Background: Mild Cognitive Impairment (MCI) is a clinical construct reputed to represent an intermediate stage on a continuum between normal aging and cognitive decline. Conceptual and prognostic ambiguity can lead to significant diagnostic challenges and there is a need for accurate screening tests which can assist clinicians with decision-making. A diagnosis of MCI is also associated with considerable uncertainty for patients who may be adjusting to cognitive difficulties along with an increased risk of developing dementia. Beliefs about MCI may influence psychosocial adjustment, and individual differences in ‘psychological flexibility (PF)’, as conceptualised by the Acceptance and Commitment Therapy (ACT) model, may also be involved in this process. Objectives: In order to evaluate the accuracy and clinical utility of a recently developed screening tool for MCI, the Montreal Cognitive Assessment (MoCA), a systematic review of validation and diagnostic test accuracy (DTA) studies for this measure was conducted. Psychosocial adjustment to a diagnosis of MCI was also a key focus. An empirical study was therefore carried out with the aim of evaluating the possible relationships between cognitive impairment, illness representations about MCI, psychological wellbeing and quality of life (QoL), and to assess the potential involvement of PF. Method: Following a systematic search of relevant electronic databases and reference lists, validation and DTA studies of the MoCA were identified and evaluated for methodological quality. For the empirical study, patients recently diagnosed with MCI were recruited from local NHS memory clinic services and completed the MoCA and a questionnaire pack assessing illness representations, PF, mood, anxiety and QoL. Results: The systematic review identified 18 validation and DTA studies. Few of the studies achieved high ratings for methodological quality and problems with representativeness and generalisability were identified. Nevertheless, sensitivity levels appeared robust across studies, though specificity was variable. For the present empirical study, participants reported a spectrum of positive and negative beliefs about MCI. Distress attributed to MCI was associated with anxiety, along with perceptions of more serious illness consequences, while higher PF was associated with higher perceived QoL and mood. Lived experience of MCI appeared to have more relevance to psychosocial adjustment than objective cognitive impairment. Conclusions: The results of the systematic review indicate that while the MoCA is a robust tool overall in the identification of cognitive impairment, estimates of accuracy may be exaggerated by inter-study variation and bias. More rigorous validation studies are therefore needed. Implications for clinical decision-making regarding MCI are discussed and recommendations for future accuracy studies are outlined. The empirical study supported the findings of previous studies of the relevance of illness representations to psychosocial adjustment in MCI and added to the evidence base by providing preliminary support for the possible involvement of PF. The results suggest that both cognitive content and PF may represent possible vehicles for therapeutic change in patients with adjustment difficulties, and indicate that further investigation of these factors is warranted. Conclusions are limited, however, by small sample size and low statistical power. Replication of these findings with a larger and more representative sample is therefore recommended.

Introduction: Dementia is a syndrome due to disease of the brain, usually of a chronic nature, in which there is disturbance of multiple higher cortical functions including Memory, Comprehension, Thinking, Judgment, Orientation, language and communication skills and abstract thinking. It is one of the most challenging disorders both in terms of prevalence and economic burden. There are currently approximately 800,000 people with dementia in UK and national cost is 17 billion per year. It is estimated that in next thirty years, number of people with dementia will increase to 1.4 million and the national cost will be over 50 billion. The exceptional advances in modern medicine in terms of prolonging life expectancy do not necessarily improve the care delivered to people with dementia. Dementia is a progressive condition where clinical recovery is not possible despite the discovery of cognition enhancing drugs. This belief leads to low expectations that tend to erode hope and foster indignity. Advances in treatment of Alzheimer’s disease have, however, stimulated new thinking and methods of service delivery. At certain stage of their illness, if not from the very beginning, personal, and social recovery becomes more meaningful for service users than their clinical recovery. Objective: To investigate whether recovery-orientated psychiatric assessment and therapeutic intervention enhances the wellbeing of people with memory problems and their family carers. Method: This study was a preliminary randomised control study. Patients were randomly allocated to recovery focus group or treatment as usual group acting as the control. Participants in the recovery focus group received a recovery-focused pre-diagnostic wellbeing assessment and counselling, diagnostic consultation with written feedback and post-diagnostic support over a period of six months. Participants in both groups were assessed using the WHO Wellbeing Index (WHO-5) as the primary outcome measure. The Mini Mental State Examination, Cornell Scale for Depression in Dementia, EuroQol-5D and Zarit Burden Interview were used as secondary outcome measures. Written records of the narrative accounts of participants in the recovery focus group were also obtained. Results: 48 patients with early dementia were recruited and agreed to take part in the study. Out of these, 34 patients completed the study, of which 17 patients were in the recovery focus group and 17 patients were in the treatment as usual group (control).There was a significant difference between the groups in terms of greater improvement in wellbeing as rated by the WHO – 5 Wellbeing Index in the recovery focus group compared to the control group. The secondary outcome measures in the areas of cognition, quality of life and caregiver burden showed no differences between the groups. However, case histories from the recovery focus group identified the main areas of improvement in improved mood, increased social interaction, reduction in carer strain and/or burden and improved self-worth and/or confidence. Conclusions: This study shows that recovery focused care can enhance the wellbeing of people with mild to moderate dementia. The additional benefits perceived by the patients and their relatives /carers include improvement in mood symptoms, social interaction and confidence as well as reduction in carer burden and strain.

Alzheimer’s disease is a debilitating, progressive neurodegenerative disorder in the elderly, characterized by severe loss of memory and higher cognitive functions. In the hundred years since its discovery, Alzheimer’s disease (AD) has traversed from the status of a ‘rare neurological oddity’ to one of the greatest challenges faced by healthcare and medicine in this millennium. A reported 44 million people currently suffer from AD but only 1 in 4 people have been diagnosed. Although AD has been an area of intense research for almost 50 years now, most studies have focused on the end stage disease. Years of study on the pathological cause underlying AD; have conclusively shown that the accumulation of the sticky peptide, Aβ, is one of the major triggers of AD pathogenesis. However, after the initial Aβ trigger, multiple processes contribute to disease progression, so that by the time a patient is diagnosed on the basis of overt behavioral phenotypes, it is difficult to understand and differentiate between the causative mechanisms and the consequential effects of the disease. It is, perhaps, because of this, that we are still struggling to find therapies for AD which will stop or at the very least slow the course of the disease. In the 2015 report on AD, issued by the Alzheimer’s association, much emphasis has been placed on the early diagnosis of AD and the revision of the diagnostic criteria for AD. According to the new guidelines proposed in 2011, AD has been divided into three stages where the first stage occurs before the appearance of overt behavioral symptoms such as memory loss, whereas by the 1984 guidelines, cognitive disabilities must have already occurred for diagnoses of AD. This proposed preclinical stage of AD has been defined, reflecting the current belief that AD pathogenesis begins almost 20 years before the occurrence of behavioral dysfunction. However, no diagnostic criteria are currently available to establish this stage. Hence, there is a need to understand the early pathogenic mechanisms of AD, which will yield early therapeutic targets as well as early diagnostic markers of AD. One of the earliest documented events in AD pathogenesis is synaptic dysfunction, which is later manifested as loss of dendritic spines. Deficits in long term potentiation (LTP) has been demonstrated in Aβ exposed hippocampal slices as well as in mouse models of AD, much before the appearance of pathological hallmarks such as plaques and tangles as well as overt behavioral phenotypes. While these and other studies indicate clearly that elevated levels of soluble Aβ peptide leads to impairment of synaptic function, the underlying molecular mechanisms are yet to be elucidated. One of the purported mediators of Aβ induced dysfunction is oxidative stress. The Aβ peptide, especially the Aβ42, is a self aggregating peptide with a propensity to form peptidyl radicals. Interaction of the peptidyl radicals with biomolecules leads to the generation of more free radical species via cascading chain reactions. Additionally, Aβ peptide has also been demonstrated to have synaptotoxic effects via its effect on NMDA receptors and calcium influx leading to deregulated reactive oxygen species (ROS) production as well as excitotoxicity. Hence, with a view to understanding Aβ mediated early synaptic dysfunction in AD, we studied early signaling changes in the synaptosomes derived from the cortex of APP/PS1 mice model of AD at various ages. The APP/PS1 model contains a mouse/human chimeric APP gene bearing the KM670/671NL Swedish mutation and the human PS1 gene with an exon 9 deletion. These mice exhibit behavioral deficits from 7 months of age while plaque deposition and gliosis become apparent by 9 months of age. We chose to study both pre-symptomatic ages (1 and 3 months old) as well as post symptomatic (9 months old) mice. Post nuclear supernatant (PNS) as well as synaptosomes were isolated from the cortex of APP/PS1 and age matched control mice. We assayed the levels of reactive oxygen species (ROS) in the PNS and the synaptosomes of post symptomatic 9 months old APP/PS1 mice and age matched controls. In contrast to reports of enhanced oxidative stress markers in the brains of AD patients, we did not find any increase in the levels of ROS in the PNS of post symptomatic APP/PS1 mice compared to age matched controls. However, synaptosomes from the cortex of these animals exhibited a significant increase in ROS levels in APP/PS1 mice compared to controls. We further found that there was significant increase in the ROS levels in synaptosomes, but not PNS, of very young asymptomatic 1 and 3 months old APP/PS1 mice. This is a first demonstration of synapse specific increase in oxidative stress in AD mice, as young as 1 month of age, indicating that disease specific mechanisms operate at the synapse much before the appearance of any overt cellular or behavioral symptoms. The increase in synaptic ROS levels correlated with a small but significant increase in the levels of Aβ42 in the brains of APP/PS1 mice compared to controls. We also found a concurrent change in the redox status of the cytoskeletal protein, actin, at the synapse. As early as 1 month of age, there was a significant decrease in the protein level of reduced actin indicating that there is an increase in the level of oxidized actin at the synapse. This loss of reduced actin was specific to the fibrillar pool of actin while no significant change was observed in the redox status of the monomeric globular pool of actin. Oxidation of actin has been demonstrated to lead to its depolymerization. Concurrently, we found a significant loss of fibrillar actin in the synaptosomes of APP/PS1 mice. Actin is the major cytoskeletal protein at the synapse. Changes in the globular to fibrillar actin ratio at the synapse at early pre-symptomatic ages in APP/PS1 mice will likely lead to structural and consequent functional changes at the synapse. This could potentially be one of the triggers of synaptic dysfunction in AD. Furthermore, changes in the Akt-mTOR signaling pathway was also observed in the synaptosomes of 1 month old APP/PS1 mice, which is sustained at 9 months. There was a significant loss of the mTOR-pS6K-4EBP1 axis in the synaptosomes, but not PNS, of APP/PS1 mice. We found that loss of Akt signaling, as evinced by loss of Akt phosphorylation, Akt kinase activity as well as loss of phosphorylation of downstream effector GSK3β, potentially underlies the loss of mTOR signaling. Further, the loss of Akt signaling is mediated by synapse specific redox modification of Akt and consequent interaction with the protein phosphatase PP2a. Loss of the Akt-mTOR signaling at the synapse is indicative of deficits in local protein translation. Loss of this essential synaptic function, which plays critical roles in synapse maintenance as well as synaptic plasticity during learning and memory, at an early age, will have long ranging impact on synaptic function such as long term potentiation (LTP) in APP/PS1 mice. Our study is the first demonstration of oxidative stress and consequent signaling changes which occur specifically at the synapse of very young 1 month old APP/PS1 mice. These changes occur much before the appearance of overt phenotype such as plaque deposition and behavioral dysfunction but sustain till the appearance of classical pathological hallmarks. Hence, the study demonstrates that disease progression starts much before previously thought and provides us a critical time window during which therapeutic strategies designed to delay or stop these changes might change the course of AD.

Bakgrund: Antalet äldre i världen ökar ständigt. Åtta procent av Sveriges befolkning, som är 65 år och äldre, har någon form av kognitiv svikt. Med åldern ökar risken för mild kognitiv svikt, vilket påverkar alla områden i människans liv. Mild kognitiv svikt är ett tillstånd som kan leda till mer omfattande kognitiv nedsättning om det inte åtgärdas i ett tidigt skede. Det är därför viktigt att tidigt upptäcka och åtgärda de första symtomen på mild kognitiv svikt.  Syfte: Syftet med studien var att undersöka vilka interventioner som kan förbättra livskvaliteten hos äldre personer med mild kognitiv svikt. Metod: Systematisk blandad litteratur översikt (Systematic mixed studie review) med narrativ sammanfattning (narrativ summary) enligt Ryan (2013) valdes som studiedesign. Artiklar söktes systematiskt i databaserna Cinahl, PubMed och PsycINFO. Följande kategorier fastställdes vid analysen: fysisk aktivitet, kognitiv stimulans, kombinerade fysiska och kognitionsstimulerande interventioner och estetiska aktiviteter. Resultat: Studiens resultat baserades på en analys av elva kvantitativa och tre kvalitativa studier som omfattade äldre personer i ålder 65+ med MCI. Dessa artiklar publicerades mellan åren 2019 och 2023 och omfattade länderna Italien (1), Kanada (1), Kina (6), Mexiko (1), Nederländerna (1), Sverige (1), Tyskland (1) och USA (2). Interventioner som inkluderades i studien omfattade: fysiska aktiviteter som Tai Chi, måttlig aerob träning och squaredans; interventioner för kognitiv stimulans med hjälp av modern teknink; fysiska aktiviteter kombinerade med kognitiv träning; samt estetiska aktiviteter som stråkkonst, akvarell och akrylmålning. Interventionerna visade varierande grad av påverkan på livskvalitet för äldre personer med MCI, men samtliga visade positiv effekt på livskvaliteten. Slutsatser: Det finns evidens som tyder på att användandet av moderna teknologier kan förbättra äldre personernas med MCI livskvalitet. Interventioner som mindfulness, reminiscens, estetiska och fysiska aktiviteter kan också ge en positiv effekt på livskvalitet hos äldre personer med MCI. / Background: The number of elderly people in the world is constantly increasing. Eight percent of Sweden's population, who are 65 years and older, have some form of cognitive impairment. With age, the risk of mild cognitive impairment increases, which affects all areas of a person's life. Mild cognitive impairment is a condition that can lead to more extensive cognitive impairment if not addressed in its early stages. It is therefore important to detect and address the first symptoms of mild cognitive impairment at an early stage.  Aim: The aim of this study was to investigate which interventions can improve the quality of life in older people with mild cognitive impairment. Method: Systematic mixed study review with narrative summary according to Ryan (2013) was chosen as the study design. Articles were systematically searched in the databases Cinahl, PubMed and PsycINFO. The following categories were established in the analysis: physical activity, cognitive stimulation, combined physical and cognition-stimulating interventions, and aesthetic activities. Results: The results of the study were based on an analysis of eleven quantitative and three qualitative studies that included older people aged 65+ with MCI. These articles were published between the years 2019 and 2023 and covered the countries Italy (1), Canada (1), China (6), Mexico (1), the Netherlands (1), Sweden (1) Germany (1), and the United States (2). Interventions in the study included: physical activities such as Tai Chi, moderate aerobic, and square dancing; interventions for cognitive stimulation using modern technology; physical activities combined with cognitive training; as well as aesthetic activities such as string art, watercolor, and acrylic painting. The interventions showed varying degrees of impact on quality of life for older people with MCI, but all showed a positive effect on quality of life.  Conclusions: There is evidence to suggest that the use of modern technologies can improve the quality of life of older people with MCI. Interventions such as mindfulness, reminiscence, aesthetic and physical activities can also have a positive effect on quality of life in older people with MCI.

Introdução: Perda de memória é um dos sintomas mais comuns em pacientes nos estágios iniciais da doença de Alzheimer; esses déficits são um reflexo do envolvimento da formação do hipocampo. O BDNF tem sido relacionado com a plasticidade do hipocampo. Neste sentido, as combinações de biomarcadores, como, por exemplo, a volumetria do hipocampo, pode apresentar um maior valor preditivo para diferenciar doença de Alzheimer do envelhecimento normal em pacientes com comprometimento cognitivo leve. Objetivo: A presente tese de doutorado teve como objetivo avaliar os níveis séricos do BDNF e o volume do hipocampo em pacientes com demência devido à doença de Alzheimer, Comprometimento Cognitivo Leve (CCL) e idosos saudáveis. Métodos: Para realização do estudo foram selecionados 10 idosos saudáveis, 10 CCL e 13 pacientes com demência devido à doença de Alzheimer pelos critérios NIA-AA. Todos participantes foram submetidos a uma avaliação cognitiva. Para as análises do BDNF, foi utilizado método de ELISA e para as análises de volumetria do hipocampo as imagens foram obtidas por meio de equipamento de ressonância de 1.5T e os volumes obtidos por meio do programa NeuroQuant®. Resultados: Idosos saudáveis apresentaram níveis séricos mais elevados de BDNF do que os CCL e pacientes com demência. O grupo de pacientes com demência apresentou menor volume total do hipocampo do que os idosos saudáveis e os CCL. Não houve correlação significativa do BDNF sérico com volume do hipocampo. Conclusão: Considerando nossos resultados em conjunto (baixos níveis de BDNF nos grupos CCL e demência devido à DA e menor volume do hipocampo na demência devido à AD), podemos supor que a diminuição dos níveis de BDNF ocorre antes da lesão neuronal expressa pela redução do hipocampo. / Introduction: Memory impairment is the most common symptom in patients in the early stages of Alzheimer's disease; this deficit is a reflection of the involvement of the hippocampal formation. BDNF has been linked to the hippocampal plasticity. Combinations of biomarkers, such as the hippocampal volumetry may have higher predictive value for differentiating Alzheimer's disease from normal aging in patients with mild cognitive impairment. Objective: The objective of present thesis was to evaluate serum levels of BDNF and hippocampal volume in patients with Mild Cognitive Impairment (MCI) and dementia due to Alzheimer's disease, and healthy elderly participants. Method: Ten healthy elderly subjects, 10 MCI and 13 patients with dementia due to Alzheimer's Disease (NIA-AA criteria) were selected for the study. All participants were assessed cognitively. The ELISA method was used for BDNF analysis, and the analysis of hippocampal volumetric images were acquired with 1.5T magnetic resonance equipment and volumes obtained with NeuroQuant® program. Results: Healthy elderly had higher BDNF serum levels than MCI and dementia due to AD patients. The group of dementia patients had lower total hippocampal volume than MCI and healthy elderly participants. No significant correlation between serum BDNF and hippocampal volume was observed. Conclusion: Taking our results together (lower BDNF levels in MCI and dementia due to AD and smaller hippocampal volume in dementia due to AD) we can hypothesize that the decrease of BDNF may start before the establishment of neuronal injury expressed by the hippocampal reduction.

Introdução: Perda de memória é um dos sintomas mais comuns em pacientes nos estágios iniciais da doença de Alzheimer; esses déficits são um reflexo do envolvimento da formação do hipocampo. O BDNF tem sido relacionado com a plasticidade do hipocampo. Neste sentido, as combinações de biomarcadores, como, por exemplo, a volumetria do hipocampo, pode apresentar um maior valor preditivo para diferenciar doença de Alzheimer do envelhecimento normal em pacientes com comprometimento cognitivo leve. Objetivo: A presente tese de doutorado teve como objetivo avaliar os níveis séricos do BDNF e o volume do hipocampo em pacientes com demência devido à doença de Alzheimer, Comprometimento Cognitivo Leve (CCL) e idosos saudáveis. Métodos: Para realização do estudo foram selecionados 10 idosos saudáveis, 10 CCL e 13 pacientes com demência devido à doença de Alzheimer pelos critérios NIA-AA. Todos participantes foram submetidos a uma avaliação cognitiva. Para as análises do BDNF, foi utilizado método de ELISA e para as análises de volumetria do hipocampo as imagens foram obtidas por meio de equipamento de ressonância de 1.5T e os volumes obtidos por meio do programa NeuroQuant®. Resultados: Idosos saudáveis apresentaram níveis séricos mais elevados de BDNF do que os CCL e pacientes com demência. O grupo de pacientes com demência apresentou menor volume total do hipocampo do que os idosos saudáveis e os CCL. Não houve correlação significativa do BDNF sérico com volume do hipocampo. Conclusão: Considerando nossos resultados em conjunto (baixos níveis de BDNF nos grupos CCL e demência devido à DA e menor volume do hipocampo na demência devido à AD), podemos supor que a diminuição dos níveis de BDNF ocorre antes da lesão neuronal expressa pela redução do hipocampo. / Introduction: Memory impairment is the most common symptom in patients in the early stages of Alzheimer's disease; this deficit is a reflection of the involvement of the hippocampal formation. BDNF has been linked to the hippocampal plasticity. Combinations of biomarkers, such as the hippocampal volumetry may have higher predictive value for differentiating Alzheimer's disease from normal aging in patients with mild cognitive impairment. Objective: The objective of present thesis was to evaluate serum levels of BDNF and hippocampal volume in patients with Mild Cognitive Impairment (MCI) and dementia due to Alzheimer's disease, and healthy elderly participants. Method: Ten healthy elderly subjects, 10 MCI and 13 patients with dementia due to Alzheimer's Disease (NIA-AA criteria) were selected for the study. All participants were assessed cognitively. The ELISA method was used for BDNF analysis, and the analysis of hippocampal volumetric images were acquired with 1.5T magnetic resonance equipment and volumes obtained with NeuroQuant® program. Results: Healthy elderly had higher BDNF serum levels than MCI and dementia due to AD patients. The group of dementia patients had lower total hippocampal volume than MCI and healthy elderly participants. No significant correlation between serum BDNF and hippocampal volume was observed. Conclusion: Taking our results together (lower BDNF levels in MCI and dementia due to AD and smaller hippocampal volume in dementia due to AD) we can hypothesize that the decrease of BDNF may start before the establishment of neuronal injury expressed by the hippocampal reduction.

Introdução: Perda de memória é um dos sintomas mais comuns em pacientes nos estágios iniciais da doença de Alzheimer; esses déficits são um reflexo do envolvimento da formação do hipocampo. O BDNF tem sido relacionado com a plasticidade do hipocampo. Neste sentido, as combinações de biomarcadores, como, por exemplo, a volumetria do hipocampo, pode apresentar um maior valor preditivo para diferenciar doença de Alzheimer do envelhecimento normal em pacientes com comprometimento cognitivo leve. Objetivo: A presente tese de doutorado teve como objetivo avaliar os níveis séricos do BDNF e o volume do hipocampo em pacientes com demência devido à doença de Alzheimer, Comprometimento Cognitivo Leve (CCL) e idosos saudáveis. Métodos: Para realização do estudo foram selecionados 10 idosos saudáveis, 10 CCL e 13 pacientes com demência devido à doença de Alzheimer pelos critérios NIA-AA. Todos participantes foram submetidos a uma avaliação cognitiva. Para as análises do BDNF, foi utilizado método de ELISA e para as análises de volumetria do hipocampo as imagens foram obtidas por meio de equipamento de ressonância de 1.5T e os volumes obtidos por meio do programa NeuroQuant®. Resultados: Idosos saudáveis apresentaram níveis séricos mais elevados de BDNF do que os CCL e pacientes com demência. O grupo de pacientes com demência apresentou menor volume total do hipocampo do que os idosos saudáveis e os CCL. Não houve correlação significativa do BDNF sérico com volume do hipocampo. Conclusão: Considerando nossos resultados em conjunto (baixos níveis de BDNF nos grupos CCL e demência devido à DA e menor volume do hipocampo na demência devido à AD), podemos supor que a diminuição dos níveis de BDNF ocorre antes da lesão neuronal expressa pela redução do hipocampo. / Introduction: Memory impairment is the most common symptom in patients in the early stages of Alzheimer's disease; this deficit is a reflection of the involvement of the hippocampal formation. BDNF has been linked to the hippocampal plasticity. Combinations of biomarkers, such as the hippocampal volumetry may have higher predictive value for differentiating Alzheimer's disease from normal aging in patients with mild cognitive impairment. Objective: The objective of present thesis was to evaluate serum levels of BDNF and hippocampal volume in patients with Mild Cognitive Impairment (MCI) and dementia due to Alzheimer's disease, and healthy elderly participants. Method: Ten healthy elderly subjects, 10 MCI and 13 patients with dementia due to Alzheimer's Disease (NIA-AA criteria) were selected for the study. All participants were assessed cognitively. The ELISA method was used for BDNF analysis, and the analysis of hippocampal volumetric images were acquired with 1.5T magnetic resonance equipment and volumes obtained with NeuroQuant® program. Results: Healthy elderly had higher BDNF serum levels than MCI and dementia due to AD patients. The group of dementia patients had lower total hippocampal volume than MCI and healthy elderly participants. No significant correlation between serum BDNF and hippocampal volume was observed. Conclusion: Taking our results together (lower BDNF levels in MCI and dementia due to AD and smaller hippocampal volume in dementia due to AD) we can hypothesize that the decrease of BDNF may start before the establishment of neuronal injury expressed by the hippocampal reduction.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18872号 / 医博第3983号 / 新制||医||1008(附属図書館) / 31823 / 京都大学大学院医学研究科医学専攻 / (主査)教授 河野 憲二, 教授 古川 壽亮, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Our lives become longer with new advancements in medicine and technology. As a result, cognition and memory impairments will become a growing concern[23]. To be able to treat cognitive decline, dementia and related diseases, the need for early detection of memory deficiencies increases. This study aimed to validate the use of a new digital interaction version of a common memory test, the Rey Auditory Verbal Learning Test (RAVLT), compared with norm from the traditional human-to-human interaction version of the same test. This was performed through userstudies with both test versions in a counterbalanced order. The results consisted of quantitative results from the tests together with qualitative data from interviews with the participants in connection to each test occasion. The results showed a slight difference in some aspects of the quantitative test results, but at the same time, no significant difference for most of the measured results. Further, the interviews demonstrated that the differences in interaction and experience between the versions of the tests could be the reason for some of the differences in the quantitative result. The conclusion from this study was that there are many difficult problems to solve for speech interfaces in neurocognitive tests like the RAVLT. In line with previous research [22], the results highlight the importance of a natural speech interaction that conforms with the basic principles of human conversation, to create a stress-free experience and test results that can be reliable and comparable.

Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Many researchers believe that an effective AD treatment will prevent the development of disease rather than treat the disease after a diagnosis. Therefore, the development of tools to detect AD-related pathology in early stages is an important goal. In this report, MRI-based markers of neurodegeneration are explored as biomarkers of AD. In the first chapter, the sensitivity of cross-sectional MRI biomarkers to neurodegenerative changes is evaluated in AD patients and in patients with a diagnosis of mild cognitive impairment (MCI), a prodromal stage of AD. The results in Chapter 1 suggest that cross-sectional MRI biomarkers effectively measure neurodegeneration in AD and MCI patients and are sensitive to atrophic changes in patients who convert from MCI to AD up to 1 year before clinical conversion. Chapter 2 investigates longitudinal MRI-based measures of neurodegeneration as biomarkers of AD. In Chapter 2a, measures of brain atrophy rate in a cohort of AD and MCI patients are evaluated; whereas in Chapter 2b, these measures are assessed in a pre-MCI stage, namely older adults with cognitive complaints (CC) but no significant deficits. The results from Chapter 2 suggest that dynamic MRI-based measures of neurodegeneration are sensitive biomarkers for measuring progressive atrophy associated with the development of AD. In the final chapter, a novel biomarker for AD, visual contrast sensitivity, was evaluated. The results demonstrated contrast sensitivity impairments in AD and MCI patients, as well as slightly in CC participants. Impaired contrast sensitivity was also shown to be significantly associated with known markers of AD, including cognitive impairments and temporal lobe atrophy on MRI-based measures. The results of Chapter 3 support contrast sensitivity as a potential novel biomarker for AD and suggest that future studies are warranted. Overall, the results of this report support MRI-based measures of neurodegeneration as effective biomarkers for AD, even in early clinical and preclinical disease stages. Future therapeutic trials may consider utilizing these measures to evaluate potential treatment efficacy and mechanism of action, as well as for sample enrichment with patients most likely to rapidly progress towards AD.