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Brain Research 1063

Short Communication

Normal hypocretin-1 (orexin-A) levels in the cerebrospinal fluid of

patients with Huntington’s disease

Andreas Meier a,*, Brit Mollenhauer b, Stefan Cohrs a, Andrea Rodenbecka, Wolfgang Jordana,

Johannes Meller c, Markus Otto a,b

aSleep Disorders Center, Department of Psychiatry and Psychotherapy, Georg-August-University, von-Siebold-Strasse 5, 37075 Goettingen, GermanybDepartment of Neurology, Georg-August-University, Goettingen, Germany

cDepartment of Nuclear Medicine, Georg-August-University, Goettingen, Germany

Accepted 25 September 2005

Available online 2 November 2005

Abstract

A significant atrophy and loss of hypocretin neurons in the brains of human patients with Huntington’s disease (HD) and in R6/2 mice

have been reported. We included 10 patients with HD and 12 patients with chorea-like hyperkinetic movement disorders (non-HD). All

patients of the HD group and eleven patients of the non-HD group showed normal hypocretin-1 levels. Thus, hypocretin-1 may not serve as

an additional diagnostic marker for HD.

D 2005 Elsevier B.V. All rights reserved.

Theme: Disorders of the nervous system

Topic: Degenerative disease: other

Keywords: Hypocretin; Huntington; Orexin

A significant atrophy and loss of hypocretin neurons in the

brains of human patients with Huntington’s disease (HD) and

in R6/2 mice have been reported [6]. It has been hypothesized

that cerebrospinal fluid level of hypocretin-1 could constitute

a novel marker for assessing the progression and the

effectiveness of therapeutic interventions in human HD

patients [6]. Therefore,we tested this hypothesis in 22 patients

who where under the differential diagnosis of having HD.

Huntington’s disease (HD) is an autosomal dominantly

inherited progressive neurodegenerative condition. It is

characterized by movement disorders, personality changes

and dementia [3]. Furthermore, psychotic symptoms and a

disrupted sleep pattern with prolonged sleep latency, frequent

nocturnal awakenings, reduced slow-wave sleep and a higher

density of sleep spindles have been reported [7]. Usually, the

clinical manifestation is in the mid-age but symptoms may

0006-8993/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.brainres.2005.09.028

* Corresponding author. Fax: +49 551 39 3887.

E-mail address: ameier2@gwdg.de (A. Meier).

also appear in younger or older patients. The progression of

the disease leads inescapably to death within 10–15 years.

The characteristic neuropathological findings in HD are

neuronal loss and astrocytosis in the striatum and massive

atrophy of caudate nucleus. There is also a loss of neurones in

the substantia nigra pars reticulate, the subthalamic nucleus

and the thalamus [3]. It is caused by a mutation in the gene

encoding huntingtin leading to expansion of a trinucleotide

repeat (CAG) [11]. Even if the function of the protein is still

unknown, mutant huntingtin may alter the function of

transcriptional factors, reduce the level of acetylated histones

and is supposed to induce a decreased expression of genes

which may play important roles in neuronal survival [3].

The hypocretin system is likely to have a role in

modulating the stability of sleep–wake cycles and in the

promotion of vigilance but also physiological functions in

addition to food intake such as regulation of blood pressure,

the neuroendocrine system and body temperature [10].

Hypocretin neurons are located in the lateral and medial

hypothalamic region exclusively but project to all relevant

(2005) 201 – 203

Fig. 1. Cerebrospinal fluid hypocretin-1 levels [pg/ml] in patients with

chorea-like hyperkinetic movement disorders and patients with genetically

characterized HD. Box plots show 10th, 25th, 50th, 75th and 90th

percentiles and outliers.

A. Meier et al. / Brain Research 1063 (2005) 201–203202

regions for the control of vigilance like locus coeruleus

(noradrenergic system), ventral tegmental area (dopaminer-

gic system), the raphe nuclei (serotonergic system), tubero-

mammillary nucleus (histaminergic system) and the

laterodorsal tegmental/pendunculopontine nucleus (choli-

nergic system) [8].

Very low or not detectable levels of CSF hypocretin-1

have been reported to be a specific finding in the neuro-

logical disorder narcolepsy with cataplexy [4], while in

narcolepsy without cataplexy and further neurological and

psychiatric conditions, only unspecific alterations of CSF

hypocretin-1 have been shown [2].

We measured the hypocretin-1 levels in the CSF of 10

patients with Huntington_s disease (HD) and in 12 patients

with chorea-like hyperkinetic movement disorders (non-

HD). Included patients consisted of 10 HD patients (6

female and 4 male). Patients of this group were suspected of

having HD, and the clinical diagnosis was confirmed by

DNA analysis for CAG expansion in the IT15 region of

chromosome 4 [11]. These patients had a mean age of 54 T 9years (mean T SD) and a mean age of onset of 52 T 9 (mean

and SD). The duration of disease until lumbar puncture was

42 T 32 months (mean T SD). Mean CAG repetition length

was 43 T 4 (mean and SD). We also included 12 control

patients (3 men and 9 women) with clinical signs of having

HD, but genetic testing [11] showed normal CAG repetition

length. The choreatic diseases of 4 patients had still not been

diagnosed at submission of this paper. In the other 8

patients, the diagnoses were as follows: idiopathic senile

chorea (N = 2), tardive dyskinesia after neuroleptic

medication combined with dementia (N = 2), and one each

with vascular encephalopathy, Wilson’s disease, amyotro-

phic lateral sclerosis and frontotemporal degeneration.

These patients had a mean age of 68 T 15 years (mean TSD) and a mean age of onset of 66 T 15 years (mean T SD).

The duration of disease until lumbar puncture was 25 T 26

months (mean T SD). The study was conducted according to

the guidelines of the Declaration of Helsinki (World

Medical Organisation 1996) [1] and approved by the ethics

committee of the University of Goettingen.

CSF hypocretin-1 measurements were performed using a

commercially available 125I radioimmunoassay kit (Phoenix

Pharmaceuticals, Belmont, CA, USA) [9]. All CSF samples

were assayed in duplicate and measured in the same kit at

one time. Measurements were evaluated using a standard

curve. Levels of CSF hypocretin-1 were determined against a

set of four internal standard CSF samples. The detection limit

was 50 pg/ml, and intra-assay variability was below 10%.

Groups were compared with the Mann–Whitney U test,

and a correlation analysis between CSF hypocretin-1 level

and number of CAG repeats was performed with the

Spearman’s Rank Correlation Test.

The mean hypocretin-1 levels (mean T SD) in the CSF of

the HD patients was 277 pg/ml T 27 pg/ml (range, 232–319

pg/ml) and 260 T 52 pg/ml (range, 140–341 pg/ml) in the

non-HD group (Fig. 1). In the HD group, there was no

correlation between CAG repetition length and CSF

hypocretin-1 level. In comparison with previously reported

data in control groups [5], all patients of the HD group and

eleven patients of the non-HD group showed normal

hypocretin-1 levels (all >200 pg/ml). One patient with M.

Wilson had an intermediate level (110–200 pg/ml).

In our study, we did not find a significant difference in

the level of hypocretin-1 in CSF between patients with

genetically characterized HD and patients with chorea-like

hyperkinetic movement disorders. There was no correlation

between hypocretin-1 levels and CAG repetition length in

the HD group. An explanation for the discrepancy between

our results and the findings reported earlier [6] may be the

duration of disease until lumbar puncture. It could be

hypothesized that, in later stages of disease, reduced levels

of hypocretin-1 occur. Indeed, it is questionable if CSF

hypocretin-1 levels will show a significant decent exceeding

the findings in other neurodegenerative disorders [2,9]

because it has been estimated that in postmortem brain

tissues of human HD patients still 70% of hypocretin

neurons remain [6]. Furthermore, in R6/2 mice, a correlation

between episodes of narcoleptic-like behavioural arrests and

the loss of hypocretin neurons has been described [6]. HD in

human patients is not familiar with narcoleptic-like beha-

vioural arrests or cataplexy even not in end-stages of illness

[3]. It can be assumed that the remaining hypocretin neurons

in HD still release a sufficient quantity of hypocretin to

prevent the occurrence of narcoleptic-like behavioural

arrests. Therefore, our findings do not support the hypoth-

esis that hypocretin-1 may serve as an additional diagnostic

marker for HD. Furthermore, a relationship between the

sleep disturbances in patients with HD and hypocretin-1

levels appears to be unlikely.

A. Meier et al. / Brain Research 1063 (2005) 201–203 203

Acknowledgments

This study was in part supported by a grant from the

ministry of health and social security and the ministry for

science and technology. For technical assistance we thank

Ms. Schreivogel (Department of Nuclear Medicine, Goet-

tingen) and Ms. Reich-Erkelenz (Department of Psychiatry

and Psychotherapy, Goettingen).

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