New perspectives on pathology in Huntington's disease - characterization of hypothalamic changes
Huntington’s disease (HD) is a neurodegenerative disorder caused by an expansion of the CAG repeat in the huntingtin gene. Non-motor symptoms and signs such as psychiatric disturbances and metabolic dysfunction are also part of the disease manifestation. These symptoms often precede the motor symptoms by decades.
The hypothalamus is an area in the brain involved in the regulation of emotions and metabolism. So far, there has been limited assessment of the extent of hypothalamic pathology in HD. We hypothesized that several of the non-motor features may be linked to hypothalamic dysfunction and pathology.
Therefore, the aim of the work in this thesis was to investigate how the hypothalamus is affected in clinical HD using neuropathological, neuroimaging and gene expression analyses.
In the Paper I and II included in this thesis, we quantified selective neuropeptide-expressing hypothalamic populations known to regulate metabolism and emotion in patients with HD compared to healthy controls. We showed that both oxytocin- and vasopressin-expressing neurons were decreased in HD cases. These reductions were suggested to appear at an early disease stage before striatal pathology has occurred.
Also in the first study, we demonstrated that the number of cocaine- and amphetamine-regulated transcript (CART)-expressing neurons was increased in HD cases. We also demonstrated that the both oxytocin- and vasopressin-expressing neurons reductions were accompanied with cell loss in the paraventricular nucleus in the hypothalamus of HD cases.
In study three, we developed a robust method to measure the hypothalamic volume in magnetic resonance imaging (MRI) in order to determine whether the hypothalamic dysfunction in HD is associated with the volume of this region.
We performed hypothalamic volumetric analyses on prodromal HD, symptomatic HD and control participants who underwent MRI scanning at baseline and 18 months follow-up as a part of the IM- AGE-HD study. We found no evidence of cross-sectional or longitudinal changes between groups in hypothalamic volume, suggesting that hypothalamic pathology in HD is not associated with volume changes.
In our forth study, we investigated whether transcriptional dysfunction in emotion and metabolism regulating factors in hypothalamic nuclei were present in HD. We found that an array of genes involved in the neuropeptide expression, autophagy, neurotropic factors, neurogenesis and receptor signaling were altered in selective hypothalamic nuclei in the HD cases.
Taken together, the results from this thesis demonstrate that hypothalamic dysfunction is a part of HD pathology, which could contribute to the pathogenesis of several non-motor symptoms of the disease. These findings might have the potential to give rise to new and more effective therapeutic interventions.
PhD Thesis Sanaz Gabery
Author: Sanaz Gabery
Supervisor: Åsa Petersén
Co-supervisor: Elisabet Englund
Department: Experimental Medical Science
Date of Defence: May 13, 2015
Place of defence: Belfragesalen, Biomedical Center, Lund, Sweden
Opponent: Professor Roger Barker
Date of publication: May 13, 2015
No of pages: 140
Type of document: PhD Thesis
ISSN: 1652-8220 ISBN: 978-91-7619-126-2