Parkinsonism and Related Disorders xxx (2016) 1e7

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Parkinsonism and Related Disorders

journal homepage: www.elsevier.com/locate/parkreldis

Neuropsychiatric symptoms are very common in premanifest and

early stage HD
Saul Martinez-Horta a, b, c, f, Jesus Perez-Perez a, b, c, Erik van Duijn e,
Ramon Fernandez-Bobadilla a, b, c, f, Mar Carceller b, d, Javier Pagonabarraga a, b, c,
Berta Pascual-Sedano a, b, c, Antonia Campolongo a, b, c, Jesus Ruiz-Idiago g,
Frederic Sampedro i, G.Bernhard Landwehrmeyer h, Spanish REGISTRY investigators of the
European Huntington's Disease Network, Jaime Kulisevsky a, b, c, f, *
a
Department of Neurology, Movement Disorders Unit, Hospital de la Santa Creu i Sant Pau, Universitat Auto
noma de Barcelona, Barcelona, Spain
b
Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain
c n Biomedica en Red-Enfermedades Neurodegenerativas (CIBERNED), Spain
Centro Investigacio
d
noma de Barcelona, Barcelona, Spain
Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Universitat Auto
e
Department of Psychiatry, Leiden University Medical Centre, Leiden, and Centre for Mental Health Care Delfland, Delft, The Netherlands
f
Universitat Oberta de Catalunya (UOC), Barcelona, Spain
g
Hospital Mare de D eu de la Merc
e, Barcelona, Spain
h
Department of Neurology, University of Ulm, Ulm, Germany
i
Faculty of Medicine, Autonomous University of Barcelona, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Background: Neuropsychiatric symptoms are common features of Huntington's disease (HD). Whereas
Received 5 September 2015 most studies have focused on cognitive and neuroimaging markers of disease progression, little is known
Received in revised form about the prevalence of neuropsychiatric symptoms in premanifest mutation carriers far-from and close-
28 January 2016
to disease onset.
Accepted 5 February 2016
Methods: We obtained neurological, cognitive and behavioral data from 230 participants classified as
premanifest far-from (preHD-A) and close-to (preHD-B) motor-based disease onset, early-symptomatic
Keywords:
(early-HD), and healthy controls. Frequency and severity of neuropsychiatric symptoms were assessed
Huntington's disease
Apathy
with the short Problem Behaviors Assessment for HD (PBA-s). The odds-ratio (OR) to present symptoms
Behavior in the clinical range was calculated using the control group as reference. Logistic regression analysis was
Neuropsychiatry used to explore relationships between neuropsychiatric symptoms and medication use.
Biomarker Results: Prevalence of depression was similar in all groups. Apathy was already present in 32% of preHD-
A increasing to 62% of early-HD patients. The probability of presenting apathetic symptoms was 15e88
times higher in preHD-A and preHD-B respectively than in healthy controls. Irritability and executive
dysfunction were present in both preHD-B and early-HD.
Conclusion: Neuropsychiatric symptoms are highly prevalent in HD, already in the premanifest stage,
with increasing prevalence of irritability, apathy and executive dysfunction closer to onset. Compared to
controls, HD mutation carriers have the highest probability to develop apathy, with an increasing
prevalence along disease stages. Our findings confirm the high prevalence of neuropsychiatric symptoms
in HD, already many years before the onset of motor symptoms, with apathy as an early manifestation
and core neuropsychiatric feature of the disease.
© 2016 Published by Elsevier Ltd.

1. Introduction

* Corresponding author. Department of Neurology, Movement Disorders Unit, Huntington's disease (HD) is an inherited, autosomal dominant,
Hospital de la Santa Creu i Sant Pau, Sant Antoni M. Claret 167, 08025 Barcelona, neurodegenerative disease resulting from a trinucleotide CAG
Spain. expansion in the HTT. In people carrying the expanded gene
E-mail address: jkulisevsky@santpau.cat (J. Kulisevsky).

http://dx.doi.org/10.1016/j.parkreldis.2016.02.008
1353-8020/© 2016 Published by Elsevier Ltd.

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2 S. Martinez-Horta et al. / Parkinsonism and Related Disorders xxx (2016) 1e7
(CAG > 36 repeats), HD clinically manifests around mid-adulthood
with a triad of progressive motor, cognitive and behavioral symp-
toms [1]. Formal neurological diagnosis of HD is based on the
presence of unequivocal motor symptoms [1]. However, besides
these characteristic motor symptoms and the progressive cognitive
decline, neuropsychiatric disturbances are a common feature of HD
[2,3]. Neuropsychiatric symptoms, including depression, apathy,
and irritability, may already be present many years before motor
symptoms appear [3,4]. While the etiology of these symptoms is
unclear, the progressive nature of the neurodegenerative process,
mainly involving the basal ganglia-thalamo-cortical circuits, is
supposed to underlie the high prevalence of neuropsychiatric
symptoms seen in patients with HD [5].
Since the availability of predictive genetic testing [6], it is
possible to assess which individuals will develop the disease before
motor symptoms are present [7]. Compelling evidence has shown
that subtle cognitive and neuroimaging changes can be identified
many years before motor-based diagnosis [8,9]. It has been sug-
gested that these changes are potential early markers of disease
progression that could be useful to monitor future disease-
modifying therapies [10]. Previous studies found that apathy,
depression and irritability are frequent neuropsychiatric symptoms
of HD, and that their prevalence and severity are already increased
in premanifest gene carriers (pre-HD) compared to healthy controls
[4,11].
In a large cross-sectional study, apathy was the only symptom
that increased significantly with disease progression [12], whereas
another cross-sectional study found a clear increase of apathy along
disease stages and a more modest increase of obsessive compulsive
behaviors, depression, irritability and psychosis [13]. Thus, apathy
shows the strongest linear association to disease progression,
indicating a direct relation with progressive neurodegeneration
[13,14]. However, the study of van Duijn et al. assessed the preva-
lence of neuropsychiatric symptoms in a mixed population of
premanifest and manifest mutation carriers [13]. The study from
Duff et al. also explored the occurrence of neuropsychiatric symp-
toms in premanifest individuals. However, the sample included
symptomatic individuals and the behavioral assessment was done
using the Symptom Checklist 90 Revised (SCL-90-R), a good but
non-specific for HD instrument. Moreover, they neither controlled
for the influence of pharmacological management nor estimated
time to disease onset [12].
Many HD studies used instruments that measure both fre-
quency and severity of neuropsychiatric symptoms, including the
behavioral component of the Unified Huntington's Disease Rating
Scale (UHDRS) and the Problem Behaviors Assessment (PBA). Both
scales are specifically designed for HD populations and measure
common neuropsychiatric symptoms of HD [4,15].
To assess the prevalence of neuropsychiatric symptoms in
relation to the presence of motor symptoms, we measured the
occurrence of neuropsychiatric symptoms using the PBA-s in a
large sample of well characterized pre-HD individuals, early
symptomatic patients and non-carriers enrolled in the Spanish
cohort of the REGISTRY Study [16].
2. Methods and materials
2.1. Sample
Two-hundred and thirty subjects from Spain who provided
written informed consent to participate in the European REGISTRY
Study from the European Huntington's Disease Network [16] were
included in the analysis. REGISTRY is a large, prospective study
observing the natural course, clinical spectrum and management of
HD in European countries [16]. In the current study, cross-sectional
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data from baseline visits was used. HD gene carriers from the
REGISTRY dataset with a UHDRS [15] total motor score below 5
points were classified as premanifest individuals. We then calcu-
lated the disease burden score (age x [CAGn e 35.5]) which is
proposed as an index of burden of pathology due to lifetime
exposure to mutant huntingtin. Then, the estimated time to disease
onset with a probability of 0.6 was calculated using the conditional
probability model developed by Langbehn et al. [17] As assumed in
previous studies, premanifest individuals with estimated years to
diagnosis over 10.8 years were classified as far-from (preHD-A) and
below 10.8 years as close-to disease onset (preHD-B) [7].
Those with a UHDRS total motor score over
5 and a Total
Functional Capacity (TFC) score between 11 and 13 were classified
as early symptomatic (early-HD). Controls were identified as: (i)
people who had a history of being at-risk for HD but were geneti-
cally confirmed to be non-carriers, and (ii) partners/principal
caregivers of a gene-positive individual, without family history of
HD. This control group experienced the same stressors that are
related to HD: the verified non-carriers grew up in the same family
circumstances and experienced the psychological stress of being at
risk, whereas the partners/caregivers currently live in similar cir-
cumstances and experience the same disease related stressors.
Sociodemographic characteristics included were age, sex and
years of education. Pharmacological treatment with antidepres-
sants, benzodiazepines, neuroleptics, anticonvulsive drugs, and
anti-choreic medication (tetrabenazine or amantadine) was recor-
ded. We excluded participants with a previous diagnosis of major
chronic psychiatric disorder (two cases of schizophrenia in non-
carriers; one case of bipolar disorder in a premanifest mutation
carrier). We also excluded participants with diagnosis of neuro-
logical disorder other than HD or a history of head trauma.
2.2. Neurological and functional assessment
The UHDRS motor subscale was used to assess the presence of a
wide range of motor alterations characterizing HD. It includes
measures for oculomotor function, dysarthria, chorea, dystonia,
parkinsonism, postural instability, and gait. The UHDRS total motor
score is the sum of all individual item scores, with higher scores
indicating greater impairment [15].
Functional capacity was assessed using the Total Functional
Capacity scale (TFC) of the UHDRS [18]. This instrument measures
the possibility to independently perform activities of daily living.
The TFC score ranges from 0 to 13 with higher scores indicating
better functional capacity.
2.3. Cognitive assessment
Cognitive functioning was assessed using the UHDRS cognitive
score [15]. Cognitive functioning is presented with the sum of the
scores of five cognitive tasks: the Verbal Fluency Test (VFT; using
three letters: FAS), the Stroop word naming, the Stroop color
naming, the Stroop interference, and the Symbol Digit Modality
Test (SDMT), as has been done in previous studies [7].
2.4. Behavioral assessment
The PBA-s was used to obtain behavioral data [4]. The PBA-s is
an 11-item semistructured interview, specifically designed to cover
a wide range of neuropsychiatric symptoms related to HD. This
scale is administered in presence of the main caregiver or a proper
companion and rates the severity (0 ¼ absent, 1 ¼ questionable,
2 ¼ mild, 3 ¼ moderate and 4 ¼ severe) and frequency (0 ¼ never/
almost never, 1 ¼ seldom, 2 ¼ sometimes, 3 ¼ frequently and
4 ¼ daily/almost daily for most or all the day) of depressed mood,
 S. Martinez-Horta et al. / Parkinsonism and Related Disorders xxx (2016) 1e7 3

suicidal ideation, anxiety, irritability, angry or aggressive behavior,
lack of initiative, perseverative thinking or behavior, obsessive-
compulsive behaviors, delusion and paranoid thinking, hallucina-
tions, and disoriented behavior during the last month. Recent
research showed five sub-scales after a factor analysis: depression,
irritability, apathy, psychosis, and dysexecutive behavior [19]. In
our study, we included mild psychiatric disturbances. In accor-
dance, we used a minimum score of
2 on any of the five assessed
domains.
2.5. Statistical analysis
Descriptive analysis of the data included means ± SD for
continuous variables and percentages for categorical variables.
Clinical and sociodemographic data were subjected to one-way
ANOVAs and post hoc comparisons. c2 test was performed for
categorical variables. Pairwise comparisons, two-way ANOVAs and
ANCOVAs were used to analyze possible group differences and
group effect interactions controlling for potentially confounding
variables. Sex, age, education, CAG repeat length, TFC, UHDRS total
motor score, UHDRS cognitive score, use of medication, and PBA-s
subscale scores were used as covariables and/or random factors
in the univariate model. The probability to present clinically
meaningful symptoms was calculated as odd-ratios (ORs) for each
symptom in each clinical group compared to controls. Logistic
regression analysis was used to explore possible correlations be-
tween neuropsychiatric symptoms and use of medication. Statis-
tical significance was set at p < 0.05. All statistical procedures were
conducted using SPSS 20.
3. Results
3.1. Clinical and sociodemographic data
Subjects were grouped as preHD-A (n ¼ 34), preHD-B (n ¼ 25),
early-HD (n ¼ 70), and controls (n ¼ 101). As seen in Table 1, groups
differed in age [F(3,229) ¼ 7.6, p ¼ 0.000] and length of CAG
[F(2,128) ¼ 14.8, p ¼ 0.225]. Motor [F(2,128) ¼ 88, p ¼ 0.000],
cognitive [F(3,202) ¼ 23.3, p ¼ 0.000] and functional scores
[F(2,128) ¼ 27.2, p ¼ 0.000] also differed between groups. Post-hoc
comparisons showed that the early-HD group obtained signifi-
cantly worse scores in all these measures compared to both pre-
manifest and gene-negative participants.
3.2. Prevalence of neuropsychiatric symptoms across the sample
Seventy-five percent of the gene carriers had at least one mild
neuropsychiatric symptom with score
2 in the past month,
Table 1
Clinical and sociodemographic data.
Pre-HD-A Pre-HD-B Early-HD HD control P
whereas up to 59% of the controls had one or more symptom(s). At
least one symptom occurred in up to 50% of the preHD-A, 80% of the
preHD-B and 85% of early-HD. The c2 test showed that prevalence
differed significantly between the four groups [c2 (3230)
p ¼ 0.000]. The increase was statistically significant between
preHD-A and preHD-B [c2 (1,59) p ¼ 0.002], but not between
preHD-B and early-HD [c2 (1,95) p ¼ 0.530]. Whereas no differ-
ences were found between controls and preHD-A [c2 (1135)
p ¼ 0.428], a significant increase was found between controls and
prevalence of neuropsychiatric symptoms in preHD-B [c2 (1126)
p ¼ 0.036] and early-HD [c2 (1171) p ¼ 0.000].
In the preHD-A group, depression and irritability were the most
prevalent neuropsychiatric symptoms (both 32%), followed by
apathy (23%) and executive dysfunction (9%) with no cases showing
psychotic symptoms. In the preHD-B group apathy was the most
common symptom (64%), followed by irritability (56%), depression
(52%), executive dysfunction (32%) and psychosis (4%). In the early-
HD group, depression was the most prevalent symptom (65%),
followed by apathy (63%), irritability (47%), executive dysfunction
(44%) and psychosis (4%). The most prevalent neuropsychiatric
symptom in controls was depression (47%), followed by irritability
(20%) and executive dysfunction (11%). Apathy and psychosis were
present in only 2% of the controls (see Fig. 1).
3.3. Odds-ratios for neuropsychiatric symptoms across disease
stages
We addressed the likelihood to present neuropsychiatric
symptoms in the clinical range (PBA-s
2) among different disease
stages by calculating the odds-ratio (OR), using the control group as
a reference. As shown in Table 3, the OR for apathy in preHD-A was
15.2. No increased probability was found for any other neuropsy-
chiatric symptom in this group. PreHD-B showed a 5.1 OR for irri-
tability, 88 for apathy and 3.8 for executive dysfunction. Early-HD
showed a 2.1 OR for depression, 3.6 for irritability, 83.7 for apathy
and 6.4 for executive dysfunction.
3.4. Pharmacotherapy across disease stages
Up to 53% of individuals in the clinical sample received phar-
macotherapy. Use of medication was particularly high in the early
manifest group. Fifty percent (n ¼ 17) of preHD-A used antide-
pressants, 9% (n ¼ 3) used benzodiazepines, 3% (n ¼ 1) used neu-
roleptics, and 3% (n ¼ 1) used anticonvulsives. Benzodiazepines
were used in 64% (n ¼ 16) of preHD-B, antidepressants in 20%
(n ¼ 5), anticonvulsive drugs as mood stabilizers in 8% (n ¼ 2), and
neuroleptics in 4% (n ¼ 1). In early-HD, 87% (n ¼ 61) used neuro-
leptics, 48% (n ¼ 34) used tetrabenazine/amantadine, 34% (n ¼ 24)
used antidepressants, 33% (n ¼ 23) used benzodiazepines, and 10%
(n ¼ 7) used anticonvulsive drugs. In the control group, 19% (n ¼ 19)
used benzodiazepines and 11% (n ¼ 11) used antidepressants. c2
comparisons showed significant differences between all groups
regarding the use of all recorded pharmacological treatments.

N 34 24 70 101 3.5. PBA-s sub-scores

Gender (f/m)a 22/12 12/13 41/29 67/34 0.142
Age (years) 34.8 (10.5) 40.4 (7.2) 47.2 (12.2) 43.3 (14.5) 0.000
Education (years) 13.7 (3.3) 13.2 (3.8) 11.8 (3.5) 13 (5) 0.144 3.5.1. Depression
CAGb 43.5 (2.9) 44.4 (3) 44.3 (3.8) e 0.225 No significant differences in the presence of symptoms of
UHDRS Totalc 0.8 (1.1) 1.4 (1.5) 22.1 (12) e 0.000 depression were found between groups [F(3,229) ¼ 0.7, p ¼ 0.549].
TFCd 12.9 (0.5) 12.9 (0.4) 11.7 (1.1) e 0.000
Significant interactions were found between depression and irri-
Cog Scoree 308.6 (89.1) 288.5 (79.9) 181.6 (73) 276.2 (93) 0.000
tability [F(3,230) ¼ 9.5, p ¼ 0.002], executive dysfunction
a
Gender represented as number of females (f) and males (m). [F(3,230) ¼ 9.9, p ¼ 0.002] and apathy [F(3,230) ¼ 41.3, p ¼ 0.000].
b
Mean CAG repeat length.
c
Mean Unified Huntington's Disease Rating Scale total motor score.
However, this effect was clearly mediated by the UHDRS motor
d
Mean Total Functional Capacity Scale score. score [F(2,144) ¼ 9.2, p ¼ 0.003], UHDRS cognitive score
e
Mean UHDRS Cognitive score. Data presented as mean (SD). [F(2,144) ¼ 3.9, p ¼ 0.4] and TFC [F(2,144) ¼ 6.8, p ¼ 0.01] (see

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4 S. Martinez-Horta et al. / Parkinsonism and Related Disorders xxx (2016) 1e7

Fig. 1. Each bar shows the percentage of cases scoring
2 for each PBA-S subscore and group.

Table 2 3.5.3. Psychosis

Behavioral data. Psychotic symptoms score was <2 in all groups without signif-
Pre-HD-A Pre-HD-B Early-HD HD control P icant differences between them. Scores
2 were observed in one
case of the preHD-B group, three of the early-HD (4.2%), and two of
Depression 4.3 (8.8) 5.2 (6.7) 5.9 (6.7) 4.4 (6.7) 0.549
Irritability 1.9 (4.4) 4.5 (5.9) 4.1 (5.4) 1.3 (3.3) 0.000
the control group (2%).
Psychosis 0 (0) 0.2 (0.8) 0.3 (1.2) 0.1 (0.6) 0.300
Apathy 1.5 (3.2) 4 (4) 4.7 (4.6) 0.1 (0.9) 0.000
3.5.4. Apathy
Executive dysfunction 0.6 (1.6) 2.1 (4.1) 3.1 (4) 1 (3.8) 0.001
Between group comparisons showed significant differences in
Data presented as mean (SD).
apathy score [F(3,229) ¼ 31.4, p ¼ 0.000]. Post-hoc comparisons
showed that preHD-A scored significantly lower than preHD-B
Tables 2 and 3). Logistic regression analysis showed a strong cor- [t(229) ¼ 2.6, p ¼ 0.015], whereas preHD-B scored significantly
relation between depression and use of antidepressant drugs higher than controls [t(229) ¼ 8.8, p ¼ 0.000]. Early-HD scored
(r2 ¼ 0.105; p ¼ 0.001) and benzodiazepines (r2 ¼ 0.105; p ¼ 0.02). significantly higher than preHD-A [t(229) ¼ 3.6, p ¼ 0.000] and
controls [t(229) ¼ 9.6, p ¼ 0.000]. No differences were found be-
tween preHD-B and early-HD. A significant group effect
3.5.2. Irritability
[F(3,220) ¼ 8.5, p ¼ 0.03] was found despite correction for signif-
A significant difference was found between groups
icant interactions with education [F(2,144) ¼ 10.1, p ¼ 0.002] and
[F(3,229) ¼ 5.1, p ¼ 0.001]. Post-hoc comparisons showed that
TFC [F(2,144) ¼ 7.1, p ¼ 0.008]. The group effect remained significant
preHD-B [t(229) ¼ 3.5, p ¼ 0.016] and early-HD [t(229) ¼ 4,
[F(3,230) ¼ 21.1, p ¼ 0.000] despite an interaction with depression
p ¼ 0.000] were more irritable than controls. Although we found a
[F(3,230) ¼ 41.3, p ¼ 0.000]. Logistic regression analysis showed a
trend to a group effect [F(3,220) ¼ 5, p ¼ 0.07], this was lost once
significant correlation between apathy scores, use of antidepres-
corrected for depression [F(3,230) ¼ 9.5, p ¼ 0.002], psychosis
sants (r2 ¼ 0.129; p ¼ 0.02) and neuroleptics (r2 ¼ 0.129; p ¼ 0.01).
[F(3,230) ¼ 4, p ¼ 0.04], and UHDRS cognitive score [F(2,144) ¼ 6.1,
p ¼ 0.01] (see Tables 2 and 3). Logistic regression analysis showed a
strong correlation between irritability and use of antidepressants 3.5.5. Executive dysfunction
(r2 ¼ 0.127; p ¼ 0.001), benzodiazepines (r2 ¼ 0.127; p ¼ 0.001) and A significant difference was found between groups
neuroleptics (r2 ¼ 0.127; p ¼ 0.01). [F(3,229) ¼ 5.6, p ¼ 0.001]. Post-hoc comparisons showed that

Table 3
Odd-ratios for clinically meaningful neuropsychiatric symptoms across disease stages.

OR 95% CI P

Pre-HD-A

Apathy 15.2 3.04e76.08 0.000

Pre-HD-B
Irritability 5.1 2.03e13.05 0.001
Apathy 88 17.40e444.95 0.000
Executive dysfunction 3.8 1.35e10.97 0.01
Early HD
Depression 2.1 1.12e3.97 0.01
Irritability 3.6 1.83e7.11 0.000
Apathy 83.7 19.04e368.51 0.000
Executive dysfunction 6.5 2.97e14.24 0.000

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 S. Martinez-Horta et al. / Parkinsonism and Related Disorders xxx (2016) 1e7
early-HD scored significantly higher than preHD-A [t(229) ¼ 3.5,
p ¼ 0.000] whereas preHD-A appeared scoring already higher than
controls [t(229) ¼ 3.4, p ¼ 0.001]. No significant group effect was
found [F(3,220) ¼ 1.8, p ¼ 0.275]. Logistic regression analysis
showed a significant correlation between executive dysfunction
and use of neuroleptics (r2 ¼ 0.051; p ¼ 0.02).
[See table 4 as additional data].
4. Discussion
In this large cohort, we assessed the prevalence of neuropsy-
chiatric symptoms in premanifest and early-stage HD patients. We
also considered the influence of motor, functional and cognitive
status and associations with pharmacological treatment.
We observed symptoms of apathy already in premanifest in-
dividuals, with a three-fold increase in the early-HD group.
Although other symptoms were also present, only apathy clearly
differentiated preHD-B and early-HD from controls and it increased
linearly with disease progression.
Behavioral assessment showed depression in all groups, with no
statistical differences between them. Depression is a common
neuropsychiatric symptom in HD [3], with prevalence varying from
35% to 52% in preHD patients up to 65% in early-HD patients in our
cohort. We found an unexpectedly high prevalence of depression in
the control group (59%), which might reflect the emotional impact
of HD on caregivers/partners which in many cases is caused by a
constant great concern about the future and disruptive inter-
personal relationships due to the emotional burden of the dis-
ease. In this line, our data support that depression in HD is not
necessarily related to the progression of the neuropathology [20].
Rather, the data suggest that having a partner with a fatal genetic
condition or growing up in an affected family, which has previously
been linked to poorer mental health at adulthood [21], has an high
impact to non-affected family members and partners as well. Other
factors can include the uncertainty of developing symptoms in the
near future, and difficulties in the management of the disease in
affected relatives [22].
Irritability and executive dysfunction were also present in
preHD-B and in early-HD but not in controls. This is in line with
other studies that have reported increased prevalence of both
symptoms in the premanifest and early stage of the disease [13,23].
The prevalence of these two symptoms was similar in both groups.
Inhibitory control and cognitive flexibility are crucial for the proper
guidance of human behavior and it disruption plays a critical role
on the emergence of behavioral alterations such as irritability and
disexecutive behavior [9,24,25]. Hence, loss of proper inhibitory
control and cognitive flexibility, which have been described in HD,
will lead to poor temper control and perseverative behavior [23].
These functions are closely linked to dorsal-lateral prefrontal cortex
and medial prefrontal cortex, structures that show early malfunc-
tioning due to the progressive impairment of related basal ganglia
projections [26,27]. Progressive neurodegeneration of this frontal-
subcortical circuitry will result in increased irritability and execu-
tive dysfunction.
Prevalence of psychotic symptoms was low in all groups,
showing similar prevalence as those reported in previous studies
[2,25]. Our results confirm that psychosis is not a characteristic of
early symptomatic HD patients [28]. However, the use of antipsy-
chotic medication could have masked the clinical expression of
subtle early psychotic symptoms, and as pointed in previous
studies, psychotic patients may be less prone to participate in
observational studies such as REGISTRY [13].
Apathy is a common neuropsychiatric feature of HD and other
neurodegenerative conditions [29]. Although the exact underlying
mechanisms of apathy in HD are not yet fully understood, previous
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5
studies have shown that apathy is closely related to disease pro-
gression [11,23,30]. In the present study, we found that 23.5% of
preHD-A individuals already presented symptoms of apathy. This
percentage increased dramatically to 64% in preHD-B and 63% in
early-HD. The odds-ratio also illustrates the high risk to present
apathy up to ten years before disease onset and the progressively
increasing risk during the course of the disease. Compared to
healthy controls, the premanifest individuals have a 15 times
higher risk to develop apathy. In several studies, apathy in HD pa-
tients has been related to the use of medication, such as neuro-
leptics and benzodiazepines [11]. In our sample, neuroleptics were
commonly used in early-HD but they were rarely used in preHD-B,
to whom benzodiazepines were frequently prescribed. Apathy can
also be a symptom of depression, but since the prevalence of
depression did not differ between the clinical groups, the increase
of apathy cannot be fully attributed to the presence of depression.
Regarding the interaction found between depression and all the
other neuropsychiatric symptoms, it is important to note that the
effect disappeared once motor and functional scores was included.
Thus, this interaction was mainly mediated by early-HD individuals
with higher scores in all the measures as a function of their clinical
status.
The linear increase of apathy in frequency, severity and its
increased risk indicates that apathy is closely related to the
neurodegenerative process of HD [14,23], and it may therefore be
considered as a core neuropsychiatric feature of HD.
It is important to emphasize that a significant number of pa-
tients does not present clinical meaningful neuropsychiatric
symptoms. Thus, while these features are increasingly recognized
to be characteristic of HD, some patients show no neuropsychiatric
symptoms in the early stages of the disease. Further study of these
gene carriers would be of interest to explore which mechanisms
could potentially explain the absence of significant neuropsychi-
atric features in those individuals.
The present results are mainly compatible with previous pub-
lished data. However, it is important to highlight the main
strengths of the current work. Importantly, we used an instrument
(PBA-s) specifically designed for the assessment of neuropsychi-
atric symptoms in HD that looks to the full spectrum of behavioral
alterations taking also into account pharmacological management.
Moreover, this is the first study using the PBA-s that compares the
results of mutation carriers with gene-negative controls that
shared similar environmental stressors. Finally, the work was done
through a large sample of exclusively Spanish population. This
represents a homogenous sample probably less affected by the
socio-demographic and cultural variables that could differently
characterize individuals from largely separated countries when
using international databases.
In conclusion, this study shows that neuropsychiatric symptoms
are highly prevalent in HD, already many years before the onset of
motor symptoms. To improve our understanding of these symp-
toms, future studies should investigate the relationship between
the presence of neuropsychiatric symptoms and other markers of
disease progression, in particular neuroanatomical changes.
Authors' roles
Saul Martínez-Horta: Conception, organization and execution of
the research project, design and execution of the data analysis,
writing of the first draft and review of the manuscript.
Jesus PerezePerez: Conception and execution of the research
project, design and execution of the data analysis and review of the
manuscript.
Erik van Duijn: Writing of the first draft and review of the
manuscript and data analysis.
6 S. Martinez-Horta et al. / Parkinsonism and Related Disorders xxx (2016) 1e7
Ramon Fernandez-Bobadilla: Design and execution of the data
analysis and review of the manuscript.
Mar Carceller: Review of the manuscript and data analysis.
Javier Pagonabarraga: Design and execution of the data analysis
and review of the manuscript.
Berta Pascual-Sedano: Review of the manuscript and data
analysis.
Antonia Campolongo: Review of the manuscript and data
analysis.
Jesus Ruiz-Idiago: Review of the manuscript and data analysis.
Frederic Sampedro: Review of the manuscript and data analysis.
G Bernhard Landwehrmeyer: Conception and execution of the
research project.
Jaime Kulisevsky: Conception and execution of the research
project, review of the manuscript.
Financial disclosures
Saul Martinez-Horta: Nothing to disclose.
Jesus PerezePerez: Nothing to disclose.
Erik van Duijn: Nothing to disclose.
Ramon Fernandez-Bobadilla: Nothing to disclose.
Mar Carceller: Nothing to disclose.
Javier Pagonabarraga: Has received honoraria for lecturing or
consultation from Boehringer Ingelheim, UCB, Allergan, Ipsen, and
Lundbeck.
Berta Pascual-Sedano: Nothing to disclose.
Antonia Campolongo: Nothing to disclose.
Jesus Ruiz-Idiago: Nothing to disclose.
Frederic Sampedro: Nothing to disclose.
G Bernhard Landwehrmeyer: Nothing to disclose.
Jaime Kulisevsky: Has received honoraria for lecturing or
consultation from the Michael J Fox Foundation, Merck Serono,
AbbVie, Boehringer Ingelheim, UCB, Zambon, MSD, Italfarmaco,
General Electric, and Lundbeck.
Acknowledgments
The authors are grateful to all the HD families involved in the
study and all the co-investigators that participate in the collection
of the Spanish Registry dataset. The Spanish REGISTRY investigators
of the European Huntington's Disease Network for the present
study are: Esteban Mun ~ oz (Parkinson disease and Movement Dis-
orders Unit, Department of Neurology, Institut Clínic de Neuro-

ncies (ICN), Institut d’Investigacions Biome
cie
diques August Pi i
Sunyer (IDIBAPS), Hospital Clínic. Barcelona, Spain), Matilde Calopa
(Department of Neurology, Hospital Universitari de Bellvitge. Bar-
celona, Spain), Esther Cubo (Department of Neurology, Hospital
Universitario de Burgos. Burgos, Spain), Jose  Lopez-Sendon
(Department of Neurology, Hospital Ramo n y Cajal. Madrid,
Spain), Pedro Jose García-Ruiz (Department of Neurology, Funda-
cion Jimenez Diaz. Madrid, Spain), Jose  Matías Arbelo (Movement
disorders unit, Department of Neurology, Hospital Insular de Gran
Canarias. Gran Canarias, Spain), Mari Carmen Duran-Herrera
(Department of Neurology, Hospital Universitario Infanta Cristina.
Badajoz, Espan~ a), Rene Ribacoba (Department of Neurology, Hos-

pital Universitario Central Asturias and Alvarez Buylla-Mieres,
Asturias, Spain), Jose  Manuel García-Moreno (Department of
Neurology, Hospital Universitario Virgen de la Macarena, Sevilla,
Spain) We want also to thank Carolyn Newey for the expert review
of the manuscript and to Ignasi Gich for statistical support.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
Please cite this article in press as: S. Martinez-Horta, et al., Neuropsychiatric symptoms are very common in premanifest and early stage HD,
Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.02.008
dx.doi.org/10.1016/j.parkreldis.2016.02.008.
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Please cite this article in press as: S. Martinez-Horta, et al., Neuropsychiatric symptoms are very common in premanifest and early stage HD,
Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.02.008