Publications by authors named "Heather Snyder"

55 Publications

Dementia in Latin America: Paving the way toward a regional action plan.

Authors:
Mario Alfredo Parra Sandra Baez Lucas Sedeño Cecilia Gonzalez Campo Hernando Santamaría-García Ivan Aprahamian Paulo Hf Bertolucci Julian Bustin Maria Aparecida Camargos Bicalho Carlos Cano-Gutierrez Paulo Caramelli Marcia L F Chaves Patricia Cogram Bárbara Costa Beber Felipe A Court Leonardo Cruz de Souza Nilton Custodio Andres Damian Myriam de la Cruz Roberta Diehl Rodriguez Sonia Maria Dozzi Brucki Lais Fajersztajn Gonzalo A Farías Fernanda G De Felice Raffaele Ferrari Fabricio Ferreira de Oliveira Sergio T Ferreira Ceres Ferretti Marcio Luiz Figueredo Balthazar Norberto Anizio Ferreira Frota Patricio Fuentes Adolfo M García Patricia J Garcia Fábio Henrique de Gobbi Porto Lissette Duque Peñailillo Henry Willy Engler Irene Maier Ignacio F Mata Christian Gonzalez-Billault Oscar L Lopez Laura Morelli Ricardo Nitrini Yakeel T Quiroz Alejandra Guerrero Barragan David Huepe Fabricio Joao Pio Claudia Kimie Suemoto Renata Kochhann Silvia Kochen Fiona Kumfor Serggio Lanata Bruce Miller Leticia Lessa Mansur Mirna Lie Hosogi Patricia Lillo Jorge Llibre Guerra David Lira Francisco Lopera Adelina Comas José Alberto Avila-Funes Ana Luisa Sosa Claudia Ramos Elisa de Paula França Resende Heather M Snyder Ioannis Tarnanas Jenifer Yokoyama Juan Llibre Juan Felipe Cardona Kate Possin Kenneth S Kosik Rosa Montesinos Sebastian Moguilner Patricia Cristina Lourdes Solis Renata Eloah de Lucena Ferretti-Rebustini Jeronimo Martin Ramirez Diana Matallana Lingani Mbakile-Mahlanza Alyne Mendonça Marques Ton Ronnielly Melo Tavares Eliane C Miotto Graciela Muniz-Terrera Luis Arnoldo Muñoz-Nevárez David Orozco Maira Okada de Oliveira Olivier Piguet Maritza Pintado Caipa Stefanie Danielle Piña Escudero Lucas Porcello Schilling André Luiz Rodrigues Palmeira Mônica Sanches Yassuda Jose Manuel Santacruz-Escudero Rodrigo Bernardo Serafim Jerusa Smid Andrea Slachevsky Cecilia Serrano Marcio Soto-Añari Leonel Tadao Takada Lea Tenenholz Grinberg Antonio Lucio Teixeira Maira Tonidandel Barbosa Dominic Trépel Agustin Ibanez

Alzheimers Dement 2021 02 20;17(2):295-313. Epub 2020 Nov 20.

Cognitive Neuroscience Center (CNC) Buenos Aires, Argentina; Universidad Autonoma del Caribe, Barranquilla, Colombia; Global Brain Health Institute (GBHI), US, Universidad de San Andres, CONICET, Universidad Autonoma del Caribe, Universidad Adolfo Ibanez, UCSF, USA.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.
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http://dx.doi.org/10.1002/alz.12202DOI Listing
February 2021

The chronic neuropsychiatric sequelae of COVID-19: The need for a prospective study of viral impact on brain functioning.

Alzheimers Dement 2021 Jan 5. Epub 2021 Jan 5.

The Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UTHSA, San Antonio, Texas, USA.

Introduction: The increasing evidence of SARS-CoV-2 impact on the central nervous system (CNS) raises key questions on its impact for risk of later life cognitive decline, Alzheimer's disease (AD), and other dementia.

Methods: The Alzheimer's Association and representatives from more than 30 countries-with technical guidance from the World Health Organization-have formed an international consortium to study the short-and long-term consequences of SARS-CoV-2 on the CNS-including the underlying biology that may contribute to AD and other dementias. This consortium will link teams from around the world covering more than 22 million COVID-19 cases to enroll two groups of individuals including people with disease, to be evaluated for follow-up evaluations at 6, 9, and 18 months, and people who are already enrolled in existing international research studies to add additional measures and markers of their underlying biology.

Conclusions: The increasing evidence and understanding of SARS-CoV-2's impact on the CNS raises key questions on the impact for risk of later life cognitive decline, AD, and other dementia. This program of studies aims to better understand the long-term consequences that may impact the brain, cognition, and functioning-including the underlying biology that may contribute to AD and other dementias.
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http://dx.doi.org/10.1002/alz.12255DOI Listing
January 2021

Retinal imaging in Alzheimer's and neurodegenerative diseases.

Alzheimers Dement 2021 01 8;17(1):103-111. Epub 2020 Oct 8.

Medical & Scientific Relations, Alzheimer's Association, Chicago, Illinois.

In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.
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http://dx.doi.org/10.1002/alz.12179DOI Listing
January 2021

Vascular contributions to cognitive impairment and dementia (VCID): A report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop.

Alzheimers Dement 2020 12 8;16(12):1714-1733. Epub 2020 Oct 8.

National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

Vascular contributions to cognitive impairment and dementia (VCID) are characterized by the aging neurovascular unit being confronted with and failing to cope with biological insults due to systemic and cerebral vascular disease, proteinopathy including Alzheimer's biology, metabolic disease, or immune response, resulting in cognitive decline. This report summarizes the discussion and recommendations from a working group convened by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to evaluate the state of the field in VCID research, identify research priorities, and foster collaborations. As discussed in this report, advances in understanding the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors may lead to potential prevention and new treatment strategies to decrease the burden of dementia. Better understanding of the social determinants of health that affect risks for both vascular disease and VCID could provide insight into strategies to reduce racial and ethnic disparities in VCID.
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http://dx.doi.org/10.1002/alz.12157DOI Listing
December 2020

Hepatitis C Virus in the Elderly in the Direct-Acting Antiviral Era: from Diagnosis to Cure.

Curr Treat Options Infect Dis 2020 Aug 11:1-14. Epub 2020 Aug 11.

Department of Internal Medicine, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Division of Hepatology, Northwell Health, 400 Community Drive, Manhasset, NY 11030 USA.

Purpose Of Review: Hepatitis C (HCV) is the most common cause of viral hepatitis in elderly individuals. This patient population previously experienced suboptimal outcomes with interferon-based regimens. Unfortunately, patients aged 65 years and older were underrepresented in phase 2 and 3 clinical trials with newer direct acting antiviral (DAA) therapies. Since the advent of second-generation DAA in 2013, numerous robust real-world experiences highlighting the efficacy and safety of DAA in the elderly have been published. This review article summarizes the cascade of care for hepatitis C from diagnosis to cure from an evidence-based perspective of the aging population.

Recent Finding: In a large study from the Veterans Affairs Healthcare System, the overall sustained virologic response (SVR) of 15,884 patients treated with DAA regimens was 91.2%. These newer therapies remained highly effective in the subset of patients aged 65 years and older with SVR rates above 90%. A Spanish National Registry reported outcomes in patients ≥ 65 years old treated for HCV with oral DAA regimens over a 2-year period. The overall SVR was 94% in the study of 1252 subjects.

Summary: Current real-world data imply DAA treatment regimens remain highly effective and safe in elderly patients when compared to the general population.
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http://dx.doi.org/10.1007/s40506-020-00231-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418288PMC
August 2020

Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease-Opportunities for Therapy.

Alzheimers Dement (Amst) 2020 3;12(1):e12053. Epub 2020 Aug 3.

CODIAK Biosciences Cambridge Massachusetts USA.

Two of the key functions of arteries in the brain are (1) the well-recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri-arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer's disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.
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http://dx.doi.org/10.1002/dad2.12053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396859PMC
August 2020

World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia.

Alzheimers Dement 2020 07 5;16(7):1078-1094. Epub 2020 Jul 5.

Division of Medical and Scientific Relations, Alzheimer's Association, Chicago, Illinois, USA.

Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
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http://dx.doi.org/10.1002/alz.12123DOI Listing
July 2020

Further understanding the connection between Alzheimer's disease and Down syndrome.

Alzheimers Dement 2020 07 16;16(7):1065-1077. Epub 2020 Jun 16.

Alzheimer's Therapeutics Research Institute and Department of Neurology, University of Southern California, Los Angeles, California, USA.

Improved medical care of individuals with Down syndrome (DS) has led to an increase in life expectancy to over the age of 60 years. In conjunction, there has been an increase in age-related co-occurring conditions including Alzheimer's disease (AD). Understanding the factors that underlie symptom and age of clinical presentation of dementia in people with DS may provide insights into the mechanisms of sporadic and DS-associated AD (DS-AD). In March 2019, the Alzheimer's Association, Global Down Syndrome Foundation and the LuMind IDSC Foundation partnered to convene a workshop to explore the state of the research on the intersection of AD and DS research; to identify research gaps and unmet needs; and to consider how best to advance the field. This article provides a summary of discussions, including noting areas of emerging science and discovery, considerations for future studies, and identifying open gaps in our understanding for future focus.
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http://dx.doi.org/10.1002/alz.12112DOI Listing
July 2020

Scientific Advising and Reviewing: On strengthening the bond between the Alzheimer's Association and the scientific community.

Alzheimers Dement 2020 07 19;16(7):1095-1098. Epub 2020 May 19.

Medical & Scientific Relations, Alzheimer's Association, Chicago, Illinois, USA.

From its inception in 1980, advancement of research was one of the primary missions of the Alzheimer's Association (also known as Alzheimer's Disease and Related Disorders Association) in addition to leading in family caregiver support, better care, public education, and awareness. Over the past 30 years, the Association has grown and expanded its engagement with the scientific community. In the past 10 years, its research budget has more than doubled, greatly increasing the number of research grants funded and the number of strategic projects supported. The leadership and members of the Medical and Scientific Advisory Council recognized that the growth of the Alzheimer's Association and the expanded mission of Medical & Scientific Relations Division necessitated a change in the mission and charge of the external scientific advisory function to the Association.
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http://dx.doi.org/10.1002/alz.12059DOI Listing
July 2020

Retinal imaging think tank convened by the Alzheimer's Association to examine its promise in the early detection of Alzheimer's.

Alzheimers Dement 2020 01;16(1):244

Independent Science Writer, Elverson, Pennsylvania, USA.

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http://dx.doi.org/10.1002/alz.12034DOI Listing
January 2020

Transplantation of kidneys from hepatitis C-infected donors to hepatitis C-negative recipients: Single center experience.

Am J Transplant 2019 11 2;19(11):3046-3057. Epub 2019 Aug 2.

James D. Eason Transplant Institute, Methodist University Hospital, Memphis, Tennessee.

Our aim was to evaluate the safety of transplanting kidneys from HCV-infected donors in HCV-uninfected recipients. Data collected from 53 recipients in a single center, observational study included donor and recipient characteristics, liver and kidney graft function, new infections and de novo donor-specific antibodies and renal histology. Treatment with a direct-acting antiviral regimen was initiated when HCV RNA was detected. The mean ± SD age of recipients was 53 ± 11 years, 34% were female, 19% and 79% of recipients were white and African American, respectively. The median and interquartile range (IQR) time between transplant and treatment initiation was 76 (IQR: 68-88) days. All 53 recipients became viremic (genotype: 1a [N = 34], 1b [N = 1], 2 [N = 3], and 3 [N = 15]). The majority (81%) of recipients did not experience clinically significant increases (>3 times higher than upper limit of the normal value) in aminotransferase levels and their HCV RNA levels were in the 5 to 6 log range. One patient developed fibrosing cholestatic hepatitis with complete resolution. All recipients completed antiviral treatment and 100% were HCV RNA-negative and achieved 12-week sustained virologic response. The estimated GFRs at end of treatment and 12-week posttreatment were 67 ± 21 mL/min/1.73 m and 67 ± 17 mL/min/1.73 m , respectively. Four recipients developed acute rejection. Kidney transplantation from HCV-infected donors to HCV-negative recipients should be considered in all eligible patients.
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http://dx.doi.org/10.1111/ajt.15530DOI Listing
November 2019

Tackling gaps in developing life-changing treatments for dementia.

Alzheimers Dement (N Y) 2019 24;5:241-253. Epub 2019 Jun 24.

Dementia Research Institute, UCL, London, UK.

Since the G8 dementia summit in 2013, a number of initiatives have been established with the aim of facilitating the discovery of a disease-modifying treatment for dementia by 2025. This report is a summary of the findings and recommendations of a meeting titled "Tackling gaps in developing life-changing treatments for dementia", hosted by Alzheimer's Research UK in May 2018. The aim of the meeting was to identify, review, and highlight the areas in dementia research that are not currently being addressed by existing initiatives. It reflects the views of leading experts in the field of neurodegeneration research challenged with developing a strategic action plan to address these gaps and make recommendations on how to achieve the G8 dementia summit goals. The plan calls for significant advances in (1) translating newly identified genetic risk factors into a better understanding of the impacted biological processes; (2) enhanced understanding of selective neuronal resilience to inform novel drug targets; (3) facilitating robust and reproducible drug-target validation; (4) appropriate and evidence-based selection of appropriate subjects for proof-of-concept clinical trials; (5) improving approaches to assess drug-target engagement in humans; and (6) innovative approaches in conducting clinical trials if we are able to detect disease 10-15 years earlier than we currently do today.
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http://dx.doi.org/10.1016/j.trci.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597931PMC
June 2019

White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities.

Alzheimers Dement (N Y) 2019 9;5:107-117. Epub 2019 Apr 9.

Molecular & Clinical Sciences Research Institute, St George's University of London and Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.
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http://dx.doi.org/10.1016/j.trci.2019.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461571PMC
April 2019

Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.

Alzheimers Dement 2019 02 13;15(2):292-312. Epub 2018 Dec 13.

Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address:

Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.
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http://dx.doi.org/10.1016/j.jalz.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368893PMC
February 2019

Military-related risk factors for dementia.

Alzheimers Dement 2018 12 8;14(12):1651-1662. Epub 2018 Nov 8.

Medical & Scientific Relations, Alzheimer's Association, Chicago, IL, USA.

Introduction: In recent years, there has been growing discussion to better understand the pathophysiological mechanisms of traumatic brain injury and post-traumatic stress disorder and how they may be linked to an increased risk of neurodegenerative diseases including Alzheimer's disease in veterans.

Methods: Building on that discussion, and subsequent to a special issue of Alzheimer's & Dementia published in June 2014, which focused on military risk factors, the Alzheimer's Association convened a continued discussion of the scientific community on December 1, 2016.

Results: During this meeting, participants presented and evaluated progress made since 2012 and identified outstanding knowledge gaps regarding factors that may impact veterans' risk for later life dementia.

Discussion: The following is a summary of the invited presentations and moderated discussions of both the review of scientific understanding and identification of gaps to inform further investigations.
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http://dx.doi.org/10.1016/j.jalz.2018.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281800PMC
December 2018

Non-alcoholic Fatty Liver Disease: A Review of Anti-diabetic Pharmacologic Therapies.

J Clin Transl Hepatol 2018 Jun 25;6(2):168-174. Epub 2018 Mar 25.

Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN, USA.

Non-alcoholic fatty liver disease (NAFLD), the most common cause of liver disease, affects approximately 75 to 100 million Americans. Patients with concurrent NAFLD and type 2 diabetes mellitus have a higher risk of progressing to advanced fibrosis and non-alcoholic steatohepatitis compared to non-diabetics. Lifestyle modifications, including weight loss, remain the mainstay of treatment for NAFLD, as there are no medications currently indicated for this disease state. Anti-diabetic pharmacologic therapies aimed at improving insulin sensitivity and decreasing insulin production have been studied to determine their potential role in slowing the progression of NAFLD. In this review, we focus on the evidence surrounding anti-diabetic medications and their ability to improve disease progression in patients with NAFLD.
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http://dx.doi.org/10.14218/JCTH.2017.00050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018310PMC
June 2018

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease.

Alzheimers Dement 2018 04;14(4):535-562

Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.
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http://dx.doi.org/10.1016/j.jalz.2018.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958625PMC
April 2018

Impact of Admission Hypertension on Rates of Acute Kidney Injury in Intracerebral Hemorrhage Treated with Intensive Blood Pressure Control.

Neurocrit Care 2018 06;28(3):344-352

Department of Pharmacy, Methodist University Hospital, 1265 Union Avenue, Memphis, TN, 38104, USA.

Background: Current guidelines recommend that rapid systolic blood pressure (SBP) lowering to 140 mmHg may be considered in intracerebral hemorrhage (ICH) patients regardless of initial SBP. However, limited safety data exist in patients presenting with varying degrees of severe hypertension. The purpose of this study was to determine whether there was an increased risk of acute kidney injury (AKI) based upon degree of presentation hypertension in ICH patients whose blood pressure was reduced intensively.

Methods: This retrospective, cohort study evaluated ICH patients treated with intensive blood pressure control (SBP ≤140 mmHg) who presented with three degrees of presentation hypertension: mild (SBP 141-179 mmHg), moderate (SBP 180-219 mmHg), and severe (SBP ≥ 220 mmHg). Univariate analysis of demographics variables, ICH severity, and factors known to impact AKI was conducted between the three groups. Post hoc testing was used to compare differences between specific groups, with a Bonferroni correction adjusting for multiple comparisons. Additionally, we conducted logistic regression analysis to determine whether baseline SBP group independently predicted AKI.

Results: We included 401 patients (177 with mild, 124 with moderate, and 100 with severe hypertension). There was a significant increase in the prevalence of AKI between groups, with the severe group experiencing the highest rate (p < 0.001). The presence of severe hypertension was also found to independently predict AKI development (odds ratio 2.6; p < 0.001).

Conclusion: Our study observed higher rates of AKI in patients presenting with severe hypertension. Further research is needed to determine the most appropriate strategies for managing blood pressure in ICH patients presenting with higher SBP.
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http://dx.doi.org/10.1007/s12028-017-0488-2DOI Listing
June 2018

Improved Outcomes in HCV Patients Following Liver Transplantation During the Era of Direct-Acting Antiviral Agents.

Clin Gastroenterol Hepatol 2018 03 31;16(3):452-453. Epub 2017 Aug 31.

Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California. Electronic address:

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http://dx.doi.org/10.1016/j.cgh.2017.08.020DOI Listing
March 2018

Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers.

Lancet Neurol 2017 08 11;16(8):661-676. Epub 2017 Jul 11.

Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Neurobiology, Care Siences and Society, Centre for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden; European Alzheimer's Disease Consortium.

The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.
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http://dx.doi.org/10.1016/S1474-4422(17)30159-XDOI Listing
August 2017

Efficacy and Safety of Sofosbuvir-Based Direct Acting Antivirals for Hepatitis C in Septuagenarians and Octogenarians.

J Clin Exp Hepatol 2017 Jun 15;7(2):93-96. Epub 2017 Mar 15.

Department of Surgery, Methodist University Hospital Transplant Institute, 1211 Union Ave, Suite 340, Memphis, TN 38104, USA.

Background/aims: Treatment of chronic hepatitis C (HCV) with newer direct acting antiviral (DAA) agents has been highly effective. Unfortunately, patients over 70 years old are underrepresented in studies. Given current recommendations to screen patients born between 1945 and 1965 for HCV, it is essential to determine the efficacy and safety of DAAs within the elderly population. This study aims to evaluate clinical outcomes of patients aged 70 years or older treated for HCV with DAAs at a single tertiary care center.

Methods: We identified 25 patients aged 70 years or older who were treated for HCV with a sofosbuvir-based regimen. Baseline demographics, prior HCV treatment history, HCV treatment regimen, adverse effects, and interruption or discontinuation of therapy were collected. The primary endpoint was sustained virologic response at 12 weeks after end of treatment (SVR12). Secondary outcomes were self-reported side effects, drug interactions, and changes in medical regimen of treated patients.

Results: All patients were genotype 1 (13 1a, 9 1b, 3 unspecified). Seventeen (68%) had cirrhosis including 1 Child's Pugh class B. Fifteen patients were treatment-naïve and 10 previously failed treatment with interferon. Seventeen patients were on ledipasvir/sofosbuvir, 4 on simeprevir/sofosbuvir/ribavirin, and 4 on simeprevir/sofosbuvir. Of 25 patients included, 96% (24/25) patients achieved SVR12. Two patients had a greater than 2 g/dL drop in hemoglobin from baseline and both were on ribavirin. Ribavirin was discontinued in 1 patient. One patient required a change in proton pump inhibitor. No patients discontinued therapy due to side effects.

Conclusions: Patients aged 70 years or older with genotype 1 achieved high rates of sustained virologic response with treatment with newer sofosbuvir-based DAAs without any undue adverse events.
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http://dx.doi.org/10.1016/j.jceh.2017.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478933PMC
June 2017

Letter to the Editor re: Nexus of Cancer & Alzheimer's.

Alzheimers Dement 2017 06 19;13(6):722. Epub 2017 Apr 19.

Division of Medical & Scientific Relations, Alzheimer's Association, Chicago, IL, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jalz.2017.03.006DOI Listing
June 2017

The biomarker-based diagnosis of Alzheimer's disease. 1-ethical and societal issues.

Neurobiol Aging 2017 04;52:132-140

Institute for Ethics, History, and the Humanities, Geneva University Medical School, Switzerland.

There is great interest in the use of biomarkers to assist in the timely identification of Alzheimer's disease (AD) in individuals with mild symptoms. However, the inclusion of AD biomarkers in clinical criteria poses socioethical challenges. The Geneva Task Force for the Roadmap of Alzheimer's Biomarkers was established to deliver a systematic strategic research agenda (aka roadmap) to promote efficient and effective validation of AD biomarkers and to foster their uptake in clinical practice. In this article, we summarize the workshop discussion of the Geneva Task Force "ethical and societal issues" working group, which comprised bioethicists, clinicians, health economists, and representatives of those affected by AD. The working group identified the following key issues that need to be included in the roadmap: improving access to services through timely diagnosis, the need for a diagnostic research protocol before moving to clinical routine, recruitment in diagnostic research protocols in the absence of effective therapy, respect for the autonomy of the individual with mild cognitive impairment in information and consent process and the right not to know biomarkers results, need for counseling programs, disclosure of the diagnosis in a structured environment and the involvement of family members, health policies including the individuals' views and the protection of their interests, and the economic costs for society.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.07.011DOI Listing
April 2017

Alzheimer's disease: The next frontier-Special Report 2017.

Alzheimers Dement 2017 Apr 14;13(4):374-380. Epub 2017 Mar 14.

Division of Medical & Scientific Relations, Alzheimer's Association, Chicago, IL, USA. Electronic address:

In the history of medicine, one means to progress is when we make the decision that our assumptions and definitions of disease are no longer consistent with the scientific evidence, and no longer serve our health care needs. The arc of scientific progress is now requiring a change in how we diagnose Alzheimer's disease. Both the National Institute on Aging-Alzheimer's Association (NIA-AA) 2011 workgroup and the International Work Group (IWG) have proposed guidelines that use detectable measures of biological changes in the brain, commonly known as biological markers, or biomarkers, as part of the diagnosis. This Special Report examines how the development and validation of Alzheimer's disease biomarkers-including those detectable in the blood or cerebral spinal fluid, or through neuroimaging-is a top research priority. This has the potential to markedly change how we diagnose Alzheimer's disease and, as a result, how we count the number of people with this disease. As research advances a biomarker-based method for diagnosis and treatment at the earliest stages of Alzheimer's disease, we envision a future in which Alzheimer's disease is placed in the same category as other chronic diseases, such as cardiovascular disease or diabetes, which can be readily identified with biomarkers and treated before irrevocable disability occurs.
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http://dx.doi.org/10.1016/j.jalz.2017.02.006DOI Listing
April 2017

Pharmacologic Treatment of Alcoholic Hepatitis: Examining Outcomes Based on Disease Severity Stratification.

J Clin Exp Hepatol 2016 Dec 18;6(4):275-281. Epub 2016 Jul 18.

Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Division of Surgery, Transplant Hepatology, 1265 Union Avenue, Memphis, TN 38104, USA.

Objectives: Maddrey discriminant function (MDF) score is a measure of disease prognosis in alcoholic hepatitis (AH) used to identify patients at highest risk of mortality and determine the need for initiation of pharmacologic treatment. The purpose of this study was to evaluate the effects of pharmacologic therapy for hospitalized AH patients as stratified by MDF score.

Methods: A retrospective review of patients with an AH diagnosis admitted to a Methodist LeBonheur Healthcare adult hospital between 06/2009 and 06/2014 was conducted. Patients ≥18 years of age with an ICD-9 code for AH were evaluated.

Results: Of the 493 patients screened, 234 met the inclusion criteria, comprised of 62 patients with an MDF ≥ 32 (treatment,  = 42 vs. no treatment,  = 20) and 172 patients with an MDF < 32 (treatment,  = 15 vs. no treatment,  = 157). For the patients with an MDF ≥ 32, there was no statistically significant difference between the treatment group vs. non-treatment group regarding 28-day mortality (31% vs. 11%, respectively;  = 0.18) and 6-month mortality (45% treatment vs. 38% non-treatment;  = 0.75). For the patients with an MDF <32, there was no statistically significant difference between the treatment group vs. non-treatment group regarding 28-day mortality (0% vs. 7%, respectively;  > 0.99) and 6-month mortality (11% treatment vs. 13% non-treatment;  > 0.99). There was no difference in incidence of acute kidney injury, hepatorenal syndrome, development of infection or hepatic encephalopathy between the treatment vs. non-treatment groups.

Conclusions: Pharmacologic treatment showed no survival benefit, regardless of disease severity. Given the mortality risk seen in mild-moderate AH patients not receiving treatment and concern for a possible treatment ceiling effect in severe AH patients, more data are needed to adequately assess the utility of MDF in selecting appropriate candidates for AH treatment.
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http://dx.doi.org/10.1016/j.jceh.2016.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157883PMC
December 2016

Exploring the nexus of Alzheimer's disease and related dementias with cancer and cancer therapies: A convening of the Alzheimer's Association & Alzheimer's Drug Discovery Foundation.

Alzheimers Dement 2017 Mar 18;13(3):267-273. Epub 2016 Dec 18.

Professor of Psychiatry, Neurology, and Epidemiology, University of Pittsburgh School of Medicine and Graduate School of Public Health, Pittsburgh, PA, USA.

Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer's disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened a one-day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations, and partnerships for future action.
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http://dx.doi.org/10.1016/j.jalz.2016.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548424PMC
March 2017

Perspective from the Alzheimer's Association: Neuroimaging Professional Interest Area of ISTAART continues impact on the field.

Alzheimers Dement (Amst) 2016 27;5:1-2. Epub 2016 Oct 27.

Medical and Scientific Relations, Alzheimer's Association, Chicago, IL, USA.

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http://dx.doi.org/10.1016/j.dadm.2016.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107647PMC
October 2016

Belatacept conversion in African American kidney transplant recipients with severe renal dysfunction.

SAGE Open Med Case Rep 2016 2;4:2050313X16674865. Epub 2016 Nov 2.

Methodist University Hospital Transplant Institute and University of Tennessee Health Science Center, Memphis, TN, USA.

Objectives: Conversion from calcineurin inhibitor-based maintenance immunosuppression to belatacept in kidney transplant recipients has been demonstrated to improve renal function while maintaining efficacy against rejection. However, conversion studies to date have excluded patients with an estimated glomerular filtration rate < 35 mL/min/1.73 m.

Methods: We describe two patients with an estimated glomerular filtration rate < 30 mL/min/1.73 m who underwent conversion from maintenance calcineurin inhibitor to belatacept.

Results: Both patients experienced improvement in renal function following conversion.

Conclusions: These results suggest that patients with more severe degrees of allograft impairment may benefit from conversion of maintenance calcineurin inhibitor to belatacept-based immunosuppression. Larger, randomized studies are warranted to evaluate the impact of such an approach.
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http://dx.doi.org/10.1177/2050313X16674865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098796PMC
November 2016

Guidelines to improve animal study design and reproducibility for Alzheimer's disease and related dementias: For funders and researchers.

Alzheimers Dement 2016 11;12(11):1177-1185

Research Division, Alzheimer's Research UK, Cambridge, UK.

The reproducibility of laboratory experiments is fundamental to the scientific process. There have been increasing reports regarding challenges in reproducing and translating preclinical experiments in animal models. In Alzheimer's disease and related dementias, there have been similar reports and growing interest from funding organizations, researchers, and the broader scientific community to set parameters around experimental design, statistical power, and reporting requirements. A number of efforts in recent years have attempted to develop standard guidelines; however, these have not yet been widely implemented by researchers or by funding agencies. A workgroup of the International Alzheimer's disease Research Funder Consortium, a group of over 30 research funding agencies from around the world, worked to compile the best practices identified in these prior efforts for preclinical biomedical research. This article represents a consensus of this work group's review and includes recommendations for researchers and funding agencies on designing, performing, reviewing, and funding preclinical research studies.
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http://dx.doi.org/10.1016/j.jalz.2016.07.001DOI Listing
November 2016

Research priorities to reduce the global burden of dementia by 2025.

Lancet Neurol 2016 Nov 11;15(12):1285-1294. Epub 2016 Oct 11.

Department of Mental Health and Substance Abuse, World Health Organization, Geneva, Switzerland. Electronic address:

At the First WHO Ministerial Conference on Global Action Against Dementia in March, 2015, 160 delegates, including representatives from 80 WHO Member States and four UN agencies, agreed on a call for action to reduce the global burden of dementia by fostering a collective effort to advance research. To drive this effort, we completed a globally representative research prioritisation exercise using an adapted version of the Child Health and Nutrition Research Initiative method. We elicited 863 research questions from 201 participants and consolidated these questions into 59 thematic research avenues, which were scored anonymously by 162 researchers and stakeholders from 39 countries according to five criteria. Six of the top ten research priorities were focused on prevention, identification, and reduction of dementia risk, and on delivery and quality of care for people with dementia and their carers. Other priorities related to diagnosis, biomarkers, treatment development, basic research into disease mechanisms, and public awareness and understanding of dementia. Research priorities identified by this systematic international process should be mapped onto the global dementia research landscape to identify crucial gaps and inform and motivate policy makers, funders, and researchers to support and conduct research to reduce the global burden of dementia. Efforts are needed by all stakeholders, including WHO, WHO Member States, and civil society, to continuously monitor research investments and progress, through international platforms such as a Global Dementia Observatory. With established research priorities, an opportunity now exists to translate the call for action into a global dementia action plan to reduce the global burden of dementia.
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http://dx.doi.org/10.1016/S1474-4422(16)30235-6DOI Listing
November 2016