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.

/pdf/nia-aa-research-framework-toward-a-biological-definition-of-1sjt6cvmd3.pdf

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

Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovas...

Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68880-6.pdf

Mild cognitive impairment

The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

/pdf/research-criteria-for-the-diagnosis-of-alzheimer-s-disease-1jpda3ww0z.pdf

Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria

Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(13)70124-8.pdf

Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration

intake were 0.82 [95% confidence interval {CI}, 0.68-0.99] and 0.82 [95% CI, 0.661.00], respectively). Among current smokers, this relationship was most pronounced (RRs, 0.65 [95% CI, 0.37-1.14] and 0.58 [95% CI, 0.30-1.12], respectively) and also was present for intake of beta carotene (RR, 0.49 [95% CI, 0.27-0.92]) and flavonoids (RR, 0.54 [95% CI, 0.31-0.96]). The associations did not vary by education or apolipoprotein E genotype. Conclusion High dietary intake of vitamin C and vitamin E may lower the risk of Alzheimer disease. JAMA. 2002;287:3223-3229 www.jama.com

https://jamanetwork.com/journals/jama/articlepdf/195058/JOC12012.pdf

Dietary Intake of Antioxidants and Risk of Alzheimer Disease

Objectives. To review studies that have reported on the prevalence of memory complaints and the relationship between memory complaints and impairment or decline (dementia) in elderly individuals

Data sources and study selection. All publications in the English language relating to memory complaints, memory impairment, cognitive disorder and dementia in MEDLINE, PSYCHLIT and EMBASE computerized databases, together with a search of relevant citations.

Data synthesis. The prevalence of memory complaints, defined as everyday memory problems, shows a large variation of approximately 25 – 50%. A high age, female gender and a low level of education are generally associated with a high prevalence of memory complaints. In community-based samples of elderly subjects an association has been found between memory complaints and memory impairment, after adjustment for depressive symptomatology. Memory complaints predict dementia after a follow-up of at least 2 years, in particular in those with mild cognitive impairment, defined as Mini Mental State Examination (MMSE) > 23. Memory complaints in highly educated elderly subjects may be predictive of dementia even when there is no indication of cognitive impairment on short cognitive screen tests. The shift in methodology which is noticeable in the recently published major studies is discussed as a possible explanation for the established association between memory complaints and decline in memory (or dementia) in elderly subjects. Three methodological factors, in particular, are responsible for the results: community-based sampling, longitudinal design and the treatment of variables such as depression, cognitive impairment and level of education.

Conclusion. Memory complaints in elderly people should no longer be considered merely as an innocent age-related phenomenon or a symptom of depression. Instead, these complaints deserve to be taken seriously, at least as a possible early sign of dementia. Copyright © 2000 John Wiley & Sons, Ltd.

Are memory complaints predictive for dementia? A review of clinical and population-based studies

Background Increased levels of inflammatory proteins have been found in the brains and plasma samples of patients with dementia. Whether the levels of inflammatory proteins in plasma samples are elevated before clinical onset of dementia is unclear. Objective To determine whether high levels of inflammatory proteins in plasma samples are associated with an increased risk of dementia. Design and Setting A case-cohort study within the Rotterdam Study, a population-based prospective cohort study in the Netherlands. Participants The source population comprises 6713 subjects who, at baseline (1990-1993), were free of dementia and underwent venipuncture. From these, we selected both a random subcohort of 727 subjects and 188 cases who had developed dementia at follow-up. Main Outcome Measures The associations between plasma levels of α1-antichymotrypsin, C-reactive protein, interleukin 6, the soluble forms of intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and the risk of dementia were examined using the Cox proportional hazards regression models. Results High levels of α1-antichymotrypsin, interleukin 6, and, to a lesser extent, C-reactive protein were associated with an increased risk of dementia; rate ratios per standard deviation increase were 1.49 (95% confidence interval, 1.23-1.81), 1.28 (95% confidence interval, 1.06-1.55), and 1.12 (95% confidence interval, 0.99-1.25), respectively. Similar associations were observed for Alzheimer disease, whereas rate ratios of vascular dementia were higher for α1-antichymotrypsin and C-reactive protein. Soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not associated with dementia. Conclusion Plasma levels of inflammatory proteins are increased before clinical onset of dementia, Alzheimer disease, and vascular dementia.

https://jamanetwork.com/journals/jamaneurology/articlepdf/785834/NOC30220.pdf

Inflammatory proteins in plasma and the risk of dementia: the rotterdam study.

Background: Increased levels of inflammatory proteins have been found in the brains and plasma samples of patients with dementia. Whether the levels of inflammatory proteins in plasma samples are elevated before clinical onset of dementia is unclear. Objective: To determine whether high levels of inflammatory proteins in plasma samples are associated with an increased risk of dementia. Design and Setting: A case-cohort study within the Rotterdam Study, a population-based prospective cohort study in the Netherlands. Participants: The source population comprises 6713 subjects who, at baseline (1990-1993), were free of dementia and underwent venipuncture. From these, we selected both a random subcohort of 727 subjects and 188 cases who had developed dementia at follow-up. Main Outcome Measures: The associations between plasma levels of1-antichymotrypsin, C-reactive protein, interleukin 6, the soluble forms of intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and the risk of dementia were examined using the Cox proportional hazards regression models. Results: High levels of1-antichymotrypsin, interleukin 6, and, to a lesser extent, C-reactive protein were associated with an increased risk of dementia; rate ratios per standard deviation increase were 1.49 (95% confidence interval, 1.23-1.81), 1.28 (95% confidence interval, 1.06-1.55), and 1.12 (95% confidence interval, 0.99-1.25), respectively. Similar associations were observed for Alzheimer disease, whereas rate ratios of vascular dementia were higher for1antichymotrypsin and C-reactive protein. Soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not associated with dementia. Conclusion: Plasma levels of inflammatory proteins are increased before clinical onset of dementia, Alzheimer disease, and vascular dementia. Arch Neurol. 2004;61:668-672

Inflammatory Proteins in Plasma and the Risk of Dementia

textBackground: We investigated the reporting and methods of prediction studies, focusing on aims, designs, participant selection, outcomes, predictors, statistical power, statistical methods, and predictive performance measures. Methods and Findings: We used a full hand search to identify all prediction studies published in 2008 in six high impact general medical journals. We developed a comprehensive item list to systematically score conduct and reporting of the studies, based on recent recommendations for prediction research. Two reviewers independently scored the studies. We retrieved 71 papers for full text review: 51 were predictor finding studies, 14 were prediction model development studies, three addressed an external validation of a previously developed model, and three reported on a model's impact on participant outcome. Study design was unclear in 15% of studies, and a prospective cohort was used in most studies (60%). Descriptions of the participants and definitions of predictor and outcome were generally good. Despite many recommendations against doing so, continuous predictors were often dichotomized (32% of studies). The number of events per predictor as a measure of statistical power could not be determined in 67% of the studies; of the remainder, 53% had fewer than the commonly recommended value of ten events per predictor. Methods for a priori selection of candidate predictors were described in most studies (68%). A substantial number of studies relied on a p-value cut-off of p<0.05 to select predictors in the multivariable analyses (29%). Predictive model performance measures, i.e., calibration and discrimination, were reported in 12% and 27% of studies, respectively. Conclusions: The majority of prediction studies in high impact journals do not follow current methodological recommendations, limiting their reliability and applicability. Please see later in the article for the Editors' Summary.

/pdf/reporting-and-methods-in-clinical-prediction-research-a-1bzcfmulns.pdf

Mirjam I. Geerlings

Papers

Dietary Intake of Antioxidants and Risk of Alzheimer Disease

Are memory complaints predictive for dementia? A review of clinical and population-based studies

Inflammatory proteins in plasma and the risk of dementia: the rotterdam study.

Inflammatory Proteins in Plasma and the Risk of Dementia

Reporting and Methods in Clinical Prediction Research: A Systematic Review