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.
Eye-tracking technology is an innovative tool that holds promise for enhancing dementia screening. In this work, we introduce a novel way of extracting salient features directly from the raw ...eye-tracking data of a mixed sample of dementia patients during a novel instruction-less cognitive test. Our approach is based on self-supervised representation learning where, by training initially a deep neural network to solve a pretext task using well-defined available labels (e.g. recognising distinct cognitive activities in healthy individuals), the network encodes high-level semantic information which is useful for solving other problems of interest (e.g. dementia classification). Inspired by previous work in explainable AI, we use the Layer-wise Relevance Propagation (LRP) technique to describe our network's decisions in differentiating between the distinct cognitive activities. The extent to which eye-tracking features of dementia patients deviate from healthy behaviour is then explored, followed by a comparison between self-supervised and handcrafted representations on discriminating between participants with and without dementia. Our findings not only reveal novel self-supervised learning features that are more sensitive than handcrafted features in detecting performance differences between participants with and without dementia across a variety of tasks, but also validate that instruction-less eye-tracking tests can detect oculomotor biomarkers of dementia-related cognitive dysfunction. This work highlights the contribution of self-supervised representation learning techniques in biomedical applications where the small number of patients, the non-homogenous presentations of the disease and the complexity of the setting can be a challenge using state-of-the-art feature extraction methods.
To investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the ...Insight 46 study.
Cognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to
F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant's perspective on SCD was evaluated in relation to MyCog score.
Anxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) -0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant's perception of SCD was generally in accordance with that of the participant.
This cross-sectional study demonstrates that symptoms of SCD are associated with both β-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer's disease pathology and SCD.
Visual short-term memory (VSTM) deficits including VSTM binding have been associated with Alzheimer's disease (AD) from preclinical to dementia stages, cross-sectionally. Yet, longitudinal ...investigations are lacking. The objective of this study was to evaluate VSTM function longitudinally and in relation to expected symptom onset in a cohort of familial Alzheimer's disease. Ninety-nine individuals (23 presymptomatic; 9 symptomatic and 67 controls) were included in an extension cross-sectional study and a sub-sample of 48 (23 presymptomatic carriers, 6 symptomatic and 19 controls), attending two to five visits with a median interval of 1.3 years, included in the longitudinal study. Participants completed the “What was where?” relational binding task (which measures memory for object identification, localisation and object-location binding under different conditions of memory load and delay), neuropsychology assessments and genetic testing. Compared to controls, presymptomatic carriers within 8.5 years of estimated symptom onset showed a faster rate of decline in localisation performance in long-delay conditions (4s) and in traditional neuropsychology measures of verbal episodic memory. This study represents the first longitudinal VSTM investigation and shows that changes in memory resolution may be sensitive to tracking cognitive decline in preclinical AD at least as early as changes in the more traditional verbal episodic memory tasks.
•VSTM function was investigated in presymptomatic and symptomatic FAD carriers.•PMCs showed faster decline in VSTM function (target localisation) than controls.•Target localisation accuracy decreased with proximity to expected symptom onset.•“What was where?” may be sensitive to tracking preclinical cognitive decline.
Understanding the earliest manifestations of Alzheimer's disease (AD) is key to realising disease-modifying treatments. Advances in neuroimaging and fluid biomarkers have improved our ability to ...identify AD pathology in vivo. The critical next step is improved detection and staging of early cognitive change. We studied an asymptomatic familial Alzheimer's disease (FAD) cohort to characterise preclinical cognitive change.
Data included 35 asymptomatic participants at 50% risk of carrying a pathogenic FAD mutation. Participants completed a multi-domain neuropsychology battery. After accounting for sex, age and education, we used event-based modelling to estimate the sequence of cognitive decline in presymptomatic FAD, and uncertainty in the sequence. We assigned individuals to their most likely model stage of cumulative cognitive decline, given their data. Linear regression of estimated years to symptom onset against model stage was used to estimate the timing of preclinical cognitive decline.
Cognitive change in mutation carriers was first detected in measures of accelerated long-term forgetting, up to 10 years before estimated symptom onset. Measures of subjective cognitive decline also revealed early abnormalities. Our data-driven model demonstrated subtle cognitive impairment across multiple cognitive domains in clinically normal individuals on the AD continuum.
Data-driven modelling of neuropsychological test scores has potential to differentiate cognitive decline from cognitive stability and to estimate a fine-grained sequence of decline across cognitive domains and functions, in the preclinical phase of Alzheimer's disease. This can improve the design of future presymptomatic trials by informing enrichment strategies and guiding the selection of outcome measures.
Young onset Alzheimer's disease (YOAD) is defined as symptom onset before the age of 65 years and is particularly associated with phenotypic heterogeneity. Atypical presentations, such as the ...clinic-radiological visual syndrome posterior cortical atrophy (PCA), often lead to delays in accurate diagnosis. Eyetracking has been used to demonstrate basic oculomotor impairments in individuals with dementia. In the present study, we aim to explore the relationship between eyetracking metrics and standard tests of visual cognition in individuals with YOAD. Fifty-seven participants were included: 36 individuals with YOAD (
= 26 typical AD;
= 10 PCA) and 21 age-matched healthy controls. Participants completed three eyetracking experiments: fixation, pro-saccade, and smooth pursuit tasks. Summary metrics were used as outcome measures and their predictive value explored looking at correlations with visuoperceptual and visuospatial metrics. Significant correlations between eyetracking metrics and standard visual cognitive estimates are reported. A machine-learning approach using a classification method based on the smooth pursuit raw eyetracking data discriminates with approximately 95% accuracy patients and controls in cross-validation tests. Results suggest that the eyetracking paradigms of a relatively simple and specific nature provide measures not only reflecting basic oculomotor characteristics but also predicting higher order visuospatial and visuoperceptual impairments. Eyetracking measures can represent extremely useful markers during the diagnostic phase and may be exploited as potential outcome measures for clinical trials.
Posterior cortical atrophy (PCA) is a degenerative condition characterized by a progressive deterioration of visual processing. Dyslexia constitutes an early and frequent visual symptom of the ...disease and previous comprehensive investigations in series of individuals have extensively documented a characteristic abundance of visual errors as the most prevalent error category in this population. Here we describe the profile of a patient with PCA, C.P., who presents an unusual prevalence of phonological, instead of purely visual, errors in his reading, in the context of an otherwise classic PCA phenotype. In keeping with the well-known PCA profile, C.P. exhibited deficits at the pre-lexical level with elements of crowding and defective early visual processing impairments but additionally showed an unusually prominent disruption of phonological processing. We also argue that our patient may have a refractory access type deficit in reading given that accuracy doubled with the introduction of a five-second response-stimulus interval. To our knowledge, no previous case of a refractory deficit affecting word reading has been reported in PCA. Our examination builds on previous knowledge about reading behaviour in PCA and describes a singular example of the rich phenotypic heterogeneity within the syndrome.
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.
Symptomatic ...mutation carriers (201 presenilin 1
and 55 amyloid precursor protein
) 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,
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.
Estimated mean survival was 11.6 (10.4-12.9) years and was similar for
and
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
and shorter duration within
mutation carriers. No differences in survival time were found between sexes or between mutations located before or beyond codon 200 within
.
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 neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed ...to examine potential drivers and correlates of brain age.
Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18–90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy.
Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 95% CI 1·5 to 3·0) and 69 years (β=2·6 1·9 to 3·3); increased cerebrovascular disease burden (1·9 1·3 to 2·6); lower cognitive performance (–1·3 –2·4 to –0·2); and increased serum neurofilament light concentration (1·2 0·6 to 1·9). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year 0·000 to 0·006 per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD.
Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility.
Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.
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