Background: Given that individuals with subjective cognitive decline (SCD) report a change that is not yet measurable with standard neuropsychological assessment measures, they are thought to be the earliest along the cognitive continuum between healthy aging and Alzheimer’s disease (AD). The current study used a neuroimaging approach to examine differences in brain function and structure between individuals with SCD and healthy controls (HC). Method: 3T resting state functional MRI and high resolution anatomical images were retrieved from 23 individuals with SCD (mean age = 72.9 years, SD = 5.4, 12 females) and 23 HC (mean age = 74.3 years, SD = 5.0, 12 females) from the screening time point from the AD Neuroimaging Initiative database. All data were processed using the FMRIB Software Library. Seed-based analyses of the default mode network (DMN) were used to compare differences in brain function between SCD and HC groups (Z > 2.3; cluster significance: p < 0.05, corrected). Voxel-based morphometry (VBM) was used to examine differences in grey matter volume between the SCD and HC groups. Results: The SCD and HC groups were not significantly different in age or education level. Results revealed significantly greater activity in the DMN including the bilateral precuneus cortex, bilateral thalamus, and right hippocampal regions in individuals with SCD relative to controls. Conversely, those with SCD showed decreased activation in the bilateral frontal pole, caudate, angular gyrus, lingual gyrus, right superior frontal gyrus, right occipital pole, right superior temporal gyrus, left superior temporal gyrus in the posterior division, left precuneus cortex, left precentral gyrus, left occipital fusiform gyrus, left temporal pole, and left cerebellum compared to HC. Finally, VBM results did not show significant differences in grey matter volume between the groups. Conclusion: Findings revealed changes in brain function but not structure between individuals with SCD and HC. Overall, this study represents a crucial step in characterizing individuals with SCD, a group recognized to be at increased risk for AD. It is imperative to identify biomarkers prior to significant decline on clinical assessment, so that disease-delaying interventions may be delivered at the earliest possible time point. / Graduate / 2020-08-15

Dementia is a growing burden for society, and it is of interest to discover it at an early stage. Both subjective cognitive decline (SCD) and subjective olfactory decline (SOD) has been associated with future cognitive decline and dementia. However, subjective measures have often been criticized and are still not fully understood. I aimed to examinate the frequency of SCD and SOD and whether they are likely to measure different things and what their longitudinal effects are. The baseline sample (N=784, 35-90 years, 51% female) were split into reported SCD, SOD, combined subjective olfactory and cognitive decline, and controls. Between-subjects and within-subjects statistical tests were conducted on a subset of participants (N=307, 45 to 90 years, 52% female) comparing SCD and SOD and their olfactory ability, cognitive performance, and demographics. In the baseline sample, a total of 21.1% reported a SOD whereas only 9.9% reported a SCD, only 2.7% reported both. SOD individuals had an emerged olfactory decline at follow up, their olfactory performance was associated with performance in several cognitive tests, this was not the case for the SCD individuals. The SOD and the SCD groups differ from each other, and they appear to be rather independent from each other. They might be complementary in understanding the aging brain.

In der vorliegenden Arbeit wurden Zusammenhänge zwischen Parametern des peripheren Cholesterolstoffwechsels mit Makrostruktur und Mikrostruktur des Hippocampus anhand multimodaler 7 Tesla Magnetresonanztomografie bei älteren, kognitiv gesunden Menschen untersucht. Dabei wurden Unterschiede zwischen den biologischen Geschlechtern der Teilnehmenden sowie Unterschiede zwischen Teilnehmenden mit und ohne subjektive kognitive Beeinträchtigungen betrachtet. Als zentrales Ergebnis zeigte sich ein Zusammenhang zwischen hohen HDL-Werten und niedrigem Hippocampusvolumen bei Frauen.:Inhaltsverzeichnis II Abkürzungsverzeichnis V Abbildungsverzeichnis VII Tabellenverzeichnis IX 1 Einführung 1 1.1 Hintergrund 1 1.2 Demenzielle Erkrankungen 2 1.3 Subjective Cognitive Decline (SCD) in präklinischer Alzheimer-Demenz 4 1.4 Ätiopathogenese der Alzheimer-Demenz 6 1.4.1 Cholesterolstoffwechsel 7 1.4.2 Rolle des Cholesterolstoffwechsels in der Pathogenese der Alzheimer-Demenz 9 1.5 Hippocampus 14 1.5.1 Struktur und Funktionen 14 1.5.2 Physiologische und pathologische Veränderungen des Hippocampus 16 1.6 Die Verbindung zwischen Hyperlipidämie, Hippocampusstruktur und Kognition 20 2 Aufgabenstellung 23 3 Materialien und Methoden 25 3.1 Studienpopulation 26 3.1.1 Ein- und Ausschlusskriterien 26 3.1.2 Rekrutierung 26 3.1.3 Einteilung in Gruppen 27 3.2 Untersuchungen 27 3.2.1 Medizinische körperliche Untersuchung 29 3.2.2 Neuropsychologische Tests und Fragebögen 30 III 3.2.3 Magnetresonanztomografie (MRT) 31 3.3 Statistische Analyse 33 4 Ergebnisse 34 4.1 Deskriptive Statistik 34 4.1.1 Demografie 34 4.1.2 Somatische Parameter 35 4.2 Periphere Parameter des Lipidstoffwechsels und Hippocampusstruktur 39 4.2.1 Gesamte Gruppe 39 4.2.2 Geschlechter 42 4.2.3 Kognitive Gruppen 45 5 Diskussion 49 5.1 Zentrale Ergebnisse 49 5.2 Cholesterol 50 5.2.1 Cholesterolstoffwechsel und Pathogenese der Alzheimer-Demenz 50 5.2.2 Der Mythos des HDL-Cholesterols 53 5.3 Hippocampus 55 5.3.1 Volumen 55 5.3.2 Subfieldvolumetrie 56 5.3.3 Mean Diffusivity (MD) 57 5.4 Unterschiede zwischen den Geschlechtern 59 5.5 Subjective Cognitive Decline (SCD) 60 5.6 Stärken und Limitationen der Studie 63 5.6.1 Studiendesign 63 5.6.2 Studienpopulation 65 5.7 Schlussfolgerungen und Ausblick 66 6 Zusammenfassung 69 7 Literatur 73 8 Erklärung über die eigenständige Abfassung der Arbeit 93 9 Lebenslauf 94 10 Publikation 95 11 Danksagung 96

Background: Subjective cognitive decline (SCD) is recognized as a risk stage for Alzheimer’s disease (AD) and other dementias, but its prevalence is not well known. We aimed to use uniform criteria to better estimate SCD prevalence across international cohorts. Methods: We combined individual participant data for 16 cohorts from 15 countries (members of the COSMIC consortium) and used qualitative and quantitative (Item Response Theory/IRT) harmonization techniques to estimate SCD prevalence. Results: The sample comprised 39,387 cognitively unimpaired individuals above age 60. The prevalence of SCD across studies was around one quarter with both qualitative harmonization/QH (23.8%, 95%CI = 23.3–24.4%) and IRT (25.6%, 95%CI = 25.1–26.1%); however, prevalence estimates varied largely between studies (QH 6.1%, 95%CI = 5.1–7.0%, to 52.7%, 95%CI = 47.4–58.0%; IRT: 7.8%, 95%CI = 6.8–8.9%, to 52.7%, 95%CI = 47.4–58.0%). Across studies, SCD prevalence was higher in men than women, in lower levels of education, in Asian and Black African people compared to White people, in lower- and middle-income countries compared to high-income countries, and in studies conducted in later decades. Conclusions: SCD is frequent in old age. Having a quarter of older individuals with SCD warrants further investigation of its significance, as a risk stage for AD and other dementias, and of ways to help individuals with SCD who seek medical advice. Moreover, a standardized instrument to measure SCD is needed to overcome the measurement variability currently dominant in the field.

Background: Subjective cognitive decline (SCD), i.e., the self-perceived feeling of worsening cognitive function, may be the first notable syndrome of preclinical Alzheimer’s disease and other dementias. However, not all individuals with SCD progress. Stability of SCD, i.e., repeated reports of SCD, could contribute to identify individuals at risk, as stable SCD may more likely reflect the continuous neurodegenerative process of Alzheimer’s and other dementias. Methods: Cox regression analyses were used to assess the association between stability of SCD and progression to MCI and dementia in data derived from the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). Results: Of 453 cognitively unimpaired individuals with a mean age of 80.5 years (SD = 4.2), 139 (30.7 %) reported SCD at baseline. Over the study period (M = 4.8 years, SD = 2.2), 84 (18.5 %) individuals had stable SCD, 195 (43.1 %) unstable SCD and 174 (38.4 %) never reported SCD. Stable SCD was associated with increased risk of progression to MCI and dementia (unadjusted HR = 1.8, 95 % CI = 1.2–2.6; p < .01), whereas unstable SCD yielded a decreased progression risk (unadjusted HR = 0.5, 95 % CI = 0.4–0.7; p < .001) compared to no SCD. When adjusted for baseline cognitive functioning, progression risk in individuals with stable SCD was significantly increased in comparison to individuals with unstable SCD, but not compared to individuals without SCD. Conclusions: Our results, though preliminary, suggest that stable SCD, i.e., repeated reports of SCD, may yield an increased risk of progression to MCI and dementia compared to unstable SCD. Baseline cognitive scores, though within a normal range, seem to be a driver of progression in stable SCD. Future research is warranted to investigate whether stability could hold as a SCD research feature.

Cette thèse vise à tester l’hypothèse selon laquelle la maladie d’Alzheimer (MA), à ses différents stades, est responsable d’un dysfonctionnement synaptique. Ce dernier, conjointement avec d’autres processus pathologiques, pourrait mener à des modifications de l’excitabilité neuronale au sein de régions cérébrales spécifiques et, en conséquence, à des altérations de la connectivité fonctionnelle au sein des réseaux neuronaux auxquels contribuent ces régions cérébrales.Deux objectifs principaux ont été visés tout au long de ce projet. Le premier ambitionnait l’identification de nouveaux marqueurs électrophysiologiques du continuum de la MA. Le second aspirait à une meilleure compréhension de la relation entre les changements électrophysiologiques, les anomalies structurelles et métaboliques ainsi que les déficits cognitifs des patients souffrant d’une MA ou étant à risque de la développer. Afin de répondre à ces buts de recherche, une approche multimodale combinant l’exploration électrophysiologique via la magnétoencéphalographie (MEG), métabolique et structurelle via un appareil hybride associant la tomographie par émission de positons avec comme traceur le fluorodésoxyglucose (FDG) et l’imagerie par résonance magnétique structurelle (TEP-IRM), et enfin cognitive via un examen neuropsychologique a été mise en place pour tous les participants qu’ils soient dans le cadre d’un vieillissement normal ou pathologique.La première étude a investigué la manière dont le continuum de la MA altère la dynamique de l’activité cérébrale spontanée et comment cette dernière est reliée aux anomalies structurelles, métaboliques et cognitives associées à la MA. Les résultats ont principalement montré des altérations dans l’activation du réseau du mode par défaut chez les patients avec une MA constituant un corrélat électrophysiologique supplémentaire du dysfonctionnement synaptique de la MA.La deuxième étude a étudié la relation entre l'activité rythmique cérébrale en bande de fréquence alpha et les altérations en mémoire épisodique verbale en utilisant la tâche de rappel libre/rappel indicé-16 items. Nos résultats ont principalement mis en évidence un nouveau corrélat électrophysiologique du dysfonctionnement à court terme en mémoire épisodique qui peut accompagner le vieillissement pathologique.Enfin, notre dernière étude a visé à fournir une vue d'ensemble des changements électrophysiologiques associés au continuum de la MA. Nos résultats ont principalement montré une diminution globale de la connectivité fonctionnelle en bande de fréquence alpha chez les patients avec une MA soutenant la théorie selon laquelle l'hypoconnectivité apparait à un stade tardif de la démence. Ceci suggère la présence d'un syndrome de déconnexion sévère dans la MA.De manière générale, ce projet de recherche a permis l’identification de marqueurs électrophysiologiques supplémentaires de la MA ainsi qu’une meilleure compréhension du lien entre les modifications électrophysiologiques et le déficit cognitif, les anomalies structurelles ainsi qu’avec les changements métaboliques observés dans la MA. / Doctorat en Sciences psychologiques et de l'éducation / info:eu-repo/semantics/nonPublished

The diagnosis of neurodegenerative diseases leading to dementia is increasingly moving to the earlier stages in an effort to find the disease-modifying treatment for these diseases. Prodromal and preclinical stages of the diseases have become the primary research interests. Neuropsychology is specifically focused on early cognitive markers and development of methods that would be able to reliably assess these markers and to evaluate the risk of progression of cognitive decline in individual cases. The theoretical part of the thesis presents the current knowledge in the field of neurodegenerative diseases, it is specifically focused on Alzheimer's disease (AD) as the most common cause of dementia. We also present the current trends in neuropsychological diagnostics of early AD and the approach to subjective and objective evaluation of cognitive functioning. Building on that, we present the rationale for the empirical part of the thesis. The empirical part of the thesis extends the existing knowledge in the field of AD. We present and discuss seven original publications that follow three basic objectives: first, to characterize subjective cognitive complaints of individuals at risk of AD, second, to evaluate the potential of selected standard and experimental neuropsychological methods to detect...

This study aimed to understand subjective cognitive decline (SCD) and functional difficulties in older age cohorts with depressive symptoms, using one scoping review and two empirical studies. We implemented the six steps of Arksey and O'Malley's procedure for the scoping review. We used the population, concept, and context (PCC) inclusion and exclusion criteria in the literature search across MEDLINE via Ebscohost, PubMed, and PsycINFO for articles published on ADL/IADL indicators of SCD in older adults with depressive symptoms and that published in English language journals from January 2011 to November 2021. The two empirical studies used the 2019 wave of the Behavioral Risk Factor Surveillance Survey dataset of older adults aged 65 and ≥ 80 from the Centers for Disease Control and Prevention. We used multiple regression and the bias-corrected percentile bootstrap with 5000 samples using standard path-analytic approaches for the moderated mediation for the two empirical studies. Findings supported that instrumental activities of daily living (IADLs) presented more difficulties for older adults with SCD than the basic activities of daily living (B-ADLs), given that IADLs require more cognitive capabilities than B-ADLs. Environmental factors like healthcare access and subjective functional difficulties predicted SCD by mentally unhealthy day (MUD) mediation and age cohort moderation. The middle age cohort (70–74) had the most pronounced effects of the MUDs mediation in the relationship between healthcare access and IADLs in older adults with SCD. The younger-old (65–69) showed more substantial MUD mediation effects in the relationship between subjective functional difficulties and SCD. Worse SCD was associated with being Asians, female older adults, and at lower education years and income levels. Findings profiled SCD indicators in daily living activities across age cohorts and the mentally unhealthy days presentation. We extend the chronic stress theory predictions on accentuated emotional vulnerability from increased functional difficulties, compounding SCD.

Background: Subjective cognitive decline (SCD), i.e., the self-perceived feeling of worsening cognitive function, may be the first notable syndrome of preclinical Alzheimer’s disease and other dementias. However, not all individuals with SCD progress. Stability of SCD, i.e., repeated reports of SCD, could contribute to identify individuals at risk, as stable SCD may more likely reflect the continuous neurodegenerative process of Alzheimer’s and other dementias. Methods: Cox regression analyses were used to assess the association between stability of SCD and progression to MCI and dementia in data derived from the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). Results: Of 453 cognitively unimpaired individuals with a mean age of 80.5 years (SD = 4.2), 139 (30.7 %) reported SCD at baseline. Over the study period (M = 4.8 years, SD = 2.2), 84 (18.5 %) individuals had stable SCD, 195 (43.1 %) unstable SCD and 174 (38.4 %) never reported SCD. Stable SCD was associated with increased risk of progression to MCI and dementia (unadjusted HR = 1.8, 95 % CI = 1.2–2.6; p < .01), whereas unstable SCD yielded a decreased progression risk (unadjusted HR = 0.5, 95 % CI = 0.4–0.7; p < .001) compared to no SCD. When adjusted for baseline cognitive functioning, progression risk in individuals with stable SCD was significantly increased in comparison to individuals with unstable SCD, but not compared to individuals without SCD. Conclusions: Our results, though preliminary, suggest that stable SCD, i.e., repeated reports of SCD, may yield an increased risk of progression to MCI and dementia compared to unstable SCD. Baseline cognitive scores, though within a normal range, seem to be a driver of progression in stable SCD. Future research is warranted to investigate whether stability could hold as a SCD research feature.

Contexte : La plainte subjective de mémoire correspond à la perception de difficultés de mémoire par le sujet, alors que les performances mnésiques objectives, évaluées par un bilan neuropsychologique, sont normales. Notre recherche visait premièrement à identifier les déterminants psychologiques de la plainte subjective de mémoire et deuxièmement, à évaluer les effets d'un programme psychoéducatif dédié à cette plainte, le programme PrévMém. Méthodologie : Les participants, qui tous se plaignaient de leur mémoire, ont été recrutés soit par les neurologues d'un service spécialisé dans la mémoire, soit par le biais d'une complémentaire santé. Un bilan neuropsychologique permettait de confirmer l'absence de troubles objectifs de mémoire. Des évaluations psychologiques (plainte de mémoire, métamémoire, dépression, anxiété, schémas précoces inadaptés de Young) par auto-questionnaires informatisés ont eu lieu avant le programme (n=144), à la fin du programme (n= 104) puis un an après la fin de celui-ci (n=34). Un bilan neuropsychologique était à nouveau réalisé un an après la fin du programme. Le programme PrévMém consistait en 5 séances de deux heures en groupe, à raison d'une séance par semaine animées par différents professionnels de santé. Résultats : A l'entrée du programme, les facteurs les plus prédictifs de la plainte de mémoire étaient les schémas de Young, en particulier celui de dépendance / incompétence. De plus, les personnes qui ont été recrutées par le biais d'une consultation dans un service hospitalier spécialisé, se distinguaient des autres par un niveau plus élevé de plainte de mémoire et de symptomatologie anxio-dépressive. Le programme PrévMém a permis de diminuer significativement le niveau de plainte de mémoire, le perfectionnisme mnésique et les inquiétudes envers la maladie d'Alzheimer. Conclusion : Notre étude a confirmé l'influence des facteurs psychologiques sur la plainte de mémoire et a mis en lumière la valeur prédictive du schéma cognitif dépendance / incompétence. Elle a également montré l'intérêt d'une prise en charge psychoéducative. Les résultats suggèrent d'introduire, dans de futures interventions psychothérapeutiques, un travail cognitif ciblé sur ce schéma de dépendance / incompétence. / Background: Subjective memory complaint refers to self-experienced memory difficulties while having normal performances on standardized neuropsychological tests. Our study aimed firstly to identify the psychological predictors of subjective memory complaint and secondly to assess the effects of a psychoeducational program dedicated to this complaint, the PrévMém program. Methods: The participants, who all voiced a memory complaint, were recruited either by neurologists from a memory clinic, or through a health insurance plan. A neuropsychological assessment was performed to confirm the absence of memory impairment. The participants were administered computerized self-report psychological assessments (memory complaint, metacognition, depression, anxiety, Young early maladaptive schemas) before the program (n = 144), at the end of the program (n = 104), and finally one year later (n = 34). Another neuropsychological assessment was also performed one year after the end of the program. The PrévMém program consisted of 5 weekly 120-minute sessions, in a group setting, led by different health professionals. Results: At the time of entrance into the program, the best determinants of subjective memory complaint were the Young early maladaptive schemas, more specifically that measuring dependence /incompetence. In addition, participants who were recruited through the memory clinic differed from the others in that they showed a higher level of memory complaint and a higher level of anxiety and depression. The PrévMém program significantly reduced the memory complaint, memory "perfectionism" and concerns towards Alzheimer's disease. Conclusion: Our study confirmed the influence of psychological factors on memory complaints and highlighted the predictive value of the dependence / incompetence cognitive schema. It also underscores the value of a psychoeducational intervention. Our results suggest that it may be worthwhile to introduce cognitive restructuring that targets the schema of dependence/incompetence in future psychotherapeutic interventions.