Publications by authors named "Rebecca Sims"

71 Publications

Cognitive Decline in Alzheimer's Disease Is Not Associated with APOE.

J Alzheimers Dis 2021 Aug 30. Epub 2021 Aug 30.

UK Dementia Research Institute, Cardiff University, Cardiff, UK.

Background: The rate of cognitive decline in Alzheimer's disease (AD) has been found to vary widely between individuals, with numerous factors driving this heterogeneity.

Objective: This study aimed to compute a measure of cognitive decline in patients with AD based on clinical information and to utilize this measure to explore the genetic architecture of cognitive decline in AD.

Methods: An in-house cohort of 616 individuals, hereby termed the Cardiff Genetic Resource for AD, as well as a subset of 577 individuals from the publicly available ADNI dataset, that have been assessed at multiple timepoints, were used in this study. Measures of cognitive decline were computed using various mixed effect linear models of Mini-Mental State Examination (MMSE). After an optimal model was selected, a metric of cognitive decline for each individual was estimated as the random slope derived from this model. This metric was subsequently used for testing the association of cognitive decline with apolipoprotein E (APOE) genotype.

Results: No association was found between the number of APOEɛ2 or ɛ4 alleles and the rate of cognitive decline in either of the datasets examined.

Conclusion: Further exploration is required to uncover possible genetic variants that affect the rate of decline in patients with AD.
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http://dx.doi.org/10.3233/JAD-210685DOI Listing
August 2021

PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522.

EMBO J 2021 Sep 13;40(17):e105603. Epub 2021 Jul 13.

UK Dementia Research Institute at Cardiff, Cardiff, UK.

Variants identified in genome-wide association studies have implicated immune pathways in the development of Alzheimer's disease (AD). Here, we investigated the mechanistic basis for protection from AD associated with PLCγ2 R522, a rare coding variant of the PLCG2 gene. We studied the variant's role in macrophages and microglia of newly generated PLCG2-R522-expressing human induced pluripotent cell lines (hiPSC) and knockin mice, which exhibit normal endogenous PLCG2 expression. In all models, cells expressing the R522 mutation show a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This manifests as enhanced release of cellular calcium ion stores in response to physiologically relevant stimuli like Fc-receptor ligation or exposure to Aβ oligomers. Expression of the PLCγ2-R522 variant resulted in increased stimulus-dependent PIP depletion and reduced basal PIP levels in vivo. Furthermore, it was associated with impaired phagocytosis and enhanced endocytosis. PLCγ2 acts downstream of other AD-related factors, such as TREM2 and CSF1R, and alterations in its activity directly impact cell function. The inherent druggability of enzymes such as PLCγ2 raises the prospect of PLCγ2 manipulation as a future therapeutic approach in AD.
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http://dx.doi.org/10.15252/embj.2020105603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408593PMC
September 2021

A Community Jury on initiating weight management conversations in primary care.

Health Expect 2021 Aug 21;24(4):1450-1458. Epub 2021 Jun 21.

Centre for Research in Evidence-Based Practice, Bond University, Gold Coast, Qld, Australia.

Background: Current guidelines recommend that patients attending general practice should be screened for excess weight, and provided with weight management advice.

Objective: This study sought to elicit the views of people with overweight and obesity about the role of GPs in initiating conversations about weight management.

Methods: Participants with a body mass index ≥25 were recruited from a region in Australia to take part in a Community Jury. Over 2 days, participants (n = 11) deliberated on two interconnected questions: 'Should GPs initiate discussions about weight management?' And 'if so, when: (a) opportunistically, (b) in the context of disease prevention, (c) in the context of disease management or (d) other?' The jury deliberations were analysed qualitatively to elicit their views and recommendations.

Results: The jury concluded GPs should be discussing weight management, but within the broader context of general health. The jury were divided about the utility of screening. Jurors felt GPs should initiate the conversation if directly relevant for disease prevention or management, otherwise GPs should provide opportunities for patients to consent to the issue being raised.

Conclusion: The jury's verdict suggests informed people affected by overweight and obesity believe GPs should discuss weight management with their patients. GPs should feel reassured that discussions are likely to be welcomed by patients, particularly if embedded within a more holistic focus on person-centred care.

Public Contribution: Members of the public took part in the conduct of this study as jurors, but were not involved in the design, analysis or write-up.
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http://dx.doi.org/10.1111/hex.13286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369079PMC
August 2021

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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http://dx.doi.org/10.1038/s41380-021-01152-8DOI Listing
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Defining functional variants associated with Alzheimer's disease in the induced immune response.

Brain Commun 2021 19;3(2):fcab083. Epub 2021 Apr 19.

Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.

Defining the mechanisms involved in the aetiology of Alzheimer's disease from genome-wide association studies alone is challenging since Alzheimer's disease is polygenic and most genetic variants are non-coding. Non-coding Alzheimer's disease risk variants can influence gene expression by affecting miRNA binding and those located within enhancers and within CTCF sites may influence gene expression through alterations in chromatin states. In addition, their function can be cell-type specific. They can function specifically in microglial enhancers thus affecting gene expression in the brain. Hence, transcriptome-wide association studies have been applied to test the genetic association between disease risk and cell-/tissue-specific gene expression. Many Alzheimer's disease-associated loci are involved in the pathways of the innate immune system. Both microglia, the primary immune cells of the brain, and monocytes which can infiltrate the brain and differentiate into activated macrophages, have roles in neuroinflammation and β-amyloid clearance through phagocytosis. In monocytes the function of regulatory variants can be context-specific after immune stimulation. To dissect the variants associated with Alzheimer's disease in the context of monocytes, we utilized data from naïve monocytes and following immune stimulation , in combination with genome-wide association studies of Alzheimer's disease in transcriptome-wide association studies. Of the nine genes with statistically independent transcriptome-wide association signals, seven are located in known Alzheimer's disease risk loci: and The transcriptome-wide association signal for and and the direction of effect replicated in an independent genome-wide association studies. Our analysis identified two novel candidate genes for Alzheimer's disease risk, and . replicated in a transcriptome-wide association study using independent expression weights. and are involved in mitochondrial function and lipid metabolism, respectively. Comparison of transcriptome-wide association study results from monocytes, whole blood and brain showed that the signal for is specific to blood and is specific to LPS stimulated monocytes.
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http://dx.doi.org/10.1093/braincomms/fcab083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087896PMC
April 2021

Multiomics integrative analysis identifies allele-specific blood biomarkers associated to Alzheimer's disease etiopathogenesis.

Aging (Albany NY) 2021 Apr 12;13(7):9277-9329. Epub 2021 Apr 12.

Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Alzheimer's disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analysed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by haplotype ( and ). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterised a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in and AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.
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http://dx.doi.org/10.18632/aging.202950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064208PMC
April 2021

Overdiagnosis of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Systematic Scoping Review.

JAMA Netw Open 2021 04 1;4(4):e215335. Epub 2021 Apr 1.

Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.

Importance: Reported increases in attention-deficit/hyperactivity disorder (ADHD) diagnoses are accompanied by growing debate about the underlying factors. Although overdiagnosis is often suggested, no comprehensive evaluation of evidence for or against overdiagnosis has ever been undertaken and is urgently needed to enable evidence-based, patient-centered diagnosis and treatment of ADHD in contemporary health services.

Objective: To systematically identify, appraise, and synthesize the evidence on overdiagnosis of ADHD in children and adolescents using a published 5-question framework for detecting overdiagnosis in noncancer conditions.

Evidence Review: This systematic scoping review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension for Scoping Reviews and Joanna Briggs Methodology, including the PRISMA-ScR Checklist. MEDLINE, Embase, PsychINFO, and the Cochrane Library databases were searched for studies published in English between January 1, 1979, and August 21, 2020. Studies of children and adolescents (aged ≤18 years) with ADHD that focused on overdiagnosis plus studies that could be mapped to 1 or more framework question were included. Two researchers independently reviewed all abstracts and full-text articles, and all included studies were assessed for quality.

Findings: Of the 12 267 potentially relevant studies retrieved, 334 (2.7%) were included. Of the 334 studies, 61 (18.3%) were secondary and 273 (81.7%) were primary research articles. Substantial evidence of a reservoir of ADHD was found in 104 studies, providing a potential for diagnoses to increase (question 1). Evidence that actual ADHD diagnosis had increased was found in 45 studies (question 2). Twenty-five studies showed that these additional cases may be on the milder end of the ADHD spectrum (question 3), and 83 studies showed that pharmacological treatment of ADHD was increasing (question 4). A total of 151 studies reported on outcomes of diagnosis and pharmacological treatment (question 5). However, only 5 studies evaluated the critical issue of benefits and harms among the additional, milder cases. These studies supported a hypothesis of diminishing returns in which the harms may outweigh the benefits for youths with milder symptoms.

Conclusions And Relevance: This review found evidence of ADHD overdiagnosis and overtreatment in children and adolescents. Evidence gaps remain and future research is needed, in particular research on the long-term benefits and harms of diagnosing and treating ADHD in youths with milder symptoms; therefore, practitioners should be mindful of these knowledge gaps, especially when identifying these individuals and to ensure safe and equitable practice and policy.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.5335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042533PMC
April 2021

The Impact of Complement Genes on the Risk of Late-Onset Alzheimer's Disease.

Genes (Basel) 2021 03 20;12(3). Epub 2021 Mar 20.

UK Dementia Research Institute at Cardiff University, School of Medicine, Cardiff, CF24 4HQ, UK.

Late-onset Alzheimer's disease (LOAD), the most common cause of dementia, and a huge global health challenge, is a neurodegenerative disease of uncertain aetiology. To deliver effective diagnostics and therapeutics, understanding the molecular basis of the disease is essential. Contemporary large genome-wide association studies (GWAS) have identified over seventy novel genetic susceptibility loci for LOAD. Most are implicated in microglial or inflammatory pathways, bringing inflammation to the fore as a candidate pathological pathway. Among the most significant GWAS hits are three complement genes: , encoding the fluid-phase complement inhibitor clusterin; encoding complement receptor 1 (CR1); and recently, encoding the complement enzyme C1s. Complement activation is a critical driver of inflammation; changes in complement genes may impact risk by altering the inflammatory status in the brain. To assess complement gene association with LOAD risk, we manually created a comprehensive complement gene list and tested these in gene-set analysis with LOAD summary statistics. We confirmed associations of and genes with LOAD but showed no significant associations for the complement gene-set when excluding and . No significant association with other complement genes, including , was seen in the IGAP dataset; however, these may emerge from larger datasets.
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http://dx.doi.org/10.3390/genes12030443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003605PMC
March 2021

Searching the Dark Genome for Alzheimer's Disease Risk Variants.

Brain Sci 2021 Mar 6;11(3). Epub 2021 Mar 6.

Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Wales CF24 4HQ, UK.

Sporadic Alzheimer's disease (AD) is a complex genetic disease, and the leading cause of dementia worldwide. Over the past 3 decades, extensive pioneering research has discovered more than 70 common and rare genetic risk variants. These discoveries have contributed massively to our understanding of the pathogenesis of AD but approximately half of the heritability for AD remains unaccounted for. There are regions of the genome that are not assayed by mainstream genotype and sequencing technology. These regions, known as the Dark Genome, often harbour large structural DNA variants that are likely relevant to disease risk. Here, we describe the dark genome and review current technological and bioinformatics advances that will enable researchers to shed light on these hidden regions of the genome. We highlight the potential importance of the hidden genome in complex disease and how these strategies will assist in identifying the missing heritability of AD. Identification of novel protein-coding structural variation that increases risk of AD will open new avenues for translational research and new drug targets that have the potential for clinical benefit to delay or even prevent clinical symptoms of disease.
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http://dx.doi.org/10.3390/brainsci11030332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999247PMC
March 2021

Genetic risk for Alzheimer's disease influences neuropathology via multiple biological pathways.

Brain Commun 2020 12;2(2):fcaa167. Epub 2020 Oct 12.

College of Medicine and Health, University of Exeter, Exeter, Devon, EX2 5DW, UK.

Alzheimer's disease is a highly heritable, common neurodegenerative disease characterized neuropathologically by the accumulation of β-amyloid plaques and tau-containing neurofibrillary tangles. In addition to the well-established risk associated with the locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer's disease. Major challenges in understanding how genetic risk influences the development of Alzheimer's disease are clinical and neuropathological heterogeneity, and the high level of accompanying comorbidities. We report a multimodal analysis integrating longitudinal clinical and cognitive assessment with neuropathological data collected as part of the Brains for Dementia Research study to understand how genetic risk factors for Alzheimer's disease influence the development of neuropathology and clinical performance. Six hundred and ninety-three donors in the Brains for Dementia Research cohort with genetic data, semi-quantitative neuropathology measurements, cognitive assessments and established diagnostic criteria were included in this study. We tested the association of genotype and Alzheimer's disease polygenic risk score-a quantitative measure of genetic burden-with survival, four common neuropathological features in Alzheimer's disease brains (neurofibrillary tangles, β-amyloid plaques, Lewy bodies and transactive response DNA-binding protein 43 proteinopathy), clinical status (clinical dementia rating) and cognitive performance (Mini-Mental State Exam, Montreal Cognitive Assessment). The ε4 allele was significantly associated with younger age of death in the Brains for Dementia Research cohort. Our analyses of neuropathology highlighted two independent pathways from ε4, one where β-amyloid accumulation co-occurs with the development of tauopathy, and a second characterized by direct effects on tauopathy independent of β-amyloidosis. Although we also detected association between ε4 and dementia status and cognitive performance, these were all mediated by tauopathy, highlighting that they are a consequence of the neuropathological changes. Analyses of polygenic risk score identified associations with tauopathy and β-amyloidosis, which appeared to have both shared and unique contributions, suggesting that different genetic variants associated with Alzheimer's disease affect different features of neuropathology to different degrees. Taken together, our results provide insight into how genetic risk for Alzheimer's disease influences both the clinical and pathological features of dementia, increasing our understanding about the interplay between genotype and other genetic risk factors.
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http://dx.doi.org/10.1093/braincomms/fcaa167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750986PMC
October 2020

APOE-ε4-related differences in left thalamic microstructure in cognitively healthy adults.

Sci Rep 2020 11 13;10(1):19787. Epub 2020 Nov 13.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Maindy Road, Cathays, Cardiff, CF24 4HQ, UK.

APOE-ε4 is a main genetic risk factor for developing late onset Alzheimer's disease (LOAD) and is thought to interact adversely with other risk factors on the brain. However, evidence regarding the impact of APOE-ε4 on grey matter structure in asymptomatic individuals remains mixed. Much attention has been devoted to characterising APOE-ε4-related changes in the hippocampus, but LOAD pathology is known to spread through the whole of the Papez circuit including the limbic thalamus. Here, we tested the impact of APOE-ε4 and two other risk factors, a family history of dementia and obesity, on grey matter macro- and microstructure across the whole brain in 165 asymptomatic individuals (38-71 years). Microstructural properties of apparent neurite density and dispersion, free water, myelin and cell metabolism were assessed with Neurite Orientation Density and Dispersion (NODDI) and quantitative magnetization transfer (qMT) imaging. APOE-ε4 carriers relative to non-carriers had a lower macromolecular proton fraction (MPF) in the left thalamus. No risk effects were present for cortical thickness, subcortical volume, or NODDI indices. Reduced thalamic MPF may reflect inflammation-related tissue swelling and/or myelin loss in APOE-ε4. Future prospective studies should investigate the sensitivity and specificity of qMT-based MPF as a non-invasive biomarker for LOAD risk.
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http://dx.doi.org/10.1038/s41598-020-75992-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666117PMC
November 2020

Consequences of health condition labelling: protocol for a systematic scoping review.

BMJ Open 2020 10 26;10(10):e037392. Epub 2020 Oct 26.

Institute for Evidence-Based Healthcare, Bond University Faculty of Health Sciences and Medicine, Gold Coast, Queensland, Australia

Introduction: When health conditions are labelled it is often to classify and communicate a set of symptoms. While diagnostic labelling can provide explanation for an individual's symptoms, it can also impact how individuals and others view those symptoms. Despite existing research regarding the effects of labelling health conditions, a synthesis of these effects has not occurred. We will conduct a systematic scoping review to synthesise the reported consequences and impact of being given a label for a health condition from an individual, societal and health practitioner perspective and explore in what context labelling of health conditions is considered important.

Methods And Analysis: The review will adhere to the Joanna Briggs Methodology for Scoping Reviews. Searches will be conducted in five electronic databases (PubMed, Embase, PsycINFO, Cochrane, CINAHL). Reference lists of included studies will be screened and forward and backward citation searching of included articles will be conducted. We will include reviews and original studies which describe the consequences for individuals labelled with a non-cancer health condition. We will exclude hypothetical research designs and studies focused on the consequences of labelling cancer conditions, intellectual disabilities and/or social attributes. We will conduct thematic analyses for qualitative data and descriptive or meta-analyses for quantitative data where appropriate.

Ethics And Dissemination: Ethical approval is not required for a scoping review. Results will be disseminated via publication in a peer-reviewed journal, conference presentations and lay-person summaries on various online platforms. Findings from this systematic scoping review will identify gaps in current understanding of how, when, why and for whom a diagnostic label is important and inform future research.
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http://dx.doi.org/10.1136/bmjopen-2020-037392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592274PMC
October 2020

Genetic risk of dementia modifies obesity effects on white matter myelin in cognitively healthy adults.

Neurobiol Aging 2020 10 29;94:298-310. Epub 2020 Jun 29.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK. Electronic address:

APOE-ε4 is a major genetic risk factor for late-onset Alzheimer's disease that interacts with other risk factors, but the nature of such combined effects remains poorly understood. We quantified the impact of APOE-ε4, family history (FH) of dementia, and obesity on white matter (WM) microstructure in 165 asymptomatic adults (38-71 years old) using quantitative magnetization transfer and neurite orientation dispersion and density imaging. Microstructural properties of the fornix, parahippocampal cingulum, and uncinate fasciculus were compared with those in motor and whole-brain WM regions. Widespread interaction effects between APOE, FH, and waist-hip ratio were found in the myelin-sensitive macromolecular proton fraction from quantitative magnetization transfer. Among individuals with the highest genetic risk (FH+ and APOE-ε4), obesity was associated with reduced macromolecular proton fraction in the right parahippocampal cingulum, whereas no effects were present for those without FH. Risk effects on apparent myelin were moderated by hypertension and inflammation-related markers. These findings suggest that genetic risk modifies the impact of obesity on WM myelin consistent with neuroglia models of aging and late-onset Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.014DOI Listing
October 2020

The multiplex model of the genetics of Alzheimer's disease.

Nat Neurosci 2020 03 28;23(3):311-322. Epub 2020 Feb 28.

Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.

Genes play a strong role in Alzheimer's disease (AD), with late-onset AD showing heritability of 58-79% and early-onset AD showing over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 50 loci are now implicated for AD, suggesting that AD is a disease of multiple components, as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD heritability has been captured, allowing researchers to calculate the accumulation of AD genetic risk through polygenic risk scores. A polygenic risk score predicts disease with up to 90% accuracy and is an exciting tool in our research armory that could allow selection of those with high polygenic risk scores for clinical trials and precision medicine. It could also allow cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.
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http://dx.doi.org/10.1038/s41593-020-0599-5DOI Listing
March 2020

Exploring women's priorities for the potential consequences of a gestational diabetes diagnosis: A pilot community jury.

Health Expect 2020 06 23;23(3):593-602. Epub 2020 Feb 23.

Institute for Evidence-Based Healthcare, Bond University, Gold Coast, Qld, Australia.

Background: There is no international diagnostic agreement for gestational diabetes mellitus (GDM). In 2014, Australia adopted a new definition and testing procedure. Since then, significantly more women have been diagnosed with GDM but with little difference in health outcomes. We explored the priorities and preferences of women potentially impacted by a GDM diagnosis.

Method: We recruited 15 women from the Gold Coast, Australia, to participate in a pilot community jury (CJ). Over two days, the women deliberated on the following: (a) which important consequences of a diagnosis of GDM should be considered when defining GDM?; (b) what should Australian health practitioners call the condition known as GDM?

Results: Eight women attended the pilot CJ, and their recommendations were a consensus. Women were surprised that the level of risk for physical harms was low but emotional harms were high. The final ranking of important consequences (high to low) was as follows: women's negative emotions; management burden of GDM; overmedicalized pregnancy; minimizing infant risks; improving lifestyle; and macrosomia. To describe the four different clinical states of GDM, the women chose three different labels. One was GDM.

Conclusions: The women from this pilot CJ prioritized the consequences of a diagnosis of GDM differently from clinicians. The current glucose threshold for GDM in Australia is set at a cut-point for adverse risks including macrosomia and neonatal hyperinsulinaemia. Definitions and guideline panels often fail to ask the affected public about their values and preferences. Community voices impacted by health policies should be embedded in the decision-making process.
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http://dx.doi.org/10.1111/hex.13036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321745PMC
June 2020

Women's experiences of a diagnosis of gestational diabetes mellitus: a systematic review.

BMC Pregnancy Childbirth 2020 Feb 7;20(1):76. Epub 2020 Feb 7.

Institute for Evidence-Based Healthcare, Bond University, Gold Coast, Australia.

Background: Gestational diabetes mellitus (GDM) - a transitory form of diabetes induced by pregnancy - has potentially important short and long-term health consequences for both the mother and her baby. There is no globally agreed definition of GDM, but definition changes have increased the incidence in some countries in recent years, with some research suggesting minimal clinical improvement in outcomes. The aim of this qualitative systematic review was to identify the psychosocial experiences a diagnosis of GDM has on women during pregnancy and the postpartum period.

Methods: We searched CINAHL, EMBASE, MEDLINE and PsycINFO databases for studies that provided qualitative data on the psychosocial experiences of a diagnosis of GDM on women across any stage of pregnancy and/or the postpartum period. We appraised the methodological quality of the included studies using the Critical Appraisal Skills Programme Checklist for Qualitative Studies and used thematic analysis to synthesis the data.

Results: Of 840 studies identified, 41 studies of diverse populations met the selection criteria. The synthesis revealed eight key themes: initial psychological impact; communicating the diagnosis; knowledge of GDM; risk perception; management of GDM; burden of GDM; social support; and gaining control. The identified benefits of a GDM diagnosis were largely behavioural and included an opportunity to make healthy eating changes. The identified harms were emotional, financial and cultural. Women commented about the added responsibility (eating regimens, appointments), financial constraints (expensive food, medical bills) and conflicts with their cultural practices (alternative eating, lack of information about traditional food). Some women reported living in fear of risking the health of their baby and conducted extreme behaviours such as purging and starving themselves.

Conclusion: A diagnosis of GDM has wide reaching consequences that are common to a diverse group of women. Threshold cut-offs for blood glucose levels have been determined using the risk of physiological harms to mother and baby. It may also be advantageous to consider the harms and benefits from a psychosocial and a physiological perspective. This may avoid unnecessary burden to an already vulnerable population.
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http://dx.doi.org/10.1186/s12884-020-2745-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006162PMC
February 2020

Author Correction: Fornix white matter glia damage causes hippocampal gray matter damage during age-dependent limbic decline.

Sci Rep 2019 Oct 17;9(1):15164. Epub 2019 Oct 17.

Experimental Psychology, University of Bristol, 12a Priory Road, Bristol, BS8 1TU, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-51737-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795844PMC
October 2019

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.

PLoS One 2019 8;14(7):e0218111. Epub 2019 Jul 8.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218111PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613773PMC
February 2020

Genetic risk for alzheimer disease is distinct from genetic risk for amyloid deposition.

Ann Neurol 2019 09 1;86(3):427-435. Epub 2019 Jul 1.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff.

Objective: Alzheimer disease (AD) is the most common form of dementia and is responsible for a huge and growing health care burden in the developed and developing world. The polygenic risk score (PRS) approach has shown 75 to 84% prediction accuracy of identifying individuals with AD risk.

Methods: In this study, we tested the prediction accuracy of AD, mild cognitive impairment (MCI), and amyloid deposition risks with PRS, including and excluding APOE genotypes in a large publicly available dataset with extensive phenotypic data, the Alzheimer's Disease Neuroimaging Initiative cohort. Among MCI individuals with amyloid-positive status, we examined PRS prediction accuracy in those who converted to AD. In addition, we divided polygenic risk score by biological pathways and tested them independently for distinguishing between AD, MCI, and amyloid deposition.

Results: We found that AD and MCI are predicted by both APOE genotype and PRS (area under the curve [AUC] = 0.82% and 68%, respectively). Amyloid deposition is predicted by APOE only (AUC = 79%). Further progression to AD of individuals with MCI and amyloid-positive status is predicted by PRS over and above APOE (AUC = 67%). In pathway-specific PRS analyses, the protein-lipid complex has the strongest association with AD and amyloid deposition even when genes in the APOE region were removed (p = 0.0055 and p = 0.0079, respectively).

Interpretation: The results showed different pattern of APOE contribution in PRS risk predictions of AD/MCI and amyloid deposition. Our study suggests that APOE mostly contributes to amyloid accumulation and the PRS affects risk of further conversion to AD. ANN NEUROL 2019;86:427-435.
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http://dx.doi.org/10.1002/ana.25530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771864PMC
September 2019

Polygenic risk and hazard scores for Alzheimer's disease prediction.

Ann Clin Transl Neurol 2019 03 18;6(3):456-465. Epub 2019 Feb 18.

MRC Centre for Neuropsychiatric Genetics and Genomics Cardiff University Cardiff United Kingdom.

Objective: Genome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS.

Methods: Quantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs -value thresholds for disease association.

Results: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at  ≤ 0.001. The strongest effect ( = 0.28, SE = 0.04,  = 2.5 × 10) was observed for PRS based upon genome-wide significant SNPs ( ≤ 5 × 10). The strength of association was weaker with less stringent SNP selection thresholds.

Interpretation: Both PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control  ≤ 10, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at > 10, the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).
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http://dx.doi.org/10.1002/acn3.716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414493PMC
March 2019

Developing and applying a deductive coding framework to assess the goals of Citizen/Community Jury deliberations.

Health Expect 2019 06 12;22(3):537-546. Epub 2019 Mar 12.

Faculty of Health Sciences and Medicine, Centre for research in Evidence-Based Practice, Bond University, Robina, Queensland, Australia.

Background: Public participation in health policy decision making is thought to improve the quality of the decisions and enhance their legitimacy. Citizen/Community Juries (CJs) are a form of public participation that aims to elicit an informed community perspective on controversial topics. Reporting standards for CJ processes have already been proposed. However, less clarity exists about the standards for what constitutes a good quality CJ deliberation-we aim to begin to address this gap here.

Methods: We identified the goals that underlie CJs and searched the literature to identify existing frameworks assessing the quality of CJ deliberations. We then mapped the items constituting these frameworks onto the CJ goals; where none of the frameworks addressed one of the CJ goals, we generated additional items that did map onto the goal.

Results: This yielded a single operationalized deductive coding framework, consisting of four deliberation elements and four recommendation elements. The deliberation elements focus on the following: jurors' preferences and values, engagement with each other, referencing expert information and enrichment of the deliberation. The recommendation elements focus on the following: reaching a clear and identifiable recommendation, whether the recommendation directly addresses the CJ question, justification for the recommendation and adoption of societal (rather than individual) perspective. To explore the alignment between this framework and the goals underlying CJs, we mapped the operationalized framework onto the transcripts of a CJ.

Conclusion: Results suggest that framework items map well onto what transpires in an actual CJ deliberation. Further testing of the validity, generalizability and reliability of the framework is planned.
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http://dx.doi.org/10.1111/hex.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543138PMC
June 2019

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

Clinical EFT (Emotional Freedom Techniques) Improves Multiple Physiological Markers of Health.

J Evid Based Integr Med 2019 Jan-Dec;24:2515690X18823691

1 National Institute for Integrative Healthcare, Fulton, CA, USA.

Emotional Freedom Technique (EFT) is an evidence-based self-help therapeutic method and over 100 studies demonstrate its efficacy. However, information about the physiological effects of EFT is limited. The current study sought to elucidate EFTs mechanisms of action across the central nervous system (CNS) by measuring heart rate variability (HRV) and heart coherence (HC); the circulatory system using resting heart rate (RHR) and blood pressure (BP); the endocrine system using cortisol, and the immune system using salivary immunoglobulin A (SigA). The second aim was to measure psychological symptoms. Participants (N = 203) were enrolled in a 4-day training workshop held in different locations. At one workshop (n = 31), participants also received comprehensive physiological testing. Posttest, significant declines were found in anxiety (-40%), depression (-35%), posttraumatic stress disorder (-32%), pain (-57%), and cravings (-74%), all P < .000. Happiness increased (+31%, P = .000) as did SigA (+113%, P = .017). Significant improvements were found in RHR (-8%, P = .001), cortisol (-37%, P < .000), systolic BP (-6%, P = .001), and diastolic BP (-8%, P < .000). Positive trends were observed for HRV and HC and gains were maintained on follow-up, indicating EFT results in positive health effects as well as increased mental well-being.
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http://dx.doi.org/10.1177/2515690X18823691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381429PMC
September 2019

Sex-specific effects of central adiposity and inflammatory markers on limbic microstructure.

Neuroimage 2019 04 5;189:793-803. Epub 2019 Feb 5.

Experimental Psychology, University of Bristol, 12a Priory Road, BS8 1TU, UK.

Midlife obesity is a risk factor of late onset Alzheimer's disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, obesity-related neuroinflammation may contribute to damage in limbic structures important in LOAD. Here, we investigated the hypothesis that systemic inflammation would mediate central obesity related effects on limbic tissue microstructure in 166 asymptomatic individuals (38-71 years old). We employed MRI indices sensitive to myelin and neuroinflammation [macromolecular proton fraction (MPF) and k] from quantitative magnetization transfer (qMT) together with indices from neurite orientation dispersion and density imaging (NODDI) to investigate the effects of central adiposity on the fornix, parahippocampal cingulum, uncinate fasciculus (compared with whole brain white matter and corticospinal tract) and the hippocampus. Central obesity was assessed with the Waist Hip Ratio (WHR) and abdominal visceral and subcutaneous fat area fractions (VFF, SFF), and systemic inflammation with blood plasma concentrations of leptin, adiponectin, C-reactive protein and interleukin 8. Men were significantly more centrally obese and had higher VFF than women. Individual differences in WHR and in VFF were negatively correlated with differences in fornix MPF and k, but not with any differences in neurite microstructure. In women, age mediated the effects of VFF on fornix MPF and k, whilst in men differences in the leptin and adiponectin ratio fully mediated the effect of WHR on fornix MPF. These results suggest that visceral fat related systemic inflammation may damage myelin-related properties of the fornix, a key limbic structure known to be involved in LOAD.
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http://dx.doi.org/10.1016/j.neuroimage.2019.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435101PMC
April 2019

An Australian community jury to consider case-finding for dementia: Differences between informed community preferences and general practice guidelines.

Health Expect 2019 06 3;22(3):475-484. Epub 2019 Feb 3.

Centre for Research in Evidence-Based Practice, Bond University, Gold Coast, Queensland, Australia.

Background: Case-finding for dementia is practised by general practitioners (GPs) in Australia but without an awareness of community preferences. We explored the values and preferences of informed community members around case-finding for dementia in Australian general practice.

Design, Setting And Participants: A before and after, mixed-methods study in Gold Coast, Australia, with ten community members aged 50-70.

Intervention: A 2-day citizen/community jury. Participants were informed by experts about dementia, the potential harms and benefits of case-finding, and ethical considerations.

Primary And Secondary Outcomes: We asked participants, "Should the health system encourage GPs to practice 'case-finding' of dementia in people older than 50?" Case-finding was defined as a GP initiating testing for dementia when the patient is unaware of symptoms. We also assessed changes in participant comprehension/knowledge, attitudes towards dementia and participants' own intentions to undergo case-finding for dementia if it were suggested.

Results: Participants voted unanimously against case-finding for dementia, citing a lack of effective treatments, potential for harm to patients and potential financial incentives. However, they recognized that case-finding was currently practised by Australian GPs and recommended specific changes to the guidelines. Participants increased their comprehension/knowledge of dementia, their attitude towards case-finding became less positive, and their intentions to be tested themselves decreased.

Conclusion: Once informed, community jury participants did not agree case-finding for dementia should be conducted by GPs. Yet their personal intentions to accept case-finding varied. If case-finding for dementia is recommended in the guidelines, then shared decision making is essential.
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http://dx.doi.org/10.1111/hex.12871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543153PMC
June 2019

Fornix white matter glia damage causes hippocampal gray matter damage during age-dependent limbic decline.

Sci Rep 2019 01 31;9(1):1060. Epub 2019 Jan 31.

Experimental Psychology, University of Bristol, 12a Priory Road, Bristol, BS8 1TU, UK.

Aging leads to gray and white matter decline but their causation remains unclear. We explored two classes of models of age and dementia risk related brain changes. The first class of models emphasises the importance of gray matter: age and risk-related processes cause neurodegeneration and this causes damage in associated white matter tracts. The second class of models reverses the direction of causation: aging and risk factors cause white matter damage and this leads to gray matter damage. We compared these models with linear mediation analysis and quantitative MRI indices (from diffusion, quantitative magnetization transfer and relaxometry imaging) of tissue properties in two limbic structures implicated in age-related memory decline: the hippocampus and the fornix in 166 asymptomatic individuals (aged 38-71 years). Aging was associated with apparent glia but not neurite density damage in the fornix and the hippocampus. Mediation analysis supported white matter damage causing gray matter decline; controlling for fornix glia damage, the correlations between age and hippocampal damage disappear, but not vice versa. Fornix and hippocampal differences were both associated with reductions in episodic memory performance. These results suggest that fornix white matter glia damage may cause hippocampal gray matter damage during age-dependent limbic decline.
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http://dx.doi.org/10.1038/s41598-018-37658-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355929PMC
January 2019

Guidelines for the Treatment of PTSD Using Clinical EFT (Emotional Freedom Techniques).

Healthcare (Basel) 2018 Dec 12;6(4). Epub 2018 Dec 12.

School of Psychology, Faculty of Society and Design, Bond University, Robina, Gold Coast, QLD 4229, Australia.

Clinical EFT (Emotional Freedom Techniques) is an evidence-based method that combines acupressure with elements drawn from cognitive and exposure therapies. The approach has been validated in more than 100 clinical trials. Its efficacy for post-traumatic stress disorder (PTSD) has been investigated in a variety of demographic groups including war veterans, victims of sexual violence, the spouses of PTSD sufferers, motor accident survivors, prisoners, hospital patients, adolescents, and survivors of natural and human-caused disasters. Meta-analyses of EFT for anxiety, depression, and PTSD indicate treatment effects that exceed those of both psychopharmacology and conventional psychotherapy. Studies of EFT in the treatment of PTSD show that (a) time frames for successful treatment generally range from four to 10 sessions; (b) group therapy sessions are effective; (c) comorbid conditions such as anxiety and depression improve simultaneously; (d) the risk of adverse events is low; (e) treatment produces physiological as well as psychological improvements; (f) patient gains persist over time; (g) the approach is cost-effective; (h) biomarkers such as stress hormones and genes are regulated; and (i) the method can be adapted to online and telemedicine applications. This paper recommends guidelines for the use of EFT in treating PTSD derived from the literature and a detailed practitioner survey. It has been reviewed by the major institutions providing training or supporting research in the method. The guidelines recommend a stepped-care model, with five treatment sessions for subclinical PTSD, 10 sessions for PTSD, and escalation to intensive psychotherapy or psychopharmacology or both for nonresponsive patients and those with developmental trauma. Group therapy, social support, apps, and online and telemedicine methods also contribute to a successful treatment plan.
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http://dx.doi.org/10.3390/healthcare6040146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316206PMC
December 2018

Increased posterior default mode network activity and structural connectivity in young adult APOE-ε4 carriers: a multimodal imaging investigation.

Neurobiol Aging 2019 01 22;73:82-91. Epub 2018 Sep 22.

Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, Wales, UK.

Young adult APOE-ε4 carriers show increased activity in posterior regions of the default mode network (pDMN), but how this is related to structural connectivity is unknown. Thirty young adults (one half of whom were APOE-ε4 carriers; mean age 20 years) were scanned using both diffusion and functional magnetic resonance imaging. The parahippocampal cingulum bundle (PHCB)-which links the pDMN and the medial temporal lobe-was manually delineated in individual participants using deterministic tractography. Measures of tract microstructure (mean diffusivity and fractional anisotropy) were then extracted from these tract delineations. APOE-ε4 carriers had lower mean diffusivity and higher fractional anisotropy relative to noncarriers in PHCB, but not in a control tract (the inferior longitudinal fasciculus). Furthermore, PHCB microstructure was selectively associated with pDMN (and medial temporal lobe) activity during a scene discrimination task known to be sensitive to Alzheimer's disease. These findings are consistent with a lifespan view of Alzheimer's disease risk, where early-life, connectivity-related changes in specific, vulnerable "hubs" (e.g., pDMN) lead to increased neural activity. Critically, such changes may reflect reduced network efficiency/flexibility in APOE-ε4 carriers, which in itself may portend a faster decline in connectivity over the lifespan and ultimately trigger early amyloid-β deposition in later life.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.08.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261847PMC
January 2019
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