Nina Silverberg

Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease

We evaluated the amounts of amyloid beta (Aβ)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimers disease (AD) pathology.

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

In 2011, the National Institute on Aging and Alzheimers Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimers disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimers 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 Alzheimers Association Research Framework, Alzheimers 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.

No evidence for cognitive dysfunction or depression in patients with mild restless legs syndrome.

Restless legs syndrome is a common disoder that may interrupt sleep and has been reported to produce daytime fatigue and/or mood changes. This study assessed whether patients with RLS have more cognitive dysfunction and depression than individuals of the same age and education who do not have RLS. The study showed that older individuals with mild RLS for at least 1 year do not have cognitive dysfunction and are not depressed compared with a control group of similar age and education.

Recommendations of the Alzheimer's Disease–Related Dementias Conference

The National Alzheimers Project Act, signed into law in 2011, mandates a National Plan to Address Alzheimers Disease that is updated annually. In the Plan, the term Alzheimer disease includes not only Alzheimer disease (AD) proper, but also several specified related dementias, namely, frontotemporal, Lewy body, vascular, and mixed dementia. In response to a specific action item in the 2012 National Plan, the National Institute of Neurological Disorders and Stroke, in collaboration with the National Institute on Aging, convened panels of experts and conducted a 2-day public conference to develop research priorities and timelines for addressing Alzheimer disease–related dementias (ADRD) in 5 topic areas: multiple etiology dementias, health disparities, Lewy body dementias including dementia with Lewy bodies and Parkinson disease dementia, frontotemporal dementia and related tauopathies, and vascular contributions to ADRD. By design, the product was up to 8 prioritized research recommendations in each topic area including estimated timelines from when work on a recommendation is started to completion or to full implementation of an ongoing activity, and recognition of shared research themes across recommendations. These included increased education and training of both researchers and health care professionals, addressing health disparities, fundamental neurobiology research, advanced diagnostics, collaborative biosample repositories, and a focus on developing effective interventions to prevent or treat ADRD by the year 2025 as targeted by the National Plan.

Assessment of cognition in early dementia.

Better tools for assessing cognitive impairment in the early stages of Alzheimers disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow for detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimers Association convened a meeting to discuss state‐of‐the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory, and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real‐world situations so as to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally, and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

Sensitivity to expectancy violations in healthy aging and mild cognitive impairment.

In this study, individuals with mild cognitive impairment (MCI) were tested to see if executive dysfunction impacts their implementation of expectancy biases in a priming task. Young adults, healthy older adults, and individuals with MCI made speed-related decisions to sequentially presented word pairs. The proportion of category related (e.g., apple-fruit) versus coordinate related (apple-pear) pairs was varied to create different expectancy biases. When the proportion of category pairs was high (80%), the control groups showed an expectancy bias: Significant inhibition was observed for coordinate pairs compared with category pairs. The MCI group also demonstrated an expectancy bias but with much larger costs for unexpected targets. The findings suggest that individuals with MCI are inordinately sensitive to expectancy violations, and these findings are discussed in terms of possible executive dysfunction.

Challenges to the recognition and assessment of Alzheimer's disease in American Indians of the southwestern United States

Little is known about Alzheimers disease (AD) and related neurodegenerative diseases in American Indian (AI) populations. To provide appropriate health care to elder AIs, whose population is expected to increase dramatically during the next 50 years, it is imperative to attain a better understanding of the interaction of culture and disease in this underserved population. Raising awareness in the AI population regarding the nature of dementia as it compares to normal aging and the development of culturally appropriate instruments to detect and stage AD are essential for future health care efforts. Barriers restricting clinical service to this population include historical factors relating to access to health care, cultural beliefs regarding aging, demographic diversity of the population, competing epidemiologic risk factors, and lack of proper assessment tools for clinicians.

Obstacles and opportunities in Alzheimer's clinical trial recruitment.

The 2012 National Plan to Address Alzheimers Disease set an ambitious goal: to both prevent and effectively treat Alzheimers disease by 2025. To reach this goal, tens of thousands of volunteers will be needed to participate in clinical trials to test promising new interventions and therapies. To mobilize these volunteers and their health care providers to participate in future clinical trials, it will be necessary to achieve a better understanding of the barriers keeping people from participating in Alzheimers research; form innovative partnerships among researchers, health care and social service providers, and the public; and develop more-effective outreach strategies. In this article we explore recruitment issues, including those unique to Alzheimers studies, and we suggest concrete steps such as establishing a structured consortium linking all of the registries of Alzheimers trials and establishing new partnerships with community and local organizations that can build trust and understanding among patients, caregivers, and providers.

Common Alzheimer’s Disease Research Ontology: National Institute on Aging and Alzheimer’s Association Collaborative Project

Alzheimers disease is recognized as a public health crisis worldwide. As public and private funding agencies around the world enhance and expand their support of Alzheimers disease research, there is an urgent need to coordinate funding strategies and leverage resources to maximize the impact on public health and avoid duplication of effort and inefficiency. Such coordination requires a comprehensive assessment of the current landscape of Alzheimers disease research in the United States and internationally. To this end, the National Institute on Aging at the National Institutes of Health and the Alzheimers Association developed the Common Alzheimers Disease Research Ontology (CADRO) as a dynamic portfolio analysis tool that can be used by funding agencies worldwide for strategic planning and coordination.

International Alzheimer's Disease Research Portfolio (IADRP) aims to capture global Alzheimer's disease research funding.

Alzheimers disease (AD) is a recognized international public health crisis. There is an urgent need for public and private funding agencies around the world to coordinate funding strategies and leverage existing resources to enhance and expand support of AD research. To capture and compare their existing investments in AD research and research‐related resources, major funding organizations are starting to utilize the Common Alzheimers Disease Research Ontology (CADRO) to categorize their funding information. This information is captured in the International Alzheimers Disease Research Portfolio (IADRP) for further analysis. As of January, 2014, over fifteen organizations from the US, Canada, Europe and Australia have contributed their information. The goal of the IADRP project is to enable funding organizations to assess the changing landscape of AD research and coordinate strategies, leverage resources, and avoid duplication of effort.