Showing papers in "Alzheimers & Dementia in 2017"

The worldwide costs of dementia 2015 and comparisons with 2010

Abstract: Introduction In 2010, Alzheimer's Disease International presented estimates of the global cost of illness (COI) of dementia. Since then, new studies have been conducted, and the number of people with dementia has increased. Here, we present an update of the global cost estimates. Methods This is a societal, prevalence-based global COI study. Results The worldwide costs of dementia were estimated at United States (US) $818 billion in 2015, an increase of 35% since 2010; 86% of the costs occur in high-income countries. Costs of informal care and the direct costs of social care still contribute similar proportions of total costs, whereas the costs in the medical sector are much lower. The threshold of US $1 trillion will be crossed by 2018. Discussion Worldwide costs of dementia are enormous and still inequitably distributed. The increase in costs arises from increases in numbers of people with dementia and in increases in per person costs.

Defining imaging biomarker cut points for brain aging and Alzheimer's disease

Abstract: Introduction Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness. Methods We examined five methods for determining cut points. Results The reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of cognitively impaired versus young clinically normal (CN) methods labeled the most people abnormal and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of cognitively impaired versus age-matched CN method labeled fewer people abnormal. Discussion In the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of cognitively impaired versus young CN method and base conservative cut points on the accuracy of cognitively impaired versus age-matched CN method.

Consensus classification of posterior cortical atrophy

Abstract: Introduction A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. Methods Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web-based quantitative survey regarding symptom frequency and the conceptualization of PCA. Results A three-level classification framework for PCA is described comprising both syndrome- and disease-level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA-AD], Lewy body disease [PCA-LBD], corticobasal degeneration [PCA-CBD], prion disease [PCA-prion]) provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome-level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum. Discussion There was strong agreement regarding the definition of the core clinico-radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single-center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios (e.g., behavioral interventions, pharmacological trials), and provide a foundation for future collaborative work.

Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis

Abstract: Introduction Cerebrospinal fluid analysis and other measurements of amyloidosis, such as amyloid-binding positron emission tomography studies, are limited by cost and availability. There is a need for a more practical amyloid β (Aβ) biomarker for central nervous system amyloid deposition. Methods We adapted our previously reported stable isotope labeling kinetics protocol to analyze the turnover kinetics and concentrations of Aβ38, Aβ40, and Aβ42 in human plasma. Results Aβ isoforms have a half-life of approximately 3 hours in plasma. Aβ38 demonstrated faster turnover kinetics compared with Aβ40 and Aβ42. Faster fractional turnover of Aβ42 relative to Aβ40 and lower Aβ42 and Aβ42/Aβ40 concentrations in amyloid-positive participants were observed. Discussion Blood plasma Aβ42 shows similar amyloid-associated alterations as we have previously reported in cerebrospinal fluid, suggesting a blood-brain transportation mechanism of Aβ. The stability and sensitivity of plasma Aβ measurements suggest this may be a useful screening test for central nervous system amyloidosis.

The effect of serum factors from patients with/without essential hypertensioin on membrane receptors from rat cerebral cortex vascular and cardiac muscle cells

Abstract: between CSF levels of RAS components and AD biomarkers. Methods: This study included 18 patients with probable AD recruited from the Behavioral and Cognitive Neurology Clinic of the Universidade Federal de Minas Gerais (UFMG), Brazil. A control group composed by 10 subjects undergoing lumbar puncture for anesthetic purpose was also enrolled. These subjects had no history of neurological and/or psychiatric disorders. After collection, CSF samples were centrifuged at 1,800 g for 10 minutes (40C) and stored at -800C until biomarker analysis. Ab40, Ab42, total tau (hTau), and phosphorylated-tau (pTau) were measured by enzyme-linked immunosorbent assay (ELISA) with commercially available kits (Innogenetics/Fujirebio, Gent, Belgium). Angiotensin (Ang) II, Ang-(1-7), ACE and ACE2 levels were also measured by ELISA according to the procedures supplied by the manufacturer (MyBioSource, San Diego, CA, USA). Results: All patients with AD met the CSF criteria for biomarker-based diagnosis, (i.e., IATI < 0.8; hTau/ Ab42 ratio > 0.52 and pTau/Ab42 ratio >0.08). Accordingly, we found decreased levels of Ab40 and Ab42, and increased levels of hTau and pTau in the CSF of patients with AD in comparison with controls (Table 1). Ang II and Ang-(1-7) were not detected in the CSF samples. Patients with AD presented decreased levels of ACE, but similar levels of ACE2 when compared with controls (Table 1; Fig.1A). Among patients with AD, ACE levels correlated positively with Ab42 levels (Fig.1B). Conclusions: CSF levels of ACE are reduced in AD, correlating with Ab42 levels. Our results strengthen the hypothesis that ACE is associated with amyloidb pathology in AD.

Implementation of subjective cognitive decline criteria in research studies.

Abstract: Introduction Subjective cognitive decline (SCD) manifesting before clinical impairment could serve as a target population for early intervention trials in Alzheimer's disease (AD). A working group, the Subjective Cognitive Decline Initiative (SCD-I), published SCD research criteria in the context of preclinical AD. To successfully apply them, a number of issues regarding assessment and implementation of SCD needed to be addressed. Methods Members of the SCD-I met to identify and agree on topics relevant to SCD criteria operationalization in research settings. Initial ideas and recommendations were discussed with other SCD-I working group members and modified accordingly. Results Topics included SCD inclusion and exclusion criteria, together with the informant's role in defining SCD presence and the impact of demographic factors. Discussion Recommendations for the operationalization of SCD in differing research settings, with the aim of harmonization of SCD measurement across studies are proposed, to enhance comparability and generalizability across studies.

Metabolic network failures in Alzheimer's disease: A biochemical road map

Abstract: Introduction The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. Methods Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. Results Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ 1–42 , tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease. Discussion Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.

Systematic review of dementia prevalence and incidence in United States race/ethnic populations

Abstract: Objective To identify incidence and prevalence of dementia in racial and ethnic populations in the United States. Methods A systematic review of literature. Results A total of 1215 studies were reviewed; 114 were included. Dementia prevalence rates reported for age 65+ years from a low of 6.3% in Japanese Americans, 12.9% in Caribbean Hispanic Americans, 12.2% in Guamanian Chamorro and ranged widely in African Americans from 7.2% to 20.9%. Dementia annual incidence for African American (mean = 2.6%; SD=1%; range, 1.4%–5.5%) and Caribbean Hispanic populations were significantly higher (mean, 3.6%; SD, 1.2%; range, 2.3%–5.3%) than Mexican American and Japanese Americans and non-Latino white populations (0.8%–2.7%), P Conclusions Data are needed for American Indian, most Asian, and Pacific Islander populations. Disaggregation of large race/ethnic classifications is warranted due to within-population heterogeneity in incidence and prevalence. African American and Caribbean Hispanic studies showed higher incidence of dementia. A nationwide approach is needed to identify communities at high risk and to tailor culturally appropriate services accordingly.

Calcium Hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis

Abstract: This article updates the Calcium Hypothesis of Alzheimer's disease and brain aging on the basis of emerging evidence since 1994 (The present article, with the subtitle “New evidence for a central role of Ca2+ in neurodegeneration,” includes three appendices that provide context and further explanations for the rationale for the revisions in the updated hypothesis—the three appendices are as follows: Appendix I “Emerging concepts on potential pathogenic roles of [Ca2+],” Appendix II “Future studies to validate the central role of dysregulated [Ca2+] in neurodegeneration,” and Appendix III “Epilogue: towards a comprehensive hypothesis.”) (Marx J. Fresh evidence points to an old suspect: calcium. Science 2007; 318:384–385). The aim is not only to re‐evaluate the original key claims of the hypothesis with a critical eye but also to identify gaps in knowledge required to validate relevant claims and delineate additional studies and/or data that are needed. Some of the key challenges for this effort included examination of questions regarding (1) the temporal and spatial relationships of molecular mechanisms that regulate neuronal calcium ion (Ca2+), (2) the role of changes in concentration of calcium ion [Ca2+] in various subcellular compartments of neurons, (3) how alterations in Ca2+ signaling affect the performance of neurons under various conditions, ranging from optimal functioning in a healthy state to conditions of decline and deterioration in performance during aging and in disease, and (4) new ideas about the contributions of aging, genetic, and environmental factors to the causal relationships between dysregulation of [Ca2+] and the functioning of neurons (see Appendices I and II). The updated Calcium Hypothesis also includes revised postulates that are intended to promote further crucial experiments to confirm or reject the various predictions of the hypothesis (see Appendix III).

Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery

Abstract: Introduction Alzheimer's disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstem's locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]). Methods The methods include unbiased stereological analyses in human brainstems to estimate LC volume and neuronal population in controls and individuals across all AD stages. Results As the Braak stage increases by 1 unit, the LC volume decreases by 8.4%. Neuronal loss started only midway through AD progression. Age-related changes spare the LC. Discussion The long gap between NFT accumulation and neuronal loss suggests that a second trigger may be necessary to induce neuronal death in AD. Imaging studies should determine whether LC volumetry can replicate the stage-wise atrophy observed here and how these changes are specific to AD. LC volumetry may develop into a screening biomarker for selecting high-yield candidates to undergo expensive and less accessible positron emission tomography scans and to monitor AD progression from presymptomatic stages.

The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement

Abstract: Introduction The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI-3, which began on August 1, 2016, is a 5-year renewal of the current ADNI-2 study. Methods ADNI-3 will follow current and additional subjects with normal cognition, mild cognitive impairment, and AD using innovative technologies such as tau imaging, magnetic resonance imaging sequences for connectivity analyses, and a highly automated immunoassay platform and mass spectroscopy approach for cerebrospinal fluid biomarker analysis. A Systems Biology/pathway approach will be used to identify genetic factors for subject selection/enrichment. Amyloid positron emission tomography scanning will be standardized using the Centiloid method. The Brain Health Registry will help recruit subjects and monitor subject cognition. Results Multimodal analyses will provide insight into AD pathophysiology and disease progression. Discussion ADNI-3 will aim to inform AD treatment trials and facilitate development of AD disease-modifying treatments.

Factors associated with the quality of life of family carers of people with dementia: A systematic review

Abstract: Introduction Family carers of people with dementia are their most important support in practical, personal, and economic terms. Carers are vital to maintaining the quality of life (QOL) of people with dementia. This review aims to identify factors related to the QOL of family carers of people with dementia. Methods Searches on terms including "carers," "dementia," "family," and "quality of life" in research databases. Findings were synthesized inductively, grouping factors associated with carer QOL into themes. Results A total of 909 abstracts were identified. Following screening, lateral searches, and quality appraisal, 41 studies ( n = 5539) were included for synthesis. A total of 10 themes were identified: demographics; carer–patient relationship; dementia characteristics; demands of caring; carer health; carer emotional well-being; support received; carer independence; carer self-efficacy; and future. Discussion The quality and level of evidence supporting each theme varied. We need further research on what factors predict carer QOL in dementia and how to measure it.

Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic.

Abstract: The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.

The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model.

Abstract: Introduction The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer's disease in autosomal dominant Alzheimer's disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation (NexGen) prevention trial. Methods In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the National Institutes of Health, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen prevention trial. Results Our expanded trial toolbox consists of a disease progression model for ADAD, primary end point DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. Conclusion These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD.

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials

Abstract: Introduction The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. Methods We used standard searches to find publications using ADNI data. Results (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and surrogate outcome measures using longitudinal structural magnetic resonance imaging may further reduce clinical trial cost and duration; (11) Advances in machine learning techniques such as neural networks have improved diagnostic and prognostic accuracy especially in challenges involving MCI subjects; and (12) Network connectivity measures and genetic variants show promise in multimodal classification and some classifiers using single modalities are rivaling multimodal classifiers. Discussion Taken together, these studies fundamentally deepen our understanding of AD progression and its underlying genetic basis, which in turn informs and improves clinical trial design.

[ec-03–02]: cryo-em structures of tau filaments from alzheimer's disease brain

Abstract: not available. TUESDAY, JULY 18, 2017

Prevalence of dementia subtypes in United States Medicare fee-for-service beneficiaries, 2011–2013

Abstract: Introduction Rapid growth of the older adult population requires greater epidemiologic characterization of dementia. We developed national prevalence estimates of diagnosed dementia and subtypes in the highest risk United States (US) population. Methods We analyzed Centers for Medicare & Medicaid administrative enrollment and claims data for 100% of Medicare fee-for-service beneficiaries enrolled during 2011–2013 and age ≥68 years as of December 31, 2013 (n = 21.6 million). Results Over 3.1 million (14.4%) beneficiaries had a claim for a service and/or treatment for any dementia subtype. Dementia not otherwise specified was the most common diagnosis (present in 92.9%). The most common subtype was Alzheimer's (43.5%), followed by vascular (14.5%), Lewy body (5.4%), frontotemporal (1.0%), and alcohol induced (0.7%). The prevalence of other types of diagnosed dementia was 0.2%. Discussion This study is the first to document concurrent prevalence of primary dementia subtypes among this US population. The findings can assist in prioritizing dementia research, clinical services, and caregiving resources.

Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study

Abstract: Introduction Small vessel disease (SVD) is a common contributor to dementia Subtle blood-brain barrier (BBB) leakage may be important in SVD-induced brain damage Methods We assessed imaging, clinical variables, and cognition in patients with mild (ie, nondisabling) ischemic lacunar or cortical stroke We analyzed BBB leakage, interstitial fluid, and white matter integrity using multimodal tissue-specific spatial analysis around white matter hyperintensities (WMH) We assessed predictors of 1 year cognition, recurrent stroke, and dependency Results In 201 patients, median age 67 (range 34–97), BBB leakage, and interstitial fluid were higher in WMH than normal-appearing white matter; leakage in normal-appearing white matter increased with proximity to WMH ( P P = 033), age ( P = 03), and hypertension ( P Discussion BBB leakage increases in normal-appearing white matter with WMH and predicts worsening cognition Interventions to reduce BBB leakage may prevent SVD-associated dementia

Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses

Abstract: Introduction Dementia is a heterogeneous neurodegenerative disease, whose etiology results from a complex interplay between environmental and genetic factors. Methods We searched PubMed to identify meta-analyses of observational studies that examined associations between nongenetic factors and dementia. We estimated the summary effect size using random-effects and fixed-effects model, the 95% CI, and the 95% prediction interval. We assessed the between-study heterogeneity (I-square), evidence of small-study effects, and excess significance. Results A total of 76 unique associations were examined. By applying standardized criteria, seven associations presented convincing evidence. These associations pertained to benzodiazepines use, depression at any age, late-life depression, and frequency of social contacts for all types of dementia; late-life depression for Alzheimer's disease; and type 2 diabetes mellitus for vascular dementia and Alzheimer's disease. Discussion Several risk factors present substantial evidence for association with dementia and should be assessed as potential targets for interventions, but these associations may not necessarily be causal.

Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation

Abstract: Introduction TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial. Methods We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes. Results We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte-derived dendritic cells. Discussion Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.

Apathy associated with neurocognitive disorders: Recent progress and future directions

Abstract: Introduction Apathy is common in neurocognitive disorders (NCDs) such as Alzheimer's disease and mild cognitive impairment. Although the definition of apathy is inconsistent in the literature, apathy is primarily defined as a loss of motivation and decreased interest in daily activities. Methods The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Syndromes Professional Interest Area (NPS-PIA) Apathy workgroup reviewed the latest research regarding apathy in NCDs. Results Progress has recently been made in three areas relevant to apathy: (1) phenomenology, including the use of diagnostic criteria and novel instruments for measurement, (2) neurobiology, including neuroimaging, neuropathological and biomarker correlates, and (3) interventions, including pharmacologic, nonpharmacologic, and noninvasive neuromodulatory approaches. Discussion Recent progress confirms that apathy has a significant impact on those with major NCD and those with mild NCDs. As such, it is an important target for research and intervention.

Transethnic genome-wide scan identifies novel Alzheimer's disease loci

Abstract: Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests ( P −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE e4 allele with NFIC SNP. We also obtained GWS evidence ( P −6 ) for gene-based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

The Vascular Impairment of Cognition Classification Consensus Study

Abstract: Introduction Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment. Methods The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines. Results VICCCS had a mean of 122 (98–153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge. Discussion VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research.

Subjective cognitive decline in cognitively normal elders from the community or from a memory clinic: Differential affective and imaging correlates.

Abstract: Introduction Subjective cognitive decline (SCD) could indicate preclinical Alzheimer's disease, but the existing literature is confounded by heterogeneous approaches to studying SCD. We assessed the differential cognitive, affective, and neuroimaging correlates of two aspects of SCD: reporting high cognitive difficulties on a self-rated questionnaire versus consulting at a memory clinic. Methods We compared 28 patients from a memory clinic with isolated SCD, 35 community-recruited elders with similarly high levels of self-reported cognitive difficulties, and 35 community-recruited controls with low self-reported cognitive difficulties. Results Increased anxiety and amyloid β deposition were observed in both groups with high self-reported difficulties, whereas subclinical depression and (hippocampal) atrophy were specifically associated with medical help seeking. Cognitive tests showed no group differences. Discussion These results further validate the concept of SCD in both community- and clinic-based groups. Yet, recruitment methods influence associated biomarkers and affective symptomatology, highlighting the heterogeneous nature of SCD depending on study characteristics.

Dysregulation of lipids in Alzheimer's disease and their role as potential biomarkers.

Abstract: The brain is highly enriched in lipids, and an intensive study of these lipids may be informative, not only of normal brain function but also of changes with age and in disease. In recent years, the development of highly sensitive mass spectrometry platforms and other high-throughput technologies has enabled the discovery of complex changes in the entire lipidome. This lipidomics approach promises to be a particularly useful tool for identifying diagnostic biomarkers for early detection of age-related neurodegenerative disease, such as Alzheimer's disease (AD), which has till recently been limited to protein- and gene-centric approaches. This review highlights known lipid changes affecting the AD brain and presents an update on the progress of lipid biomarker research in AD. Important considerations for designing large-scale lipidomics experiments are discussed to help standardize findings across different laboratories, as well as challenges associated with moving toward clinical application.

Detecting cognitive changes in preclinical Alzheimer's disease: A review of its feasibility.

Abstract: Significant progress has been made in characterizing the biological changes occurring in preclinical Alzheimer's disease (AD). Cognitive dysfunction has been viewed, however, as a late-stage phenomenon, despite increasing evidence that changes may be detected in the decades preceding dementia. In the absence of comprehensive evidence-based guidelines for preclinical cognitive assessment, longitudinal cohort and neuroimaging studies have been reviewed to determine the temporal order and brain biomarker correlates of specific cognitive functions. Episodic memory decline was observed to be the most salient cognitive function, correlating with high levels of amyloid deposition and hypoconnectivity across large-scale brain networks. Prospective studies point to early decline in both episodic and semantic memory processing as well as executive functions in the predementia period. The cognitive tests have, however, been principally those used to diagnose dementia. New procedures are required which target more finely the medial temporal lobe subregions first affected by clinically silent AD pathology.

Early and late change on the preclinical Alzheimer's cognitive composite in clinically normal older individuals with elevated amyloid β

Abstract: Introduction Sensitive detection of cognitive decline over the course of preclinical Alzheimer's disease is critical as the field moves toward secondary prevention trials. Methods We examined amyloid β (Aβ)-related change in several variations of the preclinical Alzheimer cognitive composite (PACC) and each individual PACC component in clinically normal (CN) older participants in the Harvard Aging Brain Study. We then examined the PACC variations in the Alzheimer's Disease Cooperative Study Prevention Instrument Study as a replication cohort. Results Aβ+ CN individuals demonstrated longitudinal decline on all individual PACC components and all PACC variations. Aβ group differences emerged earlier when Free and Cued Selective Reminding Test Free Recall was included in the PACC. PACC decline was associated with Clinical Dementia Rating progression. Discussion This independent data set and a replication cohort confirm the ability of the PACC to capture both early and late cognitive decline during the preclinical stages of Alzheimer's disease, which may prove advantageous in the prevention trial design.

Association of blood lipids with Alzheimer's disease: A comprehensive lipidomics analysis

Abstract: Introduction The aim of this study was to (1) replicate previous associations between six blood lipids and Alzheimer's disease (AD) (Proitsi et al 2015) and (2) identify novel associations between lipids, clinical AD diagnosis, disease progression and brain atrophy (left/right hippocampus/entorhinal cortex). Methods We performed untargeted lipidomic analysis on 148 AD and 152 elderly control plasma samples and used univariate and multivariate analysis methods. Results We replicated our previous lipids associations and reported novel associations between lipids molecules and all phenotypes. A combination of 24 molecules classified AD patients with >70% accuracy in a test and a validation data set, and we identified lipid signatures that predicted disease progression (R 2 = 0.10, test data set) and brain atrophy (R 2 ≥ 0.14, all test data sets except left entorhinal cortex). We putatively identified a number of metabolic features including cholesteryl esters/triglycerides and phosphatidylcholines. Discussion Blood lipids are promising AD biomarkers that may lead to new treatment strategies.

Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia

Abstract: This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β 1–42 , tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided