Demographic and ethnicity effects on neuropsychological test performance : implications for dementia assessment in Caribbean populations

Prevalence rates of dementia are increasing worldwide and more so in developing countries. Early and accurate diagnosis of dementia then assumes critical importance. Cross-cultural neuropsychological assessment of dementia depends on the use of instruments that have been appropriately normed and validated for target populations. While culture and ethnicity have been acknowledged as variables which significantly impact cognitive performance, they are not usually included in normative and validation studies. The main aim of this dissertation was to standardise and identify the role played by ethnicity in performance on a number of instruments used in the assessment of dementia and identify the role and interaction of ethnicity with other common demographic variables on performance for Caribbean populations. Performance on the Mini Mental State Exam (MMSE) was influenced by age, education and ethnicity and a validation of corrected scores yielded a cut-off that resulted in a 35% reduction in false positive rates among non-AD persons. The Alzheimer’s Disease Assessment Scale-cognitive section (ADAS-cog) was influenced by education and was resistant to effects of ethnicity. Cut-off scores were lower than traditionally suggested, perhaps due to higher educational levels, but resulted in very high sensitivity (89%) and specificity (89%) rates. Education influenced scores on most measures: digit span, digit cancellation, logical memory, semantic and phonemic fluency and Raven’s Coloured Progressive Matrices. Ethnicity also influenced scores on digit span backwards, digit cancellation, semantic fluency and Raven’ Matrices. Ethnic differences in performance may be attributed to differences in attention, working memory and also to differences in cognitive styles. Differences in educational attainment across cultures and generations renders earlier norms invalid and highlight the needs for norms to be periodically revised in order to be considered representative of current populations. The provision of culturally relevant and contemporary norms yielded in this study can be regarded as invaluable tools in the assessment and diagnosis of dementia in diverse populations

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

Physical, psychological, demographic and modifiable risk factors for age related cognitive impairment associated with possible dementia and frailty

The population of China is ageing. Accompanying this aging population, dementia and frailty have a growing importance. However there is little consensus on the association between dementia and frailty, in terms of how the criteria that are part of this two syndromes overlap, as both disorders are age-related and increase the risk for falls, further leading to loss of independence. To meet the above needs, the thesis describes research into different frailty diagnostic criteria, as well as its association with dementia symptoms. We examined cognitive measures that can be used for assessment of Mild Cognitive Impairment (MCI) and dementia screening (the Hopkins Verbal Learning Test, HVLT) and compared its discriminant ability with the commonly used cognitive screening tool, the Mini-Mental State Examination (MMSE) in distinguishing Cognitive Impairment (including MCI and dementia) from No Cognitive Impairment (NCI, normal controls) in two community-dwelling elderly Chinese populations and in one institutionalised elderly population in Shanghai, China. Subsequently we investigated whether physical and cognitive symptoms clustered together to form frailty phenotypes. We employed indicators that have been widely used to diagnose frailty, including physical measures (grip strength, Time-Up and Go test, 15 feet gait speed test and Berg balance test), and psychological measures (the HVLT and the MMSE) to predict cognitive impairment (CI) and frailty. Additionally, we described demographics (age, gender, education) and other potential modifiers when detecting cognitive impairment and functional disability. We then built up a model for possible frailty phenotype using various indicators. Lastly, we examined whether demographic (age, gender, education and profession), and lifestyle (smoking/alcohol history, exercise frequency, and dietary habit) could be used to predict future cognitive impairment. It was found that advanced age, lower education (no or primary level), and being vegetarian were significant risk factors for cognitive impairment. Furthermore, whereas high consumption of green vegetables is a protector against cognitive impairment, high intake of tofu was negatively related to cognitive performance among community-dwelling elderly in China.To meet the above needs, the thesis describes research into different frailty diagnostic criteria, as well as its association with dementia symptoms. We examined cognitive measures that can be used for assessment of Mild Cognitive Impairment (MCI) and dementia screening (the Hopkins Verbal Learning Test, HVLT) and compared its discriminant ability with the commonly used cognitive screening tool, the Mini-Mental State Examination (MMSE) in distinguishing Cognitive Impairment (including MCI and dementia) from No Cognitive Impairment (NCI, normal controls) in two community-dwelling elderly Chinese populations and in one institutionalised elderly population in Shanghai, China. Subsequently we employed these two cognitive measures to investigate whether they were part of the frailty syndrome among elderly from the community-based studies. We investigated whether physical and cognitive symptoms clustered together to form frailty phenotypes. We employed indicators that have been widely used to diagnose frailty, including physical measures (grip strength, Time-Up and Go test, 15 feet gait speed test and Berg balance test), and psychological measures (the HVLT and the MMSE) to predict cognitive impairment (CI). We found four distinct subtypes of elderly characterised by increasing care needs: 1. Persona elderly as defined by age >78, year of education12.7 seconds and 15 feet gait speed >4.4 seconds; 3. Persona Cognitive impairment, defined by a MMSE total score <25, a HVLT Immediate Recall (IR) score <15, and a HVLT Delayed Recall (DR) <5; 4. Persona Physical frailty (balance,) defined by a Berg Balance test score of <53. Additionally, we described demographics (age, gender, education) and other potential modifiers when detecting cognitive impairment and functional disability. We then built up a model for possible frailty phenotype using various indicators, Frailty here was defined as: 1.Low BMI as measured by this algorithm: BMI= Weight (kg)/Height (m)2 2.Weakness (upper and lower body): grip strength in the lowest quintile, adjusted for gender; and TUG get up with assistance or unable to get up 3.Slowness (lower body): TUG score in the lowest quintile, adjusted for gender; and 15 feet gait speed in the lowest quintile, adjusted for gender; 4.Poor balance: Berg Balance test score in the lowest quintile, adjusted for gender; 5.Low physical activity: engaging in exercise less than once per week. An individual with 4 or more present frailty components out of a total of 7 was considered to be frail , whereas equal or less than 3 characteristics were hypothesized to be pre-frail . Those with no present frailty components were considered as robust. Lastly, we examined whether demographic (age, gender, education and profession), and lifestyle (smoking/alcohol history, exercise frequency, and dietary habit) could be used to predict future cognitive impairment (as defined by a HVLT IR score of ≤19). The results of our studies show that compared to the MMSE, the HVLT is superior in differentiating MCI and dementia from NCI, and is also less affected by demographic factors in detecting frailty. Furthermore, in the current study, physical, psychological, demographic and other modifiable risk factors cluster together into different phenotypes of cognitive impairment and functional disability in these cohorts. A phenotype of frailty is built up using BMI, grip strength, TUG, 15 feet gait speed, balance and exercise frequency as indicators. The most common was the elderly phenotype followed by the cognitively impaired. A novel finding of the current study is that only 4.8% (8 out 168) of the whole sample fulfilled all three categories in the current study (cognitive impairment, functional disability and frailty). Finally, advanced age, lower education (no or primary level), and being vegetarian were significant risk factors for cognitive impairment. Furthermore, whereas high consumption of green vegetables is a protector against cognitive impairment, high intake of tofu was negatively related to cognitive performance among community-dwelling elderly in China