The Role of Hypothalamic and Neuroendocrine Changes in Huntington’s Disease found to increase trust, empathy and facial memory.38,57,58 Therefore, it

is possible that loss of oxytocin could be involved in the reduced recognition of facial expression of emotions that has been reported in HD patients.59–65

Neuronal populations expressing neuropeptide Y and melanin-concentrating hormone were not found to be altered in the HD hypothalamus.50,56

Hence, not all neuropeptide-expressing

populations in the hypothalamus are affected in HD. Taken together, the neuropathological studies to date show that there is neuronal loss in specific nuclei of the human HD hypothalamus as well as alterations in emotion- and metabolism-controlling neuropeptides.

Imaging of the Hypothalamus in Huntington’s Disease

The hypothalamic region has no clear anatomical borders and therefore provides a challenge for delineation in magnetic resonance images (MRIs). Using voxel-based morphometry (VBM), significant differences have been found in the grey-matter contents in the hypothalamic region between HD patients with motor symptoms and age- and sex-matched controls.66,67

A recent study continued to investigate the extent of changes in the hypothalamic region using MRI scans from the PREDICT-HD study. The PREDICT-HD study is a multicentre observational study that has enrolled a large number of individuals who have tested positive for the disease-causing huntingtin gene but who do not yet have motor symptoms, i.e. prodromal HD.68

A significant reduction in gray matter

signal was found in the hypothalamic region in prodromal HD that paralleled alterations in the striatum and insula over a decade before the expected onset of motor symptoms using VBM.69

A different approach based on mathematical modelling revealed that the gray matter content alone in the hypothalamic region in these MRIs was powerful enough to distinguish prodromal HD from controls. It was also possible to distinguish different groups of prodromal HD divided on expected time to motor onset using this approach. Another study using positron emission tomography has found reductions in dopamine D2 receptors as well as microglia activation in the hypothalamic region of prodromal HD.70

Taken

together, these results show that the hypothalamic region is affected early on in the pathogenesis of HD.

Alterations of Neuroendocrine Factors in the Cerebrospinal Fluid, Blood and Urine It is well-known that some factors secreted from neurons in the central nervous system can be measured in the CSF. In other neurodegenerative disorders, such as Alzheimer’s disease, alterations in CSF levels of tau, phosphorylated tau and the 42 amino acid form of amyloid-beta proteins are considered to reflect the disease process.71

Measurements of these factors today guide the diagnosis of Alzheimer’s disease and are used as biomarkers.

Biomarkers are usually divided into trait biomarkers – indicating a specific disease – and state biomarkers—reflecting the state in the disease process. In HD, the trait marker consisting of the mutant huntingtin gene is well established. State markers, which reflect disease process before the onset of motor symptoms in HD, are urgently needed for the evaluation of new, potential treatments. As factors in the neuroendocrine system can be measured in CSF and serum, and given the fact that this system is affected in HD, the hope of finding an altered neuroendocrine factor as a state biomarker for

EUROPEAN NEUROLOGICAL REVIEW

the disease has emerged. However, the search for a neuroendrocrine factor suitable as a biomarker is complicated. Such factors are part of interconnected and complex circuitries where the overall system strives to maintain homeostasis. Therefore, each factor is closely regulated. This is not the only challenge – a change in the level of one factor may be primary, due to the effects of the mutant HD gene, or secondary, due to changes in another part of the circuitry. Neuroendocrine factors may also be affected by the diurnal rhythm, satiety level, gender, age, medication and so forth. Variation in the available assays used to measure neuroendocrine factors is another major consideration. The reports published so far investigating the neuroendocrine system using CSF and blood measurements in HD have suffered from a large variation between and within studies.43–46

A few clinical studies investigating neuroendocrine factors in HD have revealed promising results. Increased levels of cocaine and amphetamine-regulated transcript (CART) have been found in the CSF. These levels may reflect the increased numbers of CART- immunopositive neurons detected in the human HD hypothalamus using immunohistochemistry.56,72

CART is a neuropeptide known to

increase anxiety-like behaviour in animal models and has been implicated in mood disorders.73–75

Analyses of the hypothalamic–pituitary–adrenal (HPA) axis in blood and urine have collectively pointed to an upregulation of this endocrine axis in HD.76–78

An activated HPA axis has been one of the

most consitant findings in clinical depression and may have negative effects on cognitive function and energy homeostasis.79

This nucleus functions as a circadian clock, being the principal rhythm-generating system in humans.

Moreover, a

delayed onset in the diurnal rise of melatonin has been found in HD patients, suggesting dysfunction in the hypothalamic suprachiasmatic nucleus.80

Changes in hypothalamic function can also be reflected in alterations in afferent signals from the periphery. These afferent signals to the hypothalamus include:81

• • •

leptin, a satiety signal from adipose tissue;

ghrelin, an appetite signal from the gastric mucosa; and insulin, an anabolic peptide secreted from the pancreas.

Indeed, insulin resistance has been found in the early stages of HD.82 Reduced leptin and increased ghrelin levels have been reported in later stages of HD, possibly reflecting the catabolic stage commonly occuring in advanced HD.83

Despite these results, other studies have

failed to detect a significant difference in leptin and ghrelin levels between HD patients and controls.84,85

Further studies of different

stages of HD, including prodromal HD, are therefore clearly required to elucidate how and to what extent the neuroendocrine system is affected in HD.

Current and Future Medical Treatment There is no cure or disease-modifying treatment available for HD.86 However, a variety of symptomatic treatments exist that can have significant beneficial effects on the psychiatric and motor symptoms of the disease.1–3,87

Irritability, depression and anxiety are usually treated with selective serotonin-reuptake inhibitors. Motor symptoms are treated with the monoamine-depleting agent tetrabenazine or neuroleptic agents. The common combination of psychiatric symptoms with depression and/or anxiety, motor symptoms and

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