Caregivers' concerns and supports needed to care for adults with Down syndrome.

Research regarding caregivers for individuals with Down syndrome mainly focuses on outcomes for the pediatric population and not on the experience of caregivers themselves. Our objective was to understand caregiver-reported experiences and concerns for themselves and the individual they care for through a survey of caregivers of adults with Down syndrome. We conducted a survey of N = 438 caregivers of adults with Down syndrome and asked about the perspectives of the respondents surrounding caregiving and demographics. The most common concerns among caregivers were planning for future needs (72.1%) and what happens when they (the caregiver) are gone (68.3%). Concerns they had for the individual they cared for were employment (63.2%) and friendships/relationships (63.2%). We found no significant difference in responses based on caregiver education level. Our survey identified six themes for the feedback about what clinical and research professionals should know to better serve individuals with Down syndrome, their families, and those who support them. Many caregivers discussed topics including healthcare, coordination, competence, and ability. More efforts for research into the caregiver experience for adults with Down syndrome are needed.

Caregivers evaluate independence in individuals with Down syndrome.

Independence is both a sense of autonomy and self-reliance coupled with the skills to complete tasks without assistance. Questionnaire of caregivers of individuals with Down syndrome asked about factors related to independence on six topics: safety, communication, self-care, daily living, social/leisure, and vocational/employment. Responses from 408 caregivers to an independence questionnaire were received, and summarized using means and frequencies. Top goals by topic were safety from sexual abuse, communicating wants and needs, toileting independently, living independently/semi-independently, engaging in leisure time appropriately, and reading and writing. Independence is a complex, multifactorial phenomenon which varies among individuals with DS.

Committee on High-quality Alzheimer's Disease Studies (CHADS) consensus report.

BACKGROUND: Consensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials. METHODS: An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations. RESULTS: Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative. CONCLUSIONS: This consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

Validation of online functional measures in cognitively impaired older adults.

INTRODUCTION: Assessment of functional status is associated with risk of cognitive decline and diagnosis of dementia, and can be assessed by participants and study partners (SPs). METHODS: In 770 older adults enrolled in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study and the online Brain Health Registry (BHR), we estimated associations between online assessments and clinical variables related to Alzheimer's disease (AD) risk. RESULTS: Worse online learning scores and SP-reported functional decline were associated with higher probability of AD dementia diagnosis and poor in-clinic cognitive assessment, and with higher odds of amyloid beta (Aß) positivity when combined with participants' report of less decline. SP report of functional decline conferred predictive value independent of online cognitive assessments. Participants underreported decline compared to SPs. DISCUSSION: The results support the validity of online assessments and their greater utilization in healthcare and research settings. Online SP-reported functional decline is an indicator of dementia and AD risk.

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

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.

Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia.

Importance: Amyloid positron emission tomography (PET) detects amyloid plaques in the brain, a core neuropathological feature of Alzheimer disease. Objective: To determine if amyloid PET is associated with subsequent changes in the management of patients with mild cognitive impairment (MCI) or dementia of uncertain etiology. Design, Setting, and Participants: The Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study was a single-group, multisite longitudinal study that assessed the association between amyloid PET and subsequent changes in clinical management for Medicare beneficiaries with MCI or dementia. Participants were required to meet published appropriate use criteria stating that etiology of cognitive impairment was unknown, Alzheimer disease was a diagnostic consideration, and knowledge of PET results was expected to change diagnosis and management. A total of 946 dementia specialists at 595 US sites enrolled 16 008 patients between February 2016 and September 2017. Patients were followed up through January 2018. Dementia specialists documented their diagnosis and management plan before PET and again 90 (±30) days after PET. Exposures: Participants underwent amyloid PET at 343 imaging centers. Main Outcomes and Measures: The primary end point was change in management between the pre- and post-PET visits, as assessed by a composite outcome that included Alzheimer disease drug therapy, other drug therapy, and counseling about safety and future planning. The study was powered to detect a 30% or greater change in the MCI and dementia groups. One of 2 secondary end points is reported: the proportion of changes in diagnosis (from Alzheimer disease to non-Alzheimer disease and vice versa) between pre- and post-PET visits. Results: Among 16 008 registered participants, 11 409 (71.3%) completed study procedures and were included in the analysis (median age, 75 years [interquartile range, 71-80]; 50.9% women; 60.5% with MCI). Amyloid PET results were positive in 3817 patients with MCI (55.3%) and 3154 patients with dementia (70.1%). The composite end point changed in 4159 of 6905 patients with MCI (60.2% [95% CI, 59.1%-61.4%]) and 2859 of 4504 patients with dementia (63.5% [95% CI, 62.1%-64.9%]), significantly exceeding the 30% threshold in each group (P < .001, 1-sided). The etiologic diagnosis changed from Alzheimer disease to non-Alzheimer disease in 2860 of 11 409 patients (25.1% [95% CI, 24.3%-25.9%]) and from non-Alzheimer disease to Alzheimer disease in 1201 of 11 409 (10.5% [95% CI, 10.0%-11.1%]). Conclusions and Relevance: Among Medicare beneficiaries with MCI or dementia of uncertain etiology evaluated by dementia specialists, the use of amyloid PET was associated with changes in clinical management within 90 days. Further research is needed to determine whether amyloid PET is associated with improved clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02420756.

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

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.

Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer's disease.

INTRODUCTION: The Alzheimer's Association convened a multidisciplinary workgroup to develop appropriate use criteria to guide the safe and optimal use of the lumbar puncture procedure and cerebrospinal fluid (CSF) testing for Alzheimer's disease pathology detection in the diagnostic process. METHODS: The workgroup, experienced in the ethical use of lumbar puncture and CSF analysis, developed key research questions to guide the systematic review of the evidence and developed clinical indications commonly encountered in clinical practice based on key patient groups in whom the use of lumbar puncture and CSF may be considered as part of the diagnostic process. Based on their expertise and interpretation of the evidence from systematic review, members rated each indication as appropriate or inappropriate. RESULTS: The workgroup finalized 14 indications, rating 6 appropriate and 8 inappropriate. DISCUSSION: In anticipation of the emergence of more reliable CSF analysis platforms, the manuscript offers important guidance to health-care practitioners and suggestions for implementation and future research.

The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease: Perspectives from the Research Roundtable.

The Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the "A, T, N System" (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.

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

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.

Tau: From research to clinical development.

Alzheimer's Association Research Roundtable Fall 2015-Tau: From research to clinical development. Tau pathology is recognized as the key driver of disease progression in Alzheimer's and other neurodegenerative diseases. Although this makes tau an attractive target for the development of novel diagnostic and therapeutic strategies, the mechanisms underlying the onset and progression of tau-related neurotoxicity remain elusive. Recent strides in the development of sophisticated preclinical models and the emergence of tau PET imaging and fluid biomarkers provide new opportunities to increase our understanding of tau biology, overcome translational challenges, and accelerate the advancement of tau therapeutics from bench to bedside. With this in mind, the Alzheimer's Association convened a Research Roundtable in October 2015, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of tau pathogenic pathways and review the evolution of tau therapeutics and biomarkers currently in development. The meeting provided a forum to share experience and expertise with the common goal of advancing the discovery and development of new treatment strategies and expediting the design and implementation of efficient clinical trials.

Challenges, solutions, and recommendations for Alzheimer's disease combination therapy.

Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders.

Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy.

Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H3 receptor (H3R) affinity, good selectivity and weak human Ether-à-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure-activity relationship (SAR) studies of the series culminated in the identification of ((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at ⩽10 µM, and no significant induction of any major haemodynamic effect when intravenously administered at 3mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class.

Perspective: The Alzheimer's Disease Neuroimaging Initiative and the role and contributions of the Private Partner Scientific Board (PPSB).

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partner Scientific Board (PPSB) is comprised of representatives of private, for-profit entities (including pharmaceutical, biotechnology, diagnostics, imaging companies, and imaging contract research organizations), and nonprofit organizations that provide financial and scientific support to ADNI through the Foundation for the National Institutes of Health. The PPSB serves as an independent, open, and precompetitive forum in which all private sector and not-for-profit partners in ADNI can collaborate, share information, and offer scientific and private-sector perspectives and expertise on issues relating to the ADNI project. In this article, we review and highlight the role, activities, and contributions of the PPSB within the ADNI project, and provide a perspective on remaining unmet needs and future directions.

The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update.

The Alzheimer's Disease Neuroimaging Initiative (ADNI), launched in 2004, has worked to accelerate drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimer's disease clinical treatment trials. ADNI is a naturalistic (nontreatment) multisite longitudinal study. A true public-private partnership, the initiative has set a new standard for data sharing without embargo and for the use of biomarkers in dementia research. The ADNI effort in North America is not the only such effort in the world. The Alzheimer's Association recognized these global efforts and formed Worldwide ADNI (WW-ADNI). By creating a platform for international collaboration and cooperation, WW-ADNI's goals are to harmonize projects and results across geographical regions and to facilitate data management and availability to investigators around the world. WW-ADNI projects include those based in North America, Europe, Japan, Australia, Korea, and Argentina.

Implications of leading crop production practices on environmental quality and human health.

Globally, much weight is currently being placed on agriculture to provide food for the growing population as well as feedstock for the bioenergy industry. Unfortunately, the intensification of agricultural operations to satisfy these growing needs has been associated with a number of environmental and human health risks. A review of publications on the subject was conducted and emphasis was placed on articles focusing on agriculture, environment, and public health as well as their interactions. Supporting information was also gathered from publications of various agricultural and environmental agencies. Agricultural practices with potential negative implications on the environment and human health were identified broadly as: (a) utilization of biosolids and animal manures, (b) use of agricultural chemicals, (c) management of post-harvest residue, (d) irrigation, and (e) tillage operations. Soil, water, and air contamination by nutrients, heavy metals, pathogens, and pesticides, as well as air contamination by particulate matters, noxious gases, and pathogens were among the leading environmental impacts. Some of the human-health impacts identified included neurological and reproductive defects, cardiovascular risks, cancers and other diseases (of kidney, liver, lung, and skin), skin allergies, gastroenteritis, and methemoglobinemia. Continual awareness on the impacts of the reviewed agricultural practices on environmental quality and human health and the implementation of experimentally-backed best management practices in agricultural systems remain indispensable.

Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease.

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments.

Identification and profiling of 3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)phenyl] amide as histamine H(3) receptor antagonist for the treatment of depression.

Lead optimization guided by histamine H3 receptor (H3R) affinity and calculated physico-chemical properties enabled simultaneous improvement in potency and PK properties leading to the identification of a potent, selective, devoid of hERG issues, orally bioavailable, and CNS penetrable H3R antagonist/inverse agonist 3h. The compound was active in forced-swimming tests suggesting its potential therapeutic utility as an anti-depressive agent. This Letter further includes its cardiovascular and neuropsychological/behavioral safety assessments.

Synthesis, characterization, and biological assessment of the four stereoisomers of the H(3) receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide.

This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S,3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities.

Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleep-wake disorders.

Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), K(i)=8.6 nM, rhesus monkey (rh-H3R), K(i)=1.2 nM, and rat (r-H3R), K(i)=16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders.