Brain (1997), 120, 2207–2217
Cognitive deficits in Huntington’s disease are
predicted by dopaminergic PET markers and brain
volumes
L. Bäckman,1,2,3 T.-B. Robins-Wahlin,2,3 A. Lundin,4 N. Ginovart4 and L. Farde4
1Department of Psychology, Göteborg University, Göteborg,
2Stockholm Gerontology Research Centre, 3Department of
Clinical Neuroscience and Family Medicine, Section of
Geriatrics, Karolinska Institute and 4Department of
Clinical Neuroscience, Section of Psychiatry, Karolinska
Institute, Stockholm, Sweden
Summary
The main aim of this study was to investigate the
relationship between dopaminergic markers and brain
volumes for striatal and cortical structures, and cognitive
performance in patients with Huntington’s disease and
control subjects. We used PET and MRI data as predictors
of performance in tasks assessing executive function,
visuospatial ability, episodic memory, verbal fluency, per-
ceptual speed and reasoning. The dopamine neurotransmis-
sion parameters (D1 and D2 receptor density and dopamine
transporter density) and the volumetric measurements for
caudate and putamen accounted for substantial portions
Keywords: Huntington’s disease; cognition; dopaminergic markers; PET; MRI
Abbreviations: ANOVA 5 analysis of variance; DAT 5 dopamine transporter; R-OCF 5 Rey–Osterrieth’s Complex Figure;
TMT 5 Trail Making Test; WCST 5 Wisconsin Card Sorting Test
Introduction
Huntington’s disease is a progressive, neurodegenerative
disorder with a typical clinical onset between 30 and 50
years of age. The clinical manifestations of Huntington’s
disease involve prominent motor dysfunction and cognitive
deterioration, as well as psychiatric symptoms and personality
changes (for reviews, see Brandt and Butters, 1986; Brown
and Marsden, 1988). Huntington’s disease-related deficits
have been reported in tasks assessing a variety of cognitive
skills, including episodic memory (Caine et al., 1977; Butters
et al., 1978; Moses et al., 1981), executive functions and
mental flexibility (Boll et al., 1974; Josiassen et al., 1983;
Taylor and Hansotia, 1983; Butters et al., 1985), visuospatial
ability (Fedio et al., 1979; Mayeux et al., 1983; Brouwers
et al., 1984; Mohr et al., 1991; Filoteo et al., 1995), procedural
© Oxford University Press 1997
Correspondence to: Lars Bäckman, Stockholm Gerontology
Research Center, Olivecronas väg 4, S-113 82 Stockholm,
Sweden
of the variance across the majority of cognitive tasks. In
addition, frontal volume showed a strong relationship with
all cognitive tasks. D1 binding and volume measurements
for the temporal cortex and thalamic volume showed
associations with a select number of cognitive tasks. The
overall data pattern is consistent with the view that
Huntington’s disease may be characterized as a frontostria-
tal dementia, in which cognitive deficits may result from
pathological changes at multiple sites in the frontostriatal
circuitry.
learning (Fedio et al., 1979; Martone et al., 1984) and verbal
fluency (Butters et al., 1978; Wexler, 1979; Tröster et al.,
1989; Rosser and Hodges, 1994). Importantly, processing
speed is a central component in many of the tasks described
above. Thus, the observed patterns of results are consistent
with the notion that Huntington’s disease is characterized by
a reduction in mental tempo (Brandt and Butters, 1986;
Brown and Marsden, 1988).
It is of interest to relate the cognitive deterioration to
the specific neuropathology in Huntington’s disease. The
neuropathology is characterized by a loss of medium spiny
neurons, the predominant neuronal population in the striatum
(Graveland et al., 1985; Goto et al., 1989). A more recent
observation is that frontal gyri become atrophic along with
2208 L. Bäckman et al.

Table 1 Volumes, D1- and D2-receptor binding potential and DAT binding of different brain structures in patients with
Huntington’s disease and control subjects
Structure Volume (mm3)* D 1* D2* DAT*

Huntington’s Control Huntington’s Control Huntington’s Control Huntington’s Control

disease subjects disease subjects disease subjects disease subjects

Caudate
Mean 2065.20 3834.20 0.67 1.13 1.22 2.08 0.51 1.13
SD 603.67 672.92 0.28 0.10 0.35 0.14 0.27 0.11
Putamen
Mean 3447.60 5361.80 0.84 1.28 1.48 2.46 0.60 1.27
SD 396.98 885.58 0.30 0.17 0.29 0.19 0.28 0.12
Frontal cortex
Mean 14835.20 18190.60 0.31 0.30 – – – –
SD 1590.65 726.53 0.06 0.03 – – – –
Temporal cortex
Mean 13482.40 16138.40 0.35 0.46 – – – –
SD 1574.05 2136.66 0.04 0.07 – – – –
Thalamus
Mean 4832.60 5965.20 – – – – – –
SD 624.01 607.65 – – – – – –

Adapted from Ginovart et al. (1997). *Values represent the means of both hemispheres because no significant asymmetry was observed.

the striatum (Webb and Trzepacz, 1987; Jernigan et al.,
1991). The striatum is densely innervated by dopaminergic
fibres and contains a high density of postsynaptic D1 and D2
receptors, which are located on the medium spiny neurons
(Seeman et al., 1993; Hall et al., 1994). D1 is the predominant
dopamine receptor in the neocortex (Murray et al., 1992).
Post-mortem examinations and in vivo studies with PET have
demonstrated marked reductions of D1 and D2 receptors in
the striatum of Huntington’s disease patients (Hägglund et al.,
1987; Filloux et al., 1990; Richfield et al., 1991; Sedvall
et al., 1994; Turjanski et al., 1995). Moreover, a recent PET
study demonstrated loss of D1 receptors in the frontal cortex
of Huntington’s disease patients (Sedvall et al., 1994).
Biochemical research indicates a Huntington’s disease-
related dysfunction in the presynaptic dopamine neurons that
ascend from the midbrain (Ferrante and Kowall, 1987). The
dopamine transporter (DAT) is a protein located
presynaptically on dopaminergic nerve terminals (Kuhar
et al., 1990; Giros et al., 1992), and may thus serve as a
marker for the presynaptic neuron.
In a recent PET and MRI study of Huntington’s disease
patients, we found a parallel reduction of D1 and D2 receptor
binding sites in the striatum. These reductions were related
to the duration of the illness (Ginovart et al., 1997). The
density of D1 receptors was also reduced in the temporal
cortex, but not in the frontal cortex. In addition, a Huntington’s
disease-related reduction of DAT was found in the caudate
and putamen. The MRI assessment showed striatal atrophy,
along with reduced volumes of the frontal cortex and thalamus
(see Table 1).
Striatal regions are topographically organized with
abundant reciprocal connections to the neocortex (Graybiel
and Ragsdal, 1979; Crosson, 1992) and thalamus (Dom et al.,
1976; Jayarman, 1984). There is substantial evidence that the
basal ganglia serve a key function in integrating information
through cortico-striato-thalamocortical circuits (Bruyn et al.,
1979; Gerfen, 1989; Parent, 1990). Thus, given the
Huntington’s disease-related degeneration of the striatal
nuclei, as well as their projections to cortical and subcortical
areas (Bruyn et al., 1979; Graveland et al., 1985; Alexander
et al., 1986; Reiner et al., 1988; Goto et al., 1989; Parent
and Hazrati, 1995), widespread effects on cognitive functions
are to be expected in this disease. Attempts at linking the
subcortical and cortical changes in Huntington’s disease
with cognitive performance and functional ability have been
relatively successful. Relationships between CT-based
measures of caudate atrophy and indices of both functional
and cognitive ability have been reported (Shoulson et al.,
1982; Sax et al., 1983; Starkstein et al., 1988). Bamford
et al. (1989) found strong associations between CT measures
of striatal and frontal atrophy and cognitive test performance
in a group of early-stage Huntington’s disease patients.
Starkstein et al. (1992) observed that MRI-based measures
of caudate and frontal atrophy correlated with a factor
indexing memory and speed of processing in mild to moderate
Huntington’s disease patients, although no relationships were
found with measures of putaminal or thalamic atrophy. Brandt
et al. (1995) recently reported that an MRI-based measure
of left caudate atrophy was related to memory for item and
contextual information in mild to moderate Huntington’s
disease patients; no reliable relationships with measures of
other basal ganglia structures were obtained. In another recent
report, Harris et al. (1996) found a somewhat different
outcome. In their study, Huntington’s disease-related deficits
in various cognitive tasks (i.e. visual and verbal episodic
memory, Trail Making and Stroop tests) were related to
volumetric measurements of both caudate and putamen. In
addition, measures of regional cerebral blood flow in caudate,
 PET and cognition in Huntington’s disease 2209

putamen and thalamus, derived from single photon emission between 2 and 8 years (mean 6 SD 5 5.6 6 2.5 years).
computed tomography, correlated with performance in several Exclusion criteria for the control subjects included history of
of the cognitive tasks. Interestingly, the best overall predictor mental disorder, significant somatic condition, abnormal MRI
of cognitive performance was a global measure of atrophy, and current or previous abuse of drugs or alcohol. No subject
namely the percentage of cerebrospinal fluid volume in the was on medication, and subjects were not allowed to drink
whole brain. These results suggest a more global influence any alcohol during 48 h prior to the testing.
of an impaired cortico-striato-thalamocortical system on The Huntington’s disease patients had a mean Mini-
Huntington’s disease-related cognitive deficits than has been Mental State Examination (Folstein et al., 1975) score of
implied in prior research. 25.8 6 1.3, indicating a mild to moderate global cognitive
The present investigation represents an extension of the impairment. One Huntington’s disease patient had depressive
PET and MRI study reported by Ginovart et al. (1997) (see symptoms at the time of the investigation.
Table 1). The main aim was to explore the relationship
between dopamine neurotransmission parameters and
cognitive performance in Huntington’s disease patients and
MRI and PET assessment
A detailed description of the MRI and PET assessment was
normal control subjects. To our knowledge, this is the first
provided by Ginovart et al. (1997). Briefly, a head fixation
attempt to relate dopaminergic PET markers to cognitive
system was used which allowed transfer of positioning from
functioning in Huntington’s disease. An additional purpose
MRI to PET, and repeated PET assessments with the same
was to relate volumetric MRI measurements to cognitive
positioning of the head (Bergström et al., 1981). MRI
performance. In this way, potential differences between the
examinations were performed using an MR Signa Advantage
neurotransmitter parameters and volumetric measurements
System (General Electric, Signa 1.5 T) at the Karolinska
with regard to the effects on cognitive functioning could be
Hospital, providing 124 contiguous slices of the entire brain
determined. The cognitive battery was designed to tap a wide
with a resolution in the axial plane of 1.5 mm.
variety of cognitive domains known to be implicated in
PET studies were performed on a Siemens ECAT Exact
Huntington’s disease. The battery involved tests of executive
HR 47 (Wienhard et al., 1994). Each subject participated in
function, visuospatial ability, episodic memory, verbal
three PET measurements performed on the same day. The
fluency, perceptual speed, and reasoning. Although we
PET measurements followed the procedure described by
expected a general relationship between the biological and
Farde et al. (1994, 1995). The radioligands used were
cognitive variables, a final objective was to examine the
[11C]SCH 23390 for D1 receptors, [11C]raclopride for D2
relative predictive power of the biological indices for
receptors and [11C]β-CIT for DAT (Farde et al., 1986, 1987,
performance in the respective cognitive tests.
1994, 1995). Regions of interest were drawn manually on
the MRI images. The following structures were delineated:
caudate (the head), putamen, thalamus, frontal cortex,
Method temporal cortex and cerebellum. The MRI-defined regions
of interest were used to calculate structural volumes. The
Subjects
regions of interest drawn on the MRI images were transferred
Five patients with Huntington’s disease (three men and two
to the corresponding PET images to obtain time curves for
women) and five healthy control subjects (three men and
regional brain radioactivity.
two women) were included in the study. The subjects gave
[11C]SCH 23390 and [11C]raclopride binding to D1 and D2
informed consent after the nature and possible consequences
receptors, respectively, was calculated using a ratio method
of the study were described, and the study was approved by the
(Farde et al., 1986, 1995). The cerebellum was used as a
Ethics and Radiation Safety Committees of The Karolinska
reference region for the free radioligand concentration (F),
Hospital, Stockholm. The groups were matched on age and
since this region contains negligible densities of D1 and D2
educational background. The Huntington’s disease group had
receptors (Hall et al., 1988; Cortés et al., 1989). Specific
a mean age (6 SD) of 49.4 6 7.6 years and had completed
binding (B) was defined as the total binding in a region of
an average of 11.5 6 1.5 years of formal education. The
interest reduced by F. The B : F ratio was calculated for
control subjects had a mean age of 48.0 6 7.8 years and
each region of interest, providing an index of the density of
averaged 11.9 6 0.7 years of schooling. The clinical diagnosis
available receptors (Farde et al., 1986, 1995). [11C]β-CIT
of Huntington’s disease was based on the presence of the
was analysed using a multiple-time graphic analysis (Patlak
typical motor and cognitive symptoms in patients with a
et al., 1983; Patlak and Blasberg, 1985). This analysis
family history of Huntington’s disease. The diagnosis was
provides an influx constant (Ki), which is linearly related to
confirmed by molecular genetic analysis showing a CAG
the density of the DAT (Ginovart et al., 1997).
repeat length of .37 in the gene locus for Huntington’s
disease. The exact number of CAG repeats was, however,
not known to any of the investigators, according to the Cognitive testing
Huntington Study Group policy on non-disclosure of CAG The cognitive test battery was administered by an experienced
trinucleotide repeat length. The duration of illness varied psychometrician (T.-B.R.-W.) at the Stockholm Gerontology
2210 L. Bäckman et al.
Reseach Centre. Subjects were tested individually. The time
elapsed between the brain imaging and the cognitive
assessment averaged 1.60 6 0.89 days for the Huntington’s
disease patients and 2.00 6 2.23 days for the control subjects
(P . 0.50). The total testing time for the cognitive battery
was ~3 h.
The test battery was designed to measure a broad spectrum
of cognitive functions, including executive functions [Trail
Making Test (TMT), Wisconsin Card Sorting Test (WCST)
and Tower of Hanoi], episodic memory [word recall and
Rey–Osterrieth’s Complex Figure (R-OCF)—memory];
visuospatial ability (Block Design and R-OCF—copy); verbal
fluency (Controlled Oral Word Association Test), perceptual
speed (Digit Symbol) and reasoning (Picture Arrangement).
The respective tests used are described below.
Picture Arrangement, Block Design and Digit
Symbol
Three tests from the Wechsler Adult Intelligence Scale—
Revised (WAIS-R) (Wechsler, 1981) were used: Picture
Arrangement, Block Design and Digit Symbol. Standard
rules for administration were employed, and the tests were
scored according to WAIS-R criteria. The maximum score
for Picture Arrangement was 20, for Block Design it was 51
and for Digit Symbol 93.
Trail Making Test (TMT) A and B
A version of the TMT from the Halstead–Reitan Battery
(Halstead, 1947; Reitan and Davidson, 1974; Reitan, 1979)
was given in two parts, A and B. For both parts, subjects
were presented with a white sheet of paper on which circles
were distributed. In part A, the circles were numbered from
1 to 25 and subjects were asked to draw lines to connect the
25 circles in correct order (i.e. 1–2–3– . . . –25). In part B,
the circles contained numbers from 1 to 13 and letters from
A to L. Subjects were instructed to connect the consecutively
numbered and alphabetically lettered circles, by alternating
between the two sequences (i.e. 1–A–2–B– . . . –L–13). In
both parts, subjects were told to connect the circles as fast
as possible. The number of seconds needed to finish each
part was registered. The first error observed was immediately
pointed out by the examiner, and the subject was required to
correct the error. Thereafter, the subject was asked to continue
in the proper sequence. From the second error onwards the
subject was not corrected. Performance time was unlimited.
Word recall
A total of 20 concrete nouns from different taxonomic
categories were used. The 20 words were equivalent with
respect to visual and tactual imagery, meaningfulness and
frequency, as determined from a normative Swedish study
(Molander, 1984). The list was presented at a rate of one
word every 5 s. Subjects were told to remember as many
words as possible for a subsequent free recall test. The words
were presented bimodally; that is, they were shown on printed
cards consecutively, and simultaneously read aloud by the
examiner. Following presentation of the last word in the list,
an oral free recall test was given. The recall task was
self-paced.
Controlled Oral Word Association Test
The Controlled Oral Word Association Test (Benton and
Hamsher, 1989) was administered to assess verbal fluency.
In this test, subjects are asked to produce as many words as
possible beginning with the letters F, A and S, with the
exception of proper names, numbers, and words with the
same suffix. One minute was allowed for each letter.
Rey–Osterrieth’s Complex Figure
The R-OCF (Rey, 1941; Osterreith, 1944) was given in two
parts: copy and memory. Subjects were given a blank sheet
of paper, and another sheet of paper on which the R-OCF
was printed. They were instructed to copy the figure as
accurately as possible, with no time restrictions. Following
completion, the examiner removed both the original and the
copied figure. Completion time was recorded. After a
retention interval of 4 min during which the Controlled Oral
Word Association Test was completed, subjects were again
given a blank sheet of paper, and asked to reproduce the R-
OCF from memory. Recall was self-paced. The copy and
memory tasks of the R-OCF were scored according to
standardized criteria (Taylor, 1959; Lezak, 1995). The
maximum score for each of these variables was 36.
The Wisconsin Card Sorting Test
Subjects were given two packs of 64 cards in the WCST
(Berg, 1948; Grant and Berg, 1948; Milner, 1963). One to
four instances of each of four symbols in four different
colours were printed on each card (e.g. one red triangle, two
green stars, three yellow crosses and four blue circles). The
subject’s task was to sort the cards according to a principle
inferred from the examiner’s responses to the subject’s
placement of the cards. The test involved three principles for
sorting: colour, symbol or number. The examiner responded
only ‘right’ or ‘wrong’ according to the subject’s placement
of the card, and did not answer any questions. After 10
consecutive correct placements, the examiner shifted the
principle. The test continued until the subject had made six
runs of ten correct placements, or when all 128 cards were
placed. In the current study, the number of perseverative
errors was used as the criterion variable.
The Tower of Hanoi
The puzzle of the Tower of Hanoi (Butters et al., 1985)
consisted of three pegs, forming a triangle on a plastic square

foot and five circular plastic blocks. The starting peg was
positioned next to the subject where all five blocks were
arranged, according to size, to form a tower (the smallest
block on the top and the largest on the bottom). Subjects
were asked to move the blocks as fast as possible from the
starting peg to either of the two other pegs, maintaining the
tower form. They were allowed to move only one block at
a time, and could never place a larger block on the top of a
smaller one. A minimum of 31 moves was needed for optimal
solution of the task. Completion time was registered.
Data analysis
The cognitive data were entered into separate analyses
of variance (ANOVAs), with group (Huntington’s disease
patients, control subjects) as a between-subjects variable.
For each statistically reliable effect, η2 was calculated to
determine the proportion of variance in cognitive performance
that was accounted for by group membership.
We used the dopamine parameters and brain volume data
initially reported by Ginovart et al. (1997) as correlates of
cognitive performance. These relationships may best be
determined using homogeneous groups, due to potential
aggregation bias for combined data. However, examining
within-group relationships was not judged to be feasible in
the present study, because of the relatively small sample
sizes. Thus, in order to maximize statistical power, the data
used in the regression analyses were collapsed across group.
To determine the predictive value of the dopamine
neurotransmission and morphological data for cognitive
performance, we first conducted blockwise hierarchical
regression analyses for each structure and cognitive variable.
To examine the relative influence of the dopamine and brain
volume data on cognitive performance, two sets of regressions
were performed for caudate and putamen, In the first set, the
D1, D2 and DAT data were entered first in one block, followed
by the brain volume data in the second block. In the second
set, order of entry between the two blocks was reversed. For
frontal and temporal cortex, the same strategy was applied,
although only D1 and brain volume data were available.
Finally, for thalamus, only volume data were available
to predict cognitive performance. In additional regression
analyses, we investigated the relative importance of the
different biological variables for different cognitive tasks, by
entering all biological variables in stepwise forward fashion.
Results
Cognitive data
The performance by Huntington’s disease patients and control
subjects in the cognitive tests is shown in Table 2. As can
be seen from this table, ANOVAs revealed significant effects
favouring the control subjects for 10 of the 11 tests, suggesting
a rather global cognitive deficit in the Huntington’s disease
PET and cognition in Huntington’s disease 2211
group. The only exception to this pattern was word recall,
in which the group difference did not approach conventional
significance.
Relationships between brain imaging
parameters and cognitive performance
Blockwise hierarchical regression analysis
The outcomes of the analyses of the predictive effects of the
caudate and putamen data were identical; when the block
involving D1, D2 and DAT was entered first in the equation,
it made a significant contribution to all cognitive variables
(all P , 0.05), except perseverations in the WCST and word
recall (all P . 0.20). The amount of variance accounted for
by this block was considerable, with r2-values ranging from
0.67 to 0.91. The volume data did not add to the amount of
explained variance in any instance (all P . 0.20). However,
when the order of entry of predictors was reversed, the
volume data contributed reliably to all cognitive measures
(all P , 0.05), except word recall, perseverative errors,
TMT-A and TMT-B (all P . 0.20). The r2-values for the
volume data varied between 0.48 and 0.70 across the seven
tasks for which the relationship was reliable. In these
analyses, there was no significant contribution of the block
of dopamine parameters (all P . 0.10). This pattern of
results can be understood from the fact that there were
sizeable correlations among the data on D1, D2 and DAT,
and brain volume in both caudate (r2-values ranging from
0.76 to 0.94, all P , 0.05) and putamen (r2-values ranging
from 0.73 to 0.89, all P , 0.05). Thus, once the blocks of
dopaminergic markers or volume variables were taken into
account, not much variance was left that could be explained
by the remaining block. Yet it should be noted that the
neurotransmitter parameters accounted for a greater portion
of the variance in cognitive performance than the striatal
volume variables across all measures. In addition, the
neurotransmitter parameters made a contribution to nine
cognitive measures, whereas the volume variables were
related to seven cognitive measures.
Frontal volume was related to performance in all cognitive
tasks, irrespective of whether it was entered before or after
D1 in frontal cortex (r2-values ranging between 0.50 and
0.80; P , 0.05). D1 in frontal cortex was unrelated to
performance across all measures (P . 0.50). Thalamic
volume contributed significantly to performance in verbal
fluency, R-OCF-copy, R-OCF-memory and Tower of Hanoi
(r2-values between 0.41 and 0.54; all P , 0.05), but not to
the remaining cognitive tasks (P . 0.20). Finally, when
entered first in the equation, D1 in temporal cortex made a
reliable contribution to performance in Picture Arrangement,
TMT-A, TMT-B and the Tower of Hanoi (P , 0.05), with
no explanatory variance added by temporal volume (P .
0.10). However, as was true with caudate and putamen,
reversal of order of entry between the dopamine and volume
measures resulted in the opposite pattern of results, again
2212 L. Bäckman et al.

Table 2 Summary statistics of cognitive performance in patients with Huntington’s disease

and control subjects
Test Huntington’s disease Control subjects F P η2

Digit Symbol 23.00 6 6.32 49.40 6 8.44 31.31 0.001 0.80

Block Design 18.40 6 7.83 38.60 6 9.76 13.03 0.01 0.62
Picture Arrangement 4.80 6 4.60 18.20 6 1.31 39.21 0.001 0.83
Trail Making, part A 102.60 6 43.32 32.60 6 8.08 12.61 0.01 0.61
Trail Making, part B 222.40 6 85.48 60.60 6 8.91 17.72 0.01 0.69
Tower of Hanoi 3081.20 6 675.16 906.60 6 387.97 38.99 0.001 0.83
Verbal Fluency 20.00 6 7.79 51.40 6 8.14 38.32 0.001 0.83
ROCF—copy 29.00 6 2.00 35.20 6 1.10 36.96 0.001 0.83
ROCF—memory 15.20 6 5.26 28.40 6 2.79 24.54 0.01 0.75
Word Recall 8.00 6 3.39 10.60 6 1.67 2.36 .0.05 –
Perseverative Errors 35.60 6 21.85 7.60 6 2.70 8.09 0.05 0.50

Data are shown as mean 6 SD.

Table 3 Stepwise regression analyses for predicting cognitive performance

Task Predictor variables Incremental r2 Cumulative r2 β P

Digit Symbol DAT putamen 0.74 0.74 0.86 0.001

Block Design DAT putamen 0.66 0.66 0.82 0.01
Picture Arrangement DAT putamen 0.78 0.78 0.88 0.001
Tower of Hanoi DAT putamen 0.82 0.82 20.91 0.001
D1 temporal 0.09 0.91 20.42 0.03
Verbal Fluency DAT putamen 0.78 0.78 0.88 0.001
D1 caudate 0.11 0.89 0.39 0.04
Trail Making, part A DAT putamen 0.63 0.63 20.79 0.01
Trail Making, part B Volume frontal 0.80 0.80 20.90 0.001
Ray Osterreith, copy Volume putamen 0.65 0.65 0.80 0.01
Ray Osterreith, memory Volume frontal 0.69 0.69 0.83 0.01
Word Recall Volume frontal 0.51 0.51 0.72 0.02
Perseverative Errors Volume frontal 0.70 0.70 20.84 0.01

DAT 5 dopamine transporter binding.

suggesting substantial colinearity between the two types of
biological indices.
Stepwise regression analyses
After having established that many of the biological variables
and, in particular, that the data pertaining to dopamine
parameters in caudate and putamen as well as frontal volume
were generally related to cognitive performance, we evaluated
the relative importance of the biological indices for specific
cognitive tasks. To accomplish this goal, we conducted
additional regression analyses for each of the cognitive
variables. To control for colinearity among the biological
variables, both within and between brain areas, all biological
variables were entered in stepwise forward fashion. The
outcome of the stepwise regressions is shown in Table 3.
The general impression from this table is that DAT in putamen
and frontal volume were the most important predictors of
cognitive performance, with DAT in putamen being the major
predictor in six tasks, and frontal volume being the sole
predictor in four tasks. The only exception to this pattern
was R-OCF-copy, in which the volume measure of putamen
emerged as a single predictor of performance.
Although the strong relationships between the biological
indices and cognitive performance were largely due to
substantial group differences for both sets of variables,
positive associations were also seen within groups. Illustrative
examples of these relationships are portrayed in Figs 1 and
2. These figures show the relationship between DAT in
putamen and Tower of Hanoi and frontal volume and TMT-
B, respectively.
Discussion
It is well established that Huntington’s disease is associated
with specific neuropathology in striatal and neocortical brain
regions (Graveland et al., 1985; Ferrante and Kowall, 1987;
Webb and Trzepacz, 1987; Goto et al., 1989; Filoux et al.,
1990; Jernigan et al., 1991; Richfield et al., 1991) as well
as cognitive impairment (Butters et al., 1978; Fedio et al.,
1979; Josiassen et al., 1983; Taylor and Hansotia, 1983;
Rosser and Hodges, 1994; Lange et al., 1995; Lawrence
et al., 1996). In the research reported here, we sought to link
the neuropathology of Huntington’s disease to the cognitive
deficits that accompany this disease. This was accomplished
by examining the relationship of D1, D2 and DAT densities

Fig. 1 Relationship between DAT in putamen and Tower of
Hanoi (completion time) in patients with Huntington’s disease
(closed squares) and control subjects (open squares).
Fig. 2 Relationship between frontal volume and Trail Making,
part B (completion time) in patients with Huntington’s disease
(closed squares) and control subjects (open squares).
as well as measurements of structural brain volumes (Ginovart
et al., 1997) to cognitive performance in Huntington’s disease
patients and control subjects.
The cognitive data indicated Huntington’s disease-related
impairments across all domains assessed (i.e. executive
function, visuospatial skill, episodic memory, verbal fluency,
perceptual speed and reasoning). In fact, with the exception
of word recall, all cognitive measures showed statistically
reliable differences between Huntington’s disease patients and
control subjects. However, for word recall, the performance
advantage of the control subjects did not approach
conventional significance. This pattern of results, indicating
a rather global cognitive deficit in mild to moderate stages
of Huntington’s disease, is in agreement with prior research
(for reviews, see Brandt and Butters, 1986; Brown and
Marsden, 1988).
PET and cognition in Huntington’s disease 2213
There were several intriguing relationships between the
neurotransmitter and brain volume measures and cognitive
performance. The D1, D2 and DAT data for both caudate and
putamen showed strong relationships to all cognitive tasks,
except word recall and perseverations in the WCST. Similar
relationships were seen between the morphological data for
the striatal structures and cognitive performance, although
there was no association with the TMT in these analyses.
Note that the order of entering the dopamine binding
parameters and the volume data determined which type of
biological index would show a relationship to cognitive
performance. Specifically, when the dopaminergic markers
were entered first in the regressions, the volume data made no
additional contribution to the cognitive variation. Conversely,
when the volume data were entered first, D1, D2 and DAT
did not add any explanatory variance. This pattern of results
indicates that both the neurotransmitter and volume data may
serve as markers of the pathophysiological process that
underlies impaired cognitive functioning in Huntington’s
disease.
Furthermore, the volume of the frontal cortex was strongly
related to performance in all 11 cognitive tasks, whereas
temporal volume and D1 in temporal cortex were related to
performance in four tasks only: Tower of Hanoi, Picture
Arrangement, TMT-A and TMT-B. As with the analysis of
the striatal data, order of entry determined, for the temporal
cortex, which type of index that would show a reliable
relationship with cognitive performance. Finally, thalamic
volume was associated with performance in four tasks:
R-OCF-copy, R-OCF-memory, verbal fluency and Tower
of Hanoi.
The overall pattern of results indicates that the
dopaminergic markers as well as the brain volume data were
related to performance in the majority of cognitive tasks
employed. Among the biological indices, measures of frontal
volume and dopamine binding in the striatum showed the
strongest and most consistent relationships with cognitive
performance. It is arguable that the cognitive deficits shown
by the current Huntington’s disease patients are largely
attributable to striatal and frontal lesions, given that these
patients exhibited marked reductions in dopamine binding in
the striatum as well as frontal volume (Ginovart et al., 1997).
Thus, the present results are consistent with the view that
Huntington’s disease may be characterized as a frontostriatal
dementia (Robbins et al., 1994; Lawrence et al., 1996).
Whereas the observed relationships between striatal and
frontal volumes and cognitive impairment in Huntington’s
disease replicate prior research (Shoulson et al., 1982; Sax
et al., 1983; Starkstein et al., 1988, 1992; Bamford et al.,
1989; Brandt et al., 1995), the associations between the
dopamine neurotransmission parameters and cognitive
performance constitute novel findings.
Although the cognitive data pattern may reflect
Huntington’s disease-related lesions at several levels of the
frontostriatal circuitry (Lawrence et al., 1996), stepwise
regression analyses, which controlled for colinearity among
2214 L. Bäckman et al.
predictor variables, showed that some relationships between
the biological and cognitive variables were stronger than
others. In particular, DAT in putamen emerged as the most
powerful predictor in Digit Symbol, Block Design, Picture
Arrangement, Tower of Hanoi, verbal fluency and TMT-A,
whereas frontal volume showed the strongest relationship
with R-OCF-memory, word recall, TMT-B, and perseverative
errors from the WCST. To the extent that the striatum plays
a critical role in fast cognitive performance (Cummings,
1986; Brown and Marsden, 1988; Almkvist et al., 1992;
Crosson, 1992), it is noteworthy that the rate at which
information could be processed or retrieved is extremely
important in all tasks that were predicted by the DAT
putamen variable.
Of further interest is that both lesion studies (Moscovitch,
1982; Schacter, 1987; Incisa della Rochetta and Milner, 1993;
Wheeler et al., 1995) and PET activation research with
normal subjects (Squire et al., 1992; Shallice et al., 1994;
Tulving et al., 1994; Rugg et al., 1996) indicate a strong
frontal involvement in the encoding and subsequent retrieval
of information from episodic memory, as assessed in, for
example, word recall and R-OCF-memory. Similarly, there
is evidence that proficient executive functioning, as assessed
in tasks such as the WCST and TMT-B, draws on the integrity
of the frontal cortex (Milner, 1963; Weinberger et al., 1986;
Janowsky et al., 1989; Segalowitz et al., 1992; Tranel et al.,
1994; Nagahama et al., 1996). Although these specific
relationships may be theoretically plausible, we would like
to caution that (i) the overall pattern of results indicated a
relationship between most biological and cognitive variables,
and (ii) the sample sizes used to infer these relationships
were relatively small. Thus, at present, the safest conclusion
is that the current data reflect a general influence of an
impaired frontostriatal system on the cognitive deficits that
accompany Huntington’s disease. The fact that the present
results suggest that lesions at multiple sites in the cortico-
striato-thalamocortical circuitry (i.e. caudate, putamen, frontal
cortex and thalamus) may be associated with Huntington’s
disease-related cognitive impairment should be highlighted.
Finally, it should be noted that the strong relationships
between the biological and cognitive variables were largely
due to marked group differences for both sets of variables.
Unfortunately, the relatively small sample sizes made within-
group regressions less meaningful. However, an interesting
observation was that, for many cognitive tasks, relationships
were seen also within groups. This pattern was especially
pronounced in the patients, possibly due to the generally
greater variability for both the biological and cognitive
variables in this group (see Figs 1 and 2). These findings
may suggest a disease-related as well as a general association
between the neurotransmitter parameters and brain volumes,
on the one hand, and cognitive performance, on the other.
Evidence for a relationship between volume measurements
of various cortical and subcortical structures and performance
on intelligence tests has been reported in healthy adults
(Andreasen et al., 1993). Future research should substantiate
the current findings both with regard to Huntington’s disease-
related effects and potential general effects.
Acknowledgements
We wish to thank the staff of the PET centre at the Karolinska
hospital for their assistance. This research was supported
by grants from the National Institute of Mental Health
(MH41205–8) and the Swedish Medical Research Council
(09114) to L.F., the NHR Foundation and Gadelius
Minnesfond to A.L., and the Swedish Council for Research
in the Humanities and the Social Sciences (F 67/95) to L.B.
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Received May 22, 1997. Accepted July 21, 1997