Doctoral thesis

Detecting Alzheimer’s disease (AD) : from the asymptomatic stages of healthy adults with AD genetic disposition to late stages of severe neurocognitive impairment


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Thèse de doctorat: Università della Svizzera italiana, 2021

English Background: Dementia is a syndrome characterized by progressive cognitive impairment, psychological and behavioural symptoms, and functional deficits. It is one of the leading causes of disability worldwide; its impact and the associated costs are enormous. Consequently, dementia is a global public health priority, and so is Alzheimer’s disease (AD), the most common cause of dementia in late life. Because dementia is an age-associated disease, the number of people living with dementia is expected to rise worldwide from in 2015 to 2030 because of the current demographic transition. Research in dementia diagnosis is of great importance both from a clinical and a public health perspective. Objectives: The main objectives of this PhD thesis are to examine the assessment of cognitive functions in different stages of dementia and AD, from the preclinical to late stages. In the preclinical stage, we aimed to investigate the relationship between a polygenic risk score (PRS) of genetic variants that are associated with AD and intrinsic brain functional connectivity and with cognitive performance in cognitively healthy adults. Next, we evaluated the self-reported questionnaires currently in use to assess Subjective Cognitive Decline (SCD) in older adults. SCD may be an initial symptom of AD, but evidence is still limited. We moved to the symptomatic stage of dementia and took a population perspective to provide an up-to-date estimate of dementia prevalence in selected Low- and Middle-Income Countries (LMIC) in preparation for a large-scale dementia prevalence study in these settings (STRiDE). Linked to the latter, we conducted a long overdue validation study of a brief dementia diagnostic schedule (the brief version of the 10/66 Dementia Diagnostic Schedule and Algorithm) to demonstrate its criterion and concurrent validity, before its use at scale in large epidemiological studies. We also tested the acceptability and usability of an innovative, cost-efficient and secure electronic data collection system for dementia epidemiology. Finally, we aimed to explore the role of informed consent and participatory research mechanisms in improving participation in dementia research in High-Income Counties (HIC) (i.e., Switzerland), where participation rates are traditionally low. Methods: To achieve the objectives of this PhD thesis, we used mixed methodologies. To investigate the first objective (PRS of AD and brain functional connectivity), we conducted a cross-sectional study with 139 healthy adults (age range 20 – 77 years old) between November 2020 and October 2021. Participants were recruited from a previous longitudinal study titled ‘Funktionelle und strukturelle neuronale Diskonnektion als Grundlage früher episodischer Gedächtnisstörungen der Alzheimer-Krankheit’ (‘Functional and structural neuronal disconnection as a basis/prerequisite for early neuronal memory dysfunction in Alzheimer’s Disease’) which was conducted at Goethe University Frankfurt, Germany. All participants had undergone rs-fMRI, DNA genotyping and PRS calculation, and neuropsychological testing for global cognition, working memory, verbal fluency, and executive functions. For the second objective (SCD assessment), we conducted a systematic review between April 2020 and June 2021 using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology. 16 studies met the inclusion criteria and reported development and/or validation of a total of 17 SCD questionnaires. We critically evaluated each questionnaire’s development process, its structural validity, internal consistency, test-retest reliability, convergent validity, and cross-cultural validity. For the third objective (dementia prevalence in LIMCs), we conducted a systematic review and meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta (PRISMA) guideline, between March 2018 and November 2019. 28 studies met the inclusion criteria and were included in the final analysis. For the fourth objective (validation of dementia diagnostic schedule), we carried out a cross-sectional validation study between March and August 2019. We included 229 participants (69% females) from the community and from nursing homes in Switzerland and Italy. To be eligible, participants needed to be at least 60 years old and to have an informant. 74 participants (32%) had a previous clinical diagnosis of dementia and 155 (68%) were cognitively healthy older adults. For each participant we also recruited and interviewed an informant. We administered the Italian version of the brief 10/66 dementia diagnostic schedule to all participants and their informants. The 10/66 schedule comprises the Community Screening Instrument for Dementia (CSI-D), the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) 10-word list learning task with delayed recall, and Euro-Depression (EURO-D) scale. We measured disability using the WHO Disability Assessment Schedule (WHO-DAS II) for convergent validity testing. For the final objective (role of informed consent), we conducted a qualitative study with 22 participants following the validation phase of the brief version of the 10/66 dementia diagnostic schedule. None of the 22 participants reported to have a dementia diagnosis at the time of the interview. From this work we published two papers which are presented below. Results: We found that high PRS was not significantly associated with alteration of the intrinsic functional connectivity of the PCC with other ROIs in the brain (q-FDR > 0.05). Moreover, higher PRS showed a significant association with lower scores (i.e., worse performance) in verbal fluency tests in participants older than 60 years (semantic fluency test: p-value = 0.019; phonemic fluency test: p-value = 0.033). Our systematic review of measurement properties of SCD questionnaires revealed that for none of the 17 identified questionnaires a content validity evaluation had been performed. 81.25% of the included studies performed and reported aspects of patient-reported outcome measures (PROM) development procedure (n = 13). None of the included studies tested for content validity of the developed PROMs. On the other hand, the majority of studies tested and reported structural validity (75%, n = 12) for thirteen PROMs. Internal consistency using Cronbach’s alpha was reported in 68.75% of studies (n = 11) for 13 PROMs. Test-retest reliability was reported in four studies. Only four studies (25%) indicated cross-cultural validation of SCD PROMs in other languages. Two studies evaluated and reported convergent validity with other SCD PROMs. Results from our systematic review and meta-analysis showed that pooled estimates of dementia prevalence in the selected middle-income countries ranged from 2% to 9% based on DSM-IV criteria. Prevalence was higher in studies using other diagnostic criteria (e.g., the 10/66 algorithm). Only Brazil, Mexico and India had data based on studies and methods with low risk of bias. The majority of the included studies did not explicitly state the representativeness of their sample, or whether there was non-response or selection bias. Findings from the validation study of the Italian version of the brief 10/66 dementia diagnostic schedule and algorithm demonstrated the acceptable criterion validity of the schedule against the clinical dementia diagnosis (i.e., DSM-V dementia diagnosis), with sensitivity of 87%, specificity of 61%, and agreement with the clinical diagnosis of dementia (kappa=0.40, area under the receiver operating characteristics curve=0.74). Lower false negatives than false positives were deemed acceptable for the subsequent epidemiological study, but we also highlighted a number of alternative explanations of the findings. Findings from the qualitative analysis of the validation study showed that participants held inaccurate and potentially trust- threatening beliefs regarding the role and use of informed consent. We also found that individuals welcomed the return of their individual-specific results, provided these meet a number of validity, clinical, and personal utility criteria. They justify researchers' duty to return study findings with the principles of beneficence (e.g., providing information that can help participants' medical decision-making) and justice (e.g., acknowledging participants' efforts to help research by sharing their personal information). Furthermore, individuals anticipate societal benefits of the return of individual specific study findings, including improved interpersonal relationships among individuals and decreased dementia-related stigma. Conclusion: Each of the conducted studies is an effort to provide an examination and an answer to the posed research question. In our exploratory analysis of the PRS and intrinsic functional connectivity, our results contribute to the growing body of research exploring the complex polygenicity of AD and its association with alteration in functional connectivity at rest. Further investigation of the interaction between genetic risk factors and other sociodemographic variables is warranted to understand the epigenetic nature of AD in older adults and why some individuals express the phenotype (i.e., clinical symptoms of AD) while others do not. Regarding the assessment of SCD, we conclude that the available evidence suggests that currently available measurements do not address important aspects of psychometric properties. Further work is needed to develop and validate SCD self-reported measurement with good quality measurement properties. Valid and feasible measurements would enhance the screening of older adults at risk of AD and provide a tool to follow up the progress of clinical symptoms. On the other hand, our systematic review showed that there are methodologies in use to diagnose and estimate dementia prevalence, but the various approaches and methods do vary considerably between studies. Comparison of dementia rates between countries and settings is therefore difficult. Our validation study provides evidence that the brief version of the 10/66 schedule can be used to detect dementia, and that its feasibility, acceptability, and strong cross-cultural validity can contribute to conduct studies and allow comparisons of dementia rates across different sites. We found that the fair sensitivity and specificity of the brief version of the 10/66 dementia diagnostic schedule makes it a practical instrument to identify dementia in older adults, both in the community and in residential care facilities, where up to fifty percent of people with dementia reside, at least in high income countries. Lastly, our qualitative study highlights the importance of a transparent and thorough informed consent process, especially in dementia research. This includes providing information on the scope and process, and the content of the informed consent document in a focused, age-appropriate manner. Furthermore, researchers should address the return of individual-specific study results early on during study design. Importantly, prospective participants should be involved in identifying the conditions under which results should be returned to them. Results should be shared with careful considerations regarding the perceived individual and societal benefits as well as the clinical implications that disclosing such results can have.
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