Brain Networks and Dynamics in Narcolepsy [book]

Natasha Morales Drissi
2019 Linköping University Medical Dissertations   unpublished
Populärvetenskaplig sammanfattning Narkolepsi är en kronisk sömnsjukdom där den drabbade lider av obetvinglig sömnighet. Det gör att personer med sjukdomen blir mycket trötta under dagen och får sömnattacker som inte går att förhindra. Till symtomen hör också kataplexi som innebär plötslig kraftlöshet och en känsla av förlamning i samband med känslor som glädje och ilska. En del får hallucinationer strax innan de somnar eller vaknar. Narkolepsi delas in i två typer. Typ 1 beror på en autoimmun
more » ... or på en autoimmun reaktion som innebär att kroppens immunsystem angriper de hjärnceller som producerar ett hormon som reglerar vakenhet och sömn. Personer som fick symtom efter att ha vaccinerats med vaccinet Pandemrix har narkolepsi typ 1. Narkolepsipatienter beskriver också ofta andra icke-sömnrelaterade besvär, så som svårigheter med koncentration och minnet, men också kraftig viktuppgång trots att de inte äter mer. I den här avhandlingen har en grupp narkolepsipatienter 13-20 år med narkolepsi typ 1 undersökts med magnetkamera som har mätt hjärnans struktur och aktivitet, samt undersökt sammansättning av kroppsfett. Brunt fett, också kallat aktivt fett, för att det ökar ämnesomsättningen påverkas i djur som har narkolepsi och vi trodde att det kunde vara brist på brunt fett hos narkolepsipatienter som gör att de går upp i vikt. Resultaten från mätningen av kroppsfett visade att narkolepsipatienterna inte hade mindre brunt fett än motsvarande friska individer. Däremot så hade de högre bukfetma, även om förhållandet mellan det "dåliga" fettet (som ökar risk för hjärt och kärlsjukdomar och diabetes typ 2) och det mer neutrala underhudsfettet var bättre hos narkolepsipatienterna. Resultaten visar också att narkolepsipatienter har flera avvikelser i de områden i hjärnan som behandlar uppmärksamhet. Detta påverkar troligtvis deras förmåga att ta in information och kan upplevas som att de har "dålig minne". Ett av de områden som vi fann avvikelser i har möjligheter för att kunna användas som en ny behandling för koncentrationssvårigheter i narkolepsi typ 1. ii Abstract Narcolepsy is a chronic sleep disorder, characterised by excessive daytime sleepiness with frequent uncontrollable sleep attacks. In addition to sleeprelated problems, changes in cognition have also been observed in patients with narcolepsy and have been linked to the loss of Orexin-A in a number of studies. Results from previous functional and structural neuroimaging studies would suggest that the loss of Orexin-A has numerous downstream effects in terms of both resting state glucose metabolism and perfusion and reduction in cortical grey matter. Specifically, studies investigating narcolepsy with positron emission tomography (PET) and single photon emission computed tomography (SPECT) have observed aberrant perfusion and glucose metabolism in the hypothalamus and thalamus, as well as in prefrontal cortex. A very recent PET study in a large cohort of adolescents with type 1 narcolepsy further observed that the hypo-and hypermetabolism in many of these cortico-frontal and subcortical brain regions also exhibited significant correlations with performance on a number of neurocognitive tests. These findings parallel those found in structural neuroimaging studies, where a reduction of cortical grey matter in frontotemporal areas has been observed. The Aim of this thesis was to investigate mechanisms and aetiology behind the symptoms in narcolepsy through the application of different neuroimaging techniques. I present in this thesis evidence supporting that the complaints about subjective memory deficits in narcolepsy are related to a misallocation of resources. I further describe how this has its seat in defective default mode network activation, possibly involving alterations to GABA and Glutamate signaling. In addition to this, I present our findings of a structural deviation in an area of the brainstem previously not described in the aetiology of narcolepsy. This finding may have implications for further understanding the aetiology of the disease and the specific neuronal populations involved. In addition to this, I show evidence from adipose tissue measurements in specific compartments, confirming that weight gain in narcolepsy is characterised by centrally located weight gain and may be specifically related to OX changes, but maybe not brown adipose tissue volume. iii Acknowledgments I would first like to thank my thesis advisor Professor Maria Engström. The door to your office was always open whenever I had a question about my research or writing. You have consistently allowed any paper to be my own work, yet steered me in the right the direction whenever you thought I needed it. And to my Co-supervisors Associate Professor Gunnar Cedersund for providing me with the connections that allowed me to fulfil my long-time dream of living in Japan and Professor Fredrik Elinder for always being a good sport whenever I needed that signature at the last minute. I would also like to acknowledge Dr. Suzanne T. Witt for all the support with my project and for always so generously (and patiently) sharing your knowledge. Most importantly, helping me (finally) understand what an ANOVA is and why there are so very many numbers in SPSS! A special thanks to Dr. Helene Veenstra as the second reader of this thesis, I am gratefully indebted to you for your valuable comments. I would also especially like to thank, nurses, and nurse aids at CMIV. All of you have been there to support me when I recruited patients and collected data for my Ph.D. thesis. I especially want to thank Christer for never hesitating to share with me your vast knowledge of EEG in the form of constructive criticism. And everyone else at CMIV for the cheer and camaraderie during lunch and "fika," especially Roz, Sebastian, Anette, Marcel, Thobias, Sofie and Marcus I will miss ALL of our discussions. Dr. Karin Lundengård, for giving me the honour of being your Toastmaster, it is unfortunate you had to leave before you had a chance to reciprocate. Thank you for also letting me inherit your discarded office decorations. They are my precious. I'd also like to thank everyone at Funahashi lab at Keio University, Hiyoshi Campus, for all the great memories. It gave me the energy I sorely needed to finish this thesis. iv A special thanks to all my family. Words cannot express how grateful I am to my mother, for all of the sacrifices that you've made on my behalf. For always insisting that I can do anything and be anything, that voice at the back of my head has been the one to pick me up when I was ready to give up and also to my "bonus"-father for your unrelenting optimism. To my late father Liborio Angelo Morales, I carry your name with pride. To mormor and Philip. Not a day goes by when I don't feel your presence in my mind, I am fortunate to have had your love. You are sorely missed. To my sister Alexandra for always refusing to listen to anything even remotely related to my research. You gave me the tenacity to continue talking even when no one cares to listen. To my "bonus"-sisters Eva for injecting spontaneity into my life and Elin, for being such an inspiring role model.
doi:10.3384/diss.diva-153629 fatcat:vjhkqnzdwjanbesjzcbvd2qjhy