A mathematical model of glutathione metabolism

<p>Abstract</p> <p>Background</p> <p>Glutathione (GSH) plays an important role in anti-oxidant defense and detoxification reactions. It is primarily synthesized in the liver by the transsulfuration pathway and exported to provide precursors for in situ GSH synthesis by other tissues. Deficits in glutathione have been implicated in aging and a host of diseases including Alzheimer's disease, Parkinson's disease, cardiovascular disease, cancer, Down syndrome and autism.</p> <p>Approach</p> <p>We explore the properties of glutathione metabolism in the liver by experimenting with a mathematical model of one-carbon metabolism, the transsulfuration pathway, and glutathione synthesis, transport, and breakdown. The model is based on known properties of the enzymes and the regulation of those enzymes by oxidative stress. We explore the half-life of glutathione, the regulation of glutathione synthesis, and its sensitivity to fluctuations in amino acid input. We use the model to simulate the metabolic profiles previously observed in Down syndrome and autism and compare the model results to clinical data.</p> <p>Conclusion</p> <p>We show that the glutathione pools in hepatic cells and in the blood are quite insensitive to fluctuations in amino acid input and offer an explanation based on model predictions. In contrast, we show that hepatic glutathione pools are highly sensitive to the level of oxidative stress. The model shows that overexpression of genes on chromosome 21 and an increase in oxidative stress can explain the metabolic profile of Down syndrome. The model also correctly simulates the metabolic profile of autism when oxidative stress is substantially increased and the adenosine concentration is raised. Finally, we discuss how individual variation arises and its consequences for one-carbon and glutathione metabolism.</p

Assessing cognitive dysfunction in Parkinson's disease: An online tool to detect visuo-perceptual deficits.

BackgroundPeople with Parkinson's disease (PD) who develop visuo-perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuo-perceptual deficits and can be performed by untrained personnel. Hallucinations are associated with cognitive impairment and typically involve perception of complex objects. Changes in object perception may therefore be a sensitive marker of visuo-perceptual deficits in PD.ObjectiveWe developed an online platform to test visuo-perceptual function. We hypothesised that (1) visuo-perceptual deficits in PD could be detected using online tests, (2) object perception would be preferentially affected, and (3) these deficits would be caused by changes in perception rather than response bias.MethodsWe assessed 91 people with PD and 275 controls. Performance was compared using classical frequentist statistics. We then fitted a hierarchical Bayesian signal detection theory model to a subset of tasks.ResultsPeople with PD were worse than controls at object recognition, showing no deficits in other visuo-perceptual tests. Specifically, they were worse at identifying skewed images (P &lt; .0001); at detecting hidden objects (P = .0039); at identifying objects in peripheral vision (P &lt; .0001); and at detecting biological motion (P = .0065). In contrast, people with PD were not worse at mental rotation or subjective size perception. Using signal detection modelling, we found this effect was driven by change in perceptual sensitivity rather than response bias.ConclusionsOnline tests can detect visuo-perceptual deficits in people with PD, with object recognition particularly affected. Ultimately, visuo-perceptual tests may be developed to identify at-risk patients for clinical trials to slow PD dementia. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

ReadClear: An Assistive Reading Tool for People Living with Posterior Cortical Atrophy

BACKGROUND: Progressive reading impairment is an early and debilitating symptom of posterior cortical atrophy (PCA) arising from the progressive deterioration of visual processing skills. OBJECTIVE: The goal of this study was to test the effectiveness of a purpose-built reading app (ReadClear) co-produced with people living with PCA and designed to reduce the reading difficulties experienced by this population (e.g., getting lost in the page and missing words when reading). METHODS: Twenty subjects with PCA were included in a cross-over design home-based study aimed at determining whether ReadClear could 1) enhance the subjective reading experience (reading pleasantness) and 2) improve reading accuracy (reducing the number of reading errors) compared with a sham condition (a standard e-reader). RESULTS: Reading using ReadClear provided a better subjective reading experience than sham (p = 0.018, d = 0.5) and significantly reduced the percentage of reading errors (p <  0.0001, r = 0.82), particularly errors due to omissions (p = 0.01, r = 0.50), repeated words (p = 0.002, r = 0.69), and regressions in the text (p = 0.003, r = 0.69). We found that different kinds of reading errors were related to specific neuropsychological profiles. CONCLUSION: ReadClear can assist reading in people living with PCA by reducing the number of reading errors and improving the subjective reading experience of users

Visual short-term memory impairments in presymptomatic familial Alzheimer's disease: A longitudinal observational study

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 (4 seconds) 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

Augmenting dementia cognitive assessment with instruction-less eye-tracking tests

© 2020 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.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.Peer reviewe

Unusual Pattern of Reading Errors in a Patient with Posterior Cortical Atrophy

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

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

Subjective cognitive complaints at age 70: associations with amyloid and mental health.

OBJECTIVE: 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. METHODS: 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 18F-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. RESULTS: 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. CONCLUSIONS: 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

Assessing cognitive dysfunction in Parkinson's disease: an online tool to detect visuo-perceptual deficits

Background: People with Parkinson's disease (PD) who develop visuo‐perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuo‐perceptual deficits and can be performed by untrained personnel. Hallucinations are associated with cognitive impairment and typically involve perception of complex objects. Changes in object perception may therefore be a sensitive marker of visuo‐perceptual deficits in PD. Objective: We developed an online platform to test visuo‐perceptual function. We hypothesised that (1) visuo‐perceptual deficits in PD could be detected using online tests, (2) object perception would be preferentially affected, and (3) these deficits would be caused by changes in perception rather than response bias. Methods: We assessed 91 people with PD and 275 controls. Performance was compared using classical frequentist statistics. We then fitted a hierarchical Bayesian signal detection theory model to a subset of tasks. Results: People with PD were worse than controls at object recognition, showing no deficits in other visuo‐perceptual tests. Specifically, they were worse at identifying skewed images (P  &lt; .0001); at detecting hidden objects (P  = .0039); at identifying objects in peripheral vision (P  &lt; .0001); and at detecting biological motion (P  = .0065). In contrast, people with PD were not worse at mental rotation or subjective size perception. Using signal detection modelling, we found this effect was driven by change in perceptual sensitivity rather than response bias. Conclusions: Online tests can detect visuo‐perceptual deficits in people with PD, with object recognition particularly affected. Ultimately, visuo‐perceptual tests may be developed to identify at‐risk patients for clinical trials to slow PD dementia. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Dissociable effects of APOE ε4 and β-amyloid pathology on visual working memory

Although APOE ε4 carriers are at substantially higher risk of developing Alzheimer’s disease than noncarriers, controversial evidence suggests that APOE ε4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy). In a population-based cohort born in one week in 1946 (assessed aged 69–71 years), we assessed differential effects of APOE ε4 and β-amyloid pathology (quantified using 18F-Florbetapir-PET) on visual working memory (object–location binding). In 398 cognitively normal participants, APOE ε4 and β-amyloid had opposing effects on object identification, predicting better and poorer recall, respectively. ε4 carriers also recalled locations more precisely, with a greater advantage at higher β-amyloid burden. These results provide evidence of superior visual working memory in ε4 carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer’s disease