ORCID Profile
0000-0001-7216-8679
Current Organisations
University of Cambridge
,
Medical Research Council
,
University of Oxford
,
Dementias Platform UK
,
IT University of Copenhagen
,
Alzheimer Research UK
,
Cambridge University Hospitals NHS Trust
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Publisher: BMJ
Date: 29-11-2016
Publisher: Cold Spring Harbor Laboratory
Date: 02-02-2022
DOI: 10.1101/2022.02.01.22270235
Abstract: Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. Here we assess cerebrovascular health in 45 hospitalised patients using the resting state fluctuation litudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode, as indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. Exploratory analysis suggests that the level of cerebrovascular dysfunction is associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 03-2017
Publisher: Cold Spring Harbor Laboratory
Date: 11-11-2021
DOI: 10.1101/2021.11.09.467891
Abstract: Establishing preclinical models of Alzheimer’s disease that predict clinical outcomes remains a critically important, yet to date not fully realised, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-in idual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer’s disease where we sought a match between in idual disease characteristics in cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-β burden in life, as measured by cognitive decline and brain activity levels, varies between in iduals and this vulnerability rating correlates with the in idual cellular vulnerability to extrinsic amyloid-β in vitro as measured by synapse loss and function. Our findings indicate that patient induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer’s disease pathology, but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an in idual’s in-life clinical vulnerability thus represent a tractable method of Alzheimer’s disease modelling using clinical data in combination with cellular phenotypes.
Publisher: Oxford University Press (OUP)
Date: 05-2020
Abstract: Tau pathology, neuroinflammation, and neurodegeneration are key aspects of Alzheimer’s disease. Understanding whether these features predict cognitive decline, alone or in combination, is crucial to develop new prognostic measures and enhanced stratification for clinical trials. Here, we studied how baseline assessments of in vivo tau pathology (measured by 18F-AV-1451 PET), neuroinflammation (measured by 11C-PK11195 PET) and brain atrophy (derived from structural MRI) predicted longitudinal cognitive changes in patients with Alzheimer’s disease pathology. Twenty-six patients (n = 12 with clinically probable Alzheimer’s dementia and n = 14 with amyloid-positive mild cognitive impairment) and 29 healthy control subjects underwent baseline assessment with 18F-AV-1451 PET, 11C-PK11195 PET, and structural MRI. Cognition was examined annually over the subsequent 3 years using the revised Addenbrooke’s Cognitive Examination. Regional grey matter volumes, and regional binding of 18F-AV-1451 and 11C-PK11195 were derived from 15 temporo-parietal regions characteristically affected by Alzheimer’s disease pathology. A principal component analysis was used on each imaging modality separately, to identify the main spatial distributions of pathology. A latent growth curve model was applied across the whole s le on longitudinal cognitive scores to estimate the rate of annual decline in each participant. We regressed the in iduals’ estimated rate of cognitive decline on the neuroimaging components and examined univariable predictive models with single-modality predictors, and a multi-modality predictive model, to identify the independent and combined prognostic value of the different neuroimaging markers. Principal component analysis identified a single component for the grey matter atrophy, while two components were found for each PET ligand: one weighted to the anterior temporal lobe, and another weighted to posterior temporo-parietal regions. Across the whole-s le, the single-modality models indicated significant correlations between the rate of cognitive decline and the first component of each imaging modality. In patients, both stepwise backward elimination and Bayesian model selection revealed an optimal predictive model that included both components of 18F-AV-1451 and the first (i.e. anterior temporal) component for 11C-PK11195. However, the MRI-derived atrophy component and demographic variables were excluded from the optimal predictive model of cognitive decline. We conclude that temporo-parietal tau pathology and anterior temporal neuroinflammation predict cognitive decline in patients with symptomatic Alzheimer’s disease pathology. This indicates the added value of PET biomarkers in predicting cognitive decline in Alzheimer’s disease, over and above MRI measures of brain atrophy and demographic data. Our findings also support the strategy for targeting tau and neuroinflammation in disease-modifying therapy against Alzheimer’s disease.
Publisher: BMJ
Date: 05-07-2022
Abstract: Dysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimer’s disease, contributing to cognitive and neuropsychiatric symptoms in some patients. This system offers a potential therapeutic target, although noradrenergic treatments are not currently used in clinical practice. To assess the efficacy of drugs with principally noradrenergic action in improving cognitive and neuropsychiatric symptoms in Alzheimer’s disease. The MEDLINE, Embase and ClinicalTrials.gov databases were searched from 1980 to December 2021. We generated pooled estimates using random effects meta-analyses. We included 19 randomised controlled trials (1811 patients), of which six were judged as ‘good’ quality, seven as ‘fair’ and six ‘poor’. Meta-analysis of 10 of these studies (1300 patients) showed a significant small positive effect of noradrenergic drugs on global cognition, measured using the Mini-Mental State Examination or Alzheimer’s Disease Assessment Scale—Cognitive Subscale (standardised mean difference (SMD): 0.14, 95% CI: 0.03 to 0.25, p=0.01 I 2 =0%). No significant effect was seen on measures of attention (SMD: 0.01, 95% CI: −0.17 to 0.19, p=0.91 I 2 =0). The apathy meta-analysis included eight trials (425 patients) and detected a large positive effect of noradrenergic drugs (SMD: 0.45, 95% CI: 0.16 to 0.73, p=0.002 I 2 =58%). This positive effect was still present following removal of outliers to account for heterogeneity across studies. Repurposing of established noradrenergic drugs is most likely to offer effective treatment in Alzheimer’s disease for general cognition and apathy. However, several factors should be considered before designing future clinical trials. These include targeting of appropriate patient subgroups and understanding the dose effects of in idual drugs and their interactions with other treatments to minimise risks and maximise therapeutic effects. CRD42021277500.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2017
DOI: 10.1038/NCOMMS14743
Abstract: Healthy ageing has disparate effects on different cognitive domains. The neural basis of these differences, however, is largely unknown. We investigated this question by using Independent Components Analysis to obtain functional brain components from 98 healthy participants aged 23–87 years from the population-based Cam-CAN cohort. Participants performed two cognitive tasks that show age-related decrease (fluid intelligence and object naming) and a syntactic comprehension task that shows age-related preservation. We report that activation of task-positive neural components predicts inter-in idual differences in performance in each task across the adult lifespan. Furthermore, only the two tasks that show performance declines with age show age-related decreases in task-positive activation of neural components and decreasing default mode (DM) suppression. Our results suggest that distributed, multi-component brain responsivity supports cognition across the adult lifespan, and the maintenance of this, along with maintained DM deactivation, characterizes successful ageing and may explain differential ageing trajectories across cognitive domains.
Publisher: Springer Science and Business Media LLC
Date: 19-06-2018
Publisher: Springer Science and Business Media LLC
Date: 14-10-2014
Publisher: Springer Science and Business Media LLC
Date: 22-11-2018
DOI: 10.1038/S41598-018-35439-8
Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Publisher: Springer Science and Business Media LLC
Date: 11-04-2018
DOI: 10.1038/S41398-017-0049-7
Abstract: Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12 , TLR2, RALB, and CCR5 . Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT , we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.
Publisher: Psychology Press
Date: 11-2004
Publisher: Elsevier BV
Date: 03-2013
Publisher: BMJ
Date: 22-06-2017
Publisher: Springer Science and Business Media LLC
Date: 02-10-2018
DOI: 10.1038/S41380-018-0224-0
Abstract: Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients) 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.
Publisher: Springer Science and Business Media LLC
Date: 22-07-2020
DOI: 10.1038/S41598-020-68848-9
Abstract: We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies ( n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.
Publisher: Wiley
Date: 23-08-2014
Publisher: Cold Spring Harbor Laboratory
Date: 24-04-2023
DOI: 10.1101/2023.04.17.23288471
Abstract: Pick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD. We established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521). Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65). The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies. See funding section
Publisher: Springer Science and Business Media LLC
Date: 15-10-2018
DOI: 10.1038/S41467-018-05892-0
Abstract: The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique—Subtype and Stage Inference (SuStaIn)—able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes further the technique reveals within-genotype heterogeneity. In Alzheimer’s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype ( p = 7.18 × 10 −4 ) or temporal stage ( p = 3.96 × 10 −5 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2020
Publisher: Springer Science and Business Media LLC
Date: 23-10-2018
DOI: 10.1038/S41598-018-33678-3
Abstract: Abnormal initiation and control of voluntary movements are among the principal manifestations of Parkinson’s disease (PD). However, the processes underlying these abnormalities and their potential remediation by dopamine treatment remain poorly understood. Normally, movements depend on the integration of sensory information with the predicted consequences of action. This integration leads to a suppression in the intensity of predicted sensations, reflected in a ‘sensory attenuation’. We examined this integration process and its relation to dopamine in PD, by measuring sensory attenuation. Patients with idiopathic PD (n = 18) and population-derived controls (n = 175) matched a set of target forces applied to their left index finger by a torque motor. To match the force, participants either pressed with their right index finger (‘Direct’ condition) or moved a knob that controlled a motor through a linear potentiometer (‘Slider’ condition). We found that despite changes in sensitivity to different forces, overall sensory attenuation did not differ between medicated PD patients and controls. Importantly, the degree of attenuation was negatively related to PD motor severity but positively related to in idual patient dopamine dose, as measured by levodopa dose equivalent. The results suggest that dopamine could regulate the integration of sensorimotor prediction with sensory information to facilitate the control of voluntary movements.
Publisher: Elsevier BV
Date: 02-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2016
Publisher: Cold Spring Harbor Laboratory
Date: 25-03-2019
DOI: 10.1101/582155
Abstract: The Dementias Platform UK (DPUK) Data Portal is a data repository facilitating access to data for 3 370 929 in iduals 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 (UKSeRP) 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 in idual 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. Project 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.
Publisher: SAGE Publications
Date: 08-10-2019
Abstract: Objective: Studies of “healthy” cognitive aging often focus on a limited set of measures that decline with age. The current study argues that defining and supporting healthy cognition requires understanding erse cognitive performance across the lifespan. Method: Data from the Cambridge Centre for Aging and Neuroscience (Cam-CAN) cohort was examined across a range of cognitive domains. Performance was related to lifestyle including education, social engagement, and enrichment activities. Results: Results indicate variable relationships between cognition and age (positive, negative, or no relationship). Principal components analysis indicated maintained cognitive ersity across the adult lifespan, and that cognition–lifestyle relationships differed by age and domain. Discussion: Our findings support a view of normal cognitive aging as a lifelong developmental process with erse relationships between cognition, lifestyle, and age. This reinforces the need for large-scale studies of cognitive aging to include a wider range of both ages and cognitive tasks.
Publisher: Wiley
Date: 15-04-2014
DOI: 10.1002/MDS.25872
Abstract: Corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) represent challenging neurodegenerative disorders for clinicians and nonclinical scientists alike. Although initially lumped together as "Parkinson's-Plus" syndromes, CBS and PSP are clinically and pathologically distinct from Parkinson's disease. It is now clear that behavioral and cognitive changes are common in both syndromes and affect impact quality of life and carer burden considerably. We briefly review the clinical, pathological, and neuroradiological features of each syndrome, followed by more detailed descriptions of the behavioral and cognitive deficits encountered in CBS and PSP. Clinically and pathologically heterogeneous, CBS is characterized by a wide range of cognitive and behavioral disturbances. impairments in executive function and memory are common, but nonspecific. In contrast, deficits in language and visuospatial abilities appear to be more distinctive features of CBS the relevance of specific patterns of impairment to the underlying histopathology, or prognosis, remains to be fully elucidated. As in CBS, behavioral and cognitive changes are almost universal in PSP, with a wide range of reported deficits. Apathy is very common, often paradoxically accompanied by impulsivity. Executive dysfunction is prominent, but memory and visuospatial deficits also occur. An emerging field is the study of social cognition, which appears impaired in both syndromes. As therapeutic strategies for neurodegenerative pathologies emerge, more specific diagnostic tools in CBS and PSP will be required. Careful clinicopathological correlation, and the development of biomarkers for specific histopathologies, will be important milestones on the road to effective treatments.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2018
Publisher: S. Karger AG
Date: 11-09-2014
DOI: 10.1159/000366040
Abstract: b i Background/Aims: /i /b We developed and validated the Mini-Addenbrooke's Cognitive Examination (M-ACE) in dementia patients. Comparisons were also made with the Mini Mental State Examination (MMSE). b i Method: /i /b The M-ACE was developed using Mokken scaling analysis in 117 dementia patients [behavioural variant frontotemporal dementia (bvFTD), n = 25 primary progressive aphasia (PPA), n = 49 Alzheimer's disease (AD), n = 34 corticobasal syndrome (CBS), n = 9] and validated in an independent s le of 164 dementia patients (bvFTD, n = 23 PPA, n = 82 AD, n = 38 CBS, n = 21) and 78 controls, who also completed the MMSE. b i Results: /i /b The M-ACE consists of 5 items with a maximum score of 30. Two cut-offs were identified: (1) ≤25/30 has both high sensitivity and specificity, and (2) ≤21/30 is almost certainly a score to have come from a dementia patient regardless of the clinical setting. The M-ACE is more sensitive than the MMSE and is less likely to have ceiling effects. b i Conclusion: /i /b The M-ACE is a brief and sensitive cognitive screening tool for dementia. Two cut-offs (25 or 21) are recommended. © 2014 S. Karger AG, Basel
Publisher: Cold Spring Harbor Laboratory
Date: 12-10-2023
Publisher: SAGE Publications
Date: 24-07-2013
Abstract: The aim of this paper is to increase awareness of the prevalence and cost of psychiatric and neurological disorders (brain disorders) in the UK. UK data for 18 brain disorders were extracted from a systematic review of European epidemiological data and prevalence rates and the costs of each disorder were summarized (2010 values). There were approximately 45 million cases of brain disorders in the UK, with a cost of €134 billion per annum. The most prevalent were headache, anxiety disorders, sleep disorders, mood disorders and somatoform disorders. However, the five most costly disorders (€ million) were: dementia: €22,164 psychotic disorders: €16,717 mood disorders: €19,238 addiction: €11,719 anxiety disorders: €11,687. Apart from psychosis, these five disorders ranked amongst those with the lowest direct medical expenditure per subject ( €3000). The approximate breakdown of costs was: 50% indirect costs, 25% direct non-medical and 25% direct healthcare costs. The prevalence and cost of UK brain disorders is likely to increase given the ageing population. Translational neurosciences research has the potential to develop more effective treatments but is underfunded. Addressing the clinical and economic challenges posed by brain disorders requires a coordinated effort at an EU and national level to transform the current scientific, healthcare and educational agenda.
Publisher: Wiley
Date: 03-05-2017
DOI: 10.1002/MDS.26987
Publisher: Oxford University Press (OUP)
Date: 04-10-2018
Publisher: Elsevier BV
Date: 2021
Publisher: Springer Science and Business Media LLC
Date: 14-05-2018
DOI: 10.1038/S41598-018-21308-X
Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Publisher: Springer Science and Business Media LLC
Date: 21-08-2017
DOI: 10.1038/S41598-017-09320-Z
Abstract: Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene ( ELP2 ). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35 , and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/NCOMMS13034
Abstract: The control of voluntary movement changes markedly with age. A critical component of motor control is the integration of sensory information with predictions of the consequences of action, arising from internal models of movement. This leads to sensorimotor attenuation—a reduction in the perceived intensity of sensations from self-generated compared with external actions. Here we show that sensorimotor attenuation occurs in 98% of adults in a population-based cohort ( n =325 18–88 years the Cambridge Centre for Ageing and Neuroscience). Importantly, attenuation increases with age, in proportion to reduced sensory sensitivity. This effect is associated with differences in the structure and functional connectivity of the pre-supplementary motor area (pre-SMA), assessed with magnetic resonance imaging. The results suggest that ageing alters the balance between the sensorium and predictive models, mediated by the pre-SMA and its connectivity in frontostriatal circuits. This shift may contribute to the motor and cognitive changes observed with age.
Publisher: Oxford University Press (OUP)
Date: 11-08-2011
DOI: 10.1093/BRAIN/AWR196
Publisher: Springer Science and Business Media LLC
Date: 23-04-2020
DOI: 10.1007/S10654-020-00633-4
Abstract: The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 in iduals 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 in idual 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.
Publisher: Elsevier BV
Date: 11-2015
Publisher: Springer Science and Business Media LLC
Date: 24-09-2019
DOI: 10.1038/S41598-019-50254-5
Abstract: Making sense of the external world is vital for multiple domains of cognition, and so it is crucial that object recognition is maintained across the lifespan. We investigated age differences in perceptual and conceptual processing of visual objects in a population-derived s le of 85 healthy adults (24–87 years old) by relating measures of object processing to cognition across the lifespan. Magnetoencephalography (MEG) was recorded during a picture naming task to provide a direct measure of neural activity, that is not confounded by age-related vascular changes. Multiple linear regression was used to estimate neural responsivity for each in idual, namely the capacity to represent visual or semantic information relating to the pictures. We find that the capacity to represent semantic information is linked to higher naming accuracy, a measure of task-specific performance. In mature adults, the capacity to represent semantic information also correlated with higher levels of fluid intelligence, reflecting domain-general performance. In contrast, the latency of visual processing did not relate to measures of cognition. These results indicate that neural responsivity measures relate to naming accuracy and fluid intelligence. We propose that maintaining neural responsivity in older age confers benefits in task-related and domain-general cognitive processes, supporting the brain maintenance view of healthy cognitive ageing.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Springer Science and Business Media LLC
Date: 18-12-2014
DOI: 10.1038/NCOMMS6658
Abstract: Ageing is characterized by declines on a variety of cognitive measures. These declines are often attributed to a general, unitary underlying cause, such as a reduction in executive function owing to atrophy of the prefrontal cortex. However, age-related changes are likely multifactorial, and the relationship between neural changes and cognitive measures is not well-understood. Here we address this in a large ( N =567), population-based s le drawn from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data. We relate fluid intelligence and multitasking to multiple brain measures, including grey matter in various prefrontal regions and white matter integrity connecting those regions. We show that multitasking and fluid intelligence are separable cognitive abilities, with differential sensitivities to age, which are mediated by distinct neural subsystems that show different prediction in older versus younger in iduals. These results suggest that prefrontal ageing is a manifold process demanding multifaceted models of neurocognitive ageing.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2020
DOI: 10.1007/S00401-019-02107-8
Abstract: The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
Publisher: Public Library of Science (PLoS)
Date: 09-01-2018
Publisher: Oxford University Press (OUP)
Date: 05-04-2017
DOI: 10.1093/BRAIN/AWX066
Abstract: Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small s le size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ɛ2 and ɛ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Springer Science and Business Media LLC
Date: 07-09-2016
DOI: 10.1038/SREP32527
Abstract: Memory problems are among the most common complaints as people grow older. Using structural equation modeling of commensurate scores of anterograde memory from a large (N = 315), population-derived s le ( www.cam-can.org ), we provide evidence for three memory factors that are supported by distinct brain regions and show differential sensitivity to age. Associative memory and item memory are dramatically affected by age, even after adjusting for education level and fluid intelligence, whereas visual priming is not. Associative memory and item memory are differentially affected by emotional valence, and the age-related decline in associative memory is faster for negative than for positive or neutral stimuli. Gray-matter volume in the hippoc us, parahippoc us and fusiform cortex, and a white-matter index for the fornix, uncinate fasciculus and inferior longitudinal fasciculus, show differential contributions to the three memory factors. Together, these data demonstrate the extent to which differential ageing of the brain leads to differential patterns of memory loss.
Publisher: Informa UK Limited
Date: 27-07-2020
DOI: 10.1080/14779072.2020.1797492
Abstract: Cardiovascular diseases (CVDs) are among the most frequently identified comorbidities in hospitalized patients with COVID-19. Patients with CV comorbidities are typically prescribed with long-term medications. We reviewed the management of co-medications prescribed for CVDs among hospitalized COVID-19 patients. There is no specific contraindication or caution related to COVID-19 on the use of antihypertensives unless patients develop severe hypotension from septic shock where all antihypertensives should be discontinued or severe hyperkalemia in which continuation of renin-angiotensin system inhibitors is not desired. The continuation of antiplatelet or statin is not desired when severe thrombocytopenia or severe transminitis develop, respectively. Patients with atrial fibrillation receiving oral anticoagulants, particularly those who are critically ill, should be considered for substitution to parenteral anticoagulants. An in idualized approach to medication management among hospitalized COVID-19 patients with concurrent CVDs would seem prudent with attention paid to changes in clinical conditions and medications intended for COVID-19. The decision to modify prescribed long-term CV medications should be entailed by close follow-up to check if a revision on the decision is needed, with resumption of any long-term CV medication before discharge if it is discontinued during hospitalization for COVID-19, to ensure continuity of care.
Publisher: American Medical Association (AMA)
Date: 06-01-2021
Publisher: Cambridge University Press (CUP)
Date: 19-06-2018
DOI: 10.1017/S0033291717001519
Abstract: Decades of research have investigated the impact of clinical depression on memory, which has revealed biases and in some cases impairments. However, little is understood about the effects of subclinical symptoms of depression on memory performance in the general population. Here we report the effects of symptoms of depression on memory problems in a large population-derived cohort ( N = 2544), 87% of whom reported at least one symptom of depression. Specifically, we investigate the impact of depressive symptoms on subjective memory complaints, objective memory performance on a standard neuropsychological task and, in a subs le ( n = 288), objective memory in affective contexts. There was a dissociation between subjective and objective memory performance, with depressive symptoms showing a robust relationship with self-reports of memory complaints, even after adjusting for age, sex, general cognitive ability and symptoms of anxiety, but not with performance on the standardised measure of verbal memory. Contrary to our expectations, hippoc al volume (assessed in a subs le, n = 592) did not account for significant variance in subjective memory, objective memory or depressive symptoms. Nonetheless, depressive symptoms were related to poorer memory for pictures presented in negative contexts, even after adjusting for memory for pictures in neutral contexts. Thus the symptoms of depression, associated with subjective memory complaints, appear better assessed by memory performance in affective contexts, rather than standardised memory measures. We discuss the implications of these findings for understanding the impact of depressive symptoms on memory functioning in the general population.
Publisher: Wiley
Date: 13-05-2017
DOI: 10.1002/MDS.27034
Publisher: Cold Spring Harbor Laboratory
Date: 04-02-2020
DOI: 10.1101/2020.02.04.932335
Abstract: The genetic basis of variation in the rate of disease progression of primary tauopathies has not been determined. In two independent progressive supranuclear palsy cohorts, we show that common variation at the LRRK2 locus determines survival from motor symptom onset to death, possibly through regulation of gene expression. This links together genetic risk in alpha-synuclein and tau disorders, and suggests that modulation of proteostasis and neuro-inflammation by LRRK2 inhibitors may have a therapeutic role across disorders.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Wiley
Date: 31-07-2019
Publisher: Springer Science and Business Media LLC
Date: 06-04-2020
DOI: 10.1038/S41467-020-15410-W
Abstract: The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function.
Publisher: Society for Neuroscience
Date: 16-03-2016
DOI: 10.1523/JNEUROSCI.2733-15.2016
Abstract: The maintenance of wellbeing across the lifespan depends on the preservation of cognitive function. We propose that successful cognitive aging is determined by interactions both within and between large-scale functional brain networks. Such connectivity can be estimated from task-free functional magnetic resonance imaging (fMRI), also known as resting-state fMRI (rs-fMRI). However, common correlational methods are confounded by age-related changes in the neurovascular signaling. To estimate network interactions at the neuronal rather than vascular level, we used generative models that specified both the neural interactions and a flexible neurovascular forward model. The networks' parameters were optimized to explain the spectral dynamics of rs-fMRI data in 602 healthy human adults from population-based cohorts who were approximately uniformly distributed between 18 and 88 years ( www.cam-can.com ). We assessed directed connectivity within and between three key large-scale networks: the salience network, dorsal attention network, and default mode network. We found that age influences connectivity both within and between these networks, over and above the effects on neurovascular coupling. Canonical correlation analysis revealed that the relationship between network connectivity and cognitive function was age-dependent: cognitive performance relied on neural dynamics more strongly in older adults. These effects were driven partly by reduced stability of neural activity within all networks, as expressed by an accelerated decay of neural information. Our findings suggest that the balance of excitatory connectivity between networks, and the stability of intrinsic neural representations within networks, changes with age. The cognitive function of older adults becomes increasingly dependent on these factors. SIGNIFICANCE STATEMENT Maintaining cognitive function is critical to successful aging. To study the neural basis of cognitive function across the lifespan, we studied a large population-based cohort ( n = 602, 18–88 years), separating neural connectivity from vascular components of fMRI signals. Cognitive ability was influenced by the strength of connection within and between functional brain networks, and this positive relationship increased with age. In older adults, there was more rapid decay of intrinsic neuronal activity in multiple regions of the brain networks, which related to cognitive performance. Our data demonstrate increased reliance on network flexibility to maintain cognitive function, in the presence of more rapid decay of neural activity. These insights will facilitate the development of new strategies to maintain cognitive ability.
Publisher: MDPI AG
Date: 07-12-2015
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: Start date not available
End Date: End date not available
Funder: Wellcome Trust
View Funded ActivityStart Date: 2010
End Date: 2016
Funder: Biotechnology and Biological Sciences Research Council
View Funded ActivityStart Date: 2015
End Date: 2016
Funder: Medical Research Council
View Funded ActivityStart Date: 2012
End Date: 2014
Funder: Medical Research Council
View Funded ActivityStart Date: 2021
End Date: 2026
Funder: Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2020
Funder: Medical Research Council
View Funded Activity