Background: Carriers of the APOE epsilon 4 allele are at increased risk of developing Alzheimer's disease (AD), and have been shown to have reduced cerebral metabolic rate of glucose (CMRgl) in the same brain areas frequently affected in AD. These individuals also exhibit reduced plasma levels of apolipoprotein E (apoE) attributed to a specific decrease in the apoE4 isoform as determined by quantification of individual apoE isoforms in APOE epsilon 4 heterozygotes. Whether low plasma apoE levels are associated with structural and functional brain measurements and cognitive performance remains to be investigated. Methods: Using quantitative mass spectrometry we quantified the plasma levels of total apoE and the individual apoE3 and apoE4 isoforms in 128 cognitively normal APOE epsilon 3/epsilon 4 individuals included in the Arizona APOE cohort. All included individuals had undergone extensive neuropsychological testing and 25 had in addition undergone FDG-PET and MRI to determine CMRgl and regional gray matter volume (GMV). Results: Our results demonstrated higher apoE4 levels in females versus males and an age-dependent increase in the apoE3 isoform levels in females only. Importantly, a higher relative ratio of apoE4 over apoE3 was associated with GMV loss in the right posterior cingulate and with reduced CMRgl bilaterally in the anterior cingulate and in the right hippocampal area. Additional exploratory analysis revealed several negative associations between total plasma apoE, individual apoE isoform levels, GMV and CMRgl predominantly in the frontal, occipital and temporal areas. Finally, our results indicated only weak associations between apoE plasma levels and cognitive performance which further appear to be affected by sex. Conclusions: Our study proposes a sex-dependent and age-dependent variation in plasma apoE isoform levels and concludes that peripheral apoE levels are associated with GMV, CMRgl and possibly cognitive performance in cognitively healthy individuals with a genetic predisposition to AD.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20567号 / 医博第4252号 / 新制||医||1022(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 古川 壽亮, 教授 髙橋 良輔, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Pathologisches Glücksspiel (PG) ist eine psychiatrische Erkrankung, die gerade erst im DSM-5 der gleichen Kategorie wie substanzgebundene Suchterkrankungen zugeordnet wurde. Bildgebungsstudien zu Substanzabhängigkeit beobachteten funktionelle und strukturelle Veränderungen im präfrontalen Kortex (PFC) und mesolimbischen Belohnungssystem (d.h. Striatum). Für PG wurden ähnliche Veränderungen berichtet; jedoch gibt es kaum Studien, die sich mit verschiedenen Aspekten funktioneller und struktureller Korrelate in diesen Regionen beschäftigen. Diese Arbeit untersuchte PG Patienten, alkoholabhängige (AD) Patienten und Kontrollpersonen (HC) mit Magnetresonanztomografie. In Analyse I wurden funktionelle Gehirndaten während der Belohnungsaufgabe zwischen den drei Gruppen verglichen. In Analyse II wurde das Volumen grauer Substanz mit voxelbasierter Morphometrie und in Analyse III die intrinsische Gehirnaktivität mit einer seedbasierten funktionellen Konnektivitätsanalyse von PG Patienten und HC ausgewertet. Die Analysen ergaben veränderte Aktivierungen in frontostriatalen Arealen während der Verarbeitung von Verlustvermeidung für PG Patienten im Vergleich zu HC. PG Patienten unterschieden sich dabei in ihrer Aktivierung von AD Patienten während der Antizipation von Geldverlust. Weiterhin zeigten PG Patienten erhöhte Volumina grauer Substanz und eine erhöhte funktionelle Konnektivität in frontostriatalen Arealen im Vergleich zu HC. Die Ergebnisse liefern weitere Hinweise für eine veränderte Belohnungsverarbeitung in PG und betonen die Bedeutung der Verlustvermeidungsverarbeitung. Die Volumenveränderungen im und die erhöhte Konnektivität zwischen dem PFC and Belohnungssystem deuten auf eine veränderte Interaktion zwischen diesen Regionen hin. Da solche Veränderungen in kortikostriatalen Systemen Ähnlichkeiten zu denen in Substanzabhängigkeiten aufweisen, unterstützen die Ergebnisse die neue Klassifikation des PG im DSM-5. / Pathological gambling (PG) is a psychiatric disorder newly classified under the same category as substance use disorders in the DSM-5. Neuroimaging studies on substance-related addictions reported functional and structural changes in the prefrontal cortex (PFC) and the mesolimbic reward system (i.e., striatum). For PG, findings are not that extensive, but also demonstrate altered reward processing and prefrontal function. However, there is a lack of studies focusing on different aspects of functional and structural correlates within these areas in PG. This thesis investigated PG patients, alcohol dependent (AD) patients and healthy controls with magnetic resonance imaging (MRI). In analysis I, functional brain data of a reward paradigm was compared between the three groups. In analysis II, local gray matter volume of PG patients and controls was processed via voxel-based morphometry. Resting-state data of PG patients and controls was analyzed via seed-based functional connectivity in analysis III. Results revealed altered brain responses in fronto-striatal areas during loss avoidance processing in PG patients as compared to controls. Importantly, PG patients differed in their brain responses from AD patients during the prospect of monetary loss. Moreover, PG patients showed an increase in local gray matter volume and functional connectivity in frontal-striatal areas as compared to controls. Our results add further evidence for an altered reward processing in PG and underline the importance of loss avoidance processing. Moreover, our findings of volumetric alterations within and increased connectivity between PFC and reward system, suggest an altered interaction between these brain regions. Since such alterations in cortico-striatal circuits resemble those reported for substance-related addictions, our findings support the new classification of PG in the DSM-5.