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Beyond the brain: widespread pathology in

Huntingtons disease
Jorien MM van der Burg, Maria Bjrkqvist, Patrik Brundin

Huntingtons disease (HD) is an inherited neurodegenerative disorder caused by a polyglutamine stretch in the
huntingtin protein. Today, more than 15 years after the genetic defect underlying HD was discovered, the pathogenesis
is still not well understood and there is no adequate treatment. Research into this disorder has conventionally focused
on neurological symptoms and brain pathology, particularly neurodegeneration in the basal ganglia and cerebral
cortex. Mutant huntingtin is, however, ubiquitously expressed throughout the body. Indeed, contrary to earlier
thinking, HD is associated with abnormalities in peripheral tissues. These abnormal changes are not all secondary to
brain dysfunction, but most seem to be directly caused by expression of mutant huntingtin in peripheral tissues. In
this article, we highlight this emerging eld of research and how it might aect our understanding of the pathogenesis
of this disease, the development of novel biomarkers of disease progression, and the identication of new potential
treatments.

Introduction
Huntingtons disease (HD) research has conventionally
focused on the brain for obvious reasons: HDs core
symptoms include motor abnormalities such as
hyperkinesia and hypokinesia, as well as psychiatric and
cognitive problems (the panel provides an overview of
HD). These symptoms have all been linked to
neurodegeneration in the basal ganglia and cerebral
cortex.
In addition to the classic symptoms, HD is complicated
by other features, such as weight loss and skeletal-muscle
wasting, which are not necessarily directly associated
with changes in brain functions (gure 1). These
features sometimes appear early in the disease course
and can eventually contribute substantially to both
morbidity and mortality. These symptoms have been
suggested to be secondary to general sickness or to be
the consequences of neurological dysfunction. However,
a growing body of evidence indicates that these changes
might be due to the direct eect of mutant huntingtin
(the toxic protein that causes HD) on peripheral tissues.
This thinking is largely derived from recent studies in
animal models of HD, but the fact that similar
abnormalities also occur in peripheral tissues of
patients is gradually becoming evident. In this article,
we propose that an improved understanding of changes
in peripheral tissues in HD could give insight into the
pathogenesis of the disease, lead to discovery of novel
biomarkers of disease progression, and could open new
avenues for treatment.

HD is not only a brain disorder

Several facts indicate that peripheral features of HD,
such as weight loss and skeletal-muscle wasting, might
have little or nothing to do with neurological dysfunction
or general sickness. First, huntingtin is expressed in
many tissues and organs in human beings and other
mammals.24 The precise function of huntingtin is
unclear, but this protein seems to be involved in several
cellular processes, including transcriptional events,
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protein tracking, and vesicle transport.5 Studies in

knock-out mice have revealed that absence of huntingtin
leads to defects in all three germ layers and is
embryonically lethal,6 indicating that huntingtin is
essential for many tissues. Indeed, knocking down
huntingtin expression in zebrash results in peripheral
defects, such as impaired haemoglobin production.7
Second, mutant huntingtin seems to aect organelles
and functional systems that are essential to all cells (eg,
mitochondria, the ubiquitinproteasome system,
caspases, and chaperones). As a result, cells from
peripheral tissues from patients with HD and from
animal models have, for example, mitochondrial
dysfunction817 and transcriptional defects.1822 Moreover,
intracellular huntingtin aggregatesthe hallmark of HD
neuropathologyare present in peripheral organs of
transgenic mice with HD.2325 Third, dysfunction of
peripheral cells also occurs when these cells are
isolated,1416,26,27 indicating that this eect is a direct
consequence of endogenously expressed mutant
huntingtin and is not secondary to brain dysfunction. For
example, monocytes isolated from HD gene carriers,
which express mutant huntingtin, are pathologically
hyperactive in response to stimulation from
lipopolysaccharide.26 Fourth, when mutant huntingtin is
expressed only in cardiomyocytes of wild-type mice, the
animals develop heart failure.28,29
The above observations all support the hypothesis that
peripheral abnormalities in HD could be caused directly
by local expression of mutant huntingtin and could occur
independently from neurological defects or general
malaise.

Lancet Neurol 2009; 8: 76574

Neuronal Survival Unit,
Department of Experimental
Medical Science, Wallenberg
Neuroscience Center,
Lund University BMC A10,
Lund, Sweden
(J M M van der Burg PhD,
M Bjrkqvist PhD, P Brundin MD)
Correspondence to:
Jorien MM van der Burg,
Neuronal Survival Unit,
Department of Experimental
Medical Science, Wallenberg
Neuroscience Center, Lund
University BMC A10,
221 84 Lund, Sweden
jorienvanderburg@gmail.com

Non-neuronal abnormalities might contribute

to symptoms
In this section we discuss in more detail how
abnormalities in peripheral tissues could underlie various
signs and symptoms of HD. Patients with this disorder
have several non-neurological features, including weight
loss and skeletal-muscle wasting. Although less
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Genetic disorder
Autosomal dominant neurodegenerative disorder

thoroughly investigated, glucose intolerance, osteoporosis, cardiac failure, gastrointestinal abnormalities,

and testicular atrophy might also belong to the HD
phenotype in aected patients (gure 1). These features
of the disease are clinically important as they reduce
quality of life and, in some cases, correlate with disease
progression and contribute to early death.

Epidemiology
48 per 100 000

Weight loss

Panel: Overview of Huntingtons disease*

First accurate description
In 1872 by George Huntington

Onset
First symptoms can start at any age, but mean age at onset
is between 35 and 45 years
Clinical presentation
Classic neurological symptoms
Motor symptoms
Cognitive deterioration
Psychiatric and behavioural problems
Other clinical presentation features
Weight loss
Atrophy of skeletal muscle
Sleep disturbance
Autonomic disturbances
Cause
A mutation in HTT causes the formation of the mutant
protein huntingtin. Normal individuals have less than 36 CAG
repeats in HTT. Individuals with >39 CAG repeats will develop
Huntingtons disease. Reduced penetrance occurs with
3639 CAG repeats.
Pathogenesis
The role of normal huntingtin is not completely clear, but
when mutated it causes, for example, the formation of
intracellular inclusion bodies, impaired intracellular transport,
defected gene transcription, and apoptosis.
Genetic animal models
Some of the most widely studied mouse models
R6/2: expresses exon 1 of human mutant HTT with about
150 CAG repeats
YAC 72: expresses full-length human mutant HTT with
72 CAG repeats, created using a yeast artical
chromosome as vector
YAC 128: expresses full-length human mutant HTT with
128 CAG repeats, created using a yeast artical
chromosome as vector
N17182Q: expresses the 171 amino acids at the
N-terminal of mutant huntingtin with 82 CAG repeats
HdhQ92: model with 92 CAG repeats knocked in into the
mouse Htt
Other genetic animal models
Caenorhabditis elegans models
Drosophila melanogaster models
Transgenic rhesus macaques
*A comprehensive overview of HD is provided by Walker and colleagues.1

766

One of the most common peripheral abnormalities that

aects nearly all individuals with HD, and which is not
necessarily associated with pathology of the nervous
system, is unintended weight loss. This weight loss is
progressive, beginning as minor loss in presymptomatic
gene carriers and ending with profound cachexia in
advanced-stage patients,3038 and correlates with CAG
repeat number.39 Why patients with HD lose weight is
not known. Many studies have indicated that this feature
is not secondary to hyperactivity30,34,38 or anorexia,30,35,38,40
but results from an increased metabolic rate.38,41,42 Patients
with HD with a higher body mass index at onset of
symptoms tend to have a slower rate of disease
progression,43 suggesting that weight loss could be a
valuable target for therapeutic intervention.
According to numerous studies, most of which in
transgenic mouse models, several tissues and organs
that are important in weight regulation might be aected
in HD (gures 2 and 3). For example, the digestive
system, which is important for nutrient absorption, is
dysfunctional. Patients suer from xerostomia,44 which
could aect taste, mastication, and swallowing, all of
which might contribute to weight loss. In the R6/2 mouse,
the most widely studied transgenic animal model of HD,
the number of ghrelin-producing neurons is reduced in
the stomach.41 Ghrelin normally stimulates food intake
and inhibits energy expenditure; therefore, a loss of this
hormone might contribute to weight loss. The pancreas
is also aected and both patients with HD and mice
models of the disease tend to develop impaired glucose
tolerance.4551 In a recent study by Lalic and colleagues,52
an impairment in insulin-secretion capacity alongside a
decrease in insulin sensitivity was seen in patients with
HD compared with control individuals. In mice,
pancreatic islet cells are atrophic and exhibit intranuclear
inclusions,50,53 resulting in defects in insulin, somatostatin,
and glucagon production.54 In patients, although islets
are of normal size, transcriptional dysregulation in islet
cells might underlie the increased tendency to develop
impaired glucose tolerance.55 One study indicated that
mutant huntingtin might also aect the liver.
Transcription of urea-cycle enzymes is impaired in the
liver of mice with HD, leading to high circulating
concentrations of ammonia with concomitant brain
damage and locomotor dysfunction.56 A low protein diet
reduced ammonia concentrations in the plasma, and
ameliorated brain damage and locomotor function in
these mice.56
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In addition to the digestive system, adipocytes might

be aected in HD. Endocrine signals from white adipose
tissue, which normally reect energy levels within the
body, are aected in two HD mouse models.57,58 Expression
of fat-storage genes and concentrations of the adipokine
hormones leptin and adiponectin are impaired in these
mice, which might contribute to weight loss.58 These
transcriptional defects are a direct consequence of mutant
huntingtin expression in the mouse adipocytes and can
be replicated in an adipocyte cell line.58

Skeletal-muscle atrophy
Skeletal-muscle wasting is another hallmark of HD.31,32,35,59
The mechanisms underlying muscular atrophy in this
disorder are unclear and, of note, the skeletal muscles
undergo substantial wasting, despite the muscles being
highly active as a result of hyperkinesia.
The muscle wasting is possibly due to defects caused by
the presence of mutated protein in myocytes. Mutant
huntingtin forms inclusion bodies in muscle cells of
R6/2 mice25 and disrupts gene expression similarly to its
eect in the brain.18,19,22 This nding suggests that similar
pathogenetic mechanisms are operative in neurons and
muscle cells. Apart from aecting transcriptional
regulation, mutant huntingtin is known to aect mitochondrial function.60 Studies on cultures of skeletal-muscle
cells from patients with HD revealed several mitochondrial
abnormalities, including respiratory-chain dysfunction,
morphologically abnormal cristae, cytochrome c release,
and apoptosis.6163 In vivo studies also revealed altered
muscle energy metabolism in this disorder.10
Hence, myocytes are aected in HD, possibly as a
direct eect of mutant huntingtin, and muscles undergo
atrophy as a result. This nding opens up new possible
treatment strategies and novel ways of monitoring
disease progression.

Cardiac failure
Cardiac failure occurs in about 30% of patients with HD
(compared with only 2% in age-matched controls) and is a
leading cause of death in these patients.64 Nothing is
known about the pathophysiological mechanism
underlying cardiac failure in this disorder, but failure of
the autonomic nervous system might play a part.65
Alternatively, cardiac failure might be caused by the eects
of mutant huntingtin expression in cardiomyocytes. In
R6/2 mice, the myocardium is atrophic, mitochondria in
cardiomyocytes have abnormal shapes, and cardiac output
is reduced by 50%.66 Cardiomyocyte-specic expression of
polyglutamine fragments with 83 CAG repeats in wild-type
mice induces aggregate formation, autophagy, and
necrotic death of cardiomyocytes, eventually leading to
heart failure.28,29 Taken together, these experimental data
indicate that heart failure in HD could be a direct
consequence of mutant huntingtin expression in
cardiomyocytes, and clinical studies on cardiac tissue of
patients are needed to resolve this matter.
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Muscle atrophy

Impaired glucose
tolerance

Cardiac failure

Weight loss

Osteoporosis

Testicular atrophy

Figure 1: Non-neurological features of Huntingtons disease

Testicular atrophy
The highest levels of huntingtin expression are found in
the brain and testes.3,67 Although fertility is unaected in
patients with HD,68 men have reduced testosterone
concentrations69 as well as testicular pathology with
reduced numbers of germ cells and abnormal seminiferous
tubule morphology.70 Reduced plasma concentrations of
testosterone correlate with worsening of the disease.69,71
Similarly, both the R6/2 and YAC128 mouse models of HD
have testicular atrophy, albeit to a greater extent than
patients.70,7275 In R6/2 mice, concentrations of gonadotropinreleasing hormone are reduced, which suggests that the
eects might be secondary to hypothalamic dysfunction.73
In YAC128 mice, however, testicular degeneration develops
before any evidence of decreased testosterone
concentrations or loss of gonadotropin-releasing hormone
neurons in the hypothalamus, suggesting that testicular
pathology results from a direct toxic eect of mutant
huntingtin in the testes.70

Osteoporosis
Data from two preliminary reports suggest that
osteoporosis might also be part of the HD phenotype76,77
and that its severity correlates with the number of CAG
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Skeletal muscle

Cardiovascular system

Blood

Morphological
changes

Heart rate
variability

Altered gene
transcription

Mitochondrial
dysfunction

Altered cerebral
blood ow

Mitochondrial
dysfunction

ATP production

Caspase activity

Altered gene
transcription

Inammatory
markers
(eg, interleukin 6)

Skeleton

Digestive tract
Insulin
production

Osteoporosis

Altered gene
transcription in
islet cells

Genital system

Thyroid

Testosterone
(men only)

Levels of T3

Number of
spermatids
Diameter of
seminiferous
tubules

Figure 2: Peripheral pathology in patients with Huntingtons disease

repeats.77 The reason for decreased bone mineral density

in this disorder is not known; it might be secondary to
neuroleptic treatment, might result from immobility, but
could also be a direct eect of the disorder itself. For
example, decreased bone mineral density can result from
disrupted endocrine signalling, such as increased cortisol
concentrations. R6/2 mice have decreased bone density,
along with increased concentrations of cortisol, wasting
of skeletal muscle, accumulation of abdominal fat, and
insulin resistance, similar to a Cushing-like syndrome.78
These ndings led to the observation of increased urinary
concentrations of cortisol in patients with HD.78 Recent
studies have conrmed that there are increased cortisol
concentrations in these patients,71,79 but alterations are
probably too small to cause a Cushing-like syndrome and
osteoporosis. Instead, osteoporosis in HD might be
caused by a direct eect of mutant huntingtin on
osteoblasts or osteoclasts in bone tissue. However, this
hypothesis is highly speculative and further investigations
are needed to clarify the underlying cause of decreased
bone mineral density. Studies comparing very active and
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immobile patients could, for example, clarify what role

immobility has.

Dysfunction of blood-derived cells

Blood cells are aected in many ways in HD.
Haematocytes have altered gene transcription,20,21 caspase
activity,80 and mitochondrial function.8,9,11,13 Additionally,
adenosine A2A receptor function81,82 and monoamine
oxidase activity83 are disrupted.
Blood plasma samples of patients with HD show signs
of immune activation, such as increased concentrations
of interleukins 8 and 6.26,84 Altered inammatory signalling
might contribute to several features of HD, including
weight loss and muscle wasting. Proinammatory
cytokines are associated with muscle atrophy, exerted
through inhibition of myogenic dierentiation and
enhanced apoptosis.85,86 Moreover, these cytokines can
aect energy metabolism and body weight.87
The immune system in HD might be activated in
reaction to cellular pathology, such as aggregate
formation, oxidative damage or necrotic cell death.
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Skeletal muscle

Cardiovascular system

Blood

Morphological
changes

Cardiac output

Altered gene
transcription

Mitochondrial
dysfunction

Protein nitration

Mitochondrial
dysfunction

ATP production

Thickness of myocardium

Altered gene
transcription

Inammatory
markers
(eg, interleukin 6)

Caspase activity

Bone
Bone density

Digestive tract
Inclusion bodies
Loss of
ghrelin-producing
neurons

White adipose tissue

Altered
transcription of
fat-storage genes

Inclusion bodies

Leptin and
adiponectin

Urea cycle
deciency

Genital system
Testosterone
and GnRH
Testicular atrophy
Dysorganised
seminiferous
epithelium

Insulin, glucagon,
somatostatin
production
Inclusion bodies

Figure 3: Peripheral pathology in animal models of Huntingtons disease

However, concentrations of IL-6 are already increased as

early as 16 years before the predicted onset of symptoms.26
Moreover, as mentioned earlier, isolated monocytes from
patients with HD and asymptomatic mutant HTT gene
carriers express mutant huntingtin and are pathologically
hyperactive in response to stimulation.26 These
observations all suggest that inammatory changes in
this disease result from dysfunction of immune cells and
are not secondary to brain pathology or general sickness.

Are changes in peripheral tissue secondary to

brain dysfunction?
There are many peripheral abnormalities in HD that seem
to occur independently from neuronal dysfunction.
However, brain pathology, for example in the hypothalamus,
could lead to altered endocrine signalling and secondary
changes in peripheral tissues. Several neurodegenerative
disorders, including Alzheimers disease, can also be
complicated by peripheral abnormalities,88 such as weight
loss, which could suggest a role of the brain in causing
these features. The hypothalamus is aected in patients
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with HD and in transgenic mice,89,90 and its pivotal role in

endocrine regulation means that the pathology restricted
to this brain structure can aect the whole body. Changes
have been found in several of the hypothalamicpituitary
axes and include altered concentrations of luteinising
hormone,69 growth hormone,71 and cortisol.78,79 Peptides
that could possibly be linked to caloric intake and weight
loss are also aected in this disorder.91,92 In the hypothalamus
of HD mice, the expression of vasopressin, oxytocin,
cocaine, and amphetamine-regulated transcript peptide
(CART),93 gonadotropin-releasing hormone,73 and vasoactive intestinal polypeptide and its receptor94 are reduced.
Despite multiple changes in the hypothalamic or
pituitary control of endocrine functions, results from
various studies indicate that brain dysfunction might not
be involved in the genesis of many peripheral abnormalities
in HD. Decreased concentrations of testosterone in
patients with HD do not correlate with decreased
concentrations of luteinising hormone.69 On the contrary,
patients with lowest testosterone concentrations have
normal concentrations of luteinising hormone,69
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suggesting that altered testosterone production is not

caused by defects in hypothalamicpituitary signalling.
Mice with HD can also exhibit testicular pathology without
evidence of disrupted hypothalamicpituitary signalling.70
Additionally, changes in hypothalamic peptides regulating
energy metabolism and body weight were not clearly
linked to weight loss in HD mice;41 neither did decreased
vasopressin concentrations lead to increased water
consumption in these mice.44 A study in functioning of the
hypothalamicpituitary axes in patients with HD was also
unable to link several observed peripheral abnormalities to
disrupted neuroendocrine signalling.71 Finally, some
peripheral alterations are detectable many years before
neuronal pathology is evident and neurological symptoms
are present,26 suggesting that the central and peripheral
changes are not linked.
Taken together, these ndings suggest that peripheral
abnormalities do not necessarily arise from altered
hypothalamicpituitary signalling, but are due to primary
defects in peripheral organs. Contrary to previous
thinking, peripheral defects might even contribute to
brain pathology.56,95 Therefore, HD can be viewed as a
systemic disorder, in which many organs and tissues are
aected and changes in one organ trigger malfunction in
another. To unravel the precise role of each of these
organs and tissues in this disease, animal models that
selectively express mutant huntingtin in certain organs
or brain regions, such as the mouse model with
cardiomyocyte-specic expression of mutant huntingtin,29
might be helpful.

Understanding HD by looking into peripheral

tissues
Having described the many peripheral abnormalities
and their possible origins, we now discuss how
discoveries of these defects might help to resolve
outstanding problems in HD. Investigations of
peripheral abnormalities could lead to better understanding of the pathogenesis, development of novel
therapies, and the discovery of biomarkers of disease
progression. Peripheral tissues are typically easier to
study than the CNS. Sampling of peripheral tissues (eg,
blood cells) can be minimally invasive and inexpensive
compared with techniques to study brain function, such
as advanced brain imaging. Furthermore, peripheral
cells can be isolated from living patients, enabling the
study of pathological mechanisms in cells aected by
HD throughout the disease course.

Cellular mechanisms underlying peripheral pathology

Studies in peripheral tissues now substantially contribute
to our understanding of HD pathogenesis.11,15,19,20,81,82,96,97
Changes in peripheral cells, such as mitochondrial
dysfunction,11,15 cholesterol defects,9799 and transcriptional
alterations,18,19,22 often resemble abnormalities in the brain
and provide valuable insight for disease mechanisms.
For example, a recent study in lymphocytes from patients
770

with HD detected altered transcription of neuronal

RE1/NRSE (repressor element-1/neuron restrictive
silencer element), which had only been described in
post-mortem HD brains, but also occurs in vivo.100
Conversely, studies in peripheral tissues have led to
ndings that have resulted in the realisation of similar
changes in brain tissue.
Transcriptional and mitochondrial defects are
important pathogenetic mechanisms. These defects are
involved in both peripheral and CNS pathology in this
disease and could explain many symptoms. A
transcriptional defect that could be accountable for
several clinical features of HD is the altered expression of
PPAR coactivator 1 (PGC-1). PGC-1 regulates
mitochondrial biogenesis and respiration, and is
downregulated in several tissues of patients with HD,
including brain, muscle, and fat tissue.22,58,101,102 In the
brain of knock-in HD mice (with 140 CAG repeats
inserted into the murine huntingtin gene), expression of
PGC-1 is reduced in medium-sized spiny neurons, but
increased in cholinergic interneurons.101 Therefore,
changes in PGC-1 might be linked to the selective
vulnerability of medium-sized spiny neurons that is
characteristic of this disease. Decreased expression of
PGC-1 might underlie several other HD-associated
changes. For example, this change might be linked to
cardiomyopathy in HD mice, 66 as the myocardium largely
depends on mitochondrial energy and expresses high
concentrations of PGC-1. Other organs that highly
depend on ATP, such as the kidneys, might also be
aected in HD. However, to our knowledge, a study into
this possibility has not been done.
Taken together, peripheral abnormalities often
resemble brain pathology, and certain pathogenic
mechanisms, such as transcriptional dysregulation and
mitochondrial dysfunction, could underlie many
symptoms of HD.

Novel targets for therapeutic interventions

The study of peripheral abnormalities in HD has resulted
in the discovery of novel potential therapeutic targets.
The treatment of liver and pancreas defects ameliorated
brain pathology and neurological symptoms in mice
with HD.56,95 Furthermore, treatment of non-neurological
symptoms could improve quality of life and postpone
premature death. A starting point for a novel therapy
might be the observation that a higher body mass index
is associated with a slower progression of disease.43 A
possible cause-and-eect association between increased
body weight and slower progression of neurological
symptoms in HD is not yet clear. It would be interesting
to examine whether taking measures to increase body
mass index slows down the progression of neurological
symptoms. Trejo and co-workers36 showed that a higher
caloric intake stabilises body weight in patients with HD,
but they did not specically address whether disease
progression was aected. With regard to possible eects
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of treating impaired glucose tolerance in HD, animal

studies have provided some information. Chronic
treatment with glibenclamide, a hypoglycaemic drug
that induces release of insulin, does not improve the
disease or the lifespan in R6/2 mice.53 By contrast,
metformin does increase lifespan and reduces motor
symptoms such as hind-limb clasping in male
R6/2 mice.103 The antidiabetic glucagon-like peptide 1
receptor agonist exendin-4 also exerts benecial eects
in R6/2 mice; this drug suppresses pathology in the
pancreas and the brain, leading to improved motor
function and survival.95 However, the precise mechanism
of action of exendin-4 in these experiments is not clear.
This drug also exerts anti-inammatory eects and
promotes brain plasticity, which could support functional
recovery.104
Strategies to counteract cardiac failure in HD could
possibly both improve quality of life and prevent early
death. In future studies targeting cardiomyopathy in this
neurodegenerative disease, non-invasive ultrasonography
could provide immediate and objective feedback with
regard to possible treatment eects. Treatment of other
peripheral abnormalities, including testicular degeneration has, to our knowledge, never been attempted.
Decreased concentrations of testosterone are generally
associated with decreased libido, osteoporosis, and
wasting of skeletal muscle. These signs and symptoms
have all been detected in either patients or mice with
HD.31,35,72,73,76,77 Reduced testosterone concentrations in the
blood correlate with disease severity, as measured by
motor and functional scores.71 Moreover, low concentrations of testosterone have been associated with
neuronal loss,105 which could possibly contribute to HD
neurodegeneration. Patients might therefore benet
from hormonal replacement therapy.

Discovery of new biomarkers

Biomarkers to monitor or predict disease progression in
HD are needed to assess therapeutic responses during
clinical trials. Assessment of symptoms is typically not
suciently sensitive, because of the protracted course of
the disease, and the paucity of rigorous objective tools to
assess clinical changes means that there is a risk for
observer bias. Moreover, there are no methods to assess
disease-associated changes in gene carriers who do not
have
overt
symptoms.106
Unlike
most
other
neurodegenerative diseases, every patient with HD carries
the mutation and everyone with the mutation will develop
the disease. HD therefore oers unique possibilities to
detect early changes of disease course. Direct measures of
peripherally manifested symptoms, such as xerostomia44
and weight loss,39 could possibly translate into potential
biomarkers. Changes in muscle gene expression, which
are altered during the course of the disorder, could also be
used to track disease progression.19,107 Data from several
studies have suggested that peripheral alterations that
manifest in the blood or plasma could be potential
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biomarkers of HD progression. Changes in nutritional

and metabolic markers,38,108 as well as markers of endocrine
dysfunction,71,79,109 have been suggested. Plasma
24S-hydroxycholesterol is a promising biomarker that
reects the early progression of neurodegeneration in
HD.110 Proteins of the immune system (eg, clusterin and
interleukin 6) also indicate disease progression.26,84 Altered
function of peripheral blood cells has also been suggested
as a biomarker. For example, adenosine receptor A2A
function in peripheral blood is altered in HD81 and
blood-borne immune cells from patients with HD are
hyperactive in response to stimulation from lipopolysaccharide.26
The idea that the eects of mutant huntingtin in
peripheral cells (eg, blood cells) can be used to monitor
disease progression is appealing. One major criticism of
plasma markers of neurodegenerative diseases is that
they might be non-specic, or that they could be
epiphenomena caused by a general illness state. Certainly,
in advanced HD, nutritional, metabolic, and infective
pathology are likely to confound any ndings. However,
changes that are seen even before the onset of overt
motor symptoms will be of interest.

Conclusions and future directions

Peripheral abnormalities are important features of HD.
Most of these changes have been described in animal
models of HD, but it is gradually becoming evident that
similar abnormalities occur in peripheral tissues of
patients. Such defects might result directly from mutant
huntingtin expression in peripheral tissues and might be
involved in HD symptoms. Recent studies on peripheral
pathology in HD have provided important insights into
underlying disease mechanisms. In the future, these
studies might pave the way for new therapies and new
markers to monitor disease progression. Finally,
treatment of peripheral symptoms in HD could prove
important, and positively aect quality of life and prevent
early death.

Search strategy and selection criteria

References for this Review were identied through searches
of PubMed with the search term Huntingtons disease,
crossreferenced with the terms adipose tissue, adipocyte,
biomarker, blood, cardiac, cholesterol, diabetes,
gastrointestinal, heart, huntingtin, hypothalamus,
kidney, liver, lymphocyte, muscle, osteoporosis,
pancreas, thyroid, testis, and weight loss, from 1965
to April, 2009. We mainly selected articles from the past
15 years, but we did not exclude commonly referenced older
publications. We also searched the reference lists of articles
identied by this search strategy and selected those that we
judged relevant. Several review articles were included as they
provide comprehensive overviews of some subtopics that are
included in this article.

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Contributors
JMMvdB initiated the project, drafted the rst version of the Review, and
composed the panel and gures. MB and PB contributed with additional
sections and, together with JMMvdB, edited later editions of the paper.
All authors agreed on the nal version of the review.
Conicts of interest
We have no conicts of interest.
Acknowledgments
We are active in a research environment that is sponsored by three
network grants that have HD as one of their themes, namely
NeuroFortis (Swedish Research Council Strong Research Environment),
The Nordic Center of Excellence on Neurodegeneration, and
BAGADILICO (Swedish Research Council Linnaus Grant). All these
grants have contributed to the intellectual environment that has made
this article possible.
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Walker FO. Huntingtons disease. Lancet 2007; 369: 21828.
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Hoogeveen AT, Willemsen R, Meyer N, et al. Characterization and
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3
Li SH, Schilling G, Young WS 3rd, et al. Huntingtons disease gene
(IT15) is widely expressed in human and rat tissues. Neuron 1993;
11: 98593.
4
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