington’s disease: patients and those at risk. In: Chase TN, et al, eds. Advances in Neurology, vol. 23. New York: Raven Press, 1979:239-55. 1 1 . Brouwers P, Cox CS, Martin A, Chase TN, Fedio P. Differential perceptual-spatial impairment in Huntington’s and Alzheimer’s dementias. Arch Neurol 1984;41:1073-6. 12. Jason GW, Pajurkovd EM, Suchowersky 0, et al. Presymptomatic neuropsychological impairment in Huntington’s disease. Arch Neurol 1988;45:769-73. 13. Bamford KA, C i n e ED, Kido DK, Plassche WM, Shoulson I. Clinical-pathologic correlation in Huntington’s disease: a neuropsychological and computed tomography study. Neurology 1989;39:796-801. 14. Wechsler D. Wechsler Adult Intelligence Scale-Revised. New York: The Psychological Corporation, 1981. 15. Wechsler D, Stone CP. Wechsler Memory Scale. New York: The Psychological Corporation, 1945. 16. Mattis S . Mental status examination for organic mental syndrome in the elderly. In: Bellack L, Karasu TB, eds. Geriatric psychiatry. Grune and Stratton, New York: 1976:77121. 17. Kapur N, Butters N. Visuoperceptive deficits in long-term alcoholics and alcoholics with Korsakoff‘s psychosis. J Stud Alcohol 1977;38:2025-35. 18. Oltman PK. A portable Rod-and-Frame Test apparatus. Percept Mot Skills 1968;26:503-6.
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19. Shepard R, Metzler J. Mental rotation of three dimensional objects. Science 1971;171:701-3. 20. Vandenberg SG, Kuse AR. Mental rotations, a group test of three dimensional spatial visualization. Percept Mot Skills 1978;47:59!+604. 21. Money JA. Standardized road map of direction sense. San Rafael, California: Academic Therapy Publications, 1976. 22. Ratcliff G. Spatial thought, mental rotation and the cerebral right hemisphere. Neuropsychologia 1979;17:49-54. 23. Vaid J , Lambert W, Brouwers P. On the perception of “frontness” [Abstract]. Presented at Canadian Psychological Association Meeting, Quebec City, June 1979. 24. Brown MD, Engleman L, Frane JW, et al. BMDP Statistical Sofrware. Los Angeles: University of California, 198559412. 25. Brandt J, Folstein SE, Folstein MF. Differential cognitive impairment in Alzheimer’s disease and Huntington’s disease. Ann Neurol 1988;23:555-61. 26. Berent S , Giordani B, Lehtinen S, et al. Positron emission tomographic scan investigations of Huntington’s disease: cerebral metabolic correlations of cognitive function. Ann Neurol 1988;23:541-6. 27. Tanahashi N, Meyer JS, Ishikawa Y, et al. Cerebral blood flow and cognitive testing correlate in Huntington’s disease. Arch Neurol 1985;42:1169-75. 28. Myers RH, Vonsattel JP, Stevens TJ, et al. Clinical and neuropathologic assessment of seventy of Huntington’s disease. Neurology 1988;38:341-7.
Visuospatial Cognition in Huntington’s Disease Erich Mohr, *Pim Brouwers, ?Jules J. Claus, TUlrike M. Mann, Paul Fedio, and ?Thomas N. Chase Medical Neurology Branch, NINDS, *Pediatric Branch, NCI, and ?Experimental Therapeutics Branch, NINDS, National Institutes of Health, Berhesda, Maryland, U.S.A.
Summary: The notion of specificity of visuospatial dysfunction in Huntington’s disease (HD) was evaluated in a sample of afflicted patients as a function of symptom duration, age at onset, and overall dementia severity. Factor analytic procedures indicated that overall visuospatial processing capacity (factor 1) as well as the ability for spatial manipulation (factor 3) was markedly affected in HD patients. In contrast, consistency of spatial judgment (factor 2) appeared to remain relatively intact in these patients. Age at onset seemed to have no relationship with any of these variables, whereas dementia severity demonstrated a significant relationship with overall visuospatial processing capacity. Most importantly, duration of symptoms was significantly associated with the declining ability to mentally perform spatial manipulations. The observation of circumscribed visuospatial impairment in HD patients may have important consequences for the further understanding of the neurobehavioral consequences of this disorder. Key Words: Huntington’s disease.
paired performance on visuoconstructive tasks (11). Recent observations suggest that specific visuospatial deficits can be detected in asymptomatic individuals who are known to carry the HD gene (12). Furthermore, in addition to general dysfunction on complex psychomotor tasks, visuospatial function has been shown to clearly discriminate between early and further progressed patients with HD (13). To further explore the relationship between visuospatial dysfunction in HD and duration of symptoms, age at onset, and other relevant demographic variables, and to determine possible patterns of impairment in visuospatial cognition in this disorder, we examined a wide range of these cognitive tasks in a sample of patients in various stages of this illness.
Huntington’s disease (HD), an autosomal dominant genetic disorder, is characterized clinically by progressive chorea and dementia (1). Neuropathological studies reveal marked degenerative changes in the caudate and putamen with less consistent involvement of cerebral cortex, or other brain areas (2). Similarly, regional glucose metabolic profiles show marked striatal hypometabolism (3,4) in contrast to normal glucose utilization throughout the rest of the brain, regardless of motor or cognitive symptom severity (3). Intellectual deficits described in Huntington’s disease range widely (e.g., refs. 5-9) and include specific impairments in visuospatial function (1012). Patients with HD reportedly show consistent deficits on tasks of visuoperceptual and constructive abilities when manipulation of personal space is required, while demonstrating relatively less im-
METHODS Twenty patients with HD (11 men and nine women; age (mean k SEM), 45 +- 2.8 years; range, 25-75 years), diagnosed on the basis of typical motor and cognitive signs, a positive family history,
Address correspondence and reprint requests to Dr. E. Mohr at Neuropsychology Service, Royal Ottawa Hospital, 1145 Carling Ave., Ottawa, Ontario, K1Z 7K4, Canada.
127
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and computed tomography (CT) scan evidence of caudate atrophy (duration of symptoms: mean, 6 f 0.5 years, range, 3-16 years), with a mean education of 14 f 0.7 (range, 6-20) years, consented to participate in this study after full disclosure of potential benefits and risks. None had received any centrally active medication for at least 2 months prior to study onset. Nineteen neurologically normal subjects, matched for gender, age, and education (gender: 10 males, nine females; age: mean, 43 t 2.8 years, range 20-65 years; education: mean, 15 ? 0.7 years, range, 7-20 years) served as controls. Intellectual and memory function was assessed with the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (14) and the Wechsler Memory Scale (15). Dementing symptoms were evaluated with the Mattis Dementia Rating Scale (16). Visuospatially mediated subtests of the WAIS-R (Performance tests) were included in order to examine their potential association with distinct visuospatial domains. In addition, the following neuropsychological tests were administered to examine visuospatial function. Embedded Figures Test. Patients are asked to recognize a simple geometric design in one of four complex patterns (17). Rod and Frame Test. A rod within a tilted frame has to be adjusted to the upright from a 20" left or right tilt without other reference points (18). Mental Rotation Test. Complex three-dimensional geometric designs have to be rotated to compare with a target design (19,20). Street Map Test. Right and left turns in a direction away and towards the subject on a simulated map of a small town have to be identified (21). Mental Reorientation Test. Subject has to name which hand of a figure, rotated in the fronthack, lefthight and up/down planes is black (22). Extended In-Front Test. Subjects have to identify the locations (a) in front, (b) behind, and (c) next to an object or person(s), which are placed in the center of a 3 X 3 grid and systematically vary in their orientation (23).
Performance ratings for these neuropsychological tasks did not rely on speed or motor accuracy.
Movement Disorders, Vol. 6 , No. 2 , 1991
Data were analyzed with standard analysis of variance procedures (BMDP P7D) (24) for overall differences between HD patients and controls. Factor analysis was employed to investigate the possible presence of several independent domains of visuospatial function (BMDP P4M) (24). On the basis of significant intertest correlations (r > 0.6, p < 0.01), measures within individual tests were pooled as averages, and a total of 16 variables (Table 1) were entered into a principal components factor analysis. This was first applied to the HD group alone, to highlight constellations specific to the disease; subsequently, the HD and control data were combined and analyzed to contrast patterns distinguishing HD patients from healthy subjects. Correlational measures were used to examine the extent of the relationship between the two factor solutions (patients alone and patients plus controls) and to determine their association with demographic variables (age, age at onset, symptom duration) and dementia severity (Mattis Dementia Rating Scale). TABLE 1. Test scores used in factor solutions (mean & SEM and range) HD patients (n = 20) WAIS-R Picture 8 f 0.6 (414)" Completion WAIS-R Block Design 8 f 0.6 (2-12)" WAIS-R Picture Arrangement 8 2 0.6 (3-15)" 6 0.5 (2-11)O WAIS-R Digit Symbol WAIS-R Object Assembly 6 f 0.7 (1-11)" Mental Rotation Test 8 f 1.3 (0-18)" Street Map Test Overall correct 1 1 2 0.8 (0.5-l5)O Difference between away from self 2 0.7 (-3-8)b and toward self In-Front-Of Test Consistency Orientation to front 3 I- 0.2 ( 1 4 ) Orientation to person 3 2 0.2 (1-4) Orientation to person and group 1 2 0.1 (0-2) Overall consistency 2 f 0.5 (O-6)b Rod and Frame Test Frame orientation 5 t 0.8 (1-13)" left Frame orientation right 4 0.7 (1-13)" Mental Reorientation Test 5 2 0.4 (3-8)" 14 f 0.9 (5-19)" Embedded Figures Test
*
*
*
Normal controls (n = 19) I 1 t 0.4 (8-14) 12 t 0.7 (7-18)
*
12 0.5 (8-16) 12 I- 0.6 (6-16) 12 t 0.6 (7-16) 23 2 2.9 (4-40) 15
&
0.2 (12-16)
1 t 0.3 (-1-5)
3 f 0.2 (1-4) 3 0.2 (1-4)
*
1 2 0.2 (0-2) 0 2 0.0 (0-1) 2
f 0.2 (1-3)
1 2 0.2 (1-3)
8 f 0.1 (7-8) 18 f 0.3 (14-20)
a HD patients significantly different from controls at p < 0.001. HD patients significantly different from controls at p < 0.05.
VISUOSPATIAL FUNCTION IN H D
RESULTS Overall intellectual function was significantly compromised in the HD patients compared to control subjects. This was reflected in substantially lower scores on all three WAIS-R global scores (full scale IQ, Verbal and Performance IQ; p < 0.001) (Table 2). Examination of memory function (Memory Quotient, Wechsler Memory Scale) revealed the same pattern. HD patients evidenced markedly lower Memory Quotients than controls (P < 0.001) (Table 2). The Mattis Dementia Rating Scale classified all but two of the 20 HD patients, but none of the 19 controls, as demented (Table 2). Factor Analysis HD Patients Only Visuospatial function in HD patients (Table 1) was classifable into three major independent factors, accounting together for 67% of the observed variance (Table 3). Factor 1, with 29% of the variance (varimax rotation), loaded on all five performance subtests of the WAIS-R, the Embedded Figures Test, and the Mental Reorientation Test (Table 3). Factor 2, with 24% of the variance, consisted of performance on the Rod and Frame Test, orientational consistency (fronthack) on the In-Front-Of Test, and the difference score between orientation towards and away from self on the Street Map Test (Table 3). Factor 3 , with 14% of the variance, loaded on Mental Rotation, the Mental Reorientation Test, orientational consistency (all orientations) on the In-Front-Of Test and correct right/left choices on the Street Map (Table 3). Correlation of these factor scores with demographic data (age, age at onset, education, duration of symptoms) and dementia severity (Mattis DeTABLE 2. Intellectual and memory profiles in HD and control subjects (mean k SEM and range) HD patients WAIS-R Verbal IQ WAIS-R Performance IQ WAIS-R Full Scale IQ Wechsler Memory Scale Mattis Dementia Rating Scale a
Normal controls
88 4 2.8 (67-111)" I16
+.
3.4 (86146)
81 4 3.5 (5S120)" 1 1 1
?
2.7 (86-133)
84
?
3.0 (5Sl11)" 115 2 3.1 (87-142)
82 f 3.9 (61-119)" 120 5 4.0 (81-143)
125 f 2.9 (93-143)" 142
5
0.4 (139-144)
HD patients significantly different from controls at p
0.2) (Table 6). TABLE 5. Contrast of HD versus control subjects (Combined factor solution) HD -0.702 -0.031 0.364
2 2
*
Controls 0.185" 0.286 0.245'
0.739 2 0.118 0.032 f 0.142 - 0.383 & 0.169
HD patients significantly different from controls at p < 0.001.
HD patients significantly different from controls at p < 0.05.
Movement Disorders, Val. 6 , No. 2, 1991
Factor 1
any consistent association with demographic data or dementia. Contrasting factor scores for HD patients and their controls on this factor solution (patients and controls combined) indicated highly significant performance differences between groups on factors 1 and 3 (p < 0.001, p < 0.05, respectively), but failed to yield any differences on factor 2 (Table 5).
Factor 1 Factor 2 Factor 3
HD patients only
Factor loadings
Factors
HD patients and normal controls
Factor 1 Factor 2 Factor 3
Factor 2
Factor 3
0.8812" 0.9436" -0.2179
Correlation significant at p < 0.001.
COMMENT Overall intellectual and memory function was substantially impaired in patients with HD, as has been consistently observed previously (10,11,25). In addition to global decrements in visuospatially mediated intellectual ability, specific patterns of impairments in visuospatial function emerged in these HD patients. Visuospatial cognition was classifiable into three major domains in this patient group. Factor 1, principally associated with the performance subscales of the WAIS-R, the disembedding of simple figures from complex ones (Embedded Figures) and right/ left spatial judgment (Mental Reorientation), could best be conceptualized as a factor representing overall visuospatial processing capacity. The significant association between this factor and nonspecific overall dementia severity (Mattis Dementia Rating Scale) supports the contention that this is indeed a factor capturing overall ability levels of visuospatially mediated function. Factor 2, a consistency of spatial judgment factor (loading predominantly on judgment of upright orientation on the Rod and Frame Test, consistency of judgment of orientation of a figure, object or group on the InFront-Of-Test on a simple fronthack axis and consistency of rightheft judgment regardless of personal orientation on the Street Map), was not associated with any variables reflecting duration of illness, dementia severity or age at onset. It would, therefore, appear that this factor as a whole captures a domain not specifically affected by HD, in spite of the fact that several of its components showed significant decrements in the patient group. Factor 3, on the other hand, involving spatial manipulation [the ability to match a complex threedimensional figure, rotated in space, to an unrotated original (Mental Rotation), consistency of judgment of orientation on the In-Front-Of-Test, involving all complex orientations, and the overall ability level of right/left judgment on the Street
VISUOSPATIAL FUNCTION IN HD Map], appeared to be affected significantly by HD, evidenced by the negative correlation with duration of illness. The introduction of the normal control group in the second factor solution (patients and controls combined) further clarified these contentions. Factors 1 and 2 of both solutions (patients alone and patients and controls combined) were highly similar and stable (Table 4), suggesting that neither of these factors was specifically altered by HD. Factor 3 , on the other hand, which was associated with duration of illness in the factor solution with HD patients only, was not recovered when normal controls were added, suggesting that this factor captures a domain of functioning which is increasingly affected as HD progresses. The contrast between HD patients and their controls on the combined solution further highlighted the view that decrements in visuospatial function have certain circumscribed features in Huntington’s disease. Factor 1, conceptualized as a factor of overall visuospatial processing capacity, classified patients and controls as substantially different from each other. Factor 2, consistency of spatial judgment, was essentially identical for both groups, indicating that this particular function as a whole is not affected by the disease. Factor 3, in turn, showed significant differences between patients and controls, reflecting impaired function in this domain in HD patients. Earlier neuroanatomical findings, glucose metabolic profiles and regional cerebral blood flow studies may help explain some of these observations (2,3,8,26,27). Atrophy of cerebral cortex is apparently evident early on in HD and may not be directly linked to subsequent disease progression (2). Gross reduction in overall visuospatial ability levels-which are probably reflected in factor 1, overall visuospatial processing capacity (either solution)-may well be the functional representation of this global atrophic process. Neostriatal degeneration, closely linked to disease progression (2), might on the other hand be reflected in factor 3, spatial manipulation (solution with Huntington’s patients only). This factor’s negative correlation with symptom duration would support this hypothesis. The observation of a significant correlation between caudate atrophy and cortical regional cerebral blood flow (the larger the degree of caudate atrophy, the greater the cortical rCBF) during the performance of “frontal” neuropsychological tasks in HD patients (8) might have some parallel features
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to present results. Spatial manipulation (factor 3, HD patients only) may also be associated with functional integrity of the prefrontal cortex. The longer the duration of the disease, the greater perhaps the caudate atrophy and the greater the degree of functional uncoupling between neostriatum and cortex. Although appealing, it remains to be seen whether this hypothesis will hold. Recent neuropathological evidence suggested that duration of illness might be a poor indicator of degree of neuropathological involvement (28). Rather, age at onset was reported to be a better indicator of neuropathologic grade, suggesting that patients with different ages of onset could have dissimilar neostriatal degeneration at equivalent disease duration points (28). Nevertheless, the present study failed to reveal any cognitive association with age at onset, while demonstrating a significant relationship between duration of symptoms and spatial manipulation abilities. Cognitive impairment in HD thus appears to have, in addition to the more undifferentiated global decline, domain-specific components. Current findings suggest that the ability to successfully perform spatial manipulation may well be a sensitive indicator of disease progression in HD patients. Further studies with structural correlates of this disorder will need to confirm this putative relationship.
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