Executive function & semantic memory impairments in Alzheimer’s disease — investigating the decline of executive function and semantic memory in Alzheimer’s disease through computer-supported qualitative analysis of semantic verbal fluency and its applications in clinical decision support

Alzheimer’s Disease (AD) has a huge impact on an ever-aging society in highly developed industrialized countries such as the EU member states: according to the World Alzheimer’s Association the number one risk factor for AD is age. AD patients suffer from neurodegenerative processes driving cognitive decline which eventually results in the loss of patients’ ability of independent living. Episodic memory impairment is the most prominent cognitive symptom of AD in its clinical stage. In addition, also executive function and semantic memory impairments significantly affect activities of daily living and are discussed as important cognitive symptoms during prodromal as well as acute clinical stages of AD. Most of the research on semantic memory impairments in AD draws evidence from the Semantic Verbal Fluency (SVF) task which evidentially also places high demands on the executive function level. At the same time, the SVF is one of the most-applied routine assessments in clinical neuropsychology especially in the diagnosis of AD. Therefore, the SVF is a prime task to study semantic memory and executive function impairment side-by-side and draw conclusions about their parallel or successive impairments across the clinical trajectory of AD. To effectively investigate semantic memory and executive function processes in the SVF, novel computational measures have been proposed that tap into data-driven semantic as well as temporal metrics scoring an SVF performance on the item-level. With a better and more differentiated understanding of AD-related executive function and semantic memory impairments in the SVF, the SVF can grow from a well-established screening into a more precise diagnostic tool for early AD. As the SVF is one of the most-applied easy-to-use and low-burden neurocognitive assessments in AD, such advancements have a direct impact on clinical practice as well. For the last decades huge efforts have been put on the discovery of disease-modifying compounds responding to specific AD biomarker-related cognitive decline characteristics. However, as most pharmaceutical trials failed, the focus has shifted towards population-wide early screening with cost-effective and scalable cognitive tests representing an effective mid-term strategy. Computer-supported SVF analysis responds to this demand. This thesis pursues a two-fold objective: (1) improve our understanding of the progressive executive function and semantic memory impairments and their interplay in clinical AD as measured by the SVF and (2) harness those insights for applied early and specific AD screening. To achieve both objectives, this thesis comprises work on subjects from different clinical stages of AD (Healthy Aging, amnestic Mild Cognitive Impairment—aMCI, and AD dementia) and in different languages (German & French). All results are based on SVF speech data generated either as a one-time assessment or a repeated within-participant testing. From these SVF speech samples, qualitative markers are extracted with different amount of computational support (ranging from manual processing of speech to fully automated evaluation). The results indicate, that semantic memory is structurally affected from an early clinical—amnestic Mild Cognitive Impairment (aMCI)—stage on and is even more affected in the later acute dementia stage. The semantic memory impairment in AD is particularly worsened through the patients’ inability to compensate by engaging executive functions. Hence, over the course of the disease, hampered executive functioning and therefore the inability to compensate for corrupt semantic memory structures might be the main driver of later-stage AD patients’ notably poor cognitive performance. These insights generated on the SVF alone are only made possible through computer-supported qualitative analysis on an item-per-item level which leads the way towards potential applications in clinical decision support. The more fine-grained qualitative analysis of the SVF is clinically valuable for AD diagnosis and screening but very time-consuming if performed manually. This thesis shows though that automatic analysis pipelines can reliably and validly generate this diagnostic information from the SVF. Automatic transcription of speech plus automatic extraction of the novel qualitative SVF features result in clinical interpretation comparable to manual transcripts and improved diagnostic decision support simulated through machine learning classification experiments. This indicates that the computer-supported SVF could ultimately be used for cost-effective fully automated early clinical AD screening. This thesis advances current AD research in a two-fold manner. First it improves the understanding of the decline of executive function and semantic memory in AD as measured through computational qualitative analysis of the SVF. Secondly, this thesis embeds these theoretical advances into practical clinical decision support concepts that help screen population-wide and cost-effective for early-stage AD.Die Alzheimer-Krankheit (AD) stellt eine enorme Herausforderung für die immer älter werdende Gesellschaft in hochentwickelten Industrieländern wie den EU-Mitgliedsstaaten dar. Nach Angaben der World Alzheimer's Association ist der größte Risikofaktor für AD das Alter. Alzheimer-Patienten leiden unter neurodegenerativen Prozessen, die kognitiven Abbau verursachen und schließlich dazu führen, dass Patienten nicht länger selbstbestimmt leben können. Die Beeinträchtigung des episodischen Gedächtnisses ist das prominenteste kognitive Symptom von AD im klinischen Stadium. Darüber hinaus führen auch Störungen der Exekutivfunktionen sowie der semantischen Gedächtnisleistung zu erheblichen Einschränkungen bei Aktivitäten des täglichen Lebens und werden als wichtige kognitive Symptome sowohl im Prodromal- als auch im akuten klinischen Stadium von AD diskutiert. Der Großteil der Forschung zu semantischen Gedächtnisbeeinträchtigungen bei AD stützt sich auf Ergebnisse aus dem Semantic Verbal Fluency Tests (SVF), der auch die Exekutivfunktionen stark fordert. In der Praxis ist die SVF eines der am häufigsten eingesetzten Routine- Assessments in der klinischen Neuropsychologie, insbesondere bei der Diagnose von AD. Daher ist die SVF eine erstklassige Aufgabe, um die Beeinträchtigung des semantischen Gedächtnisses und der exekutiven Funktionen Seite an Seite zu untersuchen und Rückschlüsse auf ihre parallelen oder sukzessiven Beeinträchtigungen im klinischen Verlauf von AD zu ziehen. Um semantische Gedächtnis- und Exekutivfunktionsprozesse in der SVF effektiv zu untersuchen, wurden jüngst neuartige computergestützte Verfahren vorgeschlagen, die sowohl datengetriebene semantische als auch temporäre Maße nutzen, die eine SVF-Leistung auf Item-Ebene bewerten. Mit einem besseren und differenzierteren Verständnis von ADbedingten Beeinträchtigungen der Exekutivfunktionen und des semantischen Gedächtnisses in der SVF kann sich die SVF von einem gut etablierten Screening zu einem präziseren Diagnoseinstrument für frühe AD entwickeln. Da die SVF eines der am häufigsten angewandten, einfach zu handhabenden und wenig belastenden neurokognitiven Assessments bei AD ist, haben solche Fortschritte auch einen direkten Einfluss auf die klinische Praxis. In den letzten Jahrzehnten wurden enorme Anstrengungen unternommen, um krankheitsmodifizierende Substanzen zu finden, die auf spezifische, mit AD-Biomarkern verbundene Merkmale des kognitiven Abbaus reagieren. Da jedoch die meisten pharmazeutischen Studien in jüngster Vergangenheit fehlgeschlagen sind, wird heute als mittelfristige Strategie bevölkerungsweite Früherkennung mit kostengünstigen und skalierbaren kognitiven Tests gefordert. Die computergestützte SVF-Analyse ist eine Antwort auf diese Forderung. Diese Arbeit verfolgt deshalb zwei Ziele: (1) Verbesserung des Verständnisses der fortschreitenden Beeinträchtigungen der Exekutivfunktionen und des semantischen Gedächtnisses und ihres Zusammenspiels bei klinischer AD, gemessen durch die SVF, und (2) Nutzung dieser Erkenntnisse für angewandte AD-Früherkennung. Um beide Ziele zu erreichen, umfasst diese Thesis Forschung mit Probanden aus verschiedenen klinischen AD Stadien (gesundes Altern, amnestisches Mild Cognitive Impairment-aMCI, und AD-Demenz) und in verschiedenen Sprachen (Deutsch & Französisch). Alle Ergebnisse basieren auf SVF Sprachdaten, erhoben im Querschnittdesign oder als wiederholte Testung in einem Längsschnittdesign. Aus diesen SVF-Sprachproben werden mit unterschiedlicher rechnerischer Unterstützung qualitative Marker extrahiert (von manueller Verarbeitung der Sprache bis hin zu vollautomatischer Auswertung). Die Ergebnisse zeigen, dass das semantische Gedächtnis bereits im frühen aMCI Stadium strukturell beeinträchtigt ist und im späteren akuten Demenzstadium noch stärker betroffen ist. Die strukturelle Beeinträchtigung des semantischen Gedächtnisses bei Alzheimer wird insbesondere dadurch verschlimmert, dass die Patienten nicht in der Lage sind, dies durch den Einsatz exekutiver Funktionen zu kompensieren. Daher könnten im Verlauf der Erkrankung eingeschränkte Exekutivfunktionen und damit die Unfähigkeit, degenerierte semantische Gedächtnisstrukturen zu kompensieren, die Hauptursache für die auffallend schlechten kognitiven Leistungen von AD-Patienten im Akutstadium sein. Diese Erkenntnisse basierend auf der SVF alleine werden erst durch die computergestützte qualitative Analyse auf Item-per-Item-Ebene möglich und weisen den Weg zu möglichen Anwendungen in der klinischen Entscheidungsunterstützung. Die feinkörnigere qualitative Analyse der SVF ist klinisch wertvoll für die AD-Diagnose und das Screening, aber sehr zeitaufwändig, wenn sie manuell durchgeführt wird. Diese Arbeit zeigt jedoch, dass automatische Analysepipelines diese diagnostischen Informationen zuverlässig und valide aus der SVF generieren können. Die automatische Transkription von Sprache plus die automatische Extraktion der neuartigen qualitativen SVF-Merkmale führen zu einer klinischen Interpretation, die mit manuellen Analysen vergleichbar ist. Diese Verarbeitung führt auch zu einer verbesserten diagnostischen Entscheidungsunterstützung, die durch Klassifikationsexperimente mit maschinellem Lernen simuliert wurde. Dies deutet darauf hin, dass die computergestützte SVF letztendlich für ein kostengünstiges vollautomatisches klinisches AD-Frühscreening eingesetzt werden könnte. Diese Arbeit bringt die aktuelle AD-Forschung auf zweifache Weise voran. Erstens verbessert sie unser Verständnis der kognitiven Einschränkungen im Bereich der Exekutivfunktionen und des semantischen Gedächtnisses bei AD, gemessen durch die computergestützte qualitative Analyse der SVF. Zweitens bettet diese Arbeit diese theoretischen Fortschritte in ein praktisches Konzept zur klinischen Entscheidungsunterstützung ein, das zukünftig ein bevölkerungsweites und kosteneffektives Screening für AD im Frühstadium ermöglichen könnte

Conversational affective social robots for ageing and dementia support

Socially assistive robots (SAR) hold significant potential to assist older adults and people with dementia in human engagement and clinical contexts by supporting mental health and independence at home. While SAR research has recently experienced prolific growth, long-term trust, clinical translation and patient benefit remain immature. Affective human-robot interactions are unresolved and the deployment of robots with conversational abilities is fundamental for robustness and humanrobot engagement. In this paper, we review the state of the art within the past two decades, design trends, and current applications of conversational affective SAR for ageing and dementia support. A horizon scanning of AI voice technology for healthcare, including ubiquitous smart speakers, is further introduced to address current gaps inhibiting home use. We discuss the role of user-centred approaches in the design of voice systems, including the capacity to handle communication breakdowns for effective use by target populations. We summarise the state of development in interactions using speech and natural language processing, which forms a baseline for longitudinal health monitoring and cognitive assessment. Drawing from this foundation, we identify open challenges and propose future directions to advance conversational affective social robots for: 1) user engagement, 2) deployment in real-world settings, and 3) clinical translation

Information Technologies for Cognitive Decline

Information technology (IT) is used to establish a diagnosis and provide treatment for people with cognitive decline. The condition affects many before it becomes clear that more permanent changes, like dementia, could be noticed. Those who search for information are exposed to lots of information and different technologies which they need to make sense of and eventually use to help themselves. In this research literature and information available on the Internet were systematically analyzed to present methods used for diagnosis and treatment. Methods used for diagnosis are self-testing, sensors, Virtual Reality (VR), and brain imaging. Methods used for treatment are games, websites with information and media, Virtual Reality (VR), sensors, and robots. The resulting concept of knowledge was the basis of an artifact whose main goal was to present the facts to the broad public. This implied that a user-friendly artifact was developed through three iterations using the Design Science framework. A total of nine users and IT usability experts have evaluated the artifact returning the SUS score of 85,83 for users and 87,5 for IT usability experts. Nielsen´s heuristics were assessed by IT usability experts only, returning an average score of 4,28. The general response was positive regarding both the content and the attempt to present methods used in cognitive decline. It reminds to be seen how to bring this knowledge to those who are most affected by the decline.Masteroppgave i informasjonsvitenskapINFO390MASV-INF

Evaluation of recurrent glioma and Alzheimer’s disease using novel multimodal brain image processing and analysis

Novel analysis techniques were applied to two different sets of multi-modality brain images. Localised metabolic rate within the hippocampus was assessed for its ability to differentiate between groups of healthy, mildly cognitively impaired, and Alzheimer’s disease brains, and an investigation of its potential clinical diagnostic utility was conducted. Relative uptake and retention of two PET tracers (11Carbon Methionine and 18Fluoro Thymidine) in a post-treatment glioma patient cohort was utilized to perform survival prediction analysis

Improving the accuracy of brief cognitive assessments when used as part of the process for identifying dementia in general practice.

Identifying dementia in general practice remains a considerable challenge, with mild to moderate stages of dementia potentially underdiagnosed in 30-50% of cases. The primary aim of this PhD thesis was to address the question “how can we improve the accuracy of brief cognitive assessments when used as part of the process for identifying dementia in general practice?”. This was carried out via a combination of secondary research through three evidence syntheses, and primary research via a survey of general practitioners with results triangulated with existing research and thesis findings. Through the conduct of a rapid review of clinical practice guidelines (CPGs),I found a lack of consistent recommendations for general practice regarding selection and application of brief cognitive assessment (BCA) tools There was also a paucity of guidance given within the identified CPGs on tailoring BCA choice and use for specific populations. The rapid review indicates that greater clarity and consistency is needed from CPGs relating specifically to the use of BCAs as part of the process for identifying dementia in general practice. The systematic review and overview identified an absence of existing evidence. Where evidence exists, BCAs performed inconsistently and were broadly inadequate as a tool for use in general practice dementia care. Other factors beyond diagnostic accuracy render established tests ill-suited for general practice such as administration time, cost and acceptability for clinicians and patients. A number of areas are identified both in cognitive testing and research methods where progress can be made relatively simply. This thesis demonstrates that many assumptions underlying current practice are without robust foundations, with severe implications for general practice and patient care at a time of scarce resource and growing demand. These assumptions need revising as a priority. What is needed is clear, specific, well-designed primary research to begin to unpick these complexities and realistically address the challenges presented by the identification of dementia within general practice and primary care. I provide explicit recommendations for the design and conduct of a primary comparative accuracy study alongside a trial of effectiveness and cost-effectiveness of using brief cognitive assessments as part of the process of identifying dementia in general practice in order to objectively and systematically assess the suitability of brief cognitive assessments as a tool for use in this population and setting

Factors affecting assessment, uptake and adherence to physical activities in people with dementia: an inclusive approach

Dementia is a growing problem worldwide. There is no available long term effective treatment and many cases of dementia remain undiagnosed. Within this context, appropriate, accurate and reliable cognitive assessments are important in informing the process of diagnosing dementia, and monitoring the effects of subsequent interventions. Previous research has often researched the journey of dementia in stages. This thesis, however, was guided by inclusivity, a concept applied to encapsulate the need for the inclusion of all individuals across the whole journey of dementia. Assessments utilised during diagnostics should be cross-culturally applicable, easy and quick to administer, inexpensive, non-invasive and able to identify changes in cognitive functioning. Little research has explored cognitive assessments for people with intellectual disabilities, a growing group at high risk for experiencing dementia at a younger age. Moreover, physical activity could be a key intervention for people with dementia, with the potential to slow cognitive symptoms and promote independence. However, meta-analyses show mixed outcomes for the success of physical activity interventions. This may partly be due to low levels of engagement and adherence. Therefore, both cognitive assessments and physical activity, including factors influencing adherence, are important aspects of the journey of dementia, which require more research with an inclusive approach. This thesis was divided into 2 parts to reflect the underpinning paradigms that informed the investigations in each part. Hence, a mixed methods approach is used to investigate more inclusive practices in dementia diagnostics, intervention assessment and delivery of physical activity. Applied quantitative methods were used in part 1 to assess the accuracy of a battery of cognitive assessments (Mini Mental State Examination or MMSE, Hopkins Verbal Learning Test or HVLT, Verbal Fluency or VF, and the novel: Cognitive Computerized Test Battery for Individuals with Intellectual Disabilities or CCIID) in informing dementia diagnostics for individuals with (n=30) and without (n=25) intellectual disabilities (chapters 4 and 5). The same cognitive tests were then utilised to assess the acute effects of a physical activity intervention compared to a psychosocial control activity using a cross-over design involving people with dementia (chapter 6). The second part of the thesis informed by critical realism, but continuing the inclusive approach began by exploring the barriers and facilitators to physical activity for people with dementia (chapter 7). Novel mobile methods of interviewing were applied to explore the perspectives of people with dementia towards physical activity (chapter 8). These walking interviews were also discussed in comparison to more traditional seated interviews for their application in understanding the perspectives of people with demenita. This was only the second study to conduct walking interviews with people who have dementia, but the first to discuss physical activity within this context. Chapter 9 then sought to investigate the perspectives of professionals who work to provide physical activity for and with people who have dementia. This study investigated how professionals navigate barriers and facilitate adherence to physical activity for people with dementia within the community, and hence offers a discussion of practical solutions to barriers identified in the literature and from interviews with people with dementia. The findings from the initial investigations in this thesis showed that participants with and without a pre-existing cognitive impairment who had dementia scored significantly lower on all included cognitive assessments (MMSE, VF, HVLT, Series and Jigsaw subtests and total CCIID) than their age-matched counterparts. Receiver Operating Characteristic analysis revealed that all included assessments significantly classified those who had dementia, with a high accuracy of above 0.80 for all assessments with all populations. Assessments were well tolerated by all participants, including those with an intellectual disability. Acute cognitive benefits of physical activity were demonstrated over and above a psychosocial control using an order balanced cross-over design. An increase in cognitive scores was visible on the MMSE, VF, HVLT, Series and Jigsaw subtests and total CCIID after engaging in a short bout of resistance band physical activity versus a bingo (psychosocial) activity. This study confirms earlier research with resistance band physical activities in promoting memory in older people with and without dementia, but adds another new sensitive planning and logical reasoning test (CCIID) which could be important for early stages- or different types- of dementia. This study shows that the same well tolerated cognitive tests can be used for the initial screening and subsequent assessment of interventions.Systematic literature review (chapter 7) revealed that people with dementia have problems adhering to regular physical activity. The following thematic analysis of walking interview data with people who have dementia in chapter 8 revealed four key themes as to why this might be. The themes were: i) competition, ii) physical activity across the lifespan, iii) injury and decline; and iv) barriers to physical activity. The themes indicated that competitive aspects of physical activities can be encouraging or discouraging depending upon the individual participating, by giving the activity purpose, whether this is through competition or an activity goal, more people with dementia are interested in repeatedly engaging. Furthermore, injuries and decline in physical functioning frequently impacted participants’ ability to enjoy physical activity. This often led to adapted physical activities rather than traditional sports that participants described enjoying earlier on in their lives. Each participant also discussed different logistical barriers outside of physical capabilities that limited their consistent participation in physical activity. The final study of the thesis, in chapter 9, analysed interviews with professionals, and offered methods of navigating the barriers highlighted by people with dementia; and discussed the potential for professional engagement with dementia care to increase physical activity participation and inclusively deliver interventions. This often meant providing a personalised activity that includes social interaction for the participants to further engage with, and benefit from. The professionals discussed the structure of the context in which physical activity is provided for people with dementia. Overall, this thesis argues for inclusive practices for people with dementia regardless of pre-existing cognitive ability, from diagnosis through to strategies for sustaining interventions that could offer substantial benefits. The empirical chapters are potentially limited by the small numbers of participants per study (n=9-25). However, this also allowed for in-depth analyses. The findings demonstrate the need for increased communication between healthcare professionals and people with dementia to offer more inclusive practices that can give greater insight into our understanding of dementia, as well as offer better care throughout the journey of dementia for all individuals.</div

Do informal caregivers of people with dementia mirror the cognitive deficits of their demented patients?:A pilot study

Recent research suggests that informal caregivers of people with dementia (ICs) experience more cognitive deficits than noncaregivers. The reason for this is not yet clear. Objective: to test the hypothesis that ICs ‘mirror' the cognitive deficits of the demented people they care for. Participants and methods: 105 adult ICs were asked to complete three neuropsychological tests: letter fluency, category fluency, and the logical memory test from the WMS-III. The ICs were grouped according to the diagnosis of their demented patients. One-sample ttests were conducted to investigate if the standardized mean scores (t-scores) of the ICs were different from normative data. A Bonferroni correction was used to correct for multiple comparisons. Results: 82 ICs cared for people with Alzheimer's dementia and 23 ICs cared for people with vascular dementia. Mean letter fluency score of the ICs of people with Alzheimer's dementia was significantly lower than the normative mean letter fluency score, p = .002. The other tests yielded no significant results. Conclusion: our data shows that ICs of Alzheimer patients have cognitive deficits on the letter fluency test. This test primarily measures executive functioning and it has been found to be sensitive to mild cognitive impairment in recent research. Our data tentatively suggests that ICs who care for Alzheimer patients also show signs of cognitive impairment but that it is too early to tell if this is cause for concern or not