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Neuropsychiatric Burden in Huntington’s Disease

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Article

Neuropsychiatric Burden in Huntington’s Disease

Abstract and Figures

Huntington's disease is a disorder that results in motor, cognitive, and psychiatric problems. The symptoms often take different forms and the presence of disturbances of the psychic sphere reduces patients' autonomy and quality of life, also impacting patients' social life. It is estimated that a prevalence between 33% and 76% of the main psychiatric syndromes may arise in different phases of the disease, often in atypical form, even 20 years before the onset of chorea and dementia. We present a narrative review of the literature describing the main psychopathological patterns that may be found in Huntington's disease, searching for a related article in the main database sources (Medline, ISI Web of Knowledge, Scopus, and Medscape). Psychiatric conditions were classified into two main categories: affective and nonaffective disorders/symptoms; and anxiety and neuropsychiatric features such as apathy and irritability. Though the literature is extensive, it is not always convergent, probably due to the high heterogeneity of methods used. We summarize main papers for pathology and sample size, in order to present a synoptic vision of the argument. Since the association between Huntington's disease and psychiatric symptoms was demonstrated, we argue that the prevalent and more invalidating psychiatric components should be recognized as early as possible during the disease course in order to best address psychopharmacological therapy, improve quality of life, and also reduce burden on caregivers.
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brain
sciences
Review
Neuropsychiatric Burden in Huntington’s Disease
Ricardo Augusto Paoli 1, Andrea Botturi 1, 2, *, Andrea Ciammola 3, Vincenzo Silani 3,4,
Cecilia Prunas 1, Claudio Lucchiari 5, Elisa Zugno 1and Elisabetta Caletti 1
1Department of Psychiatry, Universitàdegli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, Milan 20122, Italy; riccardo.paoli@guest.unimi.it (R.A.P.); crprunas@gmail.com (C.P.);
elisazugno@gmail.com (E.Z.); calettielisabetta@gmail.com (E.C.)
2Department of Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy
3
Department of Neurology-Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano,
Milan 20149, Italy; a.ciammola@auxologico.it (A.C.); vincenzo@silani.com (V.S.)
4Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Universitàdegli Studi di
Milano, Milan 20122, Italy
5Department of Philosophy, Universitàdegli Studi di Milano, Milan 20122, Italy; claudio.lucchiari@unimi.it
*Correspondence: andrea.botturi@istituto-besta.it; Tel.: +39-022-394-2256
Academic Editor: Daqing Ma
Received: 6 April 2017; Accepted: 13 June 2017; Published: 16 June 2017
Abstract:
Huntington’s disease is a disorder that results in motor, cognitive, and psychiatric problems.
The symptoms often take different forms and the presence of disturbances of the psychic sphere
reduces patients’ autonomy and quality of life, also impacting patients’ social life. It is estimated that
a prevalence between 33% and 76% of the main psychiatric syndromes may arise in different phases of
the disease, often in atypical form, even 20 years before the onset of chorea and dementia. We present
a narrative review of the literature describing the main psychopathological patterns that may be
found in Huntington’s disease, searching for a related article in the main database sources (Medline,
ISI Web of Knowledge, Scopus, and Medscape). Psychiatric conditions were classified into two
main categories: affective and nonaffective disorders/symptoms; and anxiety and neuropsychiatric
features such as apathy and irritability. Though the literature is extensive, it is not always convergent,
probably due to the high heterogeneity of methods used. We summarize main papers for pathology
and sample size, in order to present a synoptic vision of the argument. Since the association between
Huntington’s disease and psychiatric symptoms was demonstrated, we argue that the prevalent
and more invalidating psychiatric components should be recognized as early as possible during
the disease course in order to best address psychopharmacological therapy, improve quality of life,
and also reduce burden on caregivers.
Keywords:
Huntington’s disease; psychiatric symptoms; cognitive impairment; affective and
nonaffective disorders.
1. Introduction
Huntington’s disease (HD) is a neurodegenerative disease inherited in an autosomal dominant
fashion, characterized by progressive movement disorders associated with cognitive and psychiatric
symptoms [
1
,
2
]. The first clinical picture of the illness was provided in 1842 by Waters. Not until 1872 did
George Huntington name the disease Huntington’s chorea, after a complete description of the symptoms
and clinical course. By the 1980s, the name of the disease became known as Huntington’s disease, with the
recognition of its motor and non-motor signs and symptoms [
3
]. Following the introduction of molecular
biology techniques, a linkage was found on chromosome 4 in 1983, and 10 years later the gene for HD
was discovered [
2
]. The underlying genetic defect is an unstable CAG trinucleotide repeat expansion
in exon 1 of the HD gene, formerly called IT-15, on the short arm of chromosome 4. A repeat CAG
Brain Sci. 2017,7, 67; doi:10.3390/brainsci7060067 www.mdpi.com/journal/brainsci
Brain Sci. 2017,7, 67 2 of 15
length of 36 and longer is pathogenic and results in the synthesis of an abnormal polyglutamic tract in
Huntington’s, a widely expressed protein of uncertain function [
4
,
5
] causing accumulation of intracellular
protein aggregates, neurotrophic factor deprivation, impairment of energetic metabolism, transcriptional
deregulation and, finally, hyperactivation of programmed cell-death mechanisms. Progressive dysfunction
and neuronal loss, mainly in the caudate nucleus and in the putamen, start several years before the onset
of motor symptoms. Along with basal ganglia pathology, neurodegeneration occurs in a large cortical
region, in the thalamus, hypothalamus, and cerebellum [6,7].
Dopamine, glutamate, and
γ
-aminobutyric acid are thought to be the most affected
neurotransmitters in HD and are currently the focus of pharmacotherapy [
8
]. The age of HD onset is
inversely correlated with the length of the expansion in people with 40 or more CAG repeats, who will
inevitably manifest the disease if they live a normal lifespan. In fact, when a number of CAG repeats
between 36 and 39 presents, the penetrance is variable. In addition, it has been suggested that there
may be subtle abnormalities, possibly constituting an endophenotype, in the rare individuals who
have repeat lengths in the 27–35 range [
1
,
2
,
6
]. A recent systematic review by Wexler et al. [
9
] estimated
a general incidence rate of 7.2 million people/years.
A meta-regression made by Pringssheim et al. [
10
] confirmed a significantly lower prevalence
of HD in Asia compared to Europe, North America, and Australia. In particular, recent studies in
a different part of the world reported that the prevalence should be updated with respect to older
studies before the advent of the molecular diagnosis of Huntington disease (HTT) studies. For instance,
Fisher et al [
11
] reported a prevalence in Canada of 17.2 in the Caucasian population per 100.00 and of
13.7 per 100.000 in the general population, while an Italian study reported a prevalence of 10.85 per
100.000 [12]. A lower prevalence is registered in Japan [13,14].
In most cases, the age of onset of HD is between 35 and 45 years, whereas the mean duration of
the disease is 16 years [
15
,
16
]. Different stages of the disease may be described (premanifest, with soft
signs, phenoconversion, and manifest), each being characterized by decreasing independence and
the need for help caused by a deterioration of motor and cognitive performance and the presence of
psychiatric symptoms [13].
Currently, symptomatic treatment is available for motor and psychiatric symptoms, but there is
still no evidence that therapy can slow the evolution of brain degeneration.
2. Methods
Searches were conducted through Medline, ISI Web of Knowledge, Scopus, and Medscape.
The following keywords or combinations were used: “apathy”, “behavioral”, “depression”,
“irritability”, “neuropsychiatric symptoms”, “psychiatric”, “psychotic”, “sexuality”, and “suicidal”.
We did not consider other terms that might impact psychiatric manifestations such as sleep, aggression,
and impulsive, in order to focus the search on the main psychiatric symptoms. In so doing, some
studies about specific psychiatric manifestations might have been excluded.
A total of 3055 papers were initially identified. A screening of the articles’ abstracts was then
performed in order to consider only those articles that concerned with the topic of the review and
removing duplicates.
Additional papers were identified during the reading (also during the revision process) and
analyzed to be assessed as a potential data source.
The initial search identified 3055 articles. One thousand eight hundred and twenty-nine papers
matched with term “psychiatric”, 495 “depression”, 137 “psychotic”, 43 “suicidal”, 35 “sexuality”,
62 “apathy”, 245 “behavioral”, 135 “neuropsychiatric symptoms”, and 74 “irritability”. An initial
review of the titles and abstracts of these articles by three of the authors identified 238 articles that were
potentially relevant to the current review. The abstracts of these articles were then evaluated against
the inclusion criteria by the authors, resulting in 82 articles being identified as eligible for inclusion,
with an additional six articles identified during manuscript preparation, for a total of 88 articles. This
Brain Sci. 2017,7, 67 3 of 15
review provides a narrative synthesis of the findings from previous key reviews and empirical studies
identified in the literature search.
Inclusion and exclusion criteria:
We included articles assessing the prevalence, incidence, and phenomenology of neuropsychiatric
and psychiatric symptoms in patients with HD. We included only articles reporting data about patients
with a genetic diagnosis. This suggested a lower time limit to the search that started from 1983. We also
included articles reporting data about the preclinical presentation of psychiatric and neuropsychiatric
symptoms. We didn’t posit limits to the sample size of the studies considered.
We excluded reviews, editorials, opinion papers, letters, surveys, and articles not clearly reporting
the methodology used, the sample size, and/or not written in English.
3. Clinical Features in HD and Psychiatric Disorders
Clinical pictures of HD comprise motor abnormalities (chorea, dystonia, bradykinesia, oculomotor
dysfunction), cognitive impairment, behavioral problems, and psychiatric disorders. The latter are
major constituents of the clinical spectrum of HD and have a substantial impact on daily functioning,
constituting the most distressing aspect (for both patient and relatives) and often the reason for
hospitalization [
17
,
18
]. In the early descriptions of HD, more attention was given to its cognitive
features and dementia. Starting in the literature published in the 1990s, many facets of HD have been
described including specific psychiatric aspects. Behavioral and psychiatric symptoms (also called
prodromal) often precede the manifestation of motor abnormalities of HD [
19
]. Historical description
estimated rates for lifetime prevalence of psychiatric disorders among HD patients vary widely
between 33% and 76% [20,21].
Several recent studies have described neuropsychiatric symptoms including depressed mood,
mania, irritability, anxiety, apathy, obsessions-compulsions, and psychosis. Prevalence variation
depends on the different methods used to detect and evaluate (e.g., interview, rating scales, self-report
questionnaires) (Table 1) [1,2225].
Table 1. Neuropsychiatric disturbances in mutation carriers.
Authors Number of Patients Study Design Incidence or Prevalence
Reedeker W. et al. [22] 91
Two-year observational cohort
study in symptomatic and
pre-symptomatic patients
14 out of 91 patients had a
psychiatric disorder within two
years after symptoms onset or
genetic diagnosis (15%).
van Duijn E. et al. [1] 154
Two-year observational cohort
study in symptomatic and
pre-symptomatic patients
36 out of 140 patients had a
psychiatric disorder (25.7%).
Symptomatic mutation carriers
did not differ from
presymptomatic mutation carriers.
Murgod U. A. et al. [23] 26
One-year prospective cohort study
in symptomatic and
pre-symptomatic patients
Three out of 26 of patients (11.5%)
had psychiatric symptoms.
Paulsen J. S. et al. [24] 52
Cross-sectional observational
study in symptomatic and
pre-symptomatic patients
98% of patients had at least one
neuropsychiatric symptom.
Leroi I. et al. [25] 21 Cross-sectional observational
study in symptomatic patients
17 out of 21 patients (81%)
showed psychiatric disorders.
This result contrasts with incidence rates found in other neurodegenerative diseases
(
e.g., Parkinson’s disease,
in which an incidence rate of major depressive disorder (MDD) of 2% per
year is reported) [
26
,
27
]. Furthermore, switching to a different psychiatric disorder is not rare. Many
factors, including rigid diagnostic criteria, presence of physical symptoms, cognitive impairment, and
patient medical history collected by informal caregiver interviews are considered confounding factors [
22
].
Brain Sci. 2017,7, 67 4 of 15
3.1. Affective Disorders
The most frequent psychiatric sign occurring in HD patients consists of a depressive
symptomatology (DS) [
28
]. The diagnosis is sometimes difficult because somatic expression of
depressed mood (i.e., apathy, inactivity, and weight loss) also occurs in HD patients without psychiatric
problems [
13
]. Estimated prevalence of depression in HD varies widely, ranging from 9% to 63%,
with several studies suggesting rates between 40% and 50% (Table 2) [
29
40
]. Kirkwood et al. (2001)
suggested that sadness and depression were two of the earliest symptoms at HD onset detected by
first-degree relatives’ reports [37].
Table 2. Depression in mutations carriers.
Author Number of Patients Study Design Incidence/Prevalence
Van Duijn et al. [29] 1993
Observational cohort study in
pre-symptomatic and
symptomatic patients
586 patients (29.4%) showed middle
depression; 254 (12.7%) moderate to severe.
Epping [30] 3803 Observational cohort study in
pre-symptomatic patients
Depressive symptoms were frequent (313 out
803 had symptoms of depression, ranging
from minimal to severe), but did not increase
as a function to the proximity of diagnosis.
Thompson J. C. et al. [
31
]
111 Three-year observational cohort
study in manifest HD patients
Depression symptoms, with longitudinal
prevalence rates from 18% to 71%.
Wetzel H. H. et al. [32] 1941
Retrospective multi-site study on
symptomatic and
pre-symptomatic patients
48.2% sought help for depression and 40.3%
were prescribed anti-depressant medication.
Anderson K. E. et al. [
33
]
1642 Observational cross-sectional
study in symptomatic patients
801 patients (48.8%) reported a hystory of
treatment for depression.
Julien C. L. et al. [34] 204
Case-control study on
symptomatic, pre-symptomatic
and non-carriers participants
18 mutation carriers out 89 had a history of
major depression.
Marshall J. et al. [35] 254
Case-control study on
symptomatic, pre-symptomatic
and non-carriers participants
Preclinical mutation carriers with motor
abnormalities and HD patients showed
higher level of depression than other groups.
Paulsen J. S. et al. [36] 2835 Observational cohort study in
manifest HD patients
50.3% of participants reported seeking
treatment for depression. Lower levels of
depression were found in later stages of the
disease.
Leroi I. et al. [25] 21
Case-control study comparing HD
manifest patients, Degenerative
Cerebellar (DC) disease, and
healthy controls
10 out 21 (42.8%) HD patients reported mood
disorders. Depression was significantly
higher in HD and DC patients than healthy
controls.
Kirkwood S. C. et al. [
37
]
1238
Observational cohort study in HD
manifest patients
Prevalence of depression varied from 7.5% to
22.5% at different disease stages (279, <1 year;
289, 2–5 years; 180, 6–10 years; 93, >10 years)
with the lowest rate at the end of the illness.
Murgod U. A. et al. [23] 26
One-year prospective cohort study
in symptomatic patients
Depression was extremely common and was
present in 17 out of 26 patients (65.4%).
Craufurd D. et al. [38] 134 Observational cross-sectional
study in HD manifest patients
33% of patients reported depression
symptoms.
Kulisevsky J. et al. [39] 29
Case-control study comparing HD
patients and other movement
disorders
HD patients had higher scores of depression
on the Neuropsychiatric Inventory
evaluation than patients with a hypokinetic
movement disorder.
Pflanz S. [40] 86
Retrospective study, in manifest
HD patients (not every patient
had HTT test)
42 out of 86 patients (52%) reported clinical
depression.
The development of DS in HD could be a direct result of cerebral degeneration, for which several
neuropathological mechanisms have been proposed [
41
,
42
] linked to an early neuronal loss in the
medial caudate, which has connections to limbic structures [
43
45
]. However, depression might
equally well be a consequence of other factors, such as a psychological reaction to being at risk for
Huntington’s disease, having experienced an insecure and harmful environment, and/or awareness of
Brain Sci. 2017,7, 67 5 of 15
the disease’s onset. From a physiological point of view, only a few studies investigated the presynaptic
dopaminergic function and no data are yet available on associations with affective symptoms [46,47].
Many studies have found that depressive symptoms precede the onset of motor symptoms but
no relation between the occurrence of depressive symptoms and disease duration has so far been
reported [
48
,
49
]. However, depression may negatively correlate to cognitive decline, which is possibly
the result of concurrent decreasing illness awareness [
38
] and worsened cognitive performance. This is
an important point because, if recognized, depression may be properly treated with potential positive
consequences on emotional, cognitive, and physical well-being [
50
]. Paulsen et al. analyzed the
relationship between depressive symptoms and disease stage [
36
] and found the highest rates in the
first stages of the disease and lower rates in last stages.
Van Duijn et al. [
1
,
29
] described depression as a common characteristic of the disease course, that
tends to correlate with the proximity to the clinical onset. Depression seems to increase during the
disease course but it is not relevant in the last stage. Furthermore, authors reported that depression is
not related to CAG length.
However, in an observational study (the PREDICT protocol study), Epping et al. [30] found that
the prevalence of symptoms in prodromal HD patients is not different than the general population.
Julien et al. [
34
] suggested that depression in this early phase cannot be attributed to a general
psychological condition linked to being at risk, since it occurs only in a fraction of mutation carriers.
No gender effect was found to be significant. This is in contrast with data on the general population,
but in other neurodegenerative diseases a similar pattern is observed.
Although depression is the most common specific psychiatric diagnosis in HD, a smaller number
of patients become manic, displaying elevated or irritable mood, impulsiveness, hyperactivity,
decreased need for sleep, and grandiosity. Some authors have estimated an average rate of mania
(with variable definitions of “mania”) of 4.8%, and others have found hypomania and manic episodes
in up to 10% of HD patients [
51
]. Particular attention should be paid to suicide risk. In his
original description of the disease, George Huntington stated that there was “a tendency to insanity
and suicide”. The suicide rate estimate for HD patients is traditionally 4–6 times higher than in
the general population. However, recent studies have confirmed the need to distinguish suicide
ideation from attempted suicide, as well as considering differently several groups with different
characteristics in order not to introduce confounding data. In particular, depressive symptoms,
anxiety, and benzodiazepine consumption are considered risk factors (Table 3) [
32
,
35
,
52
54
]. A history
of suicide attempts and the presence of depression are strongly predictive of suicidal behavior in
prodromal HD. Suicide risk increases in individuals who are closer to motor diagnosis [41].
Table 3. Suicidality in mutation carriers.
Author Number of Patients Study Design Incidence/Prevalence
Hubers A. A. M. et al. [52] 2106
Observational prospective multicentric
study on symptomatic and
pre-symptomatic mutation carriers
163 symptomatic and six pre-symptomatic
patients (169 out of 2016, 8%) had suicidal
ideation at baseline. At follow-up, among the
945 patients without suicidal ideation at
baseline, 52 had developed it (6%).
Hubers A. A. M. et al. [53] 152 Two-year observational cohort study on
symptomatic and pre-symptomatic
31 out of 152 patients (20%) reported
suicidality at baseline, without differences
between symptomatic and pre-symptomatic.
At follow-up, seven out of 100 (7%)
developed suicide ideation.
Wetzel H. H. et al. [32] 1941 Retrospective multi-site study on
symptomatic and pre-symptomatic patients
360 out of 1941 reported current suicidal
ideation, while 26.5% admitted a previous
history of suicidal ideation. 184 patients
(9.5%) reported at least one suicide attempt.
Fiedorowicz J. G. et al. [
54
]
735 Retrospective study on pre-symptomatic
patients
12 out of 735 (1.6%) attempted suicide, while
one completed suicide.
Paulsen J. S. et al. [55] 4171
Observational study on pre-symptomatic
and symptomatic patients and people at
risk for disease
Suicidal ideation increased from no and soft
signs of disease to possible HD (up to 23.5%),
while decreasing in manifest HD patients.
Brain Sci. 2017,7, 67 6 of 15
3.2. Anxiety
Anxiety has often been reported in HD patients, independent of gender (17%–61%), both due
to the course of the disease and from the neurodegenerative process itself. There are contrasting
data regarding the critical stage for anxiety and depression to arise, with some studies identifying
stage 2 as the most critical and others suggesting stages 4–5. Moreover, some studies have reported
that the stage of illness in HD patients does not influence anxiety levels, contrary to depression
symptoms [
56
]. As stated above, assuming benzodiazepine seems to be an independent risk factor for
suicide (Table 4) [2224,34,36,38,52].
Table 4. Anxiety in mutations carriers.
Authors Number of Patients Study Design Incidence/Prevalence
Hubers A. A. M. et al. [52] 2106
Observational prospective multicentric
study on symptomatic and
pre-symptomatic mutation carriers
641 of 1937 (33.1%) reported significant
anxiety levels without suicidal ideation;
114 of 69 (67.5%) with suicidal ideation had
also high anxiety.
Reedeker R. C. et al. [22] 106
Two-year observation cohort study on
pre-symptomatic, symptomatic patients
and a non-carrier control group
Three patients had a diagnosis of anxiety at
baseline and four were diagnosed after
two years.
Julien C. L. et al. [34] 204
Case-control study on symptomatic,
pre-symptomatic and non-carriers
participants
No differences in anxiety levels were found
between groups.
Paulsen J. S. et al. [36] 2835 Observational cohort study in patients
with manifest HD 41% endorsed symptoms of anxiety.
Paulsen J. S. et al. [24] 52 Observational cross-sectional study in
patient with manifest HD
51.9% were found to have anxiety symptoms.
Murgod U. A. [23] 26 One-year prospective study in
symptomatic patients 61.5% showed anxiety symptoms.
Craufurd D. et al. [38] 134 Observational cross-sectional study in
HD manifest patients 37% had significant anxiety levels.
3.3. Irritability and Aggression
Irritability (Irr) is a common clinical problem in patients with neuropsychiatric disorders. It has
been described in HD, traumatic brain injury [57,58], dementias [59], and Parkinson’s disease [60].
Studies have linked irritability and hostility to other aspects of morbidity, including treatment
non-adherence [
61
], suicide attempts [
62
,
63
], and violence. While the term “irritability” is widely used
in descriptions of patient behavior, but it remains poorly defined. This lack of consensus prompted a
definition of Irr, in addition to arguing that irritable mood is separate from other mood disorders such
as depression.
Irritation may be defined as a temporary psychological state characterized by impatience,
intolerance, and poorly controlled anger. It includes elements of anger, aggression, and reduced
impulse control and can occur independently of depression. Prevalence of Irr among HD patients
varies between 35% and 73% (Table 5) [23,24,29,38,6365].
Irr without a prior history of similar symptoms occurs in most HD patients and seems to precede
motor symptoms in gene carriers [
23
,
66
]. Often Irr is described as the first sign of the disease in
pre-symptomatic patients with HD [
1
] but it may occur during all stages of the disease, more frequently
in patients whose neurological symptoms have been present for 6 to 11 years [50].
The prevalence of moderate to severe irritability/aggression increased during the disease
course [29,67].
Increasing degeneration of the striatum and the orbitofrontal-subcortical circuit contributes to the
development of socially inappropriate behaviors that initially may be manifested as subtle irritability
and, in late-stage disease, as aggressive behavior [
68
]. Nevertheless, it is established that some patients
may show paradoxical “aggressive” behavior or behavioral disinhibition following benzodiazepine
consumption [
63
]. Taken together, Irr, depression, and anxiety are three salient clinical features of
pre-symptomatic HD.
Brain Sci. 2017,7, 67 7 of 15
Table 5. Irritability in mutation carriers.
Authors Number of Patients Study Design Incidence/Prevalence
Van Duijn E. et al. [29] 1993 Observational cohort study in
pre-symptomatic and symptomatic patients
493 patients (24.7%) showed mild
irritability; 277 showed (13.9%) moderate to
severe irritability.
Reedeker N. et al. [64] 130
Two-year observation cohort study on
pre-symptomatic, symptomatic patients
and a non-carriers control group
45 out of 130 (35%) had high irritability
scores. Carriers had significantly higher
scores than non-carriers.
Orth M. et al. [65] 1766 Observational cohort study on patients
with manifest HD
244 of 1343 patients (19.1%) reported
disruptive or aggressive behavior.
Craufurd D. et al. [38] 134 Observational cross-sectional study in HD
manifest patients
44% reported irritability severity score of
2 or more.
Murgod U. A. et al. [23] 26
One-year prospective study in symptomatic
patients
19 out of 26 patients (73%) reported an
irritable behavior.
Paulsen J. S. et al. [24] 52 Observational study in patient with
manifest HD
65.4% of patients was reported to
show irritability.
Marder K. et al. [66] 960
Prospective observational study on patients
with manifest HD
63.6% showed some aggressive behavior at
their first visit.
3.4. Obsessivity
The presence of obsessive and compulsive symptoms (OCs) has been previously documented
in patients with HD as less common than other psychiatric symptoms [
65
,
69
72
]. However, a study
by Marder et al. reported that 22.3% had obsessive and compulsive symptoms at their first clinical
visit, suggesting that these symptoms may be more common than previously recognized in this
population. This symptom shows an increase with disease progression with a trend similar to the one
of depression and anxiety in the end stage of the disease. Anderson et al. reported that patients with
severe OCs have higher psychiatric co-morbidity (e.g., depression, aggression, and delusions) and
neuropsychological deficits.
OCs prevalence varies from 7% to 50% and this association is not surprising, as dysfunction of
cortico-striatal connections is also a characteristic of primary disease [
67
,
73
,
74
]. The prevalence of
moderate to severe OCs increased progressively [
29
]. van Duijn et al. also reported a higher than
normal prevalence of OCs in preclinical mutation carriers [1].
Many HD gene-carriers show personality changes with mental inflexibility in early stages, possibly
signaling future OCs (Table 6) [23,29,33,38,65,75].
Table 6. OCs in mutation carriers.
Authors Number of Patients Study Design Incidence/Prevalence
van Duijn E. et al. [29] 1993 Observational cohort study in
pre-symptomatic and symptomatic patients
252 out of 1993 patients (12.6%) showed
mild OCs; 363 showed (13.2%) moderate to
severe OCs.
Beglinger L. et al. [76] 3964
Obervational cohort study on individuals at
risk for HD
OC symptoms increased with greater
diagnostic certainty and functional
impairment. High rates of obsessive (13%)
and compulsive (7%) behaviors were found
also in patients with soft neurological signs.
Craufurd D. et al. [38] 134 Observational cross-sectional study in HD
manifest patients 5% reported obsession symptoms.
Murgod U. A. et al. [23] 26 One-year prospective study in
symptomatic patients
Four out of 26 patients reported obsessions
and three reported compulsions.
Anderson K. E. et al. [
33
]
1642 Observational study in
symptomatic patient
446 out of 1642 patients (27.2%) had OC
symptoms; 217 (48.7%) reported only
obsessive symptoms, 165 (39.6%)
experienced both obsessive and compulsive
symptoms, and 52 (11.7%) had only
compulsions.
Marder K. S. et al. [66] 960
Prospective observational study on patients
with manifest HD
22.3% had obsessive and compulsive
symptoms at their first clinic visit.
Brain Sci. 2017,7, 67 8 of 15
3.5. Psychosis
Prevalence of psychotic symptoms (PS), including paranoia and delusional and psychotic states
resembling various types of schizophrenia-like psychosis, varies between 3% and 11% [
1
]. The association
of PS with HD is a consequence of a relative hyperdopaminergic state (Table 7) [23,24,29,38,40,48,76,77].
Table 7. Psychosis in mutation carriers.
Authors Number of Patients Study Design Incidence/Prevalence
van Duijn E. et al. [29] 1993 Observational prospective study on
presymptomatic and symptomatic patients
58 (2.9%) "mild psychosis“, and 23 (1.2%)
scoring "moderate to severe psychosis“.
The highest prevalence of psychosis (2.5%)
was in stage 3.
Grabski B. et al. [77] 1 Case report
Schizophrenia-like psychotic symptoms in
a patient with confirmed Huntington’s
disease: a case report.
Chuo Y. P. et al. [78] 1 Case report
Juvenile Huntington’s disease presenting as
difficult-to-treat seizure and the first
episode of psychosis.
Pflanz S. et al. [40] 86 Retrospective study, symptomatic patients Prevalence between 8.8% to 11.5%.
Folstein et al. [48] 34 Observational study HD manifest patients
and their offsprings
Two out of 34 patients showed signs of a
psychotic disorder.
Craufurd D. et al. [38] 134 Observational cross-sectional study in HD
manifest patients 5% had signs of a psychotic disorder.
Murgod U. A. et al. [23] 26 One-year prospective study in
symptomatric patients 11.5% had signs of a psychotic disorder.
Paulsen J. S. et al. [24] 52 Observational cross-sectional study in
motor symptomatic patients
12% was diagnosed with a
psychotic disorder
Until the first half of the twentieth century, HD patients were often misdiagnosed with dementia
praecox or schizophrenia. Now, the low prevalence of PS may be explained by the relatively high use of
antipsychotics. PS do not have a specific presentation and must be carefully distinguished from non-organic
mental diseases. Some of the patients have a peculiar presentation, as reported by some case reports.
A lack of clinical fluctuation course is typical of a delirium state. PS are usually associated with
increasing cognitive impairment and tend to become less overt as the disease progresses. They were
found to be particularly important in an advanced stage of the disease. Those patients with an early
age at onset of HD seem to be at an increased risk of psychoses [
71
]. A very low prevalence should be
explained by a frequently use of neuroleptics [29].
3.6. Apathy and Neuropsychological Deficits
Apathy (AP) has been described both as a symptom (i.e., of mood disorder, altered level of
consciousness, or cognitive impairment) and as a syndrome [
78
,
79
]. It is defined as a disorder of
motivation, with the loss of or diminished goal-directed behavior, cognitive activity, and/or emotion,
as well as functional impairments that are attributable to apathy [
80
,
81
]. Clinically, it is associated with
a decline of daily living activities causing a great burden of disease and distress in caregivers, [
82
] also
after adjusting for the presence of motor and cognitive deficits. Sometimes it is hard to discriminate
apathy from depression core symptoms [
21
]. Prevalence of AP is a common neuropsychiatric feature
of HD and varies from 52% to 76% (Table 8) [
24
,
29
,
38
] and, once present, tends to persist or worsen,
with highest rate in the late stage of disease [29].
Brain Sci. 2017,7, 67 9 of 15
Table 8. Apathy symptoms in mutation carriers.
Authors Number of Patients Study Design Incidence/Prevalence
van Duijn E. et al. [29] 1993
Observational
prospective study on
presymptomatic and
symptomatic patients
385 (19.3%) presented mild apathy; 560
(28.1%) presented moderate to severe apathy.
Craufurd D. et al. [38] 134 Cross-sectional study
in HD manifest patients
70% showed apathy symptoms. Apathy was
highly correlated with duration of illness.
Paulsen J. S. et al. [24] 52 Cross-sectional study
HD manifest patients 55.8% presented apathy.
Damage to anterior cingulate-subcortical circuit structures has in particular been related with
motivational disorders, including apathy, which may also be the case in HD [
49
,
82
]. AP has also been
correlated with other symptoms of HD, particularly with cognitive impairments, including problems
with working memory, planning, problem solving, and executive function deficits [83].
Psychomotor abilities (e.g., hand-eye coordination tasks such as throwing a ball or typing) are
significantly impaired, showing a consistent decline across disease progression, while difficulties
in visuospatial and memory abilities occur later in HD [
82
]. In patients with dementia and apathy,
a faster cognitive and functional decline has been found compared to patients without apathy. One
final example of frontal behaviors that might be relevant in HD is decreased awareness or loss of
insight. Although anecdotal evidence of decreased awareness of symptoms has been reported in HD,
few studies have investigated this area. Neuropsychological deficits seem to be particularly relevant
among patients with early HD onset.
Many motor and non-motor symptoms in HD have been attributed to subcortical dysfunction
(
e.g., striatum
) and the connecting circuitry with the frontal lobes [
84
]. For example, executive
dysfunction on cognitive tasks (i.e., set shifting, response inhibition) has been linked with the
dorsolateral subcortical circuit and dorsolateral prefrontal cortex deficits [85].
On the other hand, neuroleptic sensitivity may also impact apathy, in particular increasing
sedation and emotional blunting [86].
3.7. Disinhibition, Impulsivity, and Sexual Disorders
Fewer studies have examined disinhibition, which includes impulsivity, hyperactivity, emotional
lability and “acting out”, in HD and they have not found this symptom to be particularly prominent
in these patients [
83
]. Changes in sexuality have been well documented in HD. Disorders of sexual
functioning, such as hypoactive sexual desire and inhibited orgasm have been reported in men, with
rates of 63% and 56%, respectively [
87
]. In female patients, 75% had hypoactive sexual desire, and 42%
had inhibited orgasm. Also, sexual aberrations, such as sexual assault, promiscuity, incest, indecent
exposure, and voyeurism, have all been described in HD [
64
]. The etiology of these abnormalities
may be related to specific psychiatric syndromes prevalent in HD, such as mania, to the underlying
neurotransmitter deficits of HD, or to medication effects. There is some evidence that male HD
patients with both inhibited orgasm and increased sexual interest are at higher risk of developing
paraphilias [88].
Hypersexual behavior is more prevalent in men, ranging from 3.9%–30% vs. 2.1%–25% in
women [
72
,
87
,
88
]. In a pioneer study, Dewhurst et al. [
72
] reported in their article some social
consequences of these symptoms. In 30 out of 102 patients studied, the authors found abnormal sexual
behaviors, with 18.6% showing hypersexuality. In another study, Bolt [
88
] found that only 20 (6%) out
of 334 patients had increased libido or sexual deviation, and Oliver [
89
] also reported 6% of patients
displaying similar behavior.
Craufurd et al. interviewed 134 patients attending an HD management clinic using the Problem
Behaviors Assessment for HD (PBA-HD) [
36
]. Uninhibited sexual behavior was reported by 6% of the
patients, while demanding or persistent sexual behavior was described in 5% (Table 9) [38,88].
Brain Sci. 2017,7, 67 10 of 15
Table 9. Sexual dysfunction in mutation carriers.
Authors Number of Patients Study Design Incidence/Prevalence
Craufurd D. et al. [38] 134 Observational cross-sectional
study in HD manifest patients
Eight out 134 patients (6%),
hypersexuality; 82 (61%)
hyposexuality.
Fedoroff J. P. et al. [88] 39 Observational cross-sectional
study on HD manifest patients
32 out of 39 patients experienced
at least one sexual disorder
3.8. Pre-Symptomatic HD and Psychiatric Disorders
Previous findings have suggested, although inconclusively, that psychopathology as well as
cognitive dysfunction may precede the onset of motor symptoms in many patients [
90
,
91
]. Now, with
the availability of a genetic test, it is possible to identify individuals who have CAG trinucleotide repeat
expansion in the pathological range but are not yet showing sufficient motor signs for the diagnosis of
clinical disease (i.e., pre-symptomatic gene carriers/subjects). Thus, it is now possible to study the
relationship between genetic data and individuals’ characteristics before disease onset. Indeed, several
studies have found subtle motor, cognitive, psychiatric, and neuroimaging abnormalities in HD years
before diagnosis [92].
Regarding depressive symptoms, data on pre-symptomatic patients are still controversial, with
some studies reporting a greater prevalence of MDD and depressive symptoms in both symptomatic
and pre-symptomatic mutation carriers than non-carriers, and others reporting no differences [
1
,
93
].
From the existing literature, it is unclear how early behavioral manifestations of frontal dysfunction
occur in HD. Duff et al. [
19
], using a pre-HD cohort, have previously reported on subtly elevated
psychiatric symptoms in individuals prior to diagnosis. Some of these symptoms may reflect
frontal disturbances (e.g., obsessive-compulsiveness, interpersonal sensitivity, hostility) in pre-HD.
The authors hypothesized that pre-HD, expansion-positive individuals would report higher levels
of frontal behaviors compared to expansion-negative individuals. Not only are apathy, disinhibition,
and executive dysfunction more prevalent in the gene-expanded group, they are also associated with
other markers of disease progression in HD.
4. Conclusions
Psychiatric disturbances are a constituent core of HD; this is known by the disease’s first
description. The pathways leading to psychopathology in HD are still not completely clear. Indeed,
several findings suggest that both neuropathology and environmental stress contribute to the
occurrence of neuropsychiatric phenomena [
15
]. One characteristic feature is continuous change
in the clinical presentation of symptoms, complicating nosography and pharmacological treatment.
It is clear that not only depression and anxiety are typical symptoms of HD, but also a number
of other psychological, behavioral, and cognitive symptoms that may deeply impair quality of life
of patients and relatives. Diagnosing and acknowledging the presence of psychopathology in HD is
of major importance and may help patients and their families cope better with the severe symptoms
of this progressive disease. It is thus vital to confront these problems from the beginning of the
disease journey. First of all, diagnosis communication should be the first step of a long trip in which
patients and relatives must know what is going to happen and how to face it [
17
]. Communication
support and psychological counseling should then be guided by the knowledge of the psychiatric
course that the disease could take. At the same time, a good communication channel should always
be open to patients, relatives, and the medical team in order to enable timely response to the rise of
psychiatric or cognitive symptoms. Pharmacological treatment should be properly used in a timely
fashion (e.g., avoiding Xenazine in patients with severe depression at high risk of suicidality and
preferring anti-impulsive treatment) in order to prevent breakdown and potential social and familial
consequences. In addition, drug interactions should be also monitored to prevent adverse or even
Brain Sci. 2017,7, 67 11 of 15
paradoxical reactions. An adequate symptomatic treatment can improve the quality of life of HD
patients and their caregivers [94].
The HD treatment (psychopharmacological and/or psychological support) is based at present
on a difficult integration of the still scarce experimental evidence and experience gained in the
field, integration that is left to the clinician (or the clinical team), with indisputable and urgent
decision-loading. In an attempt to define a good clinical practice in the context of HD, some treatment
algorithms have been developed whose initial assumption remains the need for tailored interventions,
responding not only to the patient’s overall health condition (co-morbidity and contraindications to
treatment) but also to the patient’s needs and preferences.
Acknowledgments: No funds were received for this study.
Author Contributions:
A.B. and R.A.P. designed the study protocol and performed the first search and related
analyses; C.P., E.C. and E.Z. supported the second phase of the analysis, reading the article and commenting
them with other authors; A.C. and V.S. read all the selected articles in order to figure out the most relevant
issues, also comparing the actual literature with the historical pictures of HD. C.L. considered psychological and
neuropsychological aspects of articles:, R.A.P., A.B. and LC wrote the first draft of the article and edited following
revisions. All authors read, discussed and accepted the final version.
Conflicts of Interest: The authors declare no conflict of interest.
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... Huntington's disease (HD) is a fatal, neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4 (OMIM 143100). Cognitive and psychiatric changes are prominent throughout the course of HD and often manifest prior to onset of motor symptoms (Epping et al., 2016;Paoli et al., 2017;You et al., 2014). Adult carriers can present with executive dysfunction, including difficulties with attention, working memory, planning, and self-monitoring (Julio et al., 2019;Larsen et al., 2015). ...
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Introduction We compared neuropsychiatric symptoms between child and adolescent huntingtin gene‐mutation carriers and noncarriers. Given previous evidence of atypical striatal development in carriers, we also assessed the relationship between neuropsychiatric traits and striatal development. Methods Participants between 6 and 18 years old were recruited from families affected by Huntington's disease and tested for the huntingtin gene expansion. Neuropsychiatric traits were assessed using the Pediatric Behavior Scale and the Behavior Rating Inventory of Executive Function. Striatal volumes were extracted from 3T neuro‐anatomical images. Multivariable linear regression models were conducted to evaluate the impact of group (i.e., gene nonexpanded [GNE] or gene expanded [GE]), age, and trajectory of striatal growth on neuropsychiatric symptoms. Results There were no group differences in any behavioral measure with the exception of depression/anxiety score, which was higher in the GNE group compared to the GE group (estimate = 4.58, t(129) = 2.52, FDR = 0.051). The growth trajectory of striatal volume predicted depression scores (estimate = 0.429, 95% CI 0.15:0.71, p = .0029), where a negative slope of striatal volume over time was associated with lower depression/anxiety. Conclusions The current findings show that GE children may have lower depression/anxiety compared to their peers. Previously, we observed a unique pattern of early striatal hypertrophy and continued decrement in volume over time among GE children and adolescents. In contrast, GNE individuals largely show striatal volume growth. These findings suggest that the lower scores of depression and anxiety seen in GE children and adolescents may be associated with differential growth of the striatum.
... Huntington's disease (HD) is a neurodegenerative disease caused by expansion of the trinucleotide repeat (cytosine adenine guanine; CAG) in the huntingtin (HTT) gene on chromosome 4 (Pender andKoroshetz 2011, Podvin et al. 2019). Apathy is a highly prevalent and functionally debilitating neuropsychiatric symptom in HD, for which there are currently no clinically effective treatments (Fritz et al. 2018, Jacobs, Hart, and Roos 2018, Martinez-Horta et al. 2016, Paoli et al. 2017. Degeneration and dysfunction within the cortico-basal gangliathalamocortical (CBGT) networks contributes to the motor, cognitive and psychiatric symptoms in HD, including apathy (Papoutsi et al. 2014, Ross et al. 2014, Ross et al. 2017. ...
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We investigated the effects of transcranial alternating current stimulation (tACS) targeted to the bilateral medial prefrontal cortex (mPFC) and administered at either delta or alpha frequencies, on brain activity and apathy in people with Huntingtons disease (HD) (n = 17). Neurotypical controls (n = 20) were also recruited for comparison. All participants underwent three 20-minute sessions of tACS; one session at alpha frequency (Individualised Alpha Frequency (IAF), or 10Hz when an IAF was not detected); one session at delta frequency (2Hz); and a session of sham tACS. Participants completed the Monetary Incentive Delay (MID) task with simultaneous recording of EEG immediately before and after each tACS condition. The MID task presents participants with cues signalling potential monetary gains or losses that increase activity in key regions of the cortico-basal ganglia-thalamocortical networks, with dysfunction of the latter network being implicated in the pathophysiology of apathy. We used the P300 and Contingent Negative Variation (CNV) event-related potentials elicited during the MID task as markers of mPFC engagement. HD participants CNV amplitude significantly increased in response to alpha-tACS, but not delta-tACS or sham. Neurotypical controls P300 and CNV were not modulated by any of the tACS conditions, but they did demonstrate a significant decrease in post-target response times following alpha-tACS. We present this as preliminary evidence of the ability of alpha-tACS to modulate brain activity associated with apathy in HD.
... These include, among others, impaired attention and set-shifting (cognitive skills key for adaptive behavior) and depression, anxiety, and irritability (common mood disorders in HD). 6,129 Both mood and cognition can also influence goal-directed behavior. For example, heightened emotional arousal, independent of motivational state, increases effort production in incentive motivation tasks, 130 while aspects of depression are associated with altered reward processing. ...
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A caregiver's all‐too‐familiar narrative ‐ “He doesn't think through what he does, but mostly he does nothing.” Apathy and impulsivity, debilitating and poorly understood, commonly co‐occur in Huntington's disease (HD). HD is a neurodegenerative disease with manifestations bridging clinical neurology and psychiatry. In addition to movement and cognitive symptoms, neurobehavioral disturbances, particularly apathy and impulsivity, are prevalent features of HD, occurring early in the disease course, often worsening with disease progression, and substantially reducing quality of life. Treatments remain limited, in part because of limited mechanistic understanding of these behavioral disturbances. However, emerging work within the field of decision‐making neuroscience and beyond points to common neurobiological mechanisms underpinning these seemingly disparate problems. These insights bridge the gap between underlying disease pathology and clinical phenotype, offering new treatment strategies, novel behavioral and physiological biomarkers of HD, and deeper understanding of human behavior. In this review, we apply the neurobiological framework of cost‐benefit decision making to the problems of apathy and impulsivity in HD. Through this decision‐making lens, we develop a mechanistic model that elucidates the occurrence of these behavioral disturbances and points to potential treatment strategies and crucial research priorities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
Chapter
Huntington’s disease (HD) is a devastating neurodegenerative disease that results in motor, cognitive, and psychiatric impairments. HD results from an autosomal dominant polyglutamine expansion in the huntingtin (HTT) gene that results in a misfolded and aggregated protein. The disease is uniformly fatal and demonstrates characteristic neuropathological changes. While the striatum is preferentially affected, the cortex and many other brain regions are involved in pathogenesis and show progressive changes throughout the disease.
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Introduction Huntington's disease (HD) is a neurodegenerative and hereditary disorder, due to the predictive diagnosis, incipient clinical characteristics have been described in the prodromal phase. Several studies have reported an increase in psychiatric symptoms in carriers of the HD gene without motor symptoms. Objective: to identify psychological distress in carriers of the mutation that causes HD, without motor symptoms, utilizing the Symptom Checklist 90 (SCL-90), and to correlate with the burden and proximity of the disease. Method A sample of 175 participants in a HD Predictive Diagnostic Program (PDP-HD) was divided into HEP carriers (39.4%) and NPEH non-carriers (61.6%) of the HD-causing mutation. By means of mathematical formulas, the disease burden and proximity to the manifest stage in the PEH group were obtained and it was correlated with the results of the SCL-90-R. Results Comparing the results obtained in the SCL-90-R of the PEH and NPEH, the difference is observed in the positive somatic male index, where the PEH obtains higher average scores. The correlations between disease burden and psychological distress occur in the domains; obsessions and compulsions, interpersonal sensitivity, hostility, global severity index and positive somatic distress index. A low correlation is observed between the burden of disease and the scores obtained in psychological discomfort. Conclusions In general, we found that the PEH group obtained a higher score in the dimensions evaluated with the SCL-90-R, showing a relationship with the burden and differences due to the proximity of the disease. Higher scores on the SCL-90-R dimensions in carriers of the HD gene may suggest an early finding of psychological symptoms in the disease.
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All of the major movement disorders (Parkinson's disease, Huntington's disease, Tourette syndrome) have important associated psychiatric dimensions. These if co-occurring together, cause signicant clinical burden and effect patients' quality of life and prognosis gets affected. Similarly, many of the major psychiatric disorders (such as Schizophrenia and Depression), involve abnormalities of movement. Many psychotropic medications are also known to cause movement disorders. A clinician should always assess the psychiatric comorbidities in relation to movement disorders that will help to build a holistic and pragmatic approach to management and consequently, improve the quality of life of the patient.
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Resumen Introducción La enfermedad de Huntington (EH) es un trastorno neurodegenerativo y hereditario. A partir del diagnóstico predictivo se han descrito características clínicas incipientes en la fase prodrómica, y varios estudios han reportado aumento de síntomas psiquiátricos en portadores de la mutación causante de la EH, sin síntomas motores, en esta fase. Objetivo Identificar malestar psicológico en portadores de la mutación causante de la EH sin síntomas motores, mediante el Symptom Checklist 90 (SCL-90), y correlacionar con la carga y cercanía de la enfermedad. Método Una muestra de 175 participantes de un Programa de Diagnóstico Predictivo de EH (PDP-EH) se dividió en portadores PEH (39,4%) y no portadores NPEH (61,6%) de la mutación causante de EH. Mediante fórmulas matemáticas se obtuvo la carga de enfermedad y cercanía a la etapa manifiesta en el grupo PEH y se correlacionó con los resultados del inventario SCL-90-R. Resultados Al comparar los resultados obtenidos en el SCL-90-R de los PEH y NPEH, la diferencia se observa en el índice de malestar por síntomas positivos, donde los portadores obtienen mayor puntuación promedio. Las correlaciones entre carga de enfermedad y síntomas psicológicos se dan en los dominios: obsesiones y compulsiones, sensibilidad interpersonal, hostilidad, índice de severidad global e índice de malestar somático positivo. Se observa una correlación baja entre la carga de enfermedad y las puntuaciones obtenidas en el malestar psicológico. Conclusiones En general encontramos que el grupo PEH obtiene un puntaje mayor en las dimensiones evaluadas con el SCL-90, muestran relación con la carga y diferencias por la cercanía de la enfermedad. Puntajes mayores en las dimensiones del SCL-90-R en portadores del gen para la EH pueden sugerir un hallazgo temprano de la sintomatología psicológica en la enfermedad.
Chapter
This reference is the definitive guide to common neurodegenerative diseases that affect humans. The book covers mechanisms of some of the most well-known neurodegenerative diseases, their biomarkers, neuropharmacology, and emerging treatment strategies. The book introduces the subject of neurodegeneration by outlining the biochemistry, pathophysiology and multifactorial neurological mechanisms (the role of genetics, environmental factors and mitochondrial damage, for example). Next, it explains some of the most studied diseases, namely, Parkinson's Disease, Alzheimer's Disease, Huntington’s Disease, and Multiple Sclerosis. Subsequent chapters delve into current knowledge about diagnostic and immunological biomarkers, followed by a summary of novel therapeutic strategies. Special attention has been given to the role of medicinal plants in attempting to treat neurodegenerative diseases, as well as the public health burden posed by these conditions. Key Features - give readers an overview of multifactorial disease mechanisms in neurodegeneration - covers some major neurodegenerative diseases in detail - covers diagnostic and immunological biomarkers - explores current therapeutic strategies and drug targets in common neurodegenerative diseases - offers a simple presentation with references for advanced readers The book is a suitable reference for all readers, including students, research scholars, and physicians who are interested in the mechanisms and treatment of neurodegenerative diseases.
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Objectives The prevalence of Huntington's disease (HD) recorded in the UK primary care records has increased twofold between 1990 and 2010. This investigation was undertaken to assess whether this might be due to an increased incidence. We have also undertaken a systematic review of published estimates of the incidence of HD. Setting Incident patients with a new diagnosis of HD were identified from the primary care records of the Clinical Practice Research Datalink (CPRD). The systematic review included all published estimates of the incidence of HD in defined populations. Participants A total of 393 incident cases of HD were identified from the CPRD database between 1990 and 2010 from a total population of 9 282 126 persons. Primary and secondary outcome measures The incidence of HD per million person-years was estimated. From the systematic review, the extent of heterogeneity of published estimates of the incidence of HD was examined using the I2 statistic. Results The data showed that the incidence of HD has remained constant between 1990 and 2010 with an overall rate of 7.2 (95% CI 6.5 to 7.9) per million person-years. The systematic review identified 14 independent estimates of incidence with substantial heterogeneity and consistently lower rates reported in studies from East Asia compared with those from Australia, North America and some—though not all—those from Europe. Differences in incidence estimates did not appear to be explained solely by differences in case ascertainment or diagnostic methods. Conclusions The rise in the prevalence of diagnosed HD in the UK, between 1990 and 2010, cannot be attributed to an increase in incidence. Globally, estimates of the incidence of HD show evidence of substantial heterogeneity with consistently lower rates in East Asia and parts of Europe. Modifiers may play an important role in determining the vulnerability of different populations to expansions of the HD allele.
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Objective: Neuropsychiatric symptoms are common in Huntington's disease and have been considered its presenting manifestation. Research characterising these symptoms in Huntington's disease is variable, however, encumbered by limitations within and across studies. Gaining a better understanding of neuropsychiatric symptoms is essential, as these symptoms have implications for disease management, prognosis, and quality of life for patients and caregivers. Method: Fifty two patients with Huntington's disease were administered standardised measures of cognition, psychiatric symptoms, and motor abnormalities. Patient caregivers were administered the neuropsychiatric inventory. Results: Ninety eight per cent of the patients exhibited neuropsychiatric symptoms, the most prevalent being dysphoria, agitation, irritability, apathy, and anxiety. Symptoms ranged from mild to severe and were unrelated to dementia and chorea. Conclusions: Neuropsychiatric symptoms are prevalent in Huntington's disease and are relatively independent of cognitive and motor aspects of the disease. Hypothesised links between neuropsychiatric symptoms of Huntington's disease and frontal-striatal circuitry were explored. Findings indicate that dimensional measures of neuropsychiatric symptoms are essential to capture the full range of pathology in Huntington's disease and are vital to include in a comprehensive assessment of the disease.
Article
Introduction Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder, that typically manifests in adulthood, clinically characterized by progressive motor, cognitive and psychiatric/behavioural symptoms. Psychiatric symptoms are common in HD. The presentation of these symptoms is highly variable, and their course does not correlate with motor or cognitive disease progression. Psychiatric symptoms often precede motor onset by many years. Objectives The authors intend to review the literature the most frequent psychiatric disorders in patients with HD. Methods Non-systematic review of the literature. Results Psychiatric symptoms have been a core feature of HD. Pre-symptomatic HD patients exhibit a greater prevalence of psychiatric symptoms, particularly affective disorders. This symptoms are presenting symptoms of HD in up to half of all people. In symptomatic HD patients, it is estimated that up to 73–98% of patients will have a major psychiatric disorder or psychiatric symptoms. Psychiatric manifestations in HD include depression, irritability, apathy, anxiety, mania, perseverations, obsessions and psychosis. Cognitive changes include progressive deficits in attention, learning, executive and sensory functions, resulting in dementia. Depression, diagnosed in half of patients with HD, is the most common and earliest symptoms prior to the motor onset. There are likely multiple causes of the psychiatric symptoms, with underlying factors including a combination of neurobiological, cognitive, psychological, social and environmental factors. Conclusions Patients with HD have high psychiatric comorbidity, that causes significant functional impairment and affect quality of life. Thus, they require a multidisciplinary approach in the recognition and treatment of psychiatric symptoms.
Article
Huntington disease (HD) prevalence shows geographic variability and has been recently updated by taking in account the mutation diagnostic test. In Italy, the last epidemiological estimation was reported well before the HTT gene discovery and the availability of the corresponding genetic test. It reported a prevalence of affected subjects ranging between 2.3 to 4.8/100,000 in some restricted areas of Northern Italy. We have performed a service-based epidemiological analysis in a very restricted geographic area named Molise, where our institutions currently operate and represent the only point of reference for rare neuropsychiatric diseases. The estimated prevalence found was of 10.85/100,000 (95% CI: 7.20-14.50), remarkably higher than that previously described before the gene test analysis was available, and expected to increase of an additional 17% by 2030, due to Italian population aging. According to our analysis, we estimate that about 6,000 subjects are currently affected by HD in Italy, and that this number will further increase in the next decades due to population aging, variable phenotype penetrance and improved life expectancy. This article is protected by copyright. All rights reserved.
Article
Background Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD. Methods The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis. Results At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9–1.0), anxiety (OR=2.14; 95%CI: 1.4–3.3), aggression (OR=2.41; 95%CI: 1.5–3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4–6.6), and a depressed mood (OR=13.71; 95%CI: 6.7–28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1–4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2–5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive. Limitations As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated. Conclusions Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines.
Article
The majority of Huntington's disease (HD) mutation carriers experience some psychopathology during their lifetime, varying from irritability to psychosis, but prevalences of particular symptoms vary widely due to diverse study populations in different stages of HD and the use of different assessment methods. The study population consisted of 1993 HD mutation carriers from 15 European countries, all participating in the observational REGISTRY study. The behavioural section of the Unified HD Rating Scale was used to examine the prevalence and correlates of five neuropsychiatric features: depression, irritability/aggression, obsessive/compulsive behaviours, apathy and psychosis. Twenty-seven per cent of the participants did not have any neuropsychiatric symptom in the last month. Moderate to severe apathy occurred in 28.1% of the participants, whereas moderate to severe depression was found in 12.7%. Irritable/aggressive symptoms were present in 13.9% of the participants, and 13.2% showed obsessive/compulsive behaviours. Moderate to severe psychotic symptoms were found in only 1.2%. Only 54.9% of all participants with moderate to severe depression used antidepressants, suggesting undertreatment of depression. Obsessive/compulsive behaviours and irritability/aggression were inversely correlated with the Total Functional Capacity score, but with apathy showing the strongest inverse association. A variety of neuropsychiatric symptoms are highly prevalent in different stages of HD in this European HD population, with apathy as the most frequent symptom. Depression, irritability/aggression and OCBs are prevalent in all stages of HD. Apathy was the key neuropsychiatric symptom occurring most often in advanced HD stages. Due to possible selection of relatively healthy participants, prevalences reported in this study might be an underestimation of prevalence in the entire HD population.