Neuropsychology of Cortical versus

Subcortical Dementia Syndromes

David P. Salmon, Ph.D.,1 and J. Vincent Filoteo, Ph.D.2

ABSTRACT

Neuropsychological studies have shown that there are several prominent differ-
ences in the patterns of cognitive deficits that occur in neurodegenerative disorders that
have their primary etiology in either cortical or subcortical brain dysfunction. Quantitative

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and qualitative differences are apparent across many cognitive domains, including memory
(in all its aspects), attention, executive functions, language and semantic knowledge, and
visuospatial abilities. These distinct patterns of deficits have been broadly characterized as
forming cortical and subcortical dementia syndromes. Differentiating between cortical and
subcortical dementia provides a heuristically useful model for understanding brain-
behavior relationships in neurodegenerative diseases and may improve the ability to
clinically distinguish among various dementing disorders.

KEYWORDS: Dementia, Alzheimer’s disease, Huntington’s disease, cognition,

memory

N europsychological research that has taken a AD is a prevalent disorder that produces a

comparative approach to the study of various dementing
disorders has shown that etiologically and neuropatho-
logically distinct neurodegenerative diseases engender
different patterns of relatively preserved and impaired
cognitive abilities. This has been most clearly shown
through the comparison of dementia syndromes associ-
ated with neurodegenerative diseases that primarily in-
volve regions of the cerebral cortex (e.g., Alzheimer’s
disease [AD], frontotemporal dementia) and those that
have their primary locus in subcortical brain structures
(e.g., Huntington’s disease [HD], Parkinson’s disease
[PD], progressive supranuclear palsy). Although it is
well known that pathological changes in these various
disorders are not limited to either cortical or subcortical
brain regions, the cortical-subcortical dementia distinc-
tion serves as a heuristically useful model for describing
the pattern of neuropsychological deficits that are ob-
served in these patient groups.
‘‘cortical’’ dementia syndrome through its effects on
limbic and neocortical brain structures. The disease is
characterized by neuronal atrophy, synapse loss, and the
abnormal accumulation of diffuse and neuritic plaques
and neurofibrillary tangles. These pathological changes
begin primarily in medial temporal lobe limbic struc-
tures (e.g., entorhinal cortex, hippocampus) and then
progress to the association cortices of the frontal,
temporal, and parietal lobes.1 Primary motor and sen-
sory cortices and most subcortical structures are rela-
tively spared. Degeneration in the basal forebrain (e.g.,
the nucleus basalis of Meynert) results in a major
decrement in neocortical and hippocampal levels of
the neurotransmitter acetylcholine.2 Consistent with
these widespread neuropathologic changes, the primary
clinical manifestation of AD is a progressive global
dementia syndrome characterized by prominent amne-
sia with additional deficits in language and semantic

1
Department of Neurosciences, University of California, San Diego;
2
Department of Psychiatry, University of California, San Diego, and
Psychology Service, San Diego Veterans Affairs Medical Center, La
Jolla, California.
Address for correspondence and reprint requests: David P. Salmon,
Ph.D., Department of Neurosciences (0948), University of California,
San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0948.
Dementia; Guest Editor, Jody Corey-Bloom, M.D., Ph.D.
Semin Neurol 2007;27:7–21. Copyright # 2007 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2006-956751. ISSN 0271-8235.
7
8 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 1 2007
knowledge (i.e., aphasia), abstract reasoning, ‘‘execu-
tive’’ functions, attention, and constructional and vi-
suospatial abilities.3
HD and PD are neurodegenerative diseases that
produce a ‘‘subcortical’’ dementia syndrome through
their effects on basal ganglia and brain stem structures.
HD is an inherited, autosomal-dominant disease that
results in the development of movement disorder (e.g.,
chorea, dysarthria, gait disturbance, oculomotor dys-
function), behavior and personality changes (e.g., de-
pression, irritability, and anxiety), and dementia due to
progressive deterioration of the neostriatum (caudate
nucleus and putamen).4–6 PD is characterized by a loss
of pigmented cells in the substantia nigra pars compacta
(resulting in a major depletion of dopamine) and the
presence of Lewy bodies (abnormal intracytoplasmic
eosinophilic neuronal inclusion bodies) in the substantia
nigra, locus ceruleus, dorsal motor nucleus of the vagus,
and the substantia innominata.7–9 Most brains of pa-
tients with PD also have Lewy bodies in the neocortex.10
PD is clinically identified by the classic motor-symptom
triad of resting tremor, rigidity, and bradykinesia, with
associated symptoms such as postural stooping, gait
disturbances (shuffling gait), masked facies, microgra-
phia, hypophonia, dysarthria, and poor prosody (mono-
toned speech).11 PD is also associated with cognitive
decline, and a recent systematic review suggests that 24
to 31% are demented.12 The cognitive dysfunction
associated with PD, HD, and other subcortical neuro-
degenerative diseases may be a consequence of damage to
so-called ‘‘frontostriatal loops’’ that are circuits consist-
ing of projections from the frontal neocortex to the
striatum, striatum to the globus pallidus, globus pallidus
to thalamus, and thalamus back to specific neocortical
regions of the frontal lobes (e.g., dorsolateral prefrontal,
orbitofrontal, and anterior cingulate cortex).13 These
circuits are believed to provide a subcortical influence
on both motor control and higher cognitive functions,
and damage to specific aspects of the circuits may explain
subtle differences in the nature of the cognitive impair-
ment manifested in various neurodegenerative diseases
that produce a subcortical dementia syndrome.13
The distinction that has been drawn between
cortical and subcortical dementia syndromes arose from
clinical observations14–16 that revealed that patients with
subcortical neurodegenerative diseases usually exhibited,
in addition to their motor disorder, slowness of thought,
impaired attention, a deficiency in planning, visuoper-
ceptual and constructional deficits, and personality
changes such as depression and apathy. They often had
only mild or moderate memory and language disturban-
ces that were quantitatively and qualitatively different
from those of patients with cortical/limbic neurodege-
nerative diseases such as AD. These clinical observations
have been confirmed by extensive neuropsychological
research that will be discussed in detail below.
The present review will focus, for the most part,
upon studies that have directly compared patients with
AD to those with HD or PD. Direct comparisons using
the same test measures with both groups ensures that any
observed differences are due to the nature of the under-
lying pathology rather than to differences in study
procedures. Most of the studies reviewed also attempt
to match the patient groups for other factors that could
potentially influence test performance, such as amount of
education and overall level or stage of global dementia.
This latter factor can be difficult to judge because of
inherent differences in the cognitive dysfunction asso-
ciated with different disorders but can be estimated with
brief mental status examinations, global dementia stag-
ing systems, or characteristics such as estimated duration
of illness. Another factor that must be considered when
comparing cognitive performance across disorders is the
difference in the usual age of onset for each disease. AD
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usually begins in later life (e.g., ages 60 to 70), whereas
HD usually begins in midlife (e.g., ages 30 to 40).
Because performance on many neuropsychological tests
declines with age, comparisons of AD and HD patients
must account for this factor through the use of age-
appropriate control groups, age-corrected normative
data, or statistical age corrections. With these caveats
in mind, differences in the nature of the cognitive
deficits that characterize the cortical and subcortical
dementia syndromes will be described. Differences in
learning and memory, attention, working memory and
executive functions, language and semantic knowledge,
and visuospatial abilities will be examined in turn.
LEARNING AND MEMORY
A deficit in learning and memory is a hallmark of the
dementia syndrome, but the nature and severity of the
deficit depends upon the distribution of neuropathologic
changes engendered by the underlying disease. This is
evident in neuropsychological studies that have com-
pared and contrasted various aspects of memory per-
formance in patients with cortical and subcortical
dementia syndromes. These studies have shown that
the processes that underlie performance on tests of
episodic memory, remote memory, and implicit memory
are differentially affected in the two dementia syn-
dromes. As described below, these findings are theoret-
ically valuable in providing information about the
specific brain structures or systems that mediate various
forms of memory and are clinically useful in improving
the differential diagnosis of various neurodegenerative
diseases.
Episodic Memory
Episodic memory refers to the storage and recollection of
temporally dated autobiographical events that depend
 NEUROPSYCHOLOGY OF CORTICAL VERSUS SUBCORTICAL DEMENTIA SYNDROMES/SALMON, FILOTEO 9

upon temporal and/or spatial contextual cues for their
retrieval. Examples of episodic memory include the
ability to recall our activities from the previous day and
the ability to remember a list of words presented 10
minutes earlier. A severe deficit in episodic memory (i.e.,
anterograde amnesia) is characteristic of the cortical
dementia syndrome of AD and has been attributed to
ineffective consolidation (i.e., storage) of new informa-
tion.17 Patients with the subcortical dementia syndrome
of HD, in contrast, exhibit mild to moderate memory
impairment that appears to result from a general deficit
in the ability to initiate and carry out the systematic
retrieval of successfully stored information.18–20 This
distinction in the episodic memory deficits associated
with the two disorders was illustrated in a study by Delis
and colleagues21 that directly compared the perform-
ances of patients with AD and patients with HD on a
rigorous test of verbal learning and memory, the Cal-
HD and AD patients could be distinguished by two
major differences in their performances. First, patients
with AD were just as impaired on the recognition trial as
they were on the immediate and delayed free recall trials,
whereas patients with HD were less impaired on the
recognition trial than on the various free recall trials. The
significant improvement shown by the HD patients
when memory was tested with a recognition procedure
has been observed in several additional studies18,19 (but
see Brandt et al22) and suggests that when the need for
effortful, strategic retrieval is reduced, the memory
impairment exhibited by these patients is greatly atte-
nuated (Fig. 1).
The second major difference observed by Delis and
colleagues was that patients with AD exhibited signifi-
cantly faster forgetting of information over the 20-minute
delay interval than did the patients with HD (also see
Butters et al23 and Troster et al24). Although patients

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ifornia Verbal Learning Test (CVLT). The CVLT is a
standardized memory test that assesses rate of learning,
retention after short- and long-delay intervals, semantic
encoding ability, recognition memory, intrusion and
perseverative errors, and response biases. In the test, a
list of 16 shopping items (four items in each of four
categories) is presented verbally on five consecutive
presentation/free recall trials. A single interference trial
with a different list of 16 items is then presented in the
same manner. Immediately after this interference trial,
free recall and then cued recall of the first list of shopping
items is assessed. Twenty minutes later, free recall and
then cued recall is again assessed, followed by a yes-no
recognition test that consists of the 16 items on the first
shopping list and 28 distractor items.
The results of this study showed that despite
comparable immediate and delayed free and cued recall
deficits (based on age-corrected normative data), the
with HD retained 70% of the initially acquired infor-
mation over the delay interval, patients with AD retained
less than 20%. This pattern of performance is consistent
with the notion that information is not effectively con-
solidated and rapidly dissipates in patients with the
cortical-limbic damage that occurs in AD. In patients
with the frontal-subcortical damage of HD, information
appears to be successfully stored but cannot be effectively
retrieved either immediately or after a delay.
Although the episodic memory deficits in cortical
and subcortical dementia syndromes are broadly differ-
ent, there is evidence that the distinction is more or less
clear depending upon the neurodegenerative disease
underlying the subcortical dementia syndrome. Massman
and colleagues25 showed that the CVLT performances of
patients with HD and PD were quite similar with a
pattern indicative of a prominent retrieval deficit (e.g.,
both had mildly deficient encoding, normal retention

Figure 1 The mean age-corrected z-scores achieved by patients with Alzheimer’s disease (AD) and Huntington’s disease (HD) on the
20-minute delayed recall and delayed recognition (i.e., discriminability) measures from the California Verbal Learning Test. The pattern of
performance for AD (recognition  recall) suggests an encoding/storage deficit, whereas the pattern for HD (recognition > recall)
suggests a retrieval deficit. (Adapted from Delis et al,21 with permission from the American Psychological Association.)
10 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 1 2007
over a delay, difficulty initiating systematic retrieval
strategies) but that the two patient groups differed in
the salience of this pattern. In general, patients with HD
had a more severe free recall deficit and showed a greater
improvement on recognition testing compared with free
recall than patients with PD. Zizak and colleagues26
recently extended these findings in a study that classified
the CVLT performances of patients with HD or PD as
demonstrating or not demonstrating a retrieval deficit
profile (i.e., significantly higher standardized scores on
CVLT recognition indices compared with free recall
indices). The results showed that a clear retrieval deficit
profile was more prevalent in patients with HD than
those with PD but only occurred in 44% of the HD
patients. In addition, the profile tended to occur in those
patients who had at least a mild to moderate level of
global dementia. Several studies have shown that the
memory performance of patients with PD can be quite
variable and difficult to classify. Filoteo and colleagues27
found that 25% of nondemented PD patients produced
a CVLT memory profile indicative of a retrieval deficit
(i.e., a subcortical dementia profile), 25% produced a
profile indicative of a deficit in encoding and storage
(i.e., a cortical dementia profile), and the remaining 50%
had no memory impairment (for similar results, see
Weintraub et al28). The lack of a retrieval deficit in the
memory performance of patients with PD has been
reported by others,29 primarily due to a high rate of
false-positive errors on recognition tests, an occurrence
not usually seen in patients with HD.
Remote Memory
A deficit in the ability to remember remote events that
were successfully remembered prior to a brain injury or
the onset of a neurological disease is known as retrograde
amnesia. This form of memory impairment often occurs
following circumscribed damage to medial temporal
lobe30 or diencephalic31 brain structures and can extend
years or decades into the past. The retrograde amnesia
associated with damage to the medial temporal-dience-
phalic memory system often follows a temporal gradient
in which information from the distant past is less
affected than information from the more recent past.
This temporal gradient has been attributed to disruption
of a long-term consolidation process,32,33 which has
been characterized by some investigators as shifting a
memory from a hippocampally mediated episodic form
to a cortically mediated semantic form.34–37 When
circumscribed hippocampal-diencephalic damage oc-
curs, there is a relative preservation of the older, more
cortically instantiated memories (but see Nadel and
Moscovitch38 for a hippocampally mediated explanation
of the temporal gradient in retrograde amnesia).
Some degree of retrograde amnesia occurs after the
onset of most neurodegenerative diseases that produce
dementia,39,40 but dissociable patterns of impairment are
associated with cortical and subcortical dementia syn-
dromes.39,41–47 On the one hand, mildly demented pa-
tients with AD often exhibit a severe and temporally
graded retrograde amnesia with memories from the dis-
tant past better retained than memories from the more
recent past.39,44,46,48 The temporal gradient is similar to
the pattern of loss exhibited by patients with circum-
scribed amnesia and has been attributed to the interrup-
tion of a long-term consolidation process that is critically
dependent upon the hippocampal-diencephalic memory
system. The interpretation of the temporal gradient of
retrograde amnesia in patients with AD is somewhat
clouded by the insidious nature of the anterograde mem-
ory deficit associated with the disease. It may be the case
that information from the most recent decade (or deca-
des) just prior to the diagnosis of AD was not learned as
well as more remote information because of a ‘‘preclinical’’
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anterograde memory impairment that often occurs before
the development of the full dementia syndrome; however,
this account is less likely to explain the discrepancy
between the AD patients’ retrograde amnesia for infor-
mation from early versus middle life epochs. The very
severe retrograde amnesia exhibited by patients with AD
for information from the most remote time periods may
result from a combination of the episodic and semantic
memory deficits that they suffer (for review, see Sal-
mon17). In AD, the temporal gradient related to the loss
of remote episodic memory is superimposed upon a
general semantic memory deficit that arises from damage
to cortical association areas (see section on language and
semantic knowledge). This semantic memory loss reduces
the amount of information available from all time peri-
ods, providing a low baseline level of performance on
which to observe the temporal gradient.
On the other hand, patients with subcortical
dysfunction due to HD,39,43 PD,42,46 multiple sclero-
sis,49 or HIV-associated dementia47 exhibit a relatively
mild retrograde amnesia that equally affects all time
periods (Fig. 2). Presumably, episodic memory that
was acquired in the past is successfully stored and
retained over time by these patients but retrieval of this
information is generally deficient, causing the remote
memory deficit to be equally distributed across decades.
This interpretation is bolstered by an analysis of cued
retrieval in a remote memory task, which indicated a
preferential cueing benefit for patients with HD or
HIV-associated dementia compared with patients with
AD.47 As described in the previous section, such a
retrieval deficit has been attributed to the frontostriatal
dysfunction that characterizes those disorders.
Implicit Memory
Although memory is usually thought of as a conscious
process in which an individual explicitly attempts to
 NEUROPSYCHOLOGY OF CORTICAL VERSUS SUBCORTICAL DEMENTIA SYNDROMES/SALMON, FILOTEO 11

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Figure 2 The mean percentage of correct responses on the Remote Memory battery as a function of life epoch (left panel). Patients
with Alzheimer’s disease exhibit a severe and temporally graded retrograde amnesia (RA), whereas patients with Huntington’s disease
or HIV dementia exhibit a mild RA that is equally severe across life epochs. The temporally graded nature of the RA of patients with
Alzheimer’s disease is more evident when the number of correct responses from each life epoch is shown as a proportion of all correct
responses (right panel). (Adapted from Sadek et al,47 with permission from the American Psychological Association.)

learn, remember, and retrieve a specific bit of informa-
tion, there are some forms of memory that can occur
implicitly without conscious awareness.50 This implicit
memory is demonstrated through facilitation of per-
formance due simply to prior exposure to the stimuli
or procedures of a given task. For example, an individ-
ual’s ability to detect a stimulus (or to identify it in a
degraded form) might be enhanced upon its second
presentation (i.e., priming), or they may show a gradual
improvement in the performance of some motor or
cognitive act with practice (i.e., motor or cognitive skill
learning). There is considerable evidence that implicit
memory is generally preserved in patients with circum-
scribed amnesia, indicating that it is not dependent upon
the hippocampal-diencephalic memory system that is
damaged in these disorders.31 The neurological basis of
implicit memory remains largely unknown; however,
studies suggest that some forms of implicit memory are
dependent upon the frontal-subcortical circuits that are
damaged in patients with HD and PD although others
may be dependent upon the activation of neocortical
association areas damaged in AD. Dissociations in the
performance of patients with cortical or subcortical
dementia syndromes on various types of implicit priming
and motor and cognitive skill learning tasks have been
noted, as described below, and may shed some light on
the neural bases of these forms of memory.
PRIMING
Several studies have shown that implicit priming is
differentially affected in cortical and subcortical demen-
tia syndromes. Shimamura and colleagues51 directly
compared the performances of patients with AD and
HD on a word-stem completion priming test previously
used by Graf and colleagues.52 In this task, subjects were
shown 10 words (e.g., motel, abstain) one at a time and
were asked to rate how much they liked each word on a
5-point scale. Following these presentation trials, the
subjects were shown 20 three-letter word stems (e.g.,
mot, abs) and were asked to complete each stem with the
first word that came to mind. Ten of the stems could be
completed using study words, and the other 10 stems
were used to assess baseline guessing rates (i.e., complet-
ing stems with target words that were not previously
presented). Despite pronounced explicit memory defi-
cits, patients with HD and patients with circumscribed
amnesia (i.e., alcoholic Korsakoff’s syndrome) displayed
significant priming by completing a greater proportion
of stems with previously presented words than with
nonpresented words. Furthermore, the magnitude of
their priming was the same as that of normal control
subjects. Patients with AD exhibited impaired priming
on this task, with little tendency to complete the word
stems with the previously presented words.
This word-stem completion priming deficit in
AD has been replicated in several subsequent stud-
ies,53–60 and the disparate pattern of impaired priming
in patients with AD and preserved priming in patients
with HD has been generalized to several other priming
paradigms, including semantic paired-associate pri-
ming53 and priming to enhance the identification of
fragmented pictures.61 Word-stem completion priming
has also been shown to be normal in nondemented
patients with PD54,57 but impaired in PD patients who
are demented.54 From a neurobiological perspective,
these studies indicate that priming is not dependent
12 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 1 2007
upon the hippocampal-diencephalic structures damaged
in patients with circumscribed amnesia or the frontal-
subcortical circuits that are damaged in HD and early
PD. Rather, this aspect of implicit memory may be
mediated by the neocortical association cortex that is
damaged in AD (and that may be compromised by
cortical Lewy bodies in PD) or from a deficiency in
the level of steady-state cortical activation that could
arise from damage to the ascending noradrenergic pro-
jection system (i.e., the locus coeruleus)62 that may be
damaged in AD and PD (see Salmon and Heindel63).
MOTOR AND COGNITIVE SKILL LEARNING
The ability to learn and retain a motor or cognitive skill
with repeated practice is another form of implicit memory
that is differentially affected in cortical and subcortical
syndromes. This was initially illustrated in a study that
directly compared the gradual development of the pursuit
rotor motor skill in patients with AD, HD, or circum-
scribed amnesia. In the pursuit rotor task, individuals
learned over repeated 20-second trials to maintain con-
tact between a handheld stylus and a small metallic disk
that rotated on a turntable.64 Patients with AD and
amnesic patients demonstrated rapid and extensive motor
learning across trials that was equivalent to that of normal
control subjects (other studies have shown similar re-
sults54,65–67). Patients with HD, in contrast, were im-
paired in learning the motor skills underlying pursuit
rotor task performance (for similar results, see Gabrieli
et al68). Heindel and colleagues64 postulated that the
neostriatal damage suffered by HD patients leads to a
deficiency in developing motor programs, which forces
them to rely on an error-correction mode of performance
rather than the more effective predictive mode of per-
formance utilized by AD patients, amnesic patients, and
normal control subjects. Importantly, the normal learning
exhibited by the patients with AD or circumscribed
amnesia show that this form of memory is not dependent
upon the hippocampal memory system necessary for
episodic memory or the neocortical association areas
that are thought to underlie priming.
Several subsequent studies using a variety of tasks
have replicated this pattern of impaired motor skill
learning in patients with HD and preserved motor skill
learning in mildly demented patients with AD. In one
study, patients with HD, but not those with AD, were
impaired in developing adaptation-mediated biasing in
a weight judgment task that required them to judge a
standard set of weights following exposure to either a
relatively heavy (heavy bias) or a relatively light (light
bias) set of weights.69 Because perceptual biasing of
weight involves the modification of programmed move-
ment parameters (i.e., motor programs; see Jones70), they
judged the standard weights the same way at all times,
and patients with AD, like normal control subjects,
perceived the standard weights as heavier following the
light bias trials and lighter following the heavy bias trials.
In another study,71 patients with HD, but not those with
AD, were impaired on a perceptual adaptation task that
required them to learn to point to a target while wearing
distorting prisms that shifted the perceived location of
objects 20 degrees to the right or left. Patients with HD
appeared unable to learn new central motor programs
through visual feedback on the accuracy of intended
movements. In a series of studies, patients with HD72,73
or PD74,75 were impaired in implicitly learning a repeat-
ing 10-item sequence of responses in a serial reaction
time task that required them to respond as quickly as
possible to the illumination of one of four lights, each
located immediately above a corresponding response
key.76 Patients with AD or circumscribed amnesia ex-
hibited a normal rate of learning the response sequence
(as evidenced by a gradual decline in response latency),
despite an inability to explicitly recall the sequence76–78
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(but see Ferraro et al74). The results of these studies
suggest that the frontal-subcortical circuits damaged in
disorders that produce a subcortical dementia syndrome
play a primary role in implicit learning of skilled motor
behavior.73
The subcortical dementia syndrome is also char-
acterized by a deficit in the acquisition and maintenance
of cognitive and perceptual skills. Several studies have
shown that patients with HD are impaired in implicitly
acquiring the visuoperceptual skill of reading mirror-
reversed text79 or the cognitive skill necessary to solve
complex problems such as the Tower of Hanoi puz-
zle.18,80 Other studies showed that similar deficits were
not apparent in patients with AD58,81–83 or circum-
scribed amnesia (for review, see Squire32).
Patients with HD and PD have also been shown
to be impaired in implicitly learning the cognitive skills
necessary to perform a probabilistic classification
task.84,85 In this task, subjects must classify stimulus
patterns as being associated with one of two outcomes
that occur equally often. The stimulus patterns are
composed of four stimuli, which are independently and
probabilistically related to the two outcomes (i.e., cor-
rectly predicted one of the outcomes 25, 43, 57 or 75% of
the time). The probabilistic structure of the task dis-
courages attempts to explicitly learn the relationship
between the stimuli and outcomes but allows implicit
learning of these relationships to take place. Although
patients with circumscribed amnesia were able to learn
the probabilistic relationship as well as normal control
subjects, nondemented patients with PD and patients
with HD were impaired in learning the probabilistic
relationship between the stimuli and outcomes even
though they had normal recall of the training episodes.
Interestingly, patients with AD showed normal learning
on this task,86 although performance was related to the
degree of subcortical integrity as measured by magnetic
resonance spectroscopy.
 NEUROPSYCHOLOGY OF CORTICAL VERSUS SUBCORTICAL DEMENTIA SYNDROMES/SALMON, FILOTEO
The studies by Knowlton and colleagues84,85 were
among the first to implicate subcortical structures (par-
ticularly the striatum) in implicit category learning. Sub-
sequent studies have attempted to determine if there are
distinct types of category learning that might be differ-
entially mediated by the striatum. One such distinction
has been made between rule-based category learning
(e.g., learning that a line stimulus is in one category if
it is long and another category if it is short) and
information-integration category learning (e.g., learning
that a line stimulus is in a particular category based upon
integrated information from two or more stimulus com-
ponents like length and orientation). In a series of studies,
patients with HD were shown to be impaired in both
rule-based and information-integration category learn-
ing,87 although nondemented patients with PD were
impaired only in information-integration category learn-
ing.88 Because of concern that the particular stimulus
conditions used in their information-integration category
learning task may have inadvertently allowed the use of a
rule-based learning processes,89 Filoteo and colleagues90
reevaluated nondimensional category learning using both
a simple linear integration condition (as in the previous
study) and a complex nonlinear integration condition that
had been shown to elicit striatal activation in healthy
subjects.91 Patients with PD exhibited normal categori-
zation learning in the linear condition but were impaired
in the nonlinear condition, and model-based analyses
indicated that most patients used an information-inte-
gration approach to learning the linear and nonlinear
categorization rules. Similar deficits in nonlinear category
rule learning occur in patients with HD87 but do not
occur in patients with circumscribed amnesia.92 The
deficit in learning the nonlinear categorization rule ex-
hibited by the patients with PD or HD suggests that the
striatum may be particularly important for implicitly
learning complex rules.
Attention, Working Memory, and Executive
Functions
Although deficits in attention, working memory, and
executive functions occur in both cortical and subcort-
ical dementia syndromes, they play a more prominent
role in defining the latter syndrome. A deficit in
attention, for example, is an early and prominent
feature of cognitive decline in patients with HD or
PD,93–95 but it is not a particularly salient feature of
early AD.96 This discrepancy is apparent in studies that
directly compared the performance of patients with HD
or AD on the attention items of the Mini-Mental State
Exam,97 the attention subscale of the Mattis Dementia
Rating Scale,98 or the Wechsler Memory Scale-Revised
Attention/Concentration Index, which entails tests of
digit span, visual memory span, and mental control.23,99
In these latter studies, patients with HD were impaired
13
on the Attention/Concentration Index and scored sig-
nificantly worse than equally demented patients with
AD. This was true in both early and more advanced
stages of the diseases.
Specific aspects of attentional processing are dif-
ferentially affected in cortical and subcortical dementia
syndromes. Lange and colleagues100 and Lawrence and
associates101 showed that patients with AD and mildly
demented patients with HD were able to effectively shift
attention between stimulus dimensions in a visual dis-
crimination task in which first one stimulus dimension
(e.g., color) and then another (e.g., shape) was reinforced
as correct. Moderately to severely demented patients
with HD, in contrast, were impaired in maintaining
the proper response set and persisted in returning to a
previously correct response strategy when attention
should have shifted. A deficit in shifting or allocating
attention has been observed in other studies of patients
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with HD100–103 and appears to be particularly evident
when attentional shifts must be internally regulated.104
A similar deficit in maintaining response set and shifting
attention across stimulus dimensions has been observed
in patients with PD105 or progressive supranuclear
palsy,106 whereas patients with AD and patients with
circumscribed frontal lobe lesions can maintain attention
but not effectively disengage from a previous set.105,107
Cortical and subcortical dementia syndromes also
differ in the nature and severity of the working memory
deficits they comprise. Working memory refers to a
limited capacity memory system in which information
that is the immediate focus of attention can be tempo-
rarily held in limited capacity language-based (i.e., the
phonological loop) or visual-based (i.e., the visuospatial
scratchpad) buffers while being manipulated through a
primary central executive system.108 The central executive
system is critically responsible for strategic aspects of
memory that facilitate the encoding and retrieval of
information in long-term memory. The subcortical de-
mentia syndrome of patients with HD or PD is charac-
terized by early deficits in all aspects of working memory,
including the maintenance of information in the tempo-
rary memory buffers (e.g., as evidenced by poor digit span
performance), inhibition of irrelevant information, and
the use of strategic aspects of memory (e.g., planning,
organization) to enhance free recall.93,100,101,109–114 The
cortical dementia syndrome of AD, in contrast, is initially
characterized by relatively mild working memory deficits
that primarily involve disruption to the central executive
with sparing of the phonological loop and visuospatial
scratchpad.115,116 It is not until later stages of AD that all
aspects of the working memory system become compro-
mised115,116 as they are in the early stages of most
subcortical dementia disorders.
The prominent deficits in attention and working
memory associated with the subcortical dementia syn-
drome are accompanied by impairment of various
14 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 1 2007
‘‘executive’’ functions involved in planning and problem
solving. These include deficits in goal-directed behav-
ior, the ability to generate multiple response alterna-
tives, the capacity to resist distraction and maintain
response set, and the cognitive flexibility to evaluate
and modify behavior (reviewed in various stud-
ies6,117,118). Deficits in these abilities are apparent on
a variety of tests that require executive functioning such
as the Wisconsin Card Sorting Test,119–122 the Stroop
Test,119,122,123 the Tower of London test,100 the Gam-
bling Decision Making task,124 and tests of verbal
concept formation.103 These deficits are not unique to
subcortical dementia, however, as extensive executive
dysfunction is also characteristic of the cortical demen-
tia syndrome of AD (for review, see Perry and
Hodges125). It may be the case that specific aspects of
executive dysfunction are more common in one syn-
drome than another, but there are few studies that have
directly compared this aspect of cognition in the two
disorders.
Language and Semantic Knowledge
A major distinction between cortical and subcortical
dementia syndromes is the prominence of language
and semantic knowledge (e.g., general knowledge of
facts, concepts, and the meanings of words) deficits in
cortical disorders such as AD and the virtual absence of
these deficits in subcortical disorders such as HD and
PD. Patients with AD are noted for mild anomia, word-
finding difficulties in spontaneous speech, and a decline
in the general structure and organization of semantic
knowledge. In contrast, patients with HD and other
forms of subcortical dementia are often dysarthric with a
slow and reduced speech output,126,127 but the semantic
knowledge that underlies their language abilities appears
to be relatively preserved.
These differences in the language and semantic
memory abilities of patients with AD and HD were
shown in a series of studies of verbal fluency that directly
compared their performances on letter fluency tasks that
required them to generate as quickly as possible (for 60
seconds) words that begin with the letters F, A, or S, and
category fluency tasks that required them to generate as
quickly as possible (for 60 seconds) exemplars from a
designated semantic category (e.g., animals, fruits, or
vegetables).128,129 Patients with HD were severely and
equivalently impaired on both types of fluency tasks,
whereas patients with AD were more impaired on the
category fluency task than on the letter fluency task.
Indeed, in the study by Butters and colleagues,128 the
AD patients exhibited a significant category fluency
deficit even though their performance on the letter
fluency task was not significantly different from that of
normal control subjects. The unique patterns of letter
and category fluency performance observed in these
studies have been replicated several times and confirmed
in several meta-analytic studies.130,131 The pattern of
performance of PD patients across types of fluency tasks
is less clear, although a meta-analytic study suggests that
these patients have slightly greater deficit on category
than letter fluency tasks.132
The results of these studies support the notion
that qualitatively different processes underlie the verbal
fluency deficits of AD and HD patients. The fact that
patients with AD are more impaired on the fluency task
that places greater demands on the integrity of semantic
memory suggests that they have a loss of semantic
knowledge or a breakdown in the organization of
semantic memory, rather than a general inability to
retrieve or access semantic knowledge. A loss of knowl-
edge of the attributes, exemplars, and organization that
define a particular semantic category is thought to reduce
the ability of patients with AD to efficiently generate
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words from a small and highly related set of exemplars.
The equivalent deficit that patients with HD exhibit on
the two fluency tasks suggests that their impairment
reflects a general retrieval deficit that is not influenced by
the demands the various tasks place on semantic mem-
ory. This interpretation of the disparate patterns is
supported by a series of studies that examined the
temporal dynamics of retrieval from semantic memory
during the letter and category fluency tasks.133,134 Ac-
cording to well-known random search models,135 if the
set size for a particular semantic category is reduced due
to a loss of semantic knowledge, mean latency should
decrease and be lower than normal. If, on the other hand,
the semantic set size remains intact but retrieval is
slowed, mean latency should increase and be higher
than normal. The results of these studies showed that
patients with AD exhibited a lower than normal mean
latency consistent with the notion that they suffer a loss
of semantic knowledge. Patients with HD, in contrast,
exhibited a higher than normal mean response latency,
which is consistent with the view that damage to frontal-
subcortical circuits results in a disruption of retrieval
processes.
Differences in the language abilities of patients
with cortical and subcortical dementia syndromes are
apparent on tests of confrontation naming. Numerous
studies have shown that patients with AD have a
significant naming impairment136–138 that is not shared
by patients with HD.6,139 Direct comparisons have
shown that patients with AD are significantly worse
than patients with HD on confrontation naming tasks
and that the two groups produce distinct patterns of
naming errors.139 Patients with AD make a greater
proportion of semantically based errors (e.g., superordi-
nate errors such as calling a ‘‘camel’’ an ‘‘animal’’) than
patients with HD, whereas patients with HD make a
greater proportion of perceptually based errors (e.g.,
calling a ‘‘pretzel’’ a ‘‘snake’’) than patients with AD.139
 NEUROPSYCHOLOGY OF CORTICAL VERSUS SUBCORTICAL DEMENTIA SYNDROMES/SALMON, FILOTEO
The tendency of patients with AD to make semantically
based errors is consistent with a disruption of the
structure and organization of semantic knowledge that
may arise from damage to cortical association areas in the
temporal, parietal, and frontal lobes.
Chan and colleagues directly compared the
structure and organization of semantic knowledge in
cortical and subcortical dementia syndromes using
cluster analysis and multidimensional scaling techni-
ques to statistically model a spatial representation of the
degree of association between concepts in semantic
memory (for reviews, see Chan et al140 and Salmon
and Chan141). The degree of association between the
various exemplars in the category ‘‘animals’’ was esti-
mated from their proximate position when generated in
a verbal fluency task or from the frequency with which
they were paired in a triadic comparison task. The
modeling showed that the network of semantic associ-
ations (i.e., the semantic network) for patients with HD
was virtually identical to that of control subjects,
whereas the semantic network of patients with AD
was abnormal in several ways. First, AD patients
focused primarily on concrete perceptual information
(i.e., size) in categorizing animals, whereas control
subjects stressed abstract conceptual knowledge (i.e.,
domesticity). Second, animals that were highly associ-
ated and clustered together for control subjects (e.g., cat
and dog) were not strongly associated for patients with
AD. Third, AD patients were less consistent than
control subjects in utilizing the various attributes of
animals in categorization (e.g., consistently considering
dog a domestic animal). These results provide further
evidence that the cortical dementia syndrome of AD is
characterized by a loss of semantic knowledge and
semantic organization that does not occur in the sub-
cortical dementia syndrome exhibited by patients with
HD.
VISUOSPATIAL ABILITIES
Although visuospatial deficits are characteristic of both
the cortical and subcortical dementia syndrome, few
studies have directly compared the two conditions to
determine if there are qualitative differences in the
processes affected. Visuospatial abilities are often ad-
versely affected early in the course of HD and decline
as the disease progresses.122,142–146 Patients with HD
have been shown to be impaired compared with age-
matched controls on many different tests of visuospa-
tial function such as the Block Design subtest of the
Wechsler Adult Intelligence Scale-Revised,147,148 the
Clock Drawing Test,144 and tests of the ability to
follow a visual ‘‘map.’’143,149 Patients with AD have
also been shown to be impaired on these and many
other visuospatial tasks (for review, see Cronin-Go-
lomb and Amick150), but relatively little is known
15
about the specific components of visuospatial process-
ing that might be differentially affected in the two
disorders.
In one of the few studies to directly compare
patients with AD and patients with HD on visuospatial
tasks, Brouwers and colleagues143 found that patients
with AD, but not those with HD, were impaired on tests
of visuoconstructional ability that required extrapersonal
orientation (e.g., copying a complex figure), whereas
patients with HD, but not those with AD, were im-
paired on visuospatial task that required personal ori-
entation (e.g., the Money Road Map Test). Thus, the
distinct pattern of deficits produced by the two groups
was interpreted as a dissociation between personal and
extrapersonal spatial orientation abilities in cortical and
subcortical dementia syndromes.
This interpretation of the visuospatial deficits
exhibited by patients with AD and patients with HD
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was supported by the results of a recent study that
examined their ability to mentally rotate representations
of objects.151 In this task, subjects were asked to simply
press a key on the side in which a stick figure held a
target ‘‘ball’’ when the figure was in the fully upright
position. The stick figures were presented in various
orientations away from the vertical, with the notion that
the subject would have to mentally rotate the figure to
make an accurate judgment concerning the side of the
target. The further the target was from vertical, the
longer the mental rotation should take. By examining
the change in response time as a function of the degree of
rotation that was required, the speed of mental rotation
could be inferred. The results showed that patients with
HD were significantly slower than normal control sub-
jects in performing the mental rotation but were as
accurate as the control subjects in making the rotation
and reporting the correct side of the target. Patients with
AD, in contrast, performed the mental rotation as
quickly as the control subjects, but were significantly
impaired in making an accurate rotation and reporting
the correct side of the target. These results suggest that
HD patients can perform mental rotation of visual
representations accurately but suffer a general brady-
phrenia (i.e., slowed thinking) that parallels the brady-
kinesia that characterizes the disorder. The impaired
ability of AD patients to perform mental rotation may
reflect a deficit in extrapersonal visual orientation sec-
ondary to neocortical damage in brain regions thought to
be involved in processing visual motion (e.g., the middle
temporal gyrus).
A recent study by Festa and colleagues152 com-
pared the performances of patients with AD and patients
with HD on a visual sensory integration task that
required subjects to detect the direction of coherently
moving dots that could be segmented from randomly
moving distractor dots by color (red versus green) or by
luminance (light gray versus dark gray). Patients with
16 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 1 2007
HD were as effective as normal control subjects in
integrating motion and color or motion and luminance
information to enhance their ability to detect the direc-
tion of motion above baseline levels of performance (i.e.,
when color or luminance did not segment coherently
moving dots). Patients with AD effectively used lumi-
nance information to enhance their motion detection, but
they were impaired in their ability to use color informa-
tion in the same way (Fig. 3). This deficit was interpreted
as an impaired ability to bind motion and color informa-
tion that is processed in distinct cortical visual systems
(the dorsal visual processing stream for motion informa-
tion, the ventral visual processing stream for color in-
formation) because the cortical pathology in AD leads to
the loss of effective interaction between distinct neo-
cortical areas.153 The ability to integrate motion and
luminance information was not affected in the same
way, presumably because both types of information are
processed within the dorsal visual processing stream.
At least one study has directly compared visuo-
constructional deficits in cortical and subcortical demen-
tia syndromes by examining the ability of patients with
AD and patients with HD to draw to command and to
copy clocks.154 In the command condition, patients were
asked to ‘‘draw a clock, put in all the numbers, and set the
hands to 10 past 11.’’ In the copy condition, they were
asked to copy a drawing of a clock. Both patient groups
were impaired on both conditions of this task, but
patients with AD were significantly worse in the com-
mand condition than in the copy condition and patients
with HD were equally impaired in both. A qualitative
analysis of the types of errors produced also revealed a
difference between the patient groups. Patients with HD
Figure 3 The mean color-motion integration index scores
achieved by normal control (NC) subjects, patients with Alzhei-
mer’s disease (AD), and patients with Huntington’s disease (HD)
on a visual sensory integration task. The color-motion integration
index reflects the gain in motion direction detection derived from
using color information that segments coherently moving targets
from distractors. Patients with (AD), but not those with (HD), are
significantly (*) impaired in integrating motion and color informa-
tion. (Adapted from Festa et al,152 with permission from the
American Psychological Association.)
tended to make graphic, visuospatial, and planning
errors in both the command and copy conditions,
whereas patients with AD tended to make conceptual
errors (e.g., misrepresenting the clock by drawing a face
without numbers or with an incorrect use of numbers;
misrepresenting the time by failing to include the hands;
incorrectly using the hands; or writing the time in the
clock face) in the command condition but not in the copy
condition. These disparate patterns of deficits are
thought to reflect distinct processing deficits in the
cortical and subcortical dementia syndromes. The defi-
cits exhibited by patients with HD appear to be a
manifestation of the planning and motor deficits that
accompany disruption of frontal-subcortical circuits,
whereas those of patients with AD seem to reflect a
deficit in accessing knowledge of the attributes, features,
and meaning of a clock.
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SUMMARY AND CONCLUSIONS
There are several prominent differences in the patterns
of cognitive deficits that occur in neurodegenerative
disorders that have their primary etiology in either
cortical or subcortical brain dysfunction. Both quantita-
tive and qualitative differences are apparent across many
cognitive domains including memory (in all of its
aspects), attention, working memory, executive func-
tions, language and semantic knowledge, and visuospa-
tial abilities. Future research on the distinction between
cortical and subcortical dementia is needed to address
several questions. First, are distinct cognitive profiles
apparent in the earliest stages of the various diseases
before the full manifestation of dementia? Second, will
neuroimaging studies in cognitively normal individuals
provide converging evidence for the respective roles of
specific cortical and subcortical brain circuits in media-
ting the cognitive processes that are differentially af-
fected in cortical and subcortical dementia syndromes?
Third, are there reliable differences in the cognitive
profiles associated with various subcortical disorders
(i.e., HD versus PD) that would help to explain the
heterogeneity observed within the subcortical dementia
syndrome? As the answers to these and other questions
provide knowledge of the processes underlying the
cognitive deficits associated with different neurodege-
nerative disorders, a better understanding of the neuro-
logical substrates of cognition will emerge, and the
ability to clinically distinguish among disorders should
improve.
ACKNOWLEDGMENTS
The preparation of this article was supported, in part, by
funds from NIA grants AG-05131 and AG-12963 to
the University of California, San Diego, and NINDS
grant NS-41372 to the Veterans Medical Research
 NEUROPSYCHOLOGY OF CORTICAL VERSUS SUBCORTICAL DEMENTIA SYNDROMES/SALMON, FILOTEO
Foundation, San Diego. The authors have no conflicts to
disclose.
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