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All content in this area was uploaded by Pedro J García-Ruiz
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Content uploaded by Pedro J García-Ruiz
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Severity of Cognitive Impairment in Juvenile and
Late-Onset Huntington Disease
Estrella Go´mez-Tortosa, MD; Antonio del Barrio, PhD; Pedro J. Garcı´a Ruiz, MD; Rosario Sa´nchez Pernaute, MD;
Javier Benı´tez, MD; Alicia Barroso, PhD; F. Javier Jime´nez, MD; Justo Garcı´a Ye´benes, MD
Objectives: To compare the severity of cognitive im-
pairment among groups of patients with different age
ranges at the onset of Huntington disease (HD) and to
evaluate the variable influence of motor and cognitive defi-
cits on functional disability across different ages at the
onset of HD.
Design: Cross-sectional multidisciplinary evaluation of
patients referred to our institution for care related to a
possible diagnosis of HD.
Setting: The Huntington disease program in the De-
partments of Neurology and Genetics at the Fundacio´n
Jime´nez Dı´az, Madrid, Spain.
Participants: Seventy-one patients with Huntington dis-
ease were classified into 3 groups depending on age at
onset of motor symptoms: juvenile onset, 25 years of age
or younger (group 1, n=15); adult onset, from 26 to 50
years (group 2, n=43); and late onset, 51 years or older
(group 3, n=13). Age- and education-matched controls
(n=50) were included to compare cognitive perfor-
mance with patients in groups 1 and 3.
Measures: Cognitive evaluation encompassed a wide
neuropsychological battery to assess global cognitive func-
tioning and visuospatial, prefrontal, and memory func-
tions. Clinical data included motor and functional vari-
ables measured by using the Unified Huntington’s Disease
Rating Scale. Genetic analysis determined the number of
CAG trinucleotide repeats.
Results: Patients in group 1 scored 2.9 points and pa-
tients in group 3 scored 4.2 points below their respective
controls on the Mini-Mental State Examination. Patients
in groups 1 and 3 were similarly impaired in verbal memory.
Visual function was much more impaired in patients in
group 3, and prefrontal functions were slightly worse in
patients in group 1. Cognitive scores were correlated only
with time of evolution for patients in group 2. Functional
scores were not significantly different among the 3 groups,
but 11 (85%) of the patients in group 3 were in stage I or
II vs 10 (67%) of the patients in group 1. Total functional
capacity correlated better with the Mini-Mental State Ex-
amination score for patients in group 3 and with motor defi-
cits (akinesia) and prefrontal dysfunction for patients in
group 1. The mean±SD CAG repeat length decreased from
59.9±12.6 for patients in group 1 to 46.2±3.5 for patients
in group 2 and 41.7±2.6 for patients in group 3. Longer
CAG repeats in the HD study population correlated with
akinetic features but not with cognitive performance.
Conclusions: Despite the much greater genetic defect,
cognitive status is slightly better preserved in patients with
juvenile-onset HD. Cognitive impairment in patients with
juvenile- and late-onset HD differs in the severity of vi-
sual and prefrontal deficits. Functional disability in pa-
tients with late-onset HD depends more on global cog-
nitive status, while in patients with juvenile-onset HD,
it is conditioned more by motor deficits and prefrontal
dysfunction.
Arch Neurol. 1998;55:835-843
HUNTINGTON disease (HD)
is an inherited neuro-
degenerative disorder
characterized by the pres-
ence of movement dis-
orders, cognitive decline, and behavioral
disturbances.1-5 The age at onset is usu-
ally between the third and fifth decades,
but symptoms may develop from the
first to the ninth decades. Much of the
variation in age at onset seems to be ac-
counted for by the number of trinucleo-
tide repeats within the HD gene, with
longer CAG repeats implying earlier on-
set of the disease.6-10 Yet, the amount of ge-
netic defect does not seem to influence other
clinical features, such as the nature of symp-
toms at onset,7,8,10 and there are contra-
dictory reports about the influence of the
genetic defect on the rate of progression
of the disease.11,12
Patients with onset of HD at juve-
nile ages have the longest CAG repeats
and frequently have a rigid akinetic syn-
drome rather than the typical choreic
movements.13-15 The severity of neuro-
pathological involvement and the degree
of functional disability are classically re-
ORIGINAL CONTRIBUTION
From the Departments of
Neurology (Drs Go´ mez-Tortosa,
del Barrio, Garcı´a Ruiz, Sa´nchez
Pernaute, and Garcı´a Ye´benes)
and Genetics (Drs Benı´tez and
Barroso), and the Research Unit
(Dr Jime´nez), Fundacio´n
Jime´nez Dı´az, Madrid, Spain.
Dr Go´ mez-Tortosa is now with
the Alzheimer’s Research Unit,
Massachusetts General Hospital,
Boston.
ARCH NEUROL / VOL 55, JUNE 1998
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PARTICIPANTS AND METHODS
PARTICIPANTS
We studied 71 patients with a clinical diagnosis of HD who
received care in our institution from June 1, 1992, to De-
cember 31, 1996. Ten other patients were not included be-
cause they did not complete the study, occasionally because
of lack of consent, but mainly because of advanced disease
with severe disability. The 71 patients included belonged to
47 kindreds. They were subdivided into groups according to
age at onset of motor symptoms: group 1, juvenile onset, 25
years of age or younger (n= 15); group 2, adult onset, 26 to
50 years (n= 43); and group 3, late onset, 51 years or older
(n= 13). We extended the classic limit of 20 years for juvenile-
onset HD because in our study population, 6 of 8 patients
with disease onset between 20 and 25 years of age, had a rigid
akinetic syndrome, which more closely resembled the juve-
nile phenotype than the adult, or classic, phenotype of HD.
The limit for late-onset HD was defined according to Myers
et al.17 All patients excluded from the study had adult-onset
HD. The age at onset was stated according to the relatives’
report, after a careful anamnesis searching for the first mo-
tor symptoms or signs of the disease in the lives of the pa-
tients. The time of evolution was counted in years from the
time of the first evidence of motor symptoms.
Demographic data for the patients are summarized in
Table 1. Education was recorded according to a 5-point
scale indicating the level of schooling completed: 1, pri-
mary school; 2, secondary school (until 14 years of age);
3, high school (until 18 years of age); 4, college diploma;
and 5, university degree. Patients in groups 1 and 3 be-
longed to 12 kindreds each, allowing enough variability to
avoid characteristics based only on intrafamilial features.
Two control groups matched for age and educational
level were included to compare cognitive performance with
groups 1 and 3. Juvenile controls (group 4) included 22
subjects, mean±SD age, 22.9±4.6 years (range, 17-32 years);
18 (81%) had completed secondary or high school. Group
5, the control group for group 3, comprised 28 subjects,
mean±SD age, 63.1±5.5 years (range, 52-72 years); 20
(71.5%) had completed secondary or high school.
CLINICAL EVALUATION
Motor impairment was assessed by using the Unified Hun-
tington’s Disease Rating Scale, in which 0 indicates no impair-
ment and 4 indicates severe impairment.29 We considered the
following variables: finger taps (manual akinesia), arm rigid-
ity, and axial bradykinesia, dystonia, and chorea. Chorea is
rated from 0 to 4 in 7 body regions (ie, face, bucco-orolingual,
trunk, and each extremity), giving a total score of 0 to 28 points,
and dystonia is rated in 5 regions (ie, trunk and each extrem-
ity), giving a total score of 0 to 20 points. Motor evaluation
was conducted by 2 experienced neurologists (R.S.P. and
P.J.G.R.) who shared the same criteria in the rating, 0 to 4.
Functional status was rated according to the Total Func-
tional Capacity (TFC) score, which ranges from 0 (severely
impaired) to 13 (normal) and assesses a patient’s capacity
in relevant functional domains including employability, fi-
nancial tasks, domestic responsibilities, and self-care skills.
The stage of illness, rated from I to V according to the cri-
teria of Shoulson and Fahn,30 was based on the following TFC
scores: I, 11 to 13; II, 7 to 10; III, 3 to 6; IV, 1 to 2; and V, 0.
GENETIC ANALYSIS
Molecular analysis was performed on genomic DNA iso-
lated from peripheral lymphocytes. Amplification of
CAG repeats was performed by using primers designed
by Riess et al31; polymerase chain reactions were per-
formed with an end-labeled primer, and the products
were separated in a sequencing gel (8%). Alleles were
identified by sizing relative to an M13 sequencing lad-
der. The analysis confirmed the diagnosis with more
than 38 CAG repeats in the IT15 gene on chromosome
47in all patients in groups 1 through 3 in the present
study.
NEUROPSYCHOLOGICAL ASSESSMENT
We selected a wide battery of neuropsychological tests
emphasizing the functions reported to be most affected in
HD, such as prefrontal, visuospatial, and memory tasks.
One neuropsychologist (A.B.) evaluated all patients by
using the following tests: Mini-Mental State Examination
(MMSE)32; digit span (forward and backward)33; Symbol
Digit Modalities Test34; Verbal fluency (1 category and 1
letter)35; copy the Rey Complex Figure36; immediate and
delayed recall of the Rey Complex Figure; Hooper Visual
Organization Test37; Stroop test38 (age-corrected); Trail
Making A and B Tests39 (time in seconds to complete each
task, with a maximum of 10 minutes allowed); California
Verbal Learning Test40 (items learned at the last trial, free
[ie, without any help or clue] short- and long-term recall,
and percentage of recognition).
To simplify analysis and to define profiles of func-
tional impairment, test scores evaluating related functions
were grouped in a single factor by principal-component
factor analysis41 (Table 2). The functions measured in
each factor and the tests used are listed in Table 2 along
with the correlation coefficients, the percentage of vari-
ance, and the eigenvalues. The MMSE score, as a measure
of overall cognitive status, was considered independently.
A global principal-component factor analysis using an
interest correlation matrix resulted in the same 3 func-
tional factors accounting for 76.4% of the overall variance,
but individual factor analysis was preferred to minimize
the effect of missing values. For each participant, unit-
weighted standardized scores were computed for each fac-
tor. For all factors, higher scores indicated better perfor-
mance.
ANALYSIS OF THE DATA
First, the comparison of genetic, motor, and functional vari-
ables among groups 1, 2, and 3 was done by 1-way analy-
sis of variance (ANOVA) and post hoc Student-Newman-
Keuls comparison tests. Second, cognitive performance of
groups 1, 2, and 3, together with groups 4 and 5, also was
compared by using 1-way ANOVA and post hoc tests. Dif-
ferences were considered significant at P,.05. The distri-
bution of participants in each group according to sex, edu-
cational level, and stage of the disease (patients only) was
evaluated by using the x2test. Finally, we considered the
influence of motor and cognitive variables on functional
impairment by groups by using Pearson correlation coef-
ficients. Data are given as mean±SD unless otherwise in-
dicated.
ARCH NEUROL / VOL 55, JUNE 1998
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ported as much greater in patients with juvenile-onset
HD.16 Patients with late-onset HD may have CAG re-
peats in the lower pathological range, and their clinical
picture is similar to that of patients with adult-onset HD,
but they have less functional impairment and evolution
of the disease is more benign.16-19 In addition to the dif-
ferences related to age at onset, including differences in
symptoms, rate of disease progression, functional im-
pairment, and the neuropathological lesion, patients with
juvenile-onset HD are believed to have a severe cogni-
tive impairment, while patients with late-onset HD have
minimal mental deterioration. Major cognitive disabili-
ties in adult HD include attentional deficits, problems with
sequencing and planning, disorders in new learning and
retrieval of information, and visuospatial dysfunc-
tion.20-27 However, to our knowledge, there are no re-
ports of formal cognitive evaluations of patients with HD
in whom onset was at extreme age ranges.
As part of a prospective multicenter study of HD,
we evaluated a large population by using an extensive
cognitive protocol. A preliminary examination of the data
suggested that the performance of the youngest group
of patients, who had predominant rigid akinetic fea-
tures, was much better than expected. On the contrary,
patients who were the oldest at onset seemed to have very
poor scores. Therefore, the first objective of this study
was to compare the severity of cognitive impairment
among groups of patients with different age ranges at the
onset of HD, with a focus on the comparison between
patients with juvenile-onset HD and patients with late-
onset HD. Because age differences are relevant to cogni-
tive performance, the severity of cognitive deterioration
was evaluated by comparing the oldest and youngest
groups with age-matched controls.
A review of the literature suggested that the sever-
ity of cognitive impairment in patients with juvenile- or
late-onset HD had been determined more on the basis
of functional capacity scores, report of symptoms, or both,
than on formal cognitive assessments. Because func-
tional capability for the activities of daily living depends
on motor and cognitive functioning,28 and the motor pro-
file is strikingly different for patients with juvenile-
onset HD, it was possible that the influence of motor and
cognitive features on functional scores could be differ-
ent depending on age. The influence of symptoms on func-
tional capacity also is likely to vary depending on the daily
activity requirements, which are probably quite differ-
ent for a 20-year-old than for a 60-year-old person. We
hypothesized that functional disability of patients with
juvenile-onset HD could depend more on their motor dis-
turbance than on their cognitive status, if the latter was
truly demonstrated as better preserved than expected. The
second aim of this study was to evaluate the variable in-
fluence of motor and cognitive deficits on functional dis-
ability across different ages at the onset of HD.
RESULTS
MOTOR AND FUNCTIONAL ASSESSMENT
Table 3 summarizes motor and functional scores and
genetic data for groups 1, 2, and 3. The mean time of
Table 1. Demographic Data for Patients With Huntington Disease
Group*
Total
(N = 71)
1
(n = 15)
2
(n = 43)
3
(n = 13)
Male 9 31 7 47
Female 6 12 6 24
Age, mean ± SD (range), y
At onset of disease 18.9 ± 5.6 (7.0-25.0) 36.7 ± 6.7 (26.0-48.0) 57.8 ± 5.5 (51.0-65.0) 36.8 ± 13.7 (7.0-65.0)
When studied 23.7 ± 4.9 (13.0-31.0) 43.6 ± 8.8 (28.0-64.0) 62.9 ± 4.8 (53.0-68.0) 42.9 ± 14.4 (13.0-68.0)
Completed secondary or high school, No. (%) 13 (86) 36 (83) 10 (77) 58 (82)
*
Group 1 patients had juvenile-onset (25 years old or younger) Huntington Disease (HD); group 2, adult-onset (26-50 years old) HD; and group 3,
late-onset (older than 50 years) HD.
Table 2. Definitions of the Cognitive Factors
Factor/Functional Area/
Tests Included
Correlation
Coefficient
Percentage of
Variance/Eigenvalue
1/Visual 81.5/3.2587
Rey Complex Figure
Copy 0.8488
Immediate memory 0.9122
Delayed memory 0.9335
Hooper Visual Organization Test 0.9137
2/Prefrontal 64.2/6.4218
Verbal fluency
1 category 0.7952
1 letter 0.7812
Stroop test (age-corrected)
Word 0.8229
Color 0.8669
Interference 0.7747
Symbol Digit Test 0.8685
Trail-Making Test
A −0.7727
B −0.8676
Digit span
Forward 0.7187
Backward 0.7278
3/Verbal memory 89.1/3.5623
California Verbal Learning Test
Last trial 0.9597
Short-term recall 0.9631
Long-term recall 0.9721
Recognition 0.8768
ARCH NEUROL / VOL 55, JUNE 1998
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evolution was not significantly different across the 3
groups (4.8, 7.0, and 5.0 years, respectively). There-
fore, variation in the severity of symptoms among the
groups should not be accounted for by different times
of evolution. Differences were significant in the com-
parison of all motor variables. Group 1 differed signifi-
cantly from groups 2 and 3 with a pattern of increased
rigidity, axial and manual bradykinesia, dystonia, and
reduced chorea. The profile for group 3 was opposite,
with predominant chorea and a trend toward reduced
manual akinesia and rigidity, although it was not sig-
nificantly different compared with the profile for
group 2. The mean TFC scores were similar among
the 3 groups with HD. The distribution of patients in
groups 1, 2, and 3 according to Shoulson and Fahn
stages was not significantly different (x26=5.6; P=.47).
Patients classified in stage I were group 1, 5 (33%);
group 2, 18 (42%); and group 3, 7 (54%). Patients
classified in stage II were group 1, 5 (33%); group 2, 8
(19%); and group 3, 4 (31%); and in stage III were
group 1, 5 (33%); group 2, 13 (30%); and group 3, 2
(15%). Stage IV included only 4 patients (9%) from
group 2.
GENETIC ANALYSIS
The number of CAG repeats in the HD study popula-
tion was 48.2±8.8 (range, 39.0-90.0). There was a sig-
nificant gradient in the CAG repeat length (Table 3) from
group 1 (mean, 59.9 repeats; range, 46.0-90.0 repeats)
to group 2 (mean 46.2 repeats; range, 41.0-56.0 re-
peats), and group 3 (mean, 41.7 repeats; range, 39.0-
47.0 repeats), with overlapping ranges. Longer CAG re-
peats in the HD study population were correlated with
younger age at onset (r=−0.48; P,.001). However, the
strongest correlation between age at onset and number
of repeats was in group 1, and the correlation decreased
steadily in groups 2 and 3 (Figure 1). Longer CAG re-
peats in the HD study population also correlated with in-
creased akinesia (r=0.35; P,.05) and bradykinesia
(r=0.57; P,.001). Figure 2 shows the correlation of the
number of repeats with motor and functional scores by
groups. The sex of the transmitting parent was balanced
in groups 1 and 2, but was mainly by the paternal line
within group 1 (P,.05).
COGNITIVE PERFORMANCE
Results for groups 1 through 5 are summarized in Table 4
and shown in Figure 3. Distribution by sex and edu-
cational level was not significantly different among the
groups (for sex, x24=4.5; P= .34; and for educational level,
x216= 21.0; P=.18). In general, the cognitive scores for the
groups showed the following declining profile: group 4,
group 5, group 1, group 2, and group 3.
For the groups with HD, group 1 performed signifi-
cantly better than group 2 on the MMSE and in the ver-
bal memory factor and significantly better than group 3
on the MMSE and in the visual and verbal memory fac-
tors. Group 2 performed better than group 3 only in the
visual factor. Groups 1 and 3 differed significantly from
groups 4 and 5, respectively, in all cognitive variables (ie,
MMSE and visual, prefrontal, and verbal memory fac-
tors). As shown in Figure 3, the lower verbal memory
scores compared with the scores for the respective con-
trol groups was similar for group 1 (1.38 points lower;
65
55
45
35
25
15
5
35 40 45 50 55 60 65 70 75 80 85 90
CAG Repeats, No.
Age at Onset, y
Group 1,
r
=
–0.80
Group 2,
r
=
–0.64
Group 3,
r
=
–0.22
Figure 1.
A negative correlation was found between the length of the CAG
trinucleotide repeat and the age at onset (
r
=−0.48;
P,
.001 for the
Huntington disease [HD] study population). The correlation has its highest
significance within group 1 and decreases to nonsignificant values for group
3. Group 1 patients (n= 15) had juvenile-onset (25 years old or younger) HD;
group 2 (n= 43), adult-onset (26-50 years old) HD; and group 3 (n=13),
late-onset (51 years or older) HD.
Table 3. Genetic Data and Motor and Functional Scores*
Group 1
(n = 15)
Group 2
(n = 43)
Group 3
(n = 13)
ANOVA
rP
Time of evolution, y 4.8 ± 2.6 7.0 ± 5.0 5.0 ± 3.9 1.80 .17
Affected parent (M/P) 1/14 22/21 5/6† . . . . . .
No. of CAG repeats 59.9 ± 12.6‡§ 46.2 ± 3.5§ 41.7 ± 2.6 31.53 ,.001
Score
Manual akinesia 2.3 ± 0.6§ 1.9 ± 1.0 1.3 ± 0.7 4.31 .02
Rigidity 1.6 ± 0.7‡§ 0.8 ± 1.0 0.4 ± 0.5 7.60 .001
Axial bradykinesia 2.7 ± 1.3‡§ 0.9 ± 1.1 0.8 ± 1.0 13.77 ,.001
Chorea 4.9 ± 3.7‡§ 12.0 ± 7.0 13.2 ± 4.0 8.52 ,.001
Dystonia 5.2 ± 4.1§ 2.7 ± 4.3 1.3 ± 1.9 3.17 .05
TFC 8.6 ± 3.0 8.2 ± 3.9 9.8 ± 2.6 0.93 .40
*
Data are given as mean ± SD. M/P indicates maternal/paternal; TFC, Total Functional Capacity scale; and ANOVA, analysis of variance. See the footnote for
Table 1 for a description of the groups. Ellipses indicate not applicable.
†
Unknown in 2 cases.
‡
P
,
.05 vs group 2, post hoc comparison.
§
P
,
.05 vs group 3, post hoc comparison.
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95% confidence interval [CI], 1.05-1.70) and group 3
(1.36 points lower; 95% CI, 0.82-1.90). The difference
for the visual factor was much greater for group 3 (1.67
points lower than group 5; 95% CI, 0.85-2.49) than for
group 1 (0.83 points lower than group 4; 95% CI, 0.22-
1.43). The difference for the prefrontal factor was slightly
greater for group 1 (1.58 points lower than group 4; 95%
CI, 1.10-2.07) than for group 3 (1.24 points lower than
group 5; 95% CI, 0.65-1.84). For the MMSE, group 1
scores were 2.90 points lower (95% CI, 1.67-4.18) and
group 3 scores 4.20 points lower (95% CI, 1.53-6.85) than
groups 4 and 5, respectively.
In the HD study population, as well as in group 2,
all factor scores were significantly correlated with the
MMSE score (P,.005) and the time of evolution (P,.01)
but not with the number of repeats. In group 1, the cog-
nitive factors did not correlate with the MMSE score or
with the time of evolution. Scores for the prefrontal fac-
tor were almost significantly correlated with the num-
ber of CAG repeats (r=−0.57, P= .06). For group 3, there
were no significant correlations among cognitive fac-
tors, time of evolution, or number of repeats.
CORRELATIONS WITH
FUNCTIONAL DISABILITY
The TFC score for all patients with HD, correlated well
with time of evolution of the disease (r=−0.68, P,.001),
with global cognitive status as assessed by the MMSE
(r=0.49, P,.05), with prefrontal performance (r=0.76,
P,.001), and the following motor variables: chorea
(r=−0.59, P,.05), manual akinesia (r=−0.72, P=.001),
4
3
2
1
0
–135 40 45 50 55 60 65 70 75 80 85 90
CAG Repeats, No.
Axial Bradykinesia Score
Group 1,
r
=
0.50
Group 2,
r
=
0.30
Group 3,
r
=
0.55
13
9
11
7
5
3
1
–135 40 45 50 55 60 65 70 75 80 85 90
CAG Repeats, No.
Total Functional Capacity Score
Group 1,
r
=
–0.68
Group 2,
r
=
0.06
Group 3,
r
=
–0.36
29
24
19
14
9
4
–1
Chorea Score
Group 1,
r
=
0.26
Group 2,
r
=
–0.08
Group 3,
r
=
–0.16
4
3
2
1
0
–1
Manual Akinesia Score
Group 1,
r
=
0.53
Group 2,
r
=
0.06
Group 3,
r
=
0.69
A B
C D
Figure 2.
Correlations between the length of the CAG trinucleotide repeat and clinical features. A, Chorea score. B, Manual akinesia score. C, Axial bradykinesia
score. D, Total Functional Capacity score. Correlations for the Huntington disease study population were significant only for manual akinesia (
r
=0.35;
P,
.05) and
axial bradykinesia (
r
=0.57;
P,
.001). Correlations by groups are significant when
r.
0.50. For a description of the groups, see the legend for Figure 1.
Table 4. Cognitive Performance Scores*
Test or Factor/Functional Area
Group ANOVA
1 2 345
rP
Mini-Mental State Examination 26.1†‡ 22.7 23.2 29.0 27.4 16.8 ,.001
1/Visual 0.1223‡ −0.3846‡ −1.4368 0.9506 0.2366 16.25 ,.001
2/Prefrontal −0.3263 −0.6699 −0.9796 1.2574 0.2687 15.45 ,.001
3/Verbal memory −0.1182†‡ −0.6322 −0.8330 1.2611 0.5325 26.95 ,.001
*
Data are given as the mean for each group. The Mini-Mental State Examination (MMSE) score is the untreated score, while the score for each factor is a global
score calculated by principal-component analysis in which 0 would be the mean and 1 the SD, considering all subjects. ANOVA indicates analysis of variance. For
a description of groups 1 through 3, see the footnote for Table 1. Control groups were matched for age and educational level. Group 4 was the control group for
group 1; group 5, for group 3. See Table 2 for a description of the factors. Data not shown in the table include the following: comparison between any HD group
and group 4 was significant (
P,
.05) for all cognitive variables; comparison between HD groups and group 5 was significant (
P,
.05) in all cases except the
visual factor (vs groups 1 and 2) and the MMSE score (vs group 1); group 4 vs group 5 was significantly different in all except MMSE score.
†P ,
.05 vs group 2, post hoc comparison.
‡P ,
.05 vs group 3, post hoc comparison.
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and axial bradykinesia (r=−0.64, P= .005). There was
no significant correlation between TFC scores and age
at onset.
Correlations between the TFC scores and the cog-
nitive and motor variables for groups 1 and 3 are given
in Table 5. In group 1, TFC scores, manual akinesia,
axial bradykinesia, and prefrontal deficits were highly in-
tercorrelated. However, in group 3, the TFC score was
well correlated with the MMSE, but there were no sig-
nificant correlations with the motor variables. The TFC
score in group 2 correlated significantly with all motor
and cognitive variables (the highest correlation with the
TFC score was obtained with chorea, the MMSE score,
and the prefrontal and verbal memory factors; data not
shown).
In group 1, the TFC score correlated with number
of CAG repeats (r=−0.68; P,.01) (Figure 2) but not with
the time of evolution, while in groups 2 and 3, the TFC
scores correlated strongly with the time of evolution
(r=−0.72 and r=−0.71, respectively; P,.01 for both) but
not with the repeat length.
COMMENT
Before the availability of genetic analysis, several au-
thors reported differences in motor symptoms and se-
verity of HD depending on age at onset, emphasizing the
different rate of clinical progression and the variable neu-
ropathological involvement.16-18,42,43 During the last few
years, the length of the abnormal CAG repeat sequence
has been implicated as the major determinant of age at
onset,6-10 the degree of atrophy in the striatum,44,45 and
the rate of clinical progression.12,46 The longest repeats
and, therefore, the earliest onset seem to be related to a
more severe expression of the disease. A distinct motor
profile is associated with juvenile-onset HD.13-15 How-
ever, to our knowledge, no studies have evaluated the
severity of cognitive impairment at various age ranges
through formal neuropsychological assessments and
with appropriate controls. In the present study, we at-
tempted to compare the severity of cognitive impair-
ment among groups of patients with different age ranges
at the onset of HD and to evaluate the variable influence
of motor and cognitive deficits on functional disability
across different ages at the onset of HD. This was done
in an attempt to determine whether the severity of cog-
nitive deficits in juvenile and late-onset HD is in agree-
ment with other clinical and genetic features.
Our cohort was suited to this study because it
included patients in whom the onset of disease oc-
curred at different ages and who belonged to enough
kindreds to avoid conclusions based only on intrafamil-
ial characteristics. Six of 8 patients who were between
20 and 25 years old at onset had a predominant rigid
akinetic syndrome that more closely resembled the
juvenile phenotype than the adult, or classic, HD phe-
notype, so the limit defining juvenile onset was ex-
tended to 25 years. Except for 1 case, all patients in
group 1 had their first symptoms of the disease between
14 and 25 years of age. As reported by van Dijk et al,15
the distinction between juvenile- and adult-onset cases
is more clear when the motor phenotype and the age at
onset are considered than when only age at onset is
considered. The cutoff point of 25 years of age permit-
ted us to conduct a more coherent study relating sever-
ity of cognitive impairment to specific motor profiles. In
fact, in their review of rigid akinetic forms of HD, Bit-
tenbender and Quadfasel13 reported a mean age at onset
of 22.2 years in these forms of HD.
The mean time of evolution of the disease was simi-
lar for groups 1, 2, and 3. However, it is possible that these
data would be more accurate for group 1 because the pa-
tients were likely to be under close scrutiny from par-
ents or tutors, with more margin for error possible for
groups 2 and 3. Several authors have reported a similar
survival and rate of progression in patients with HD in-
dependent of age at onset,8,11,47,48 so it could be assumed
that the 3 groups with HD were in a similar stage of dis-
ease evolution. Nevertheless, other studies have found a
faster rate of progression in patients with juvenile-onset
HD,12,18,42,43 which could mean that 5 years might be half
of the evolution for a patient with juvenile-onset HD but
just a third of the evolution for a patient with adult-
onset HD. Even in this situation, the better cognitive pres-
ervation would be emphasized among patients with ju-
venile-onset HD, despite a greater genetic defect and a
more advanced stage of the disease.
As previously described,13-15 the motor profile in ju-
venile-onset HD was characterized by a predominant rigid
bradykinetic syndrome, with less chorea and more dys-
tonia than adult-onset HD. In an opposite profile, as re-
ported by Myers et al,17 late-onset HD more closely re-
sembled adult-onset HD, as manifested by prominent
choreic movements, with a slight trend in our data to-
ward less rigid akinetic features. This distinction shown
by the Unified Huntington’s Disease Rating Scale em-
phasizes the value of this simple scale from 0 to 4 when
rating motor signs. It is unlikely that motor symptoms
would have been substantially influenced by treatment
in groups 1 and 3 because none of the patients had re-
ceived neuroleptic drugs. At the time of the study, most
patients were receiving only calcium antagonists, and only
1.5
1.0
0.5
0
–0.5
–1.0
–1.5
30
29
27
25
23
21
28
26
24
22
20
Visual Prefrontal Verbal Memory MMSE
Factor
Cognitive Function
Factor Scores
MMSE Score
Group 1
Group 2
Group 4
Group 5
Group 3
Figure 3.
Cognitive performance. MMSE indicates Mini-Mental State
Examination. For a description of groups 1 through 3, see the legend for
Figure 1. Control groups were matched for age and educational level. Group
4 was the control group for group 1; group 5, for group 3. See Table 2 for a
description of the factors.
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a few in group 2 were receiving tetrabenazine to amelio-
rate chorea. It is also unlikely that treatment with cal-
cium antagonists (eg, nicardipine hydrochloride) had
substantially influenced the outcome of the cognitive
evaluation.
Cognitive performance was globally deteriorated in
patients with HD, in agreement with the findings of many
previous studies.20-27 There was a steady decline in all neu-
ropsychological scores from younger to older ages. That
is, group 1 performed more successfully than groups 2
and 3 in most of the neuropsychological tasks. Group 2
had better scores than group 3, but only the visual fac-
tor was significantly worse for group 3. This age-related
gradient resembled, but for some factors exceeded, the
mild deterioration noted with aging among the healthy
controls. A higher educational level could be expected
for groups 2 and 3 than for group 1, because the onset
of the disease interfered with education of patients in
group 1. These differences in educational level may con-
found the comparison of cognitive performance among
the groups with HD. However, the patients in group 3
who were oldest at disease onset did not finish high school
or college because of socioeconomic limitations, while
many patients in group 1, with onset of the disease at the
end of the second decade of life, were able to complete
high school.
More important than the comparison between juve-
nile- and late-onset HD was the magnitude of the differ-
ences between groups 1 and 3 and groups 4 and 5, their
respective controls. Global cognitive status as measured by
the MMSE was slightly more impaired for group 3 (ie, scores
were 4.2 points below those for group 5) than for group 1
(scores were 2.9 points below those for group 4). Scores
for the verbal memory factor were similar between groups
1 and 3 in relation to groups 4 and 5, respectively. Scores
for the prefrontal factor, however, were slightly more im-
paired for patients in group 1, while scores for the visual
factor were much worse for patients in group 3.
In general, cognitive performance was better pre-
served in group 1, except for functions in the prefrontal
factor. This was the only cognitive measure in which pa-
tients in group 1 had a relatively greater deficit com-
pared with group 4. Two of the tests included in this fac-
tor (Symbol Digit and Trail Making tests) involved motor
performance, and the scores were probably adversely af-
fected by the prominent rigid bradykinetic syndrome evi-
dent in patients in group 1. Many other variables in this
factor did not require motor function (eg, verbal flu-
ency, Stroop test, and digit span) but some were sub-
jected to time constraints. We observed that patients in
group 1 were relatively successful in the cognitive tasks
but performed them slowly, regardless of the presence
of motor involvement. It is possible that this relative pre-
frontal deficit reflects a global bradyphrenia in patients
with juvenile-onset HD as the cognitive correlate of the
motor bradykinetic syndrome. This is supported by the
high correlation between both manual akinesia and axial
bradykinesia and scores for the prefrontal factor. How-
Table 5. Correlation Coefficients Between Functional Disability and Motor and Cognitive Variables*
TFC Chorea Akinesia Rigidity Bradykinesia Dystonia MMSE
Factor
12 3
TFC . . . −.798† . . . −.781† . . . . . . . . . .713 . . .
Chorea . . . . . . −.584 . . . . . . .582 . . . . . . . . .
Akinesia . . . . . . . . . .777† . . . . . . . . . −.644 . . .
Rigidity . . . . . . .632 . . . . . . . . . . . . . . . . . .
Bradykinesia . . . . . . . . . . . . . . . . . . . . . −.754 . . .
Dystonia . . . . . . . . . . . . . . . . . . . . . . . . .684
MMSE .642 . . . . . . . . . . . . −.601 . . . . . . . . .
Factor
1 . . . .725 . . . . . . −.762 . . . .834 .660 . . .
2 ... ... ... ... ... ... ... ... ...
3 ... ... ... ... −.613 ... ... ... ...
*
The upper right of the table corresponds to correlations within group 1, while the lower left refers to group 3. Only correlations with significance greater than
P,
.05 are shown. Akinesia refers to the extremities and bradykinesia refers to the trunk. TFC indicates Total Functional Capacity scale; MMSE, Mini-Mental State
Examination; and ellipses, data not shown because
P.
.05. For a description of the groups, see the footnote for Table 1; for a description of the factors, see Table 2.
†P,
.001.
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ever, analysis of the neuropsychological data as global
factors did not allow for further qualitative analysis of
cognitive performance, for which an independent analy-
sis of the tests would have been more appropriate. The
relative cognitive preservation in younger patients sug-
gests that they might benefit from special and continu-
ous educational support.
The visual factor encompassed a visuoconstructive
task, immediate and delayed visual memory, and visuo-
perception. Although the motor component is required
to copy and, later on, reproduce by memory a complex
figure, the tasks were not timed, and the imprecision of
the drawing due to choreic movements was not penal-
ized. The severe visual impairment in patients in group
3 was not likely due to primary visual problems, accord-
ing to data from the anamnesis (the patients did not un-
dergo a standardized ophthalmologic examination at the
time of the study). Other causes, such as oculomotor im-
pairment; high visual-association deficits; excessive, and,
perhaps neglected, visual loss related to aging; or a com-
bination of these factors, could contribute to the failure
on tasks that were part of the visual factor.
Despite these distinct motor and cognitive features
in patients in groups 1 and 3, no significant differences
in functional capacity scores were found across the 3
groups with HD. There was an advantage for group 3 in
the distribution according to the Shoulson and Fahn stages
of the disease, with 11 (85%) of the patients in stages I
or II vs 10 (67%) of the patients in group 1 in those stages.
This distribution supports the classical idea of greater
functional disability associated with juvenile HD.16 One
important point is the difficulty of scoring the abilities
of young patients by using the available functional scales
and staging systems. Items such as occupation and man-
agement of finances could be difficult to apply to young
adults who may have never achieved an independent life
before the onset of their disease. Sometimes the score was
determined by guessing rather than by a clear demon-
stration of the capacity. Our group of patients with ju-
venile-onset HD was studied at a mean of 23.7 years of
age, and only 1 patient demonstrated full capacity for oc-
cupation and management of finances. However, sev-
eral patients were considered able to perform low-skill
jobs or manage finances with some assistance.
The correlation of the clinical deficits with func-
tional scores was different across the groups. For group
2, all motor and cognitive variables were correlated sig-
nificantly. For group 1, the TFC score was highly cor-
related with manual and axial bradykinesia and with the
prefrontal factor, while for group 3, the TFC score cor-
related only with the MMSE score. It is surprising that
in the light of the very low cognitive performance of group
3, the TFC score was slightly better than that for group
1. Two explanations can account for this. First, bradyki-
netic features are a major reason for disability among pa-
tients with HD (as seen in patients with juvenile-onset
HD), which is not the case for patients with late-onset
HD. Motor disability, produced by chorea, in patients in
their sixties did not seem to handicap daily functioning
to a great extent. Second, cognitive requirements for pa-
tients in group 3 were probably quite restricted. A rou-
tine and the simplification of daily living activities at these
ages may mask a severe cognitive dysfunction and ap-
pear, instead, as an acceptable functional capacity. The
contrary occurs at juvenile ages, when the requirements
during a period of maximum intellectual and physical de-
velopment are much higher for motor and cognitive ca-
pabilities. A determination of the deficits that most
strongly condition functional disability at different ages
may be useful for the selection of the most beneficial thera-
peutic strategies. Functional scores correlated with the
time of evolution for patients with adult- and late-onset
HD, but not for patients with juvenile-onset HD.
Finally, genetic definition of groups 1, 2, and 3 agreed
with several previous reports that found a larger num-
ber of CAG repeats with earlier-onset HD.6-10 The num-
ber of repeats for group 1, 59.9±12.6, was almost 14 re-
peats more than for group 2, 46.2±3.5. Group 3 had a
shorter range of repeats (41.7±2.6). James et al19 also found
very short CAG repeats in patients who were older than
60 years at the onset of the disease. Repeat length ranges
in groups 1, 2, and 3 greatly overlapped, with no clear
cutoff points that would allow for a definite prediction
of the age at onset of the disease. However, the data sug-
gest that when the number of repeats is more than 55, a
young onset of HD is likely, while for patients with 39
to 41 repeats, HD might not manifest until late in life.
The greatest correlation with age at onset was within group
1, and the correlations were nonsignificant for group 3.
For group 1, the disease was mainly inherited through
the paternal line, as reported by multiple studies.6,8,9,49-52
For group 3, the sex of the transmitting parent was bal-
anced, but unknown in 2 patients. However, we found
no predominance for maternal inheritance as has been
described in these cases.13,53,54
In summary, patients in group 1 had the longest CAG
repeat lengths and a motor disturbance characterized by
rigid akinetic features. However, cognitive impairment
was less significant than at other ages at onset, except
for prefrontal dysfunction. Motor and prefrontal dys-
function strongly conditioned the TFC scores in this
group. On the other hand, the inheritance of CAG re-
peats in the very low range was common in group 3. This
late-onset HD more closely resembled adult-onset cho-
rea in motor features and manifested with significant
cognitive impairment, in particular severe visuospatial
dysfunction. Functional capability in group 3 was
more dependent on cognitive functioning than on mo-
tor performance.
Accepted for publication October 17, 1997.
This work was supported in part by grant FIS 91/
0159 from the Fondo de Investigaciones Sanitarias, Madrid,
Spain.
Corresponding author: Estrella Go´mez-Tortosa, MD,
PhD, Alzheimer’s Research Unit, CNY 6405, Massachu-
setts General Hospital East 149, 13th St, Charlestown, MA
02129.
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