Advanced

New perspectives on pathology in Huntington's disease - characterization of hypothalamic changes

Gabery, Sanaz LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:47.
Abstract (Swedish)
Popular Abstract in English

Huntingtons sjukdom (HS), även kallad danssjukan, är en ärftlig och dödlig sjukdom som leder till ofrivilliga motoriska rörelser. Personer med HS får vanligtvis symtom i medelål- dern och avlider efter 15–20 år. Diagnosen ställs klinisk när de första ofrivilliga rörelserna uppträder. Dessa symtom kan kopplas till celldöd i de delar av hjärna som styr vår rörelse. Sjukdomen orsakas av en förlängd repetition av DNA-sekvens i själva huntingtongenen, som kodar för proteinet huntingtin som finns i de flesta av kroppens celler. Det förlängda proteinet kan ansamlas i cellerna och i sin tur orsaka olika skador som kan medföra cell- död. HS ärvs på ett autosomalt dominant sätt, vilket innebär att en... (More)
Popular Abstract in English

Huntingtons sjukdom (HS), även kallad danssjukan, är en ärftlig och dödlig sjukdom som leder till ofrivilliga motoriska rörelser. Personer med HS får vanligtvis symtom i medelål- dern och avlider efter 15–20 år. Diagnosen ställs klinisk när de första ofrivilliga rörelserna uppträder. Dessa symtom kan kopplas till celldöd i de delar av hjärna som styr vår rörelse. Sjukdomen orsakas av en förlängd repetition av DNA-sekvens i själva huntingtongenen, som kodar för proteinet huntingtin som finns i de flesta av kroppens celler. Det förlängda proteinet kan ansamlas i cellerna och i sin tur orsaka olika skador som kan medföra cell- död. HS ärvs på ett autosomalt dominant sätt, vilket innebär att en förälder bär på den förändrade huntingtongenen, löper barnen 50 procent risk att ärva den.

Personer med HS får ofta symtom som upplevs svåra att hantera många år innan de motoriska svårigheterna uppstår. Till dessa tidiga symtom hör personlighetsförändringar som depression, ångest och irritabilitet och även sömnstörning och ämnesomsättnings- besvär. Hypotalamus som är hjärnans hormoncentral har till uppgift är att reglera ämne- somsättning, sömn och känslor. Vi tror att hypotalamus kan ha en försämrad funktion vid HS som till en viss del kan förklara uppkomsten utav de tidiga icke motoriska symptom. Syftet med denna avhandling var att kartlägga i vilken utsträckning förändringar sker i hypotalamus i HS. Hittills har enbart enstaka undersökningar gjorts av denna region vid HS. Vi har analyserat hypotalamusvävnad från avlidna individer med HS och de som var utan sjukdom i hjärnan medan de levde. Vi har även analyserat hypotalamus regionen med magnetrsonans (MR) kamera.

Våra resultat visade att specifika nervceller i hypotalamus som tillverkar oxytocin (ett ämne vars funktion är att minska ångest), vasopressin (ett ämne som är inblandad i regler- ing av aggression, blodtryck och temperatur) och orexin (som styr födointag och känslor) är minskade vid HS hypotalamusvävnaderna. Våra resultat tydde på att oxytocin och va- sopressin minskningen sker i ett tidigt stadium av i sjukdomsförloppet. Vi kunde även se att CART (cocaine-amphetamine-regulated transcript, som styr aptit och ångest) nivån var ökad vid HS. Analyserna gjorda med magnet kamera visade inga indikationer på förtvining utav hypotalamus. Däremot kunde vi med ytterligare analyser av hypotalamusvävnaderna se att styrningen produktionen av viktiga gener som reglerar känslor och ämnesomsättning är påverkade vid i HS.

Resultaten som presenterats i denna avhandling talar för att hypotalamus till en viss ut- sträckning är påverkad vid HS. Detta kan förklara till en viss del uppkomsten av de tidiga personlighetsförändringar och ämnesomsättningsbesvär hos drabbade personer. Det skulle därför vara önskvärt med behandlingsmetoder riktad mot hypotalamus vilket kan fördröja eller hindra de tidiga symtomen. (Less)
Abstract
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 pathol- ogy. Therefore, the aim of the work in this thesis was to investigate how the hypothala- mus is affected in clinical HD using... (More)
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 pathol- ogy. Therefore, the aim of the work in this thesis was to investigate how the hypothala- mus 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-ex- pressing 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 ap- pear 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 hypotha- lamic 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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Barker, Roger, Department of Clinical Neuroscience University of Cambridge Cambridge, UK
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Huntington’s disease, huntingtin, hypothalamus, oxytocin, vasopressin, orexin, CART, neuroendocrinology, MRI, 3 Tesla, volymetric analysis
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:47
pages
175 pages
publisher
Translational Neuroendocrinology
defense location
Belfragsalen, BMC D15, Klinikgatan 32, Lund
defense date
2015-05-13 09:00
ISSN
1652-8220
ISBN
978-91-7619-126-2
language
English
LU publication?
yes
id
5372bb7e-1063-4da7-851e-7c737cbbce08 (old id 5275133)
date added to LUP
2015-04-22 09:12:37
date last changed
2016-09-19 08:44:49
@phdthesis{5372bb7e-1063-4da7-851e-7c737cbbce08,
  abstract     = {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 pathol- ogy. Therefore, the aim of the work in this thesis was to investigate how the hypothala- mus is affected in clinical HD using neuropathological, neuroimaging and gene expression analyses.<br/><br>
In the Paper I and II included in this thesis, we quantified selective neuropeptide-ex- pressing 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 ap- pear 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.<br/><br>
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 hypotha- lamic 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.<br/><br>
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.<br/><br>
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.},
  author       = {Gabery, Sanaz},
  isbn         = {978-91-7619-126-2},
  issn         = {1652-8220},
  keyword      = {Huntington’s disease,huntingtin,hypothalamus,oxytocin,vasopressin,orexin,CART,neuroendocrinology,MRI,3 Tesla,volymetric analysis},
  language     = {eng},
  pages        = {175},
  publisher    = {Translational Neuroendocrinology},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {New perspectives on pathology in Huntington's disease - characterization of hypothalamic changes},
  volume       = {2015:47},
  year         = {2015},
}