Familial Alzheimer’s disease: preclinical disease and pathophysiology biomarkers

It is now well recognised that Alzheimer’s disease (AD) has a long presymptomatic period, with evidence of amyloid deposition being detected approximately 20 years before the onset of cognitive decline. This clinically silent period opens up a treatment window at a potentially more tractable stage of the disease. As we move towards AD prevention trials, there is a need for robust and sensitive methods that can detect and track disease progression, especially during this asymptomatic period. Familial Alzheimer’s disease (FAD) is an autosomal dominant condition that has many shared clinical, radiological, and neuropathological features with the more common sporadic form of disease. In addition, the age at onset in FAD is reasonably consistent between successive generations. Therefore, study of FAD mutation carriers provides an opportunity to prospectively characterise the sequence, and timings, of key pathological changes in AD. In addition, this reasonably pathologically pure form of AD provides a valuable opportunity to better understand the molecular drivers of disease onset. The studies presented in this thesis aim to facilitate the identification of biomarkers of FAD, with the overarching aim of identifying biomarkers of preclinical disease and/or key pathological processes. A multimodal approach is taken, with both presymptomatic and mildly symptomatic individuals being included. Chapter 1 introduces the background to the problems addressed in this thesis by providing an overview of early onset and familial Alzheimer’s disease and its preclinical period. Chapter 1 also outlines some of the key pathological drivers of AD onset, and specifically FAD. Chapter 2 then outlines the methodological approaches that are common to the different studies reported in this thesis. The first data chapter of this thesis (Chapter 3) performs data-driven modelling of cognitive performance in a clinically asymptomatic FAD cohort to demonstrate the sequence and timing of early cognitive change in FAD (Chapter 3). Following on from this the trajectory of a promising AD biomarker, plasma phospho-tau181 (p-tau181), 3 in FAD is explored (Chapter 4). This study, which was the first to examine the utility of plasma p-tau181 in FAD, showed that increased levels are detected in presymptomatic mutation carriers and that increases begin over a decade prior to estimated symptom onset. The ability of imaging measures of tau, specifically longitudinal tau positron emission topography (PET) scanning, to detect presymptomatic change is also examined (Chapter 5). In contrast to blood measures of p-tau181, this study did not find evidence of increased tau signal in presymptomatic mutation carriers, instead it showed tau burden in FAD increases in close temporal proximity to symptom onset. Finally, Chapter 6 investigates the influence of FAD genotype on plasma amyloid beta ratios. This study, the first to investigate inter-mutation differences in plasma amyloid beta profiles, showed evidence of marked inter-group differences as well as associations between the relative production of longer (≥ 42 amino acids length) amyloid beta peptides and the estimated timing of symptom onset in Presenilin1 mutation carriers. The thesis draws together these different approaches and discusses how they advance our understanding of the neurobiology of AD and their potential utility in both clinical assessment and presymptomatic therapeutic trials

Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset.

Familial Alzheimer’s disease (FAD), caused by mutations in Presenilin (PSEN1/2) and Amyloid Precursor Protein (APP) genes, is associated with an early age at onset (AAO) of symptoms. AAO is relatively consistent within families and between carriers of the same mutations, but differs markedly between individuals carrying different mutations. Gaining a mechanistic understanding of why certain mutations manifest several decades earlier than others is extremely important in elucidating the foundations of pathogenesis and AAO. Pathogenic mutations affect the protease (PSEN/γ-secretase) and the substrate (APP) that generate amyloid β (Aβ) peptides. Altered Aβ metabolism has long been associated with AD pathogenesis, with absolute or relative increases in Aβ42 levels most commonly implicated in the disease development. However, analyses addressing the relationships between these Aβ42 increments and AAO are inconsistent. Here, we investigated this central aspect of AD pathophysiology via comprehensive analysis of 25 FAD-linked Aβ profiles. Hypothesis- and data-driven approaches demonstrate linear correlations between mutation-driven alterations in Aβ profiles and AAO. In addition, our studies show that the Aβ (37 + 38 + 40) / (42 + 43) ratio offers predictive value in the assessment of ‘unclear’ PSEN1 variants. Of note, the analysis of PSEN1 variants presenting additionally with spastic paraparesis, indicates that a different mechanism underlies the aetiology of this distinct clinical phenotype. This study thus delivers valuable assays for fundamental, clinical and genetic research as well as supports therapeutic interventions aimed at shifting Aβ profiles towards shorter Aβ peptides

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Disease duration in autosomal dominant familial Alzheimer disease: A survival analysis.

OBJECTIVE: To use survival modeling to estimate disease duration in autosomal dominant familial Alzheimer disease (ADAD) and ascertain whether factors influencing age at onset also affect survival. METHODS: Symptomatic mutation carriers (201 presenilin 1 [PSEN1] and 55 amyloid precursor protein [APP]) from ADAD families referred to the Dementia Research Centre, between 1987 and 2019, were included. Survival was assessed with respect to age at onset, year of birth, APOE ε4 status, cognitive presentation, and sex using multilevel mixed-effects Weibull survival models. The contribution of mutation and family to variance in age at onset and duration was also assessed. RESULTS: Estimated mean survival was 11.6 (10.4-12.9) years and was similar for APP and PSEN1 mutations. Sixty-seven percent of the variance in age at onset was explained by mutation and 72% by mutation and family together. In contrast, only 6% of the variance in disease duration was explained by mutation specificity and 18% by family membership. Irrespective of gene, survival appeared longer for successive generations and in individuals with atypical presentations. Older age at onset was associated with longer duration within PSEN1 and shorter duration within APP mutation carriers. No differences in survival time were found between sexes or between mutations located before or beyond codon 200 within PSEN1. CONCLUSIONS: Survival is influenced by mutation to a much lesser extent than age at onset. Survival time has increased over time and is longer in atypical presentations. These insights may inform the interpretation of disease-modifying therapy trials in ADAD

A Delphi study to determine the European core curriculum for Master programmes in genetic counselling.

Genetic counsellors have been working in some European countries for at least 30 years. Although there are great disparities between the numbers, education, practice and acceptance of these professionals across Europe, it is evident that genetic counsellors and genetic nurses in Europe are working autonomously within teams to deliver patient care. The aim of this study was to use the Delphi research method to develop a core curriculum to guide the educational preparation of these professionals in Europe. The Delphi method enables the researcher to utilise the views and opinions of a group of recognised experts in the field of study; this study consisted of four phases. Phases 1 and 4 consisted of expert workshops, whereas data were collected in phases 2 and 3 (n=35) via online surveys. All participants in the study were considered experts in the field of genetic counselling. The topics considered essential for genetic counsellor training have been organised under the following headings: (1) counselling; (2) psychological issues; (3) medical genetics; (4) human genetics; (5) ethics, law and sociology; (6) professional practice; and (7) education and research. Each topic includes the knowledge, skills and attitudes required to enable genetic counsellors to develop competence. In addition, it was considered by the experts that clinical practice should comprise 50% of the educational programme. The core Master programme curriculum will enable current courses to be assessed and inform the design of future educational programmes for European genetic counsellors

Eye-tracking indices of impaired encoding of visual short-term memory in familial Alzheimer's disease.

The basis of visual short-term memory (VSTM) impairments in preclinical Alzheimer's disease (AD) remains unclear. Research suggests that eye movements may serve as indirect surrogates to investigate VSTM. Yet, investigations in preclinical populations are lacking. Fifty-two individuals from a familial Alzheimer's disease (FAD) cohort (9 symptomatic carriers, 17 presymptomatic carriers and 26 controls) completed the "Object-localisation" VSTM task while an eye-tracker recorded eye movements during the stimulus presentation. VSTM function and oculomotor performance were compared between groups and their association during encoding investigated. Compared to controls, symptomatic FAD carriers showed eye movement patterns suggestive of an ineffective encoding and presymptomatic FAD carriers within 6 years of their expected age at symptom onset, were more reliant on the stimuli fixation time to achieve accuracy in the localisation of the target. Consequently, for shorter fixation times on the stimuli, presymptomatic carriers were less accurate at localising the target than controls. By contrast, the only deficits detected on behavioural VSTM function was in symptomatic individuals. Our findings provide novel evidence that encoding processes may be vulnerable and weakened in presymptomatic FAD carriers, most prominently for spatial memory, suggesting a possible explanation for the subtle VSTM impairments observed in the preclinical stages of AD

Reduced acquisition time PET pharmacokinetic modelling using simultaneous ASL–MRI: proof of concept

International audiencePharmacokinetic modelling on dynamic positron emission tomography (PET) data is a quantitative technique. However, the long acquisition time is prohibitive for routine clinical use. Instead, the semi-quantitative standardised uptake value ratio (SUVR) from a shorter static acquisition is used, despite its sensitivity to blood flow confounding longitudinal analysis. A method has been proposed to reduce the dynamic acquisition time for quantification by incorporating cerebral blood flow (CBF) information from arterial spin labelling (ASL) magnetic resonance imaging (MRI) into the pharmacokinetic modelling. In this work, we optimise and validate this framework for a study of ageing and preclinical Alzheimer's disease. This methodology adapts the simplified reference tissue model (SRTM) for a reduced acquisition time (RT-SRTM) and is applied to [ 18 F]-florbetapir PET data for amyloid-b quantification. Evaluation shows that the optimised RT-SRTM can achieve amyloid burden estimation from a 30-min PET/MR acquisition which is comparable with the gold standard SRTM applied to 60 min of PET data. Conversely, SUVR showed a significantly higher error and bias, and a statistically significant correlation with tracer delivery due to the influence of blood flow. The optimised RT-SRTM produced amyloid burden estimates which were uncorrelated with tracer delivery indicating its suitability for longitudinal studies

Development of the Tilburg Pregnancy Distress Scale: the TPDS

Contains fulltext : 96807.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Pregnant women with high levels of stress, depression and/or anxiety are at increased risk for adverse perinatal outcomes and impaired neurologic and emotional development of the offspring. Pregnancy specific instruments to measure psychological functioning during gestation are scarce and do not define items based on in-depth interviews of pregnant and recently delivered women. The current study developed a pregnancy specific scale that measures psychological functioning using in-depth interviews. METHODS: Three focus groups were formed to discuss issues most relevant to pregnancy distress; 22 candidate items were derived for pilot testing (study I, n = 419) its psychometric properties by means of explorative factor analyses (EFA). This resulted in a 17-item TPDS which was further explored by confirmatory factor analyses (CFA) and concurrent and construct validity assessment (study II, n = 454). RESULTS: EFA in study I suggested a two component solution (negative affect (NA) and partner involvement (PI)). CFA in study II resulted in a higher order model of the NA subscale into three more subscales: NA regarding confinement, delivery and general health. TPDS, EPDS and GAD-7 were all significantly correlated. CONCLUSIONS: The TPDS constitutes a valid and user friendly instrument to assess pregnancy distress. In addition to its proven ability to pick up pregnancy specific negative affect it also includes an important sub-scale measuring perceived partner involvement

Longitudinal measurement of serum neurofilament light in presymptomatic familial Alzheimer's disease.

BACKGROUND: To investigate how serum neurofilament light (NfL) concentration changes through the course of disease in familial Alzheimer's disease (FAD) and to assess when NfL concentration first increases. METHODS: NfL was measured using an ultrasensitive immunoassay in 117 serum samples from 61 individuals from families with PSEN1 or APP mutations in a longitudinal study (mean ± SD = 1.9 ± 1.1 visits/patient; inter-visit interval = 1.8 ± 1.1 years). The relationship between NfL concentration and estimated years to/from symptom onset (EYO) was modelled using linear regression, including all time points and robust standard errors to allow for repeated measurements, adjusting for age at visit and sex. Also, for the 27 participants who became symptomatic (during or before the study), NfL concentration was also modelled against known actual years to/from onset (AYO). RESULTS: There were 15 non-carriers and 46 mutation carriers (21 symptomatic; 25 presymptomatic). NfL concentration was increased (p = 0.045) in mutation carriers compared with non-carriers 15 years prior to expected symptom onset, increasing progressively thereafter. There was a significant inter- and intra-individual variability in the longitudinal pattern of change. Modelling NfL for the 27 mutation carriers with known AYO also showed a progressive increase over time. CONCLUSIONS: There is evidence that serum NfL is increased more than a decade before the onset of clinical symptoms in FAD and rises thereafter. While there is variability in change over time, both within and between individuals, and more work is needed to understand the sources of this variability, serum NfL remains a promising, accessible biomarker of early neurodegeneration in presymptomatic Alzheimer's disease