Handbook of Clinical Neurology, Vol.

100 (3rd series)

Hyperkinetic Movement Disorders
W.J. Weiner and E. Tolosa, Editors
# 2011 Elsevier B.V. All rights reserved

Chapter 2

Huntington’s disease
KAREN E. ANDERSON*
Movement Disorders Division, Department of Neurology, School of Medicine, University of Maryland,
Baltimore, MD, USA

INTRODUCTION GENETICS AND DISEASE MECHANISM

Huntington’s disease (HD) is an autosomal-dominant
neurodegenerative disorder caused by the abnormal
expansion of a nucleic acid triplet repeat. Chorea
and dystonia are the most prominent neurological fea-
tures. Cognitive impairments and psychiatric symp-
toms are present in virtually all HD patients. These
behavioral symptoms are often more challenging than
the movement disorder, increasing caregiver burden.
Treatment is available for many problematic beha-
viors, and can positively impact patient and caregiver
quality of life.
EPIDEMIOLOGY
Prevalence of HD is estimated at approximately 5 per
100 000; it is less common among those of non-Euro-
pean ancestry (Hayden et al., 1980; Folstein et al.,
1987). Diagnosis is most often made in the third or
fourth decade of life, but onset may occur from
childhood through the eighth decade (Folstein, 1989;
Gilstad and Reich, 2003). With the availability of
genetic testing, the diagnosis of HD is now made
more frequently in those who have onset of chorea
in their 60s or even 70s without a known family his-
tory of HD. Previously, these patients with later-onset
chorea would often have been told they had “senile”
or “benign” chorea in the absence of a family history.
Late-onset HD may be confused with Parkinson’s dis-
ease, hydrocephalus, or other neurodegenerative con-
ditions in the absence of a known family history of
HD (Reuter et al., 2000; Caserta and Sullivan, 2009).
The genetic abnormality underlying HD is caused by
an abnormal expansion of trinucleotide repeats coding
for glutamine at the N-terminus of the huntingtin pro-
tein. The increase occurs in sequences of cytosine, ade-
nine, and guanine (CAG) in exon 1 of the HD gene,
located on chromosome 4. The gene is expressed
throughout the body (Strong et al., 1993). The normal
function of huntingtin is unknown. Excitotoxicity,
mitochondrial dysfunction, and dysregulation of gene
expression have all been suggested as pathological
mechanisms (Difiglia, 1990; Beal, 1992; Nucifora et al.,
2001). The HD gene is transmitted in an autosomal-
dominant pattern of inheritance; each child of an
affected individual has a 50% chance of inheriting the
gene. Normal individuals have 9–29 CAG repeats. Those
who develop clinically apparent symptoms of HD have a
higher repeat number, usually 39 or over. Expansions
and, rarely, contractions, in CAG repeat number in
successive generations occur, and should also be
addressed in counseling (Wheeler et al., 2007; Nahhas
et al., 2009). The CAG repeat number is inversely corre-
lated with age of symptom onset.
Genetic counseling at a certified testing program is
recommended by the Huntington’s Disease Society of
America (HDSA) for those seeking presymptomatic at-
risk testing for the HD gene. The HDSA advises against
testing for the HD gene in minors. Adverse outcomes,
such as severe depression and suicide attempts, have
occurred following genetic testing. Concerns about genetic
discrimination due to HD family history are also important
to address during counseling (Bombard et al., 2009).

*Correspondence to: Karen E. Anderson, M.D., Assistant Professor, Psychiatry & Neurology, Department of Neurology, Move-
ment Disorders Division, University of Maryland, School of Medicine, Baltimore, MD 21201, USA. Tel: 410 328-7810, Fax: 410
328-0167, E-mail: kanderson@psych.umaryland.edu
16 K.E. ANDERSON
The distinctive neuropathological change in HD is the
decline in the number of medium spiny striatal neurons.
The first neuropathological change in HD is in the asso-
ciative areas of the striatum (Vonsattel and Difiglia,
1998; Middleton and Strick, 2000). Caudate changes
predominate, but cell death also occurs in the globus
pallidus. As the disease advances, widespread atrophy
occurs (Vonsattel et al., 1985; Hedreen et al., 1991).
BRAIN IMAGING FINDINGS
More advanced basal ganglia atrophy correlates
positively with longer CAG repeat length in magnetic res-
onance imaging studies (Harris et al., 1992; Aylward et al.,
1997; Rosas et al., 2001). Generalized atrophy occurs
(Aylward et al., 1998). Cortical thinning and volume
reductions in other regions are present even in early stages
of HD (Rosas et al., 2002, 2003, 2008).
Striatal neuropathology is evident on structural
imaging before a clinical diagnosis can be made. The
PREDICT-HD study seeks to identify markers of HD
in individuals who have undergone predictive genetic
testing, are gene-positive, but have not been given a
clinical diagnosis of HD. In this premanifest popula-
tion, subtle motor signs were associated with a higher
probability of HD diagnosis and smaller striatal
volumes (Aylward et al., 2000; Biglan et al., 2009).
Functional studies show caudate and putamenal hypo-
metabolism, along with some frontal metabolic reduc-
tions that correlate with decline in function (Kuhl et al.,
1982; Young et al., 1986; Berent et al., 1988; Bartenstein
et al., 1997). Positron emission tomography studies of
dopamine function have found both striatal and cortical
receptor abnormalities (Bäckman et al., 1997; Pavese
et al., 2003). Longitudinal diffusion tensor imaging
studies show that a significant reduction of fractional
anisotropy, a measure of white-matter integrity, between
baseline and follow-up was evident throughout the brain.
In addition, a diffusion tensor imaging indicator of axon
stability showed significant longitudinal decreases in HD
subjects. These results suggest there is white-matter
degeneration in HD, and support the concept that axonal
injury may occur in HD. Such changes may serve as
future biomarkers in HD (Weaver et al., 2009).
NEUROLOGICAL SYMPTOMS
Abnormal involuntary movements (chorea and dystonia)
and impairment of gait, saccades, smooth pursuit, dysar-
thria, and swallowing are seen in all patients. These symp-
toms progress over 10–15 years, leading to severe
disability and death. Chorea, the involuntary writhing,
nonstereotyped, nonrepetitive movement that is the hall-
mark of the disease, typically worsens in the middle
stages of the illness and then decreases as the patient
becomes more debilitated, bradykinetic, and rigid. Dysto-
nia worsens as the disease progresses. Late-onset disease
is characterized by a slower course. Older patients are
sometimes misdiagnosed with a parkinsonian syndrome
(Reuter et al., 2000). Patients with juvenile-onset HD,
whose symptoms began prior to age 20, have a distinctly
different clinical picture. Parkinsonism is their predomi-
nant neurological feature, often accompanied by seizures
and myoclonus. Chorea is minimal, making diagnosis
challenging in cases lacking a family history, e.g., adop-
tions or mistaken paternity. Psychiatric and cognitive
changes may be the most prominent features, further
obscuring the diagnosis (Ribaı̈ et al., 2007). Deterioration
of function in juvenile-onset cases is rapid compared with
adult-onset disease. Although juvenile cases are usually
attributed to CAG expansions greater than 60 repeats,
there are reported cases of juvenile-onset HD in indivi-
duals with lower numbers of repeats (Ribaı̈ et al., 2007).
Dysphagia and dysarthria are two common problems
in HD. Communication becomes severely impaired in
advanced stages, compounding patient and caregiver frus-
tration. Dysphagia and choking are common in HD and
worsen as the disease progresses. Impulsivity and cogni-
tive impairment often add to this problem, with patients
stuffing more food into their mouths than they are reason-
ably able to swallow or forgetting to cut food into small
pieces if they are not supervised. Kagel and Leopold
(1992) studied dysphagia in HD and found many abnorm-
alities, including swallow incoordination, repetitive swal-
lows, prolonged laryngeal elevation, inability to stop
respiration, coughing on foods, and choking on liquids.
Videofluoroscopic swallowing studies confirmed the
abnormalities, and identified aspiration. Another study
found increased solid food dsyphagia in people with HD
(Trejo et al., 2004). Lanska et al. (1988) found choking
to be commonly associated with death in HD. Speech
and swallowing evaluation and treatment are helpful in
managing these symptoms (Bonelli et al., 2004).
COGNITIVE SYMPTOMS
Cognitive deficits are prominent symptoms of HD.
Impairment of attention, visuospatial processing, and
memory occur early. HD patients also exhibit deficits
in executive function on tests requiring planning,
problem solving, and cognitive flexibility, even in early
disease. Decline in cognitive ability relates to the num-
ber of years the patient has been affected by HD and,
even more closely, to the severity of motor symptoms,
particularly deficits in voluntary movement (Brandt
et al., 1984; Jason et al., 1997; Klempı́r et al., 2009).
Due to the varying definitions of “dementia,” it is not
surprising that research on the prevalence of dementia
in HD is varied. Dementia prevalence is reported at rates
 HUNTINGTON’S DISEASE 17
of 15–95% (Heathfield, 1967; Oliver, 1970). Other work show specific impairment in person-centered spatial
states that 90% of patients with HD develop dementia judgment. For example, people with HD (but not Parkin-
over the course of the illness (Gontkovsky, 1998). This son’s disease) experience difficulty with map reading and
wide variability is also undoubtedly due to differing popu- typically misjudge distances and the relationship of their
lations and cognitive assessments. At least in the early body to walls and other potential obstacles.
stages, HD dementia does not fit the standard Diagnostic
and Statistical Manual IV definition of dementia as a syn- EXECUTIVE MEMORY DEFICITS
drome of acquired intellectual impairment, with memory
Among the most consistently reported cognitive impair-
impairment and an additional cognitive impairment
ments in HD are deficits in executive memory function
(aphasia, apraxia, agnosia, or deficits in executive func-
(Josiassen et al., 1983; Brandt, 1991; Pillon et al., 1991;
tioning; American Psychiatric Association, 1994).
Lange et al., 1995). This domain encompasses perfor-
Since cognitive changes in HD are gradual, any acute
mance in many crucial areas including reasoning,
change in cognition or overall mental status should
planning, judgment, decision-making, attention, learning,
warrant a search for neurological compromise. Due to
memory, flexibility, and timing. Impairment in executive
generalized brain atrophy, which can begin relatively
memory has wide-ranging implications not only on cogni-
early in the condition, clinicians should have a low
tive assessments, but also on practical functions in
threshold for obtaining brain imaging to rule out a sub-
everyday life.
dural hematoma or other intracranial injury after even
HD patients demonstrate impairment on various
mild head trauma if there is a change in mental status.
standard executive function tests, including the Wis-
Cognitive dysfunction is already present in some
consin Card Sorting Test, the Stroop Color Word Test,
individuals who carry the HD gene expansion but do
and the Tower of London (Paulsen et al., 1996a;
not show neurological signs or symptoms. Neuropsy-
Savage, 1997; Watkins et al., 2000). In fact, brief tests
chological testing of these people shows gradual
of executive function have shown utility as tools for
decline in cognitive function, although not all cases
differential diagnosis. For example, the Serial Sevens
follow a steady path of functional loss (Snowden
item on the Mini-Mental Status Exam, and an abbre-
et al., 2003). The insidious nature of the changes adds
viated battery of frontal lobe tests have been demon-
to the difficulty in distinguishing cognitive symptoms
strated to be sensitive to HD cognitive deficits
from the types of deficits any individual may show
(Rothlind and Brandt, 1993; Paulsen et al., 1995). The
if fatigued, depressed, or anxious. Questions about
Montreal Cognitive Assessment, another brief test with
possible early cognitive changes can lead to heightened
an emphasis on executive function, has also been
anxiety in those at risk for HD and should be
found to be sensitive to HD-related cognitive change
addressed during evaluation.
(Nasreddine et al., 2005; Mickes et al., 2008).
Simulated gambling paradigms have shown that HD
Visuospatial deficits patients consistently make fewer advantageous choices
than healthy controls or patients with Parkinson’s
Deficits in the ability to copy simple geometric designs,
disease, even when level of cognitive impairment is
to copy block designs, and put together puzzles are
similar across disease populations (Stout et al., 2001).
evident in HD. Some of these problems reflect motor
Several HD patients indicated that one or more of the
symptoms, but performance is also impaired on
card decks were “bad” but continued to make selections
untimed perceptual tasks that do not depend on motor
from the identified “bad” decks. Deficits on tasks
skills. Visuospatial performance deficits may be some
requiring decision-making may be due to various
of the earliest cognitive changes seen in HD (Josiassen
cognitive impairments, including learning, attention,
et al., 1983; Hodges et al., 1990; Pillon et al., 1991).
inhibition, or diminished appreciation for consequences.
Memory deficits in HD include slowed rates of
HD patients may be less able to learn from feedback
learning and impaired recall (Weingartner et al., 1979;
and to modulate future responses based on prior experi-
Butters, 1984), which improves with cuing (Butters
ence. The impact of these impairments in daily life is
et al., 1988; Massman et al., 1990; Pillon et al., 1991).
far-ranging and severe.
Impairment has been reported in the perception of per-
sonal space (Potegal, 1971). Mohr et al. (1991) examined
ATTENTION AND WORKING MEMORY
whether visuospatial deficits in basal ganglia disease are
a nonspecific function of dementia severity. Findings The initial studies of cognition in HD consistently
suggested that general visuospatial processing capacity found the most severe performance deficits on
is impaired as a nonspecific effect of cognitive decline assessments of attention and working memory, such
in both HD and Parkinson’s disease; only HD patients as Digit Span (Boll et al., 1974; Josiassen et al., 1983;
18 K.E. ANDERSON
Strauss and Brandt, 1986). More recent studies have
emphasized dysfunction in unique aspects of atten-
tion, including resource allocation, set shifting, and
vigilance (Hanes et al., 1995; Lange et al., 1995; Lawr-
ence et al., 1996). Sprengelmeyer et al. (1995) reported
that HD patients are able to maintain alertness with
external direction, but fail when internal monitoring
is required. HD patients perseverate on prior
responses and demonstrate difficulty in revising
information regarding task rules during performance
(Lange et al., 1995). Thompson and others (2010) sug-
gest the attentional deficits in HD lead to poor ability
to automate daily tasks, resulting in decreased
efficiency.
Learning and memory deficits
Even early HD patients show verbal learning deficits
on sensitive tests (Hamilton, 1998). The deficit is one
of encoding and retrieval, because recognition memory
is often preserved (Butters et al., 1986; Delis et al.,
1991). HD patients perform near normal when a less
challenging memory assessment is used, such as offer-
ing choices of, or recognizing, items. Recognition
memory may not be preserved in moderate to
advanced disease (Kramer et al., 1988; Lang et al.,
2000). Retention is relatively normal in HD as distinct
from “cortical dementias” such as Alzheimer’s disease
(Butters et al., 1988; Massman et al., 1990; Delis et al.,
1991). HD patients demonstrate no temporal gradient
in memory performance; memory performance is
mildly impaired for all periods of their lives (Butters
and Albert, 1982).
Skill learning is dependent upon normal function of
the basal ganglia. Sequence skill learning deficits may
be due to working memory limitations. Paulsen et al.
(1993) reported that skill learning was only impaired
when external immediate feedback was unavailable.
Willingham and his colleagues (1996) showed intact
skill learning when visual feedback was available to
HD patients, but showed defective skill learning when
patients were required to learn without immediate
feedback.
Cognitive deficits prior to diagnosis
In the earliest stages of HD, memory deficits, visuo-
spatial skill decline, and an attention disorder often
lead to changes in performance at work or in the home.
Performance deficits on neuropsychological testing are
seen in carriers of the HD CAG expansion before a
clinical diagnosis can be made (Langbehn et al.,
2007). Further complicating the picture, cognitive
domains are not affected in a uniform fashion in
preclinical and early HD (Snowden et al., 2002).
PSYCHIATRIC SYMPTOMS
Psychiatric symptoms may occur at any point in HD,
including prior to the onset of motor abnormalities (Duff
et al., 2007). Depression is commonly reported as a pro-
dromal symptom. Subtle personality changes have also
been reported prior to neurological diagnosis, although
many of these studies are problematic since data were
retrospective. Changes reported include impulsivity, emo-
tional lability, and lack of empathy for others (Brothers
and Meadows, 1955; Heathfield, 1967; Dewhurst et al.,
1969; Lishman, 1998). Overall prevalence of psychiatric
symptoms in HD has been reported from 30% to over
70% (van Duijn et al., 2007). Craufurd and colleagues
(2001) found that loss of energy and initiative, poor perse-
verance and quality of work, impaired judgment, poor
self-care, and emotional blunting were all reported with
high frequency by HD patients. A study of outpatients
using careful evaluation with standard measures and
information from caregivers found that 98% of HD
patients had at least one psychiatric symptom, demon-
strating that as more information becomes available and
evaluations are conducted, most patients are likely to
have some behavioral disturbances (Paulsen et al., 2001).
Virtually all psychiatric symptoms described in the gen-
eral population may be seen in persons with HD, although
some appear to be more particular to the illness.
Unlike the somewhat predictable progression of
motor and cognitive symptoms, no generalized pattern
for psychiatric disease has been demonstrated. Apathy
is the one exception; it may worsen as the illness
progresses (Levy et al., 1998; Paulsen et al., 2001;
Thompson et al., 2002). CAG repeat length has not been
shown to correlate positively with presence or severity
of psychiatric symptoms (Zappacosta et al., 1996;
Berrios et al., 2001; Vassos et al., 2008). Severe psychi-
atric symptoms are one of the main factors in the
decision to institutionalize a patient (Wheelock et al.,
2003). Since they are often amenable to treatment with
standard psychopharmacological agents, providing
relief from these symptoms can impact greatly on qual-
ity of life for both patients and caregivers.
Irritability and aggression
Irritability and, at times, accompanying agitation in
HD patients is commonly observed and can be a source
of significant disability to patients and troublesome to
their caregivers. Uncontrolled irritability can poten-
tially increase the likelihood of nursing home place-
ment. Irritability is defined as a deficit in filtering
environmental stimuli combined with a faulty inhibi-
tory capacity, leading to impulsive and exaggerated
reactions to common situations. It is reported in 40–
80% of patients (Paulsen et al., 1996b, 2001; Murgod
 HUNTINGTON’S DISEASE
et al., 2001; van Duijn et al., 2007). Aggression, when it
occurs in HD, usually accompanies irritability. Aggres-
sive behavior in HD ranges from threatening verbal
outbursts to property damage and physical harm to
others. A study of 960 patients found that over 60%
of patients or caregivers reported aggressive patient
behavior (Marder et al., 2000). Chatterjee et al. (2005)
found that patients report a lower level of irritability
than that in proxy reports by caregivers. The discrep-
ancy suggests impairment of patient insight with
respect to this symptom. A retrospective study found
over a third of HD patients in nursing homes were
aggressive (Nance and Sanders, 1996). Irritability and
hostility measures have been shown to be significantly
elevated in those who are presymptomatic but known
to carry the HD expansion, compared to those who
are at risk but do not have the expansion (Berrios
et al., 2002; Kirkwood et al., 2002; Vassos et al., 2007). from 3% to 7% have been reported. Over 25% of patients
Behavioral techniques, such as adherence to a
schedule to minimize the unexpected, may be helpful
(Moskowitz and Marder, 2001). Education of care-
givers in how to identify and avoid situations that trig- HD were twice that in the general population and 10% of
ger irritability, and how to minimize its effects if it
does occur, is extremely important. Combined with
the impulsivity seen in HD, irritability can quickly esca- to those in the general population: depression, access to
late into physical aggression with minimal or no provo-
cation. Evaluation to rule out medical illness, delirium, divorce or termination from a job), and being unmarried.
medication toxicity, or physical discomfort should be
conducted in patients whose communication may be
impaired or when a behavioral change is particularly
uncharacteristic. Irritability and aggression both
respond to pharmacotherapy in many cases, sometimes
in combination with behavioral interventions. If medi-
cations are used to control these behaviors the lowest
effective dose should be administered. Exceptions
may occur in patients who are particularly aggressive;
individual patients may require high doses of medica-
tion to control these behavioral problems.
Apathy
Apathy, which is decreased motivation, is common in
HD. Those with mild apathy may not initiate novel
activities but participate in them if engaged; for
patients with severe apathy, even routine activities
require prompting. Up to half of all patients had apa-
thy in various studies (Pflanz et al., 1991; Craufurd
et al., 2001; Paulsen et al., 2001). It has been shown
to increase with duration of illness (Caine and
Shoulson, 1983; Levy et al., 1998; Thompson et al.,
2002). Apathy is often difficult to differentiate from
depression, especially as the disease progresses and
communication diminishes due to dysarthria or
impaired cognition.
19
Pharmacological interventions are not particularly
helpful for apathy. Structuring daily activities may be
useful, as with irritability and aggression. Education of
family members about differences between apathy and
depression, and how to cope with apathetic individuals,
may be the most useful intervention.
Affective disorders
Changes in mood are quite common in HD. Thirty to
70% of patients report depressed mood (van Duijn
et al., 2007). Depression frequently occurs either with
or following onset of motor abnormalities, arguing
against simple reactive mood changes (Baxter et al.,
1992; Paulsen et al., 2001; Berrios et al., 2002).
Suicide rates in HD are increased fourfold compared
with the general population. Completed suicide rates
attempt suicide at some point in the illness, particularly in
their fifth or sixth decade (Schoenfeld et al., 1984; Farrer,
1986). Paulsen et al. (2005a) found rates of depression in
patients reported at least one past suicide attempt. Risk
factors for suicidal behavior in HD patients are similar
weapons, living alone, childlessness, recent loss (e.g., a
HD patients who express suicidal ideation should be
evaluated immediately, since risk of suicide attempts
and completion is high. Findings by Paulsen and others
(2005b) suggest two critical periods for increased risk
of suicide in HD. The first is immediately before receiv-
ing a formal diagnosis of HD, and the second is when
independence first diminishes.
Increased levels of mood symptoms are seen in
those individuals who choose to undergo genetic test-
ing for HD (Codori et al., 2004). Suicidal ideation
may occur during the genetic testing process in at-risk
persons, regardless of final outcome (Almqvist et al.,
1999; Robins Wahlin et al., 2000). The involvement of
a psychiatrist in the care of those who seek predictive
testing is particularly important, due to these issues
(Scourfield et al., 1997).
The prevalence of mania and hypomania is increased
in HD. From the limited data available, mania appears
to occur in approximately 5% of patients. Including
hypomania, 10% of patients are affected with these
symptoms (Folstein, 1989).
Treatment of mood disorders in HD is particularly
important, given the high rate of suicide. Many
patients will improve greatly with standard doses of
antidepressants. If irritability or psychosis accompanies
the depression, addition of a small dose of an atypical
neuroleptic can be helpful.
20 K.E. ANDERSON
Anxiety disorders
Anxiety disorders have received little study in HD. Older
work describes anxiety as a frequent prodromal symp-
tom (Dewhurst et al., 1969). Newer work demonstrates
anxiety is an issue in manifest disease (Craufurd et al.,
2001). Obsessive and compulsive symptoms occur with
high frequency in HD patients (Marder et al., 2000;
Anderson et al., 2001; Paulsen et al., 2001). Beglinger
and colleagues (2007) found the probability of obsessive
and compulsive symptoms is more than three times
greater by the time a patient shows clearly manifest dis-
ease than in at-risk people with no apparent motor symp-
toms. The same group also reported obsessive worrying
and checking in at-risk individuals, prior to diagnosis
compared to normal controls (Beglinger et al., 2008).
Anxiety disorders usually respond to standard treat-
ment. A selective serotonin reuptake inhibitor (SSRI) is
first-line treatment. The tricyclic clomipramine is par-
ticularly useful in the treatment of obsessive and com-
pulsive symptoms, but often is poorly tolerated due to
side-effects. As in the general population, when antide-
pressants are used, especially SSRIs, higher doses may
be needed to achieve maximal control of these symp-
toms. Augmentation with an atypical neuroleptic may
be helpful in some cases. There have been no studies
of behavior therapy for anxiety in HD. These techni-
ques are highly effective in the general population
for treatment of anxiety disorders.
Psychotic symptoms
Psychotic symptoms are seen in 3–11% of patients (van
Duijn et al., 2007). Psychosis is more prevalent in
patients with younger onset of disease (Paulsen et al.,
2001). Delusions of persecution are probably the most
common psychotic symptoms. Most HD patients with
psychosis do not meet diagnostic criteria for schizophre-
nia (Berrios et al., 2002), although a few HD families
with schizophrenic-like psychosis have been reported
(Tsuang et al., 1998; Corrêa et al., 2006). Delusions
and auditory hallucinations, although rare, are among
the many psychiatric symptoms in HD associated with
nursing home placement (Wheelock et al., 2003).
Psychosis and paranoia in HD respond to standard
pharmacotherapy, usually atypical or typical neurolep-
tics. It is usually preferable to start with an atypical
neuroleptic, due to the more favorable side-effect pro-
file. Standard, high-potency agents such as haloperidol
may be the first choice in patients who are in need
of rapid treatment or would benefit from suppression
of chorea. This is particularly important for patients
who are agitated and psychotic, which is a dangerous
combination that must be treated swiftly, usually with
sedating medications.
TREATMENT
There is no proven treatment to prevent symptom onset
or slow disease progression in people with the HD gene
expansion. Agents such as omega fatty acids and mino-
cycline have been studied following promising work in
animal models, without definitive benefits in human
clinical trials (Huntington Study Group TREND-HD
Investigators, 2008). In a recent Cochrane review, phar-
macological interventions were appraised and none
proved to be effective as a disease-modifying therapy
for HD (Mestre et al., 2009). There are numerous treat-
ment trials in progress or about to begin and the hope
remains that this work will lead to therapies that delay
symptom onset or modify the course of manifest HD
(see Huntington’s Study Group website for ongoing
trials of creatine, coenzyme Q, ACR-16, and other
agents; see Hersch and Rosas, 2008, for recent review
and commentary on neuroprotective trials for HD).
In 2008, tetrabenazine became the first therapy
approved for symptomatic treatment of HD in the USA.
Tetrabenazine selectively depletes central monoamines
by reversibly binding to the type 2 vesicular monoamine
transporter. It has been used in Europe for many years
to treat chorea and other movement disorders, and was
shown to be effective in reducing chorea severity in a ran-
domized clinical trial in the USA (Huntington Study
Group, 2006). Tetrabenazine is not without significant
side-effects, including sedation, akathisia, depressed
mood, and anxiety. It carries a special Food and Drug
Administration “black box” warning in the USA; due to
its mechanism of action, it may exacerbate underlying
psychiatric conditions; its use has been linked to suicidal
behavior and completed suicide (Huntington Study
Group, 2006). It is important to stress to patients and
families that tetrabenazine has not been shown to modify
disease course, but is rather a symptomatic treatment
for reduction of chorea. It is beneficial in a select group
of patients who are functionally or socially impaired
by involuntary movements, and requires expertise in
dosing escalation and monitoring at maintenance
dose. Side-effects, including severe depression, can be
delayed in onset. Individual patient tolerance of side-
effects may decrease as the disease progresses. Since
side-effects of tetrabenazine can mimic HD symptoms
(including worsening psychiatric symptoms, gait and bal-
ance impairment, and sedation), reassessment of treat-
ment benefits and reduction or discontinuation of
medication should be considered periodically.
There are no medications approved for treatment of
cognitive decline in HD. Agents used for treatment of
Alzheimer’s disease and other potential treatments for
HD dementia have not been shown to be useful. A
novel antihistamine, latrepirdine (Dimebon), is being
 HUNTINGTON’S DISEASE
studied by the Huntington Study Group as a possible
therapy for cognitive decline in HD.
Treatment of psychiatric symptoms is extremely
important, and can greatly improve quality of life in
these patients and reduce the burden on their caregivers.
Prior reviews and treatment guidelines have summarized
the limited research on treatment of behavioral symp-
toms in HD (Leroi and Michalon, 1998, Rosenblatt
et al., 1999; Anderson and Marder, 2002). There have
been few clinical trials of agents to treat psychiatric
symptoms, and no medication is approved specifically
for treatment of behavioral symptoms in HD. Clinical
experience suggests using standard psychiatric medica-
tions, sometimes in lower or higher doses than used in
the general population. Anderson and Marder (2002)
outlined suggestions for a stepwise approach to evalua-
tion and treatment of various problematic behaviors.
Many behavioral interventions are extremely useful,
especially in later life, such as adherence to a set sched-
ule, offering limited choices to avoid frustrating the
patient, and walking away rather than engaging in an
argument with a patient (Moskowitz and Marder, 2001).
Other measures to improve quality of life and main-
tain function in HD patients include physical therapy,
speech and swallowing assessment and therapy, dietary
interventions to maintain weight, and modification of
diet to prevent choking. As in all neurodegenerative
illness, maintenance of physical function and indepen-
dence at the highest possible level may impact greatly
on overall quality of life and mental outlook. Support
for families and others involved in a patient’s care is an
important component of treatment. This includes assis-
tance in finding respite care, and providing referrals for
counseling if mental health issues arise in caregivers.
The challenge of treating a hereditary condition means
clinicians must be interested in the well-being of the entire
family, rather than the usual focus on a single patient.
REFERENCES
Almqvist EW, Bloch M, Brinkman R et al. (1999). A world-
wide assessment of the frequency of suicide, suicide
attempts or psychiatric hospitalization after predictive test-
ing for Huntington disease. Am J Hum Genet 64: 1293–1304.
American Psychiatric Association (1994). Diagnostic and
statistical manual of mental disorders (4th ed., text rev.).
Washington, DC.
Anderson KE, Marder KM (2002). Huntington’s Disease. In:
RT Johnson, JW Griffin, JC McArthur (Eds.), Current Ther-
apy in Neurologic Disease. 6th Edn. Mosby, Philadelphia,
USA, pp. 282–287.
Anderson KE, Louis ED, Stern Y et al. (2001). Cognitive
correlates of obsessive and compulsive symptoms in
Huntington’s disease. Am J Psychiatry 158: 799–801.
21
Aylward EH, Li Q, Stine OC et al. (1997). Longitudinal change
in basal ganglia volume in patients with Huntington’s
disease. Neurology 48: 394–399.
Aylward EH, Anderson NB, Bylsma FW et al. (1998). Fron-
tal lobe volume in patients with Huntington’s disease.
Neurology 50: 252–258.
Aylward EH, Codori AM, Rosenblatt A et al. (2000). Rate of
caudate atrophy in presymptomatic and sympto-
matic stages of Huntington’s disease. Mov Disord 15:
552–560.
Bäckman L, Robins-Wahlin TB, Lundin A et al. (1997). Cog-
nitive deficits in Huntington’s disease are predicted by
dopaminergic PET markers and brain volumes. Brain
120 (Pt 12): 2207–2217.
Bartenstein P, Weindl A, Spiegel S et al. (1997). Central
motor processing in Huntington’s disease. A PET study.
Brain 120: 1553–1567.
Baxter LR, Mazziotta JC, Pahl JJ et al. (1992). Psychiatric,
genetic, and positron emission tomographic evaluation
of persons at risk for Huntington’s disease. Arch Gen
Psychiatry 49: 148–152.
Beal MF (1992). Does impairment of energy metabolism
result in excitotoxic neuronal death in neurodegenerative
illnesses? Ann Neurol 31: 119–130.
Beglinger LJ, Langbehn DR, Duff K et al. (2007). Probability
of obsessive and compulsive symptoms in Huntington’s
disease. Biol Psychiatry 61: 415–418.
Beglinger LJ, Paulsen JS, Watson DB et al. (2008). Obsessive
and compulsive symptoms in prediagnosed Huntington’s
disease. J Clin Psychiatry 69: 1758–1765.
Berent S, Giordani B, Lehtinen S et al. (1988). Positron
emission tomographic scan investigations of Hunting-
ton’s disease: cerebral metabolic correlates of cognitive
function. Ann Neurol 23: 541–546.
Berrios GE, Wagle AC, Markova IS et al. (2001). Psychiatric
symptoms and CAG repeats in neurologically asymptom-
atic Huntington’s disease gene carriers. Psychiatry Res
102: 217–225.
Berrios GE, Wagle AC, Markova IS et al. (2002). Psychiatric
symptoms in neurologically asymptomatic Huntington’s
disease gene carriers: a comparison with gene negative at
risk subjects. Acta Psychiatr Scand 105: 224–230.
Biglan KM, Ross CA, Langbehn DR et al. (2009). Motor
abnormalities in premanifest persons with Huntington’s
disease: The PREDICT-HD study. Mov Disord 24 (12):
1763–1772.
Boll TJ, Heaton R, Reitan R (1974). Neuropsychological and
emotional correlates of Huntington’s disease. Journal of
Mental and Nervous Disorders 158: 61–69.
Bombard Y, Veenstra G, Friedman JM et al. (2009). Canadian
Respond-HD Collaborative Group. Perceptions of genetic
discrimination among people at risk for Huntington’s dis-
ease: a cross sectional survey. BMJ 338: b2175.
Bonelli RM, Hofmann P (2004). A review of the treatment
options for Huntington’s disease. Expert Opin Pharmac-
other 5 (4): 767–776.
Brandt J (1991). Cognitive impairments in Huntington’s
disease: insights into the neuropsychology of the striatum.
22 K.E. ANDERSON
In: S Corkin, J Grafman, F Boller (Eds.), Handbook of
Neuropsychology, Vol. 5. Elsevier, Amsterdam.
Brandt J, Strauss ME, Larus J et al. (1984). Clinical corre-
lates of dementia and disability in Huntington’s disease.
J Clin Neuropsychol 6: 401–412.
Brothers CRD, Meadows AW (1955). An investigation
of Huntington’s chorea in Victoria. J Ment Sci 101:
548–563.
Butters N (1984). The clinical aspects of memory disorders:
contributions from experimental studies of amnesia and
dementia. J Clin Neuropsychol 6: 17–36.
Butters N, Albert MS (1982). Processes underlying failures to
recall remote events. In: LS Cermak (Ed.), Human, Mem-
ory, and Amnesia. Erlbaum, Hillsdale, NJ, pp. 257–274.
Butters N, Wolfe J, Granholm E et al. (1986). An assessment
of verbal recall, recognition, and fluency abilities in
patients with Huntington’s disease. Cortex 22: 11–32.
Butters N, Salmon DP, Cullum CM et al. (1988). Differentia-
tion of amnesic and demented patients with the Wechsler
Memory Scale-Revised. Clin Neuropsychol 2: 133–148.
Caine ED, Shoulson I (1983). Psychiatric syndromes in Hun-
tington’s disease. Am J Psychiatry 140: 728–733.
Caserta MT, Sullivan E (2009). Late-onset Huntington’s
disease masquerading as normal pressure hydrocephalus.
J Neuropsychiatry Clin Neurosci 21: 97–98.
Chatterjee A, Anderson KE, Moskowitz CB et al.
(2005). A comparison of self-report and caregiver assess-
ment of depression, apathy, and irritability in Huntington’s
disease. J Neuropsychiatry Clin Neurosci 17: 378–383.
Codori AM, Slavney PR, Rosenblatt A et al. (2004). Preva-
lence of major depression one year after predictive testing
for Huntington’s disease. Genet Test 8: 114–119.
Corrêa BB, Xavier M, Guimarães J (2006). Association of
Huntington’s disease and schizophrenia-like psychosis
in a Huntington’s disease pedigree. Clin Pract Epidemol
Ment Health 2: 1.
Craufurd D, Thompson JC, Snowden JS (2001). Behavioural
changes in Huntington’s disease. Neuropsychiatry
Neuropsychol Behav Neurol 14: 219–226.
Delis DC, Massman PJ, Butters N et al. (1991). Profiles of
demented and amnesic patients on the California Verbal
Learning Test: implications for the assessment of mem-
ory disorders. Psychological Assessment: A Journal of
Consulting and Clinical Psychology 3: 19–26.
Dewhurst K, Oliver J, Trick KLK et al. (1969). Neuro-
psychiatric aspects of Huntington’s disease. Confin Neurol
31: 258–268.
Difiglia M (1990). Excitotoxic injury of the neostriatum is a
model for Huntington’s disease. Trends Neurosci 13:
286–289.
Duff K, Paulsen JS, Beglinger LJ et al. (2007). Psychiatric
symptoms in Huntington’s disease before diagnosis: the
predict-HD study. Biol Psychiatry 62: 1341–1346.
Farrer LA (1986). Suicide and attempted suicide in Hunting-
ton disease: implications for preclinical testing of persons
at risk. Am J Med Genet 24: 305–311.
Folstein SE (1989). Huntington Disease: A Disorder of
Families. The Johns Hopkins Press, Baltimore.
Folstein SE, Chase GA, Wahl WE et al. (1987). Huntington’s
disease in Maryland: clinical aspects of racial variation.
Am J Hum Genet 41: 168–179.
Gilstad J, Reich SG (2003). Chorea in an octogenarian.
Neurologist 9: 165–166.
Gontkovsky ST (1998). Huntington’s disease: a neuropsy-
chological overview. J Cogn Rehab 16: 6–9.
Hamilton JM (1998). Cognitive, motor, and behavioral corre-
lates of functional decline in Huntington’s disease. Clini-
cal Psychology. University of California, San Diego.
p. 58.
Hanes KR, Andrewes DG, Pantelis C (1995). Cognitive
flexibility and complex integration in Parkinson’s
disease, Huntington’s disease, and schizophrenia. J Int
Neuropsychol Soc 1: 545–553.
Harris GJ, Pearlson GD, Peyser CE et al. (1992). Putamen
volume reduction on magnetic resonance imaging
exceeds caudate changes in mild Huntington’s disease.
Ann Neurol 31: 69–75.
Hayden MR, MacGregor JM, Beighton PH (1980). The prev-
alence of Huntington’s chorea in South Africa. S Afr Med
J 2: 193–196.
Heathfield KW (1967). Huntington’s chorea. Investigation
into the prevalence of this disease in the area covered
by the North East Metropolitan Regional Hospital Board.
Brain 90: 203–232.
Hedreen JC, Peyser CE, Folstein SE, Ross CA (1991). Neuro-
nal loss in layers V and VI of cerebral cortex in Hunting-
ton’s disease. Neurosci Lett. 133 (2): 257–261.
Hersch SM, Rosas HD (2008). Neuroprotection for Hunting-
ton’s disease: ready, set, slow. Neurotherapeutics 5:
226–236.
Hodges JR, Salmon DP, Butters N (1990). Differential
impairment of semantic and episodic memory in
Alzheimer’s and Huntington’s diseases: A controlled pro-
spective study. J Neurol Neurosurg Psychiatry 53: 1089–1095.
Huntington Study Group (2006). Tetrabenazine as antichorea
therapy in Huntington disease: a randomized controlled
trial. Neurology 66: 366–372.
Huntington Study Group TREND-HD Investigators (2008).
Randomized controlled trial of ethyl-eicosapentaenoic
acid in Huntington disease: the TREND-HD study. Arch
Neurol 65: 1582–1589.
Jason GW, Suchowersky O, Pajurkova EM et al. (1997).
Cognitive manifestations of Huntington’s disease in rela-
tion to genetic structure and clinical onset. Arch Neurol
54: 1081–1088.
Josiassen RC, Curry LM, Mancall EL (1983). Development
of neuropsychological deficits in Huntington’s disease.
Arch Neurol 40: 791–796.
Kagel MC, Leopold NA (1992). Dysphagia in Huntington’s
disease: a 16-year retrospective. Dysphagia 7 (2): 106–114.
Kirkwood SC, Siemers E, Viken R et al. (2002). Longitudinal
personality changes among presymptomatic Huntington
disease gene carriers. Neuropsychiatry Neuropsychol
Behav Neurol 15: 192–197.
Klempı́r J, Klempı́rová O, Stochl J, Spacková N et al.
(2009). The relationship between impairment of
 HUNTINGTON’S DISEASE
voluntary movements and cognitive impairment in Hun-
tington’s disease. J Neurol. 256 (10): 1629–1633.
Kramer JH, Delis DC, Blusewicz MJ et al. (1988). Verbal
memory errors in Alzheimer’s and Huntington’s demen-
tias. Dev Neuropsychol 4: 1–15.
Kuhl DE, Phelps ME, Markham CH et al. (1982). Cerebral
metabolism and atrophy in Huntington’s disease deter-
mined by 18FDG and computed tomographic scan. Ann
Neurol 12: 425–434.
Langbehn DR, Paulsen JS (2007). Huntington Study Group.
Predictors of diagnosis in Huntington disease. Neurology
68: 1710–1717.
Lang CJG, Majer M, Balan P (2000). Recall and recognition
in Huntington’s disease. Arch Clin Neuropsychology 15:
361–371.
Lange KW, Sahakian BJ, Quinn NP et al. (1995). Compari-
son of executive and visuospatial memory function in
Huntington’s disease and dementia of Alzheimer type
matched for degree of demetia. J Neurol Neurosurg
Psychiatry 58: 598–606.
Lanska DJ, Lanska MJ, Lavine L, Schoenberg BS (1988). Con-
ditions associated with Huntington’s disease at death. A
case-control study. Arch Neurol. 45 (8): 878–880.
Lawrence AD, Sahakian BJ, Hodges JR et al. (1996). Execu-
tive and mnemonic functions in early Huntington’s
disease. Brain 119: 1633–1645.
Leroi I, Michalon M (1998). Treatment of the psychiatric
manifestations of Huntington’s disease: a review of the
literature. Can J Psychiatry 43: 933–940.
Levy ML, Cummings JL, Fairbanks LA et al. (1998). Apathy
is not depression. J Neuropsychiatry Clin Neurosci 10:
314–319.
Lishman AW (1998). Senile dementias, presenile demen-
tias, and pseudodementias. In: AW Lishman (Ed.),
Organic Psychiatry: The Psychological Consequences
of Cerebral Disorder. Blackwell Science, Oxford,
pp. 468–469.
Marder K, Zhao H, Myers RH et al. (2000). Rate of func-
tional decline in Huntington’s disease. Huntington Study
Group. Neurology 54: 452–458.
Massman PJ, Delis DC, Butters N et al. (1990). Are all sub-
cortical dementias alike? Verbal learning and memory in
Parkinson’s and Huntington’s disease patients. J Clin Exp
Neuropsychol 12: 729–744.
Mestre T, Ferreira J, Coelho MM (2009). Therapeutic inter-
ventions for disease progression in Huntington’s disease.
Cochrane Database Syst Rev, 8 (3): CD006455.
Mickes L, Kane A, Jacobson M et al. (2008). A comparison
of two brief cognitive screening instruments in
Huntington Disease (HD). Neurotherapeutics 5: 37–373.
Middleton FA, Strick PL (2000). Basal ganglia and cerebel-
lar loops: motor and cognitive circuits. Brain Res Rev 31:
236–250.
Mohr E, Brouwers P, Claus JJ et al. (1991). Visuospatial cogni-
tion in Huntington’s disease. Mov Disord 6: 127–132.
Moskowitz CB, Marder K (2001). Palliative care for people
with late-stage Huntington’s disease. Neurol Clin 19:
849–865.
23
Murgod UA, Saleem Q, Anand A et al. (2001). A clinical
study of patients with genetically confirmed Huntington’s
disease from India. J Neurol Sci 190: 73–78.
Nahhas F, Garbern J, Feely S et al. (2009). An intergenera-
tional contraction of a fully penetrant Huntington disease
allele to a reduced penetrance allele: interpretation of
results and significance for risk assessment and genetic
counseling. Am J Med Genet A 149A: 732–736.
Nance MA, Sanders G (1996). Characteristics of individuals
with Huntington disease in long-term care. Mov Disord
11: 542–548.
Nasreddine ZS, Phillips NA, Bédirian V et al. (2005). The
Montreal Cognitive Assessment, moca: a brief screening
tool for mild cognitive impairment. J Am Geriatr Soc
53: 695–699.
Nucifora FC Jr., Sasaki M, Peters MF et al. (2001). Interference
by huntingtin and atrophin-1 with cbp-mediated transcrip-
tion leading to cellular toxicity. Science 291: 2423–2428.
Oliver JE (1970). Huntington’s chorea in Northamptonshire.
Br J Psychiatry 116: 241–253.
Paulsen JS, Butters N, Salmon DP et al. (1993). Prism adap-
tation in Alzheimer’s and Huntington’s disease. Neuro-
psychology 7: 73–81.
Paulsen JS, Butters N, Sadek JR et al. (1995). Distinct cogni-
tive profiles of cortical and subcortical dementia in
advanced illness. Neurology 45: 951–956.
Paulsen JS, Stout JC, Delapena J et al. (1996a). Frontal
behavioral syndromes in cortical and subcortical demen-
tia. Assessment 3: 327–337.
Paulsen JS, Como P, Rey G et al. (1996b). The clinical util-
ity of the Stroop test in a multicenter study of Hunting-
ton’s disease. J Int Neuropsychol Soc 2: 35.
Paulsen JS, Ready RE, Hamilton JM et al. (2001). Neuropsy-
chiatric aspects of Huntington’s disease. J Neurol Neuro-
surg Psych 71: 310–314.
Paulsen JS, Nehl C, Hoth KF et al. (2005a). Depression and
stages of Huntington’s disease. J Neuropsychiatry Clin
Neurosci 17: 496–502.
Paulsen JS, Hoth KF, Nehl C et al. (2005b). Critical periods
of suicide risk in Huntington’s disease. Am J Psychiatry
162: 725–731.
Pavese N, Andrews TC, Brooks DJ et al. (2003). Progres-
sive striatal and cortical dopamine receptor dysfunction
in Huntington’s disease: a PET study. Brain 126:
1127–1135.
Pflanz S, Besson JAO, Ebmeier KP et al. (1991). The clinical
manifestation of mental disorder in Huntington’s disease:
a retrospective case record study of disease progression.
Acta Psychiatr Scand 83: 53–60.
Pillon B, Dubois B, Ploska A et al. (1991). Severity and
specificity of cognitive impairment in Alzheimer’s, Hun-
tington’s and Parkinson’s diseases and progressive supra-
nuclear palsy. Neurology 41: 634–643.
Potegal M (1971). A note on spatial motor deficits in patients
with Huntington’s disease: a test of a hypothesis. Neurop-
sychologia 9: 233–235.
Reuter I, Hu MT, Andrews TC et al. (2000). Late onset levo-
dopa responsive Huntington’s disease with minimal chorea
24 K.E. ANDERSON
masquerading as Parkinson plus syndrome. J Neurol Neu-
rosurg Psychiatry. 68 (2): 238–241.
Ribaı̈ P, Nguyen K, Hahn-Barma V et al. (2007). Psychiatric
and cognitive difficulties as indicators of juvenile Hun-
tington disease onset in 29 patients. Arch Neurol
64: 813–819.
Robins Wahlin TB, Bäckman L, Lundin A et al. (2000). High
suicidal ideation in persons testing for Huntington’s dis-
ease. Acta Neurol Scand 102: 150–161.
Rosas HD, Goodman J, Chen YI et al. (2001). Striatal
volume loss in HD as measured by MRI and the influence
of CAG repeat. Neurology 25: 1025–1028.
Rosas HD, Liu AK, Hersch S et al. (2002). Regional and
progressive thinning of the cortical ribbon in Hunting-
ton’s disease. Neurology 58: 695–701.
Rosas HD, Koroshetz WJ, Chen YI et al. (2003). Evidence
for more widespread cerebral pathology in early HD: an
MRI-based morphometric analysis. Neurology 27:
1615–1620.
Rosas HD, Salat DH, Lee SY et al. (2008). Complexity and
heterogeneity: what drives the ever-changing brain in
Huntington’s disease? Ann N Y Acad Sci 1147: 196–205.
Rosenblatt A, Ranen NG, Nance MA et al. (1999). A physi-
cian’s guide to the management of Huntington’s disease:
Huntington’s Disease Society of America. New York.
Rothlind JC, Brandt J (1993). A brief assessment of frontal
and subcortical functions in dementia. J Neuropsychiatry
Clin Neurosci 5: 73–77.
Savage CR (1997). Neuropsychology of subcortical demen-
tias. Psychiatr Clin North Am 20: 911–931.
Schoenfeld M, Myers RH, Cupples LA et al. (1984). Increased
rate of suicide among patients with Huntington’s disease.
J Neuro Neurosurg Psychiatry 47: 1283–1287.
Scourfield J, Soldan J, Gray J et al. (1997). Huntington’s dis-
ease: psychiatric practice in molecular genetic prediction
and diagnosis. Br J Psychiatry 170: 146–149.
Snowden JS, Craufurd D, Thompson J et al. (2002). Psycho-
motor, executive, and memory function in preclinical
Huntington’s disease. J Clin Exp Neuropsychol 24:
133–145.
Snowden JS, Gibbons ZC, Blackshaw A et al. (2003). Social
cognition in frontotemporal dementia and Huntington’s
disease. Neuropsychologia 41: 688–701.
Sprengelmeyer R, Lange H, Homberg V (1995). The pattern
of attentional deficits in Huntington’s disease. Brain 118:
145–152.
Stout JC, Rodawalt WC, Siemers ER (2001). Risky decision
making in Huntington’s disease. J Int Neuropsychol Soc
7: 92–101.
Strauss ME, Brandt J (1986). An attempt at presymptomatic
identification of Huntington’s disease with the WAIS.
J Clin Exp Neuropsychol 8: 210–228.
Strong TV, Tagle DA, Valdes JM et al. (1993). Wide-
spread expression of the human and rat Huntington’s dis-
ease gene in brain and nonneural tissues. Nat Genet 5:
259–265.
Thompson JC, Snowden JS, Craufurd D et al. (2002). Behav-
ior in Huntington’s disease: Dissociating cognition-based
and mood-based changes. J Neuropsychiatry Clin Neu-
rosci 14: 37–43.
Thompson JC, Poliakoff E, Sollom AC et al. (2010). Automatic-
ity and attention in Huntington’s disease: when two hands
are not better than one. Neuropsychologia 48 (1): 171–178.
Trejo A, Tarrats RM, Alonso ME et al. (2004). Nutrition
20 (2): 192–196.
Tsuang D, DiGiacomo L, Lipe H et al. (1998). Familial
aggregation of schizophrenia-like symptoms in Hunting-
ton’s disease. Am J Med Genet 81: 323–327.
van Duijn E, Kingma EM, van der Mast RC (2007). Psycho-
pathology in verified Huntington’s disease gene carriers.
J Neuropsychiatry Clin Neurosci 19: 441–448.
Vassos E, Panas M, Kladi A et al. (2007). Higher levels of
extroverted hostility detected in gene carriers at risk for
Huntington’s disease. Biol Psychiatry 62: 1347–1352.
Vassos E, Panas M, Kladi A et al. (2008). Effect of CAG
repeat length on psychiatric disorders in Huntington’s
disease. J Psychiatr Res 42: 544–549.
Vonsattel JP, Difiglia M (1998). Huntington’s disease.
J Neuropathol Exp Neurol 57: 369–384.
Vonsattel JP, Myers RH, Stevens TJ et al. (1985). Neuropath-
ological classification of Huntington’s disease. J Neuro-
pathol Exp Neurol 44 (6): 559–577.
Watkins LH, Rogers RD, Lawrence AD et al. (2000). Impaired
planning but intact decision making in early Huntington’s
disease: implications for specific fronto-striatal pathology.
Neuropsychologia 38: 1112–1125.
Weaver KE, Richards TL, Liang O et al. (2009). Longitudinal
diffusion tensor imaging in Huntington’s disease. Exp
Neurol 216 (2): 525–529.
Weingartner H, Caine ED, Ebert MH et al. (1979). Imagery,
encoding, and retrieval of information from memory:
some specific encoding-retrieval changes in Huntington’s
disease. J Abnorm Psychol 88: 52–58.
Wheeler VC, Persichetti F, McNeil SM et al. (2007). US-
Venezuela Collaborative Research Group. Factors asso-
ciated with HD CAG repeat instability in Huntington dis-
ease. J Med Genet 44 (11): 695–701.
Wheelock VL, Tempkin T, Marder K et al. (2003). Predictors
of nursing home placement in Huntington disease.
Neurology 60: 998–1001.
Willingham DB, Koroshetz WJ, Peterson EW (1996). Motor
skills have diverse neural bases: spared and impaired skill
acquisition in Huntington’s disease. Neuropsychology 10:
315–321.
Young AB, Penney JB, Starosta-Rubinstein S et al.
(1986). PET scan investigations of Huntington’s disease:
cerebral metabolic correlates of neurological features
and functional decline. Ann Neurol 20: 296–303.
Zappacosta B, Monza D, Meoni C et al. (1996). Psychiatric
symptoms do not correlate with cognitive decline, motor
symptoms, or CAG repeat length in Huntington’s disease.
Arch Neurol 53: 493–497.