Publications by authors named "Craig W Ritchie"

99 Publications

Disease Modelling of Cognitive Outcomes and Biomarkers in the European Prevention of Alzheimer's Dementia Longitudinal Cohort.

Front Big Data 2021 20;4:676168. Epub 2021 Aug 20.

MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom.

A key challenge for the secondary prevention of Alzheimer's dementia is the need to identify individuals early on in the disease process through sensitive cognitive tests and biomarkers. The European Prevention of Alzheimer's Dementia (EPAD) consortium recruited participants into a longitudinal cohort study with the aim of building a readiness cohort for a proof-of-concept clinical trial and also to generate a rich longitudinal data-set for disease modelling. Data have been collected on a wide range of measurements including cognitive outcomes, neuroimaging, cerebrospinal fluid biomarkers, genetics and other clinical and environmental risk factors, and are available for 1,828 eligible participants at baseline, 1,567 at 6 months, 1,188 at one-year follow-up, 383 at 2 years, and 89 participants at three-year follow-up visit. We novelly apply state-of-the-art longitudinal modelling and risk stratification approaches to these data in order to characterise disease progression and biological heterogeneity within the cohort. Specifically, we use longitudinal class-specific mixed effects models to characterise the different clinical disease trajectories and a semi-supervised Bayesian clustering approach to explore whether participants can be stratified into homogeneous subgroups that have different patterns of cognitive functioning evolution, while also having subgroup-specific profiles in terms of baseline biomarkers and longitudinal rate of change in biomarkers.
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http://dx.doi.org/10.3389/fdata.2021.676168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417903PMC
August 2021

Resting-state brain connectivity in healthy young and middle-aged adults at risk of progressive Alzheimer's disease.

Neurosci Biobehav Rev 2021 10 24;129:142-153. Epub 2021 Jul 24.

Edinburgh Dementia Prevention and Centre for Clinical Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom.

Functional brain connectivity of the resting-state networks has gained recent attention as a possible biomarker of Alzheimer's Disease (AD). In this paper, we review the literature of functional connectivity differences in young adults and middle-aged cognitively intact individuals with non-modifiable risk factors of AD (n = 17). We focus on three main intrinsic resting-state networks: The Default Mode network, Executive network, and the Salience network. Overall, the evidence from the literature indicated early vulnerability of functional connectivity across different at-risk groups, particularly in the Default Mode Network. While there was little consensus on the interpretation on directionality, the topography of the findings showed frequent overlap across studies, especially in regions that are characteristic of AD (i.e., precuneus, posterior cingulate cortex, and medial prefrontal cortex areas). We conclude that while resting-state functional connectivity markers have great potential to identify at-risk individuals, implementing more data-driven approaches, further longitudinal and cross-validation studies, and the analysis of greater sample sizes are likely to be necessary to fully establish the effectivity and utility of resting-state network-based analyses.
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http://dx.doi.org/10.1016/j.neubiorev.2021.07.024DOI Listing
October 2021

Protocol of the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy.

BMJ Open 2021 06 24;11(6):e043114. Epub 2021 Jun 24.

Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK.

Introduction: The Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy (CPSS), sponsored by Janssen Pharmaceutical Research & Development LLC, is an Alzheimer's disease (AD) biomarker enriched observational study that began 3 July 2015 CPSS aims to identify and validate determinants of AD, alongside cognitive, functional and biological changes in older adults with or without detectable evidence of AD pathology at baseline.

Methods And Analysis: CPSS is a dual-site longitudinal cohort (3.5 years) assessed quarterly. Cognitively normal participants (60-85 years) were recruited across Greater London and Edinburgh. Participants are classified as high, medium (amnestic or non-amnestic) or low risk for developing mild cognitive impairment-Alzheimer's disease based on their Repeatable Battery for the Assessment of Neuropsychological Status performance at screening. Additional AD-related assessments include: a novel cognitive composite, the Global Preclinical Alzheimer's Cognitive Composite, brain MRI and positron emission tomography and cerebrospinal fluid analysis. Lifestyle, other cognitive and functional data, as well as biosamples (blood, urine, and saliva) are collected. Primarily, study analyses will evaluate longitudinal change in cognitive and functional outcomes. Annual interim analyses for descriptive data occur throughout the course of the study, although inferential statistics are conducted as required.

Ethics And Dissemination: CPSS received ethical approvals from the London-Central Research Ethics Committee (15/LO/0711) and the Administration of Radioactive Substances Advisory Committee (RPC 630/3764/33110) The study is at the forefront of global AD prevention efforts, with frequent and robust sampling of the well-characterised cohort, allowing for detection of incipient pathophysiological, cognitive and functional changes that could inform therapeutic strategies to prevent and/or delay cognitive impairment and dementia. Dissemination of results will target the scientific community, research participants, volunteer community, public, industry, regulatory authorities and policymakers. On study completion, and following a predetermined embargo period, CPSS data are planned to be made accessible for analysis to facilitate further research into the determinants of AD pathology, onset of symptomatology and progression.

Trial Registration Number: The CHARIOT:PRO SubStudy is registered with clinicaltrials.gov (NCT02114372). Notices of protocol modifications will be made available through this trial registry.
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http://dx.doi.org/10.1136/bmjopen-2020-043114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230926PMC
June 2021

Developing an Explainable Machine Learning-Based Personalised Dementia Risk Prediction Model: A Transfer Learning Approach With Ensemble Learning Algorithms.

Front Big Data 2021 26;4:613047. Epub 2021 May 26.

Edinburgh Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh Medical School, Edinburgh, United Kingdom.

Alzheimer's disease (AD) has its onset many decades before dementia develops, and work is ongoing to characterise individuals at risk of decline on the basis of early detection through biomarker and cognitive testing as well as the presence/absence of identified risk factors. Risk prediction models for AD based on various computational approaches, including machine learning, are being developed with promising results. However, these approaches have been criticised as they are unable to generalise due to over-reliance on one data source, poor internal and external validations, and lack of understanding of prediction models, thereby limiting the clinical utility of these prediction models. We propose a framework that employs a transfer-learning paradigm with ensemble learning algorithms to develop explainable personalised risk prediction models for dementia. Our prediction models, known as , are initially trained and tested using a publicly available dataset ( = 84,856, mean age = 69 years) with 14 years of follow-up samples to predict the individual risk of developing dementia. The decision boundaries of the best source model are further updated by using an alternative dataset from a different and much younger population ( = 473, mean age = 52 years) to obtain an additional prediction model known as the . We further apply the SHapely Additive exPlanation (SHAP) algorithm to visualise the risk factors responsible for the prediction at both population and individual levels. The best source model achieves a geometric accuracy of 87%, specificity of 99%, and sensitivity of 76%. In comparison to a baseline model, our target model achieves better performance across several performance metrics, within an increase in geometric accuracy of 16.9%, specificity of 2.7%, and sensitivity of 19.1%, an area under the receiver operating curve (AUROC) of 11% and a transfer learning efficacy rate of 20.6%. The strength of our approach is the large sample size used in training the source model, transferring and applying the "knowledge" to another dataset from a different and undiagnosed population for the early detection and prediction of dementia risk, and the ability to visualise the interaction of the risk factors that drive the prediction. This approach has direct clinical utility.
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http://dx.doi.org/10.3389/fdata.2021.613047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187875PMC
May 2021

Evidence of cerebral hemodynamic dysregulation in middle-aged APOE ε4 carriers: The PREVENT-Dementia study.

J Cereb Blood Flow Metab 2021 Nov 2;41(11):2844-2855. Epub 2021 Jun 2.

Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

Accumulating evidence suggests vascular dysregulation in preclinical Alzheimer's disease. In this study, cerebral hemodynamics and their coupling with cognition in middle-aged apolipoprotein ε4 carriers (APOEε4+) were investigated. Longitudinal 3 T T1-weighted and arterial spin labelling MRI data from 158 participants (40-59 years old) in the PREVENT-Dementia study were analysed (125 two-year follow-up). Cognition was evaluated using the COGNITO battery. Cerebral blood flow (CBF) and cerebrovascular resistance index (CVRi) were quantified for the flow territories of the anterior, middle and posterior cerebral arteries. CBF was corrected for underlying atrophy and individual hematocrit. Hemodynamic measures were the dependent variables in linear regression models, with age, sex, years of education and APOEε4 carriership as predictors. Further analyses were conducted with cognitive outcomes as dependent variables, using the same model as before with additional APOEε4 × hemodynamics interactions. At baseline, APOEε4+ showed increased CBF and decreased CVRi compared to non-carriers in the anterior and middle cerebral arteries, suggestive of potential vasodilation. Hemodynamic changes were similar between groups. Interaction analysis revealed positive associations between CBF changes and performance changes in delayed recall (for APOEε4 non-carriers) and verbal fluency (for APOEε4 carriers) cognitive tests. These observations are consistent with neurovascular dysregulation in middle-aged APOEε4+.
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http://dx.doi.org/10.1177/0271678X211020863DOI Listing
November 2021

Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.

Alzheimers Dement 2021 07 3;17(7):1189-1204. Epub 2021 Apr 3.

Department of Radiology and Nuclear Medicine, Amsterdam UMC Location VUmc, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands.

Background: We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles.

Materials And Methods: From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R  = 0.98, P < 0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages.

Results: Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P < 0.001).

Discussion: In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.
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http://dx.doi.org/10.1002/alz.12292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359976PMC
July 2021

The association between anxiety disorders and hippocampal volume in older adults.

Psychol Aging 2021 Mar 4;36(2):288-297. Epub 2021 Mar 4.

Centre for Dementia Prevention.

The hippocampus, through its mediation of fear responses is thought to play a central role in the onset and maintenance of anxiety disorders. Prevalence of anxiety disorders remains high in older populations; however, little is known about their association with hippocampal changes in this age group. Due to differing levels of cortisol as adults age, age-related decreases in hippocampal volume, and the suggestion that age-related loss of neurogenesis results in anxiety disorders, this area requires investigation. We examined the association between hippocampal volume and anxiety disorders (social anxiety disorder, generalized anxiety disorder, agoraphobia, panic disorder, obsessive compulsive disorder and posttraumatic stress disorder) in 534 older adults participating in the Enquête de Santé Psychologique-Risques, Incidence et Traitement (ESPRIT) study of late-life neuropsychiatric disorders. Anxiety disorders were diagnosed using the Mini International Neuropsychiatric Interview MINI, French version 5.00. Cross-sectional analyses adjusted for age, educational level, gender, Mini-Mental State Examination scores, National Adult Reading Test scores, whole brain volume and depression found that a diagnosis of generalized anxiety disorder was positively associated with larger hippocampal volume. No other anxiety disorder was significantly associated with hippocampal volume. The present study is the first to examine the association between several anxiety disorders and hippocampal volume in an older population and the results highlight the need for further research relating to the relationship between hippocampal volume and anxiety disorders in older adults. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pag0000597DOI Listing
March 2021

Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer's subjects?

Alzheimers Res Ther 2021 02 17;13(1):47. Epub 2021 Feb 17.

Derbyshire Healthcare NHS Foundation Trust, Derby, UK.

Background: Type 2 diabetes is a risk factor for Alzheimer's disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects.

Methods: In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function.

Results: In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs.

Conclusions: In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.
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http://dx.doi.org/10.1186/s13195-021-00784-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890851PMC
February 2021

Plasma and cerebrospinal fluid ABeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting.

Cochrane Database Syst Rev 2021 Feb 10;2:CD010945. Epub 2021 Feb 10.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Background: Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes.

Objectives: To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome.

Search Methods: We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies.

Selection Criteria: We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype.

Data Collection And Analysis: Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42.

Main Results: We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity.

Authors' Conclusions: Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.
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http://dx.doi.org/10.1002/14651858.CD010945.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078224PMC
February 2021

Higher midlife CAIDE score is associated with increased brain atrophy in a cohort of cognitively healthy middle-aged individuals.

J Neurol 2021 May 9;268(5):1962-1971. Epub 2021 Jan 9.

Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Level E4 Cambridge Biomedical Campus, Cambridge, CB2 0SP, UK.

Background: Structural brain changes associated with Alzheimer's disease (AD) can occur decades before the onset of symptoms. The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score has been suggested to be associated with accelerated brain atrophy in middle-aged subjects but the regional specificity of atrophic areas remains to be elucidated.

Methods: 3T T1-weighted magnetic resonance imaging scans of 160 cognitively healthy middle-aged participants (mean age = 52) in the PREVENT-Dementia cohort, from baseline and from follow-up after 2 years, were examined. Images were preprocessed using Computational Anatomy Toolbox 12. Voxel-based morphometry was performed in FSL 6.0.1 to identify areas of grey matter (GM) volume differences both cross-sectionally and longitudinally between subjects with high and low baseline CAIDE score (CAIDE score was dichotomized at cohort-median). A GM percentage of change map was created for each subject for evaluation of atrophy over 2 years. Analyses were adjusted for age, gender, education and total intracranial volume.

Results: Compared to subjects with CAIDE score ≤ 6 (low risk), subjects with CAIDE score > 6 (high risk) showed lower GM volume in the temporal, occipital, and fusiform cortex and lingual gyrus at baseline, and greater percentage of GM loss over 2 years in the supramarginal gyrus, angular gyrus, precuneus, lateral occipital cortex, superior parietal lobule and cingulate gyrus (corrected P < 0.05).

Conclusion: This study demonstrated accelerated GM atrophy concentrated in several AD signature cortical regions in healthy middle-aged subjects with high CAIDE scores.
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http://dx.doi.org/10.1007/s00415-020-10383-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068701PMC
May 2021

Inherited risk of dementia and the progression of cerebral small vessel disease and inflammatory markers in cognitively healthy midlife adults: the PREVENT-Dementia study.

Neurobiol Aging 2021 02 2;98:124-133. Epub 2020 Nov 2.

Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

Cerebral small vessel disease (SVD) and inflammation are increasingly recognized as key contributors to Alzheimer's disease (AD), although the timing, trajectory, and relation between them early in the disease process is unclear. Therefore, to investigate very early-stage changes, we compared 158 healthy midlife adults with and without inherited AD predisposition (APOE4 carriership (38% positive), parental family history (FH) of dementia (54% positive)) on markers of SVD (white matter hyperintensities (WMH), cerebral microbleeds), and inflammation (C-reactive protein (CRP), fibrinogen), cross-sectionally and longitudinally over two years. While WMH severity was comparable between groups at baseline, longitudinal progression of WMH was greater in at-risk groups (APOE4+ and FH+). Topographically, APOE4 was associated exclusively with deep, but not periventricular, WMH progression after adjusting for FH. Conversely, APOE4 carriers displayed lower CRP levels than noncarriers, but not fibrinogen. Furthermore, interaction analysis showed that FH moderated the effect of SVD and inflammation on reaction time, an early feature of SVD, but not episodic memory or executive function. Findings suggest that vascular and inflammatory changes could occur decades before dementia onset, and may be of relevance in predicting incipient clinical progression.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895800PMC
February 2021

Artificial Intelligence, Speech, and Language Processing Approaches to Monitoring Alzheimer's Disease: A Systematic Review.

J Alzheimers Dis 2020 ;78(4):1547-1574

Usher Institute, Edinburgh Medical School, The University of Edinburgh, Scotland, UK.

Background: Language is a valuable source of clinical information in Alzheimer's disease, as it declines concurrently with neurodegeneration. Consequently, speech and language data have been extensively studied in connection with its diagnosis.

Objective: Firstly, to summarize the existing findings on the use of artificial intelligence, speech, and language processing to predict cognitive decline in the context of Alzheimer's disease. Secondly, to detail current research procedures, highlight their limitations, and suggest strategies to address them.

Methods: Systematic review of original research between 2000 and 2019, registered in PROSPERO (reference CRD42018116606). An interdisciplinary search covered six databases on engineering (ACM and IEEE), psychology (PsycINFO), medicine (PubMed and Embase), and Web of Science. Bibliographies of relevant papers were screened until December 2019.

Results: From 3,654 search results, 51 articles were selected against the eligibility criteria. Four tables summarize their findings: study details (aim, population, interventions, comparisons, methods, and outcomes), data details (size, type, modalities, annotation, balance, availability, and language of study), methodology (pre-processing, feature generation, machine learning, evaluation, and results), and clinical applicability (research implications, clinical potential, risk of bias, and strengths/limitations).

Conclusion: Promising results are reported across nearly all 51 studies, but very few have been implemented in clinical research or practice. The main limitations of the field are poor standardization, limited comparability of results, and a degree of disconnect between study aims and clinical applications. Active attempts to close these gaps will support translation of future research into clinical practice.
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http://dx.doi.org/10.3233/JAD-200888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836050PMC
September 2021

Trauma and depressive symptomatology in middle-aged persons at high risk of dementia: the PREVENT Dementia Study.

J Neurol Neurosurg Psychiatry 2020 Oct 21. Epub 2020 Oct 21.

Department of Psychiatry, University of Cambridge, Cambridge, UK.

Objective: Depression and trauma are associated with changes in brain regions implicated in Alzheimer's disease. The present study examined associations between childhood trauma, depression, adult cognitive functioning and risk of dementia.

Methods: Data from 378 participants in the PREVENT Dementia Study aged 40-59 years. Linear and logistic models were used to assess associations between childhood trauma, depression, dementia risk, cognitive test scores and hippocampal volume.

Results: Childhood trauma was associated with depression and reduced hippocampal volume but not current cognitive function or dementia risk. Poorer performance on a delayed face/name recall task was associated with depression. Childhood trauma was associated with lower hippocampal volume however poorer cognitive performance was mediated by depression rather than structural brain differences.

Conclusion: Depressive symptomatology may be associated with dementia risk via multiple pathways, and future studies should consider subtypes of depressive symptomatology when examining its relationship to dementia.
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http://dx.doi.org/10.1136/jnnp-2020-323823DOI Listing
October 2020

Cognitive Dispersion Is Not Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease: Results from the European Prevention of Alzheimer's Dementia (EPAD) v500.0 Cohort.

J Alzheimers Dis 2020 ;78(1):185-194

Edinburgh Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Background: Cognitive dispersion, variation in performance across cognitive domains, is posited as a non-invasive and cost-effective marker of early neurodegeneration. Little work has explored associations between cognitive dispersion and Alzheimer's disease (AD) biomarkers in healthy older adults. Even less is known about the influence or interaction of biomarkers reflecting brain pathophysiology or other risk factors on cognitive dispersion scores.

Objective: The main aim of this study was to examine whether higher cognitive dispersion was associated with cerebrospinal fluid (CSF) levels of amyloid-β (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), and amyloid positivity in a cohort of older adults at various severities of AD. A secondary aim was to explore which AD risk factors were associated with cognitive dispersion scores.

Methods: Linear and logistic regression analyses explored the associations between dispersion and CSF levels of Aβ42, t-tau, and p-tau and amyloid positivity (Aβ42 < 1000 pg/ml). Relationships between sociodemographics, APOEɛ4 status, family history of dementia, and levels of depression and dispersion were also assessed.

Results: Dispersion did not emerge as associated with any of the analytes nor amyloid positivity. Older (β= -0.007, SE = 0.002, p = 0.001) and less educated (β= -0.009, SE = 0.003, p = 0.009) individuals showed greater dispersion.

Conclusion: Dispersion was not associated with AD pathology, but was associated with age and years of education, highlighting individual differences in cognitive aging. The use of this metric as a screening tool for existing AD pathology is not supported by our analyses. Follow-up work will determine if dispersion scores can predict changes in biomarker levels and/or positivity status longitudinally.
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http://dx.doi.org/10.3233/JAD-200514DOI Listing
September 2021

Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden.

Clin Epigenetics 2020 07 31;12(1):115. Epub 2020 Jul 31.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.

Background: Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five 'epigenetic clocks' which provide an index of how much an individual's biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an individual's biological ageing. This measure of ageing is termed DunedinPoAm. In this study, we test the association between these six epigenetic measures of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries (n ≤ 9537, Generation Scotland: Scottish Family Health Study).

Results: DNAm GrimAge predicted incidence of clinically diagnosed chronic obstructive pulmonary disease (COPD), type 2 diabetes and ischemic heart disease after 13 years of follow-up (hazard ratios = 2.22, 1.52 and 1.41, respectively). DunedinPoAm predicted the incidence of COPD and lung cancer (hazard ratios = 2.02 and 1.45, respectively). DNAm PhenoAge predicted incidence of type 2 diabetes (hazard ratio = 1.54). DNAm Telomere Length associated with the incidence of ischemic heart disease (hazard ratio = 0.80). DNAm GrimAge associated with all-cause mortality, the prevalence of COPD and spirometry measures at the study baseline. These associations were present after adjusting for possible confounding risk factors including alcohol consumption, body mass index, deprivation, education and tobacco smoking and surpassed stringent Bonferroni-corrected significance thresholds.

Conclusions: Our data suggest that epigenetic measures of ageing may have utility in clinical settings to complement gold-standard methods for disease assessment and management.
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http://dx.doi.org/10.1186/s13148-020-00905-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394682PMC
July 2020

Performance validity test failure in clinical populations-a systematic review.

J Neurol Neurosurg Psychiatry 2020 09 10;91(9):945-952. Epub 2020 Jul 10.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Performance validity tests (PVTs) are widely used in attempts to quantify effort and/or detect negative response bias during neuropsychological testing. However, it can be challenging to interpret the meaning of poor PVT performance in a clinical context. Compensation-seeking populations predominate in the PVT literature. We aimed to establish base rates of PVT failure in clinical populations without known external motivation to underperform. We searched MEDLINE, EMBASE and PsycINFO for studies reporting PVT failure rates in adults with defined clinical diagnoses, excluding studies of active or veteran military personnel, forensic populations or studies of participants known to be litigating or seeking disability benefits. Results were summarised by diagnostic group and implications discussed. Our review identified 69 studies, and 45 different PVTs or indices, in clinical populations with intellectual disability, degenerative brain disease, brain injury, psychiatric disorders, functional disorders and epilepsy. Various pass/fail cut-off scores were described. PVT failure was common in all clinical groups described, with failure rates for some groups and tests exceeding 25%. PVT failure is common across a range of clinical conditions, even in the absence of obvious incentive to underperform. Failure rates are no higher in functional disorders than in other clinical conditions. As PVT failure indicates invalidity of other attempted neuropsychological tests, the finding of frequent and unexpected failure in a range of clinical conditions raises important questions about the degree of objectivity afforded to neuropsychological tests in clinical practice and research.
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http://dx.doi.org/10.1136/jnnp-2020-323776DOI Listing
September 2020

Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults.

Genome Med 2020 07 8;12(1):60. Epub 2020 Jul 8.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.

Background: The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets.

Methods: In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches).

Results: We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn's disease.

Conclusions: Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.
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http://dx.doi.org/10.1186/s13073-020-00754-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346642PMC
July 2020

Midlife alcohol consumption and longitudinal brain atrophy: the PREVENT-Dementia study.

J Neurol 2020 Nov 20;267(11):3282-3286. Epub 2020 Jun 20.

Centre for Dementia Prevention, University of Edinburgh, Edinburgh, UK.

Background And Aims: Consensus is lacking on whether light to moderate consumption of alcohol compared to abstinence is neuroprotective. In this study, we investigated the relationship between self-reported alcohol use and brain volume change over 2 years in middle-aged subjects.

Methods: A sample of 162 subjects (aged 40-59 at baseline) from the PREVENT-Dementia programme underwent MRI scans on two separate occasions (mean interval 734 days; SD 42 days). We measured longitudinal rates of brain atrophy using the FSL Siena toolbox, and change in hippocampal volume from segmentation in SPM.

Results: Controlling for age and sex, there were no significant associations of either total brain, ventricular, or hippocampal volume change with alcohol consumption. Adjusting for lifestyle, demographic and vascular risk factors did not alter this.

Conclusions: We did not find any evidence of influence of alcohol consumption on changes in brain volume over a 2-year period in 40-60-year-olds.
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http://dx.doi.org/10.1007/s00415-020-10000-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578123PMC
November 2020

Associations between midlife chronic conditions and medication use with anxiety and depression: A cross-sectional analysis of the PREVENT Dementia study.

J Comorb 2020 Jan-Dec;10:2235042X20920443. Epub 2020 May 5.

Edinburgh Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Background: Multimorbidity including physical and mental illness is increasing in prevalence. We aimed to investigate the associations between physical conditions and medication use with anxiety and depression in midlife.

Methods: We conducted an observational cross-sectional study of volunteers in the PREVENT Dementia study. Using logistic and linear regression, we investigated the association between increasing numbers of self-reported chronic physical conditions and medications with self-reported depression and anxiety disorder, and scores on the Center for Epidemiologic Studies Depression (CES-D) scale and Spielberger State-Trait Anxiety Inventory (STAI) state subtest.

Results: Of the 210 participants, 148 (71%) were women and 188 (90%) Caucasian. The mean age was 52 (standard deviation (SD) = 5.5) years. The mean number of physical conditions was 2.2 (SD = 1.9) and medications 1.7 (SD = 2.2). Each additional physical condition was associated with increased odds of self-reported depression (odds ratio (OR) 1.41, 95% confidence interval (CI) 1.11-1.80; = 0.004, adjusted for age and gender) and anxiety disorder (OR 1.70, 95% CI 1.30-2.37; 0.001). Increasing medication use was associated with self-reported depression (adjusted OR per additional medication 1.35, 95% CI 1.08-1.71; = 0.008) but not anxiety disorder. For each additional condition, CES-D scores increased by 0.72 (95% CI 0.11-1.33; = 0.020) and for each extra medication, by 0.88 (95% CI 0.32-1.44; = 0.002). There was no significant association between increasing conditions and medications with STAI scores. In models accounting for antidepressant use, all associations were attenuated.

Conclusions: Having more physical conditions is associated with anxiety and depression in midlife, and taking more medications is associated with depression but not anxiety.
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http://dx.doi.org/10.1177/2235042X20920443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218309PMC
May 2020

Hippocampal Subfield Volumes in Middle-Aged Adults at Risk of Dementia.

J Alzheimers Dis 2020 ;75(4):1211-1218

Department of Psychiatry, University of Cambridge, UK.

Background: Alzheimer's disease (AD) begins decades before the onset of dementia. There is a need to investigate biomarkers of early AD for use in clinical trials and to facilitate early intervention.

Objective: We aimed to determine whether changes in hippocampal subfield volumes in healthy middle-aged adults were associated with risk of future dementia.

Methods: We included 150 participants from the PREVENT-Dementia cohort, which recruited subjects aged 40-59 with or without a family history of dementia (FHD; included here were 81 with FHD and 69 without). Hippocampal subfield volumes were segmented from high resolution T2-weighted 3T MRI images taken at baseline and 2-year follow-up.

Results: FHD and greater 20 year-risk of dementia due to cardiovascular risk factors were both associated with lower CA1 volume. FHD was also associated with a relative increase in combined CA3, CA4, and dentate gyrus volume between baseline and follow-up.

Conclusion: CA1 atrophy may commence as early as middle-age in those with a high risk of future dementia, while increases in CA3, CA4, and dentate gyrus volume may be a response to early AD in the form of inflammation or neurogenesis.
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http://dx.doi.org/10.3233/JAD-200238DOI Listing
May 2021

Multi-National, Cross-Sectional Survey of Healthcare Resource Utilization in Patients with All Stages of Cognitive Impairment, Analyzed by Disease Severity, Country, and Geographical Region.

J Alzheimers Dis 2020 ;75(4):1141-1152

Centre for Observational and Real-World Evidence, Merck & Co., Inc., Kenilworth, NJ, USA.

Background: Alzheimer's disease (AD) is one of the most disabling conditions worldwide and the disease burden increases with the aging global population. There are only a few prospective studies using real-world data to support effective healthcare resource utilization (HCRU) in AD.

Objective: To confirm the association between HCRU and AD severity in a real-world population, including patients with all cognitive impairment (CI) severities.

Methods: Data were drawn from a multi-national, cross-sectional survey of physicians and their consulted patients with all stages (very mild, mild, moderate, and severe) of CI including AD conducted in France, Germany, Italy, Spain, UK, US, and Canada. Elements of HCRU including medical consultations, professional caregiver hours, hospitalization, and institutionalization were compared between CI severity subgroups, and by country and region.

Results: 6,143 CI patients were included with very mild (n = 659), mild (n = 2,473), moderate (n = 2,603), and severe (n = 408) dementia. HCRU increased with increasing CI severity (p < 0.001) for the majority of elements measured. Further analyses of overall and regional populations also confirmed significant increases in most HCRU elements with increasing disease severity. The general trend toward increased HCRU with increased CI severity was also seen in individual countries. Individual country data appeared to indicate that earlier intervention decreased hospitalizations and full-time institutionalization at the later (more severe) disease stages.

Conclusion: Our findings confirmed that HCRU increases with increasing CI severity. Effective intervention in early disease could therefore reduce or delay incurring greater HCRU costs associated with more severe disease. Further studies are needed to confirm this hypothesis.
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http://dx.doi.org/10.3233/JAD-190760DOI Listing
May 2021

11β-hydroxysteroid dehydrogenase type 1 inhibitor use in human disease-a systematic review and narrative synthesis.

Metabolism 2020 07 23;108:154246. Epub 2020 Apr 23.

Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Introduction: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an intracellular enzyme that catalyses conversion of cortisone into cortisol; correspondingly, 11β-HSD1 inhibitors inhibit this conversion. This systematic review focuses on the use of 11β-HSD1 inhibitors in diseases known to be associated with abnormalities in hypothalamic pituitary adrenal (HPA) axis function.

Methods: The databases screened for suitable papers were: MedLine, EMBASE, Web of Science, ClinicalTrials.gov, and Cochrane Central.

Results: 1925 papers were identified, of which 29 were included in the final narrative synthesis. 11β-HSD1 and its inhibitors have been studied in diabetes, obesity, metabolic syndrome (MetS), and Alzheimer's disease (AD). Higher expression of 11β-HSD1 is seen in obesity and MetS, but has not yet been described in obesity or AD. Genetic studies identify 11β-HSD1 SNPs of interest in populations with diabetes, MetS, and AD. One phase II trial successfully reduced HbA1c in a diabetic population, however trials in MetS, obesity, and AD have not met primary endpoints.

Conclusions: Translation of this research from preclinical studies has proved challenging so far, however this is a growing area of research and more studies should focus on understanding the complex relationships between 11β-HSD1 and disease pathology, especially given the therapeutic potential of 11β-HSD1 inhibitors in development.
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http://dx.doi.org/10.1016/j.metabol.2020.154246DOI Listing
July 2020

The Dementias Platform UK (DPUK) Data Portal.

Eur J Epidemiol 2020 Jun 23;35(6):601-611. Epub 2020 Apr 23.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.
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http://dx.doi.org/10.1007/s10654-020-00633-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320955PMC
June 2020

The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: Longitudinal findings from the Catch-Cog study cohort.

Alzheimers Dement (N Y) 2020 17;6(1):e12020. Epub 2020 Apr 17.

Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience, Amsterdam Amsterdam UMC the Netherlands.

Introduction: In an attempt to capture clinically meaningful cognitive decline in early dementia, we developed the Cognitive-Functional Composite (CFC). We investigated the CFC's sensitivity to decline in comparison to traditional clinical endpoints.

Methods: This longitudinal construct validation study included 148 participants with subjective cognitive decline, mild cognitive impairment, or mild dementia. The CFC and traditional tests were administered at baseline, 3, 6, and 12 months. Sensitivity to change was investigated using linear mixed models and effect sizes.

Results: CFC scores declined over time (= -.16,  .001), with steepest decline observed in mild Alzheimer's dementia (= -.25,  .001). The CFC showed medium-to-large effect sizes at succeeding follow-up points ( = .08-.42), exhibiting greater change than the Clinical Dementia Rating scale ( = .02-.12). Moreover, change on the CFC was significantly associated with informant reports of cognitive decline (= .38, < .001).

Discussion: By showing sensitivity to decline, the CFC could enhance the monitoring of disease progression in dementia research and clinical practice.
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http://dx.doi.org/10.1002/trc2.12020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164406PMC
April 2020

Volumetric alterations in the hippocampal subfields of subjects at increased risk of dementia.

Neurobiol Aging 2020 07 14;91:36-44. Epub 2020 Mar 14.

Department of Psychiatry, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, UK.

The hippocampus is one of the first regions to demonstrate atrophy during the prodromal stage of Alzheimer's disease. Volumetric analysis of its individual subfields could provide biomarkers with higher sensitivity than whole hippocampal volume during an earlier disease stage. We quantified the hippocampal subfields volume in a large cohort comprising healthy participants (aged 40-59) with dementia family history (FH) and controls (without FH), examined at 2 time points across 2 years. Subfield volumes were quantified using both a T1-weighted and a high-resolution T2 hippocampal magnetic resonance imaging acquisition with Freesurfer. The participants were stratified based on dementia FH, APOE genotype, and CAIDE (Cardiovascular Risk Factors, Aging and Dementia) risk score. Whole hippocampal volume did not differ between the groups. The volume of the molecular layer was lower in participants with an APOE ε4 genotype, but there were no differences between subjects with and without dementia FH or with an increasing CAIDE score. The molecular layer may be the first hippocampal region to demonstrate volumetric alterations in subjects at risk of dementia.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.03.006DOI Listing
July 2020

Cognitive Functions as Predictors of Alzheimer's Disease Biomarker Status in the European Prevention of Alzheimer's Dementia Cohort.

J Alzheimers Dis 2020 ;74(4):1203-1210

Centre for Dementia Prevention, University of Edinburgh, UK.

Alterations in Alzheimer's disease (AD) biomarkers have been observed decades before the onset of dementia. Cognitive dysfunction, while central to the clinical diagnosis of AD, has long been considered as a late-stage phenomenon. This assumption is currently challenged and signals on some cognitive tests are now being observed within the preclinical stage. As part of the European Prevention of Alzheimer's Dementia (EPAD) project, a battery of cognitive tests has been proposed (the EPAD Neuropsychological Examination, ENE) which is designed to detect cognitive changes in persons without clinical signs of AD but who are at high risk. Analysis of results from the 361 participants with complete measures and without dementia recruited into the EPAD Longitudinal Cohort Study showed that the majority have elevated biomarker levels, with significant associations between an episodic verbal memory task and tau, while amyloid-β (Aβ) was associated with a central executive task. These preliminary findings suggest that profiles of cognitive performance may be specific to a given biomarker, with a primarily hippocampal task being associated with higher levels of tau and a frontal executive task being associated with higher levels of Aβ. While previous research has focused on the relationship between cognition and levels of Aβ, our findings suggest that p-tau may potentially be a more significant correlate.
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http://dx.doi.org/10.3233/JAD-191108DOI Listing
May 2021

Measuring multimorbidity beyond counting diseases: systematic review of community and population studies and guide to index choice.

BMJ 2020 02 18;368:m160. Epub 2020 Feb 18.

Edinburgh Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.

Objectives: To identify and summarise existing indices for measuring multimorbidity beyond disease counts, to establish which indices include mental health comorbidities or outcomes, and to develop recommendations based on applicability, performance, and usage.

Design: Systematic review.

Data Sources: Seven medical research databases (Medline, Web of Science Core Collection, Cochrane Library, Embase, PsycINFO, Scopus, and CINAHL Plus) from inception to October 2018 and bibliographies and citations of relevant papers. Searches were limited to English language publications.

Eligibility Criteria For Study Selection: Original articles describing a new multimorbidity index including more information than disease counts and not focusing on comorbidity associated with one specific disease. Studies were of adults based in the community or at population level.

Results: Among 7128 search results, 5560 unique titles were identified. After screening against eligibility criteria the review finally included 35 papers. As index components, 25 indices used conditions (weighted or in combination with other parameters), five used diagnostic categories, four used drug use, and one used physiological measures. Predicted outcomes included mortality (18 indices), healthcare use or costs (13), hospital admission (13), and health related quality of life (7). 29 indices considered some aspect of mental health, with most including it as a comorbidity. 12 indices are recommended for use.

Conclusions: 35 multimorbidity indices are available, with differing components and outcomes. Researchers and clinicians should examine existing indices for suitability before creating new ones.

Systematic Review Registration: PROSPERO CRD42017074211.
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http://dx.doi.org/10.1136/bmj.m160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190061PMC
February 2020

Mechanical property alterations across the cerebral cortex due to Alzheimer's disease.

Brain Commun 2020 17;2(1):fcz049. Epub 2019 Dec 17.

Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, UK.

Alzheimer's disease is a personally devastating neurodegenerative disorder and a major public health concern. There is an urgent need for medical imaging techniques that better characterize the early stages and monitor the progression of the disease. Magnetic resonance elastography (MRE) is a relatively new and highly sensitive MRI technique that can non-invasively assess tissue microstructural integrity via measurement of brain viscoelastic mechanical properties. For the first time, we use high-resolution MRE methods to conduct a voxel-wise MRE investigation and state-of-the-art region of interest analysis of the viscoelastic properties of the cerebral cortex in patients with Alzheimer's disease ( = 11) compared with cognitively healthy older adults ( = 12). We replicated previous findings that have reported significant volume and stiffness reductions at the whole-brain level. Significant reductions in volume were also observed in Alzheimer's disease when white matter, cortical grey matter and subcortical grey matter compartments were considered separately; lower stiffness was also observed in white matter and cortical grey matter, but not in subcortical grey matter. Voxel-based morphometry of both cortical and subcortical grey matter revealed localized reductions in volume due to Alzheimer's disease in the hippocampus, fusiform, middle, superior temporal gyri and precuneus. Similarly, voxel-based MRE identified lower stiffness in the middle and superior temporal gyri and precuneus, although the spatial distribution of these effects was not identical to the pattern of volume reduction. Notably, MRE additionally identified stiffness deficits in the operculum and precentral gyrus located within the frontal lobe; regions that did not undergo volume loss identified through voxel-based morphometry. Voxel-based-morphometry and voxel-based MRE results were confirmed by a complementary region-of-interest approach in native space where the viscoelastic changes remained significant even after statistically controlling for regional volumes. The pattern of reduction in cortical stiffness observed in Alzheimer's disease patients raises the possibility that MRE may provide unique insights regarding the neural mechanisms which underlie the development and progression of the disease. The measured mechanical property changes that we have observed warrant further exploration to investigate the diagnostic usefulness of MRE in cases of Alzheimer's disease and other dementias.
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http://dx.doi.org/10.1093/braincomms/fcz049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976617PMC
December 2019

Prescreening for European Prevention of Alzheimer Dementia (EPAD) trial-ready cohort: impact of AD risk factors and recruitment settings.

Alzheimers Res Ther 2020 01 6;12(1). Epub 2020 Jan 6.

Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Background: Recruitment is often a bottleneck in secondary prevention trials in Alzheimer disease (AD). Furthermore, screen-failure rates in these trials are typically high due to relatively low prevalence of AD pathology in individuals without dementia, especially among cognitively unimpaired. Prescreening on AD risk factors may facilitate recruitment, but the efficiency will depend on how these factors link to participation rates and AD pathology. We investigated whether common AD-related factors predict trial-ready cohort participation and amyloid status across different prescreen settings.

Methods: We monitored the prescreening in four cohorts linked to the European Prevention of Alzheimer Dementia (EPAD) Registry (n = 16,877; mean ± SD age = 64 ± 8 years). These included a clinical cohort, a research in-person cohort, a research online cohort, and a population-based cohort. Individuals were asked to participate in the EPAD longitudinal cohort study (EPAD-LCS), which serves as a trial-ready cohort for secondary prevention trials. Amyloid positivity was measured in cerebrospinal fluid as part of the EPAD-LCS assessment. We calculated participation rates and numbers needed to prescreen (NNPS) per participant that was amyloid-positive. We tested if age, sex, education level, APOE status, family history for dementia, memory complaints or memory scores, previously collected in these cohorts, could predict participation and amyloid status.

Results: A total of 2595 participants were contacted for participation in the EPAD-LCS. Participation rates varied by setting between 3 and 59%. The NNPS were 6.9 (clinical cohort), 7.5 (research in-person cohort), 8.4 (research online cohort), and 88.5 (population-based cohort). Participation in the EPAD-LCS (n = 413 (16%)) was associated with lower age (odds ratio (OR) age = 0.97 [0.95-0.99]), high education (OR = 1.64 [1.23-2.17]), male sex (OR = 1.56 [1.19-2.04]), and positive family history of dementia (OR = 1.66 [1.19-2.31]). Among participants in the EPAD-LCS, amyloid positivity (33%) was associated with higher age (OR = 1.06 [1.02-1.10]) and APOE ɛ4 allele carriership (OR = 2.99 [1.81-4.94]). These results were similar across prescreen settings.

Conclusions: Numbers needed to prescreen varied greatly between settings. Understanding how common AD risk factors link to study participation and amyloid positivity is informative for recruitment strategy of studies on secondary prevention of AD.
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http://dx.doi.org/10.1186/s13195-019-0576-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945608PMC
January 2020

Association between midlife dementia risk factors and longitudinal brain atrophy: the PREVENT-Dementia study.

J Neurol Neurosurg Psychiatry 2020 02 5;91(2):158-161. Epub 2019 Dec 5.

Department of Psychiatry, University of Cambridge, Cambridge, Cambridgeshire, UK.

Background: Increased rates of brain atrophy on serial MRI are frequently used as a surrogate marker of disease progression in Alzheimer's disease and other dementias. However, the extent to which they are associated with future risk of dementia in asymptomatic subjects is not clear. In this study, we investigated the relationship between the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) risk score and longitudinal atrophy in middle-aged subjects.

Materials And Methods: A sample of 167 subjects (aged 40-59 at baseline) from the PREVENT-Dementia programme underwent MRI scans on two separate occasions (mean interval 735 days; SD 44 days). We measured longitudinal rates of brain atrophy using the FSL Siena toolbox.

Results: Annual percentage rates of brain volume and ventricular volume change were greater in those with a high (>6) vs low CAIDE score-absolute brain volume percentage loss 0.17% (CI 0.07 to 0.27) and absolute ventricular enlargement 1.78% (CI 1.14 to 2.92) higher in the at risk group. Atrophy rates did not differ between subjects with and without a parental history of dementia, but were significantly correlated with age. Using linear regression, with covariates of age, sex and education, CAIDE score >6 was the only significant predictor of whole brain atrophy rates (p=0.025) while age (p=0.009), sex (p=0.002) and CAIDE>6 (p=0.017) all predicted ventricular expansion rate.

Conclusion: Our results show that progressive brain atrophy is associated with increased risk of future dementia in asymptomatic middle-aged subjects, two decades before dementia onset.
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http://dx.doi.org/10.1136/jnnp-2019-321652DOI Listing
February 2020
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