Alzheimer's Association Research Framework Research Articles

Early diagnosis of prodromal dementia with Lewy bodies using clinical history of probable REM sleep behaviour disorder and cardiac 123 I-MIBG scintigraphy in memory clinics.

Rapid eye movement sleep behaviour disorder (RBD) is associated with reduced cardiac 123 I-metaiodobenzylguanidine (MIBG) uptake and often precedes the onset of Lewy body (LB) disorders. We investigated the role of cardiac 123 I-MIBG scintigraphy in relation to probable RBD for the clinical diagnosis of prodromal dementia with Lewy bodies (DLB) in memory clinics. We reviewed clinical profiles of 60 consecutive patients who underwent cardiac 123 I-MIBG scintigraphy in our memory clinics. The diagnostic threshold of 2.20 was used as the cut-off for the heart-to-mediastinum ratio at the delayed phase. Cardiac 123 I-MIBG abnormality was identified in 28 patients at baseline; six were cognitively unimpaired, six had mild cognitive impairment (MCI)-LB, and 16 had probable DLB based on the National Institute on Aging and Alzheimer's Association Research Framework. Although the number of core features increased in accordance with the progression of three cognitive categories, there were no differences in the prevalence of probable RBD and the cardiac MIBG scintigraphy indices among them. During the observation period, two cognitively unimpaired patients with probable RBD progressed to MCI-LB, and three MCI-LB patients with probable RBD developed DLB. The prevalence of final diagnosis of probable MCI-LB or DLB was significantly higher in these patients (85%) than the remaining 32 patients without (9%). Of 25 patients with probable RBD, 22 (88%) had a cardiac 123 I-MIBG abnormality regardless of cognitive conditions. Only one patient consulted a sleep centre for the abnormal sleep behaviour before visiting our memory clinics. Regarding the gender differences, male predominance was not identified and sleep-related injury more frequently occurred in men (7/12, 58%) than in women (1/10, 10%). Proactive detection of probable RBD plus cardiac 123 I-MIBG abnormality provides the opportunity for an early diagnosis of prodromal DLB in memory clinics. This approach warrants further follow-up studies with polysomnographic and pathological verification.

Functional connectivity differences in Alzheimer's disease and amnestic mild cognitive impairment associated with AT(N) classification and anosognosia

Alzheimer's continuum biological profiles (A+T−N−, A+T+N−, A+T−N+, and A+T+N+) were established in the 2018 National Institute on Aging and Alzheimer's Association research framework for Alzheimer's disease (AD). We aim to assess the relation between AT(N) biomarker profiles and brain functional connectivity (FC) and assess the neural correlates of anosognosia. We assessed local functional coupling and between-network connectivity through between-group intrinsic local correlation and independent component analyses. The neural correlates of anosognosia were assessed via voxel-wise linear regression analysis in prodromal AD. Statistical significance for the FC analysis was set at p ≤ 0.05 false discovery rate (FDR)-corrected for cluster size. One hundred and twenty-one and 73 participants were included in the FC and the anosognosia analysis, respectively. The FC in the default mode network is greater in prodromal AD than AD with dementia (i.e., local correlation: T = 8.26, p-FDR < 0.001, k = 1179; independent component analysis: cerebellar network, T = 4.01, p-FDR = 0.0012, k = 493). The default mode network is persistently affected in the early stages of Alzheimer's biological continuum. The anterior cingulate cortex (T = 2.52, p-FDR = 0.043, k = 704) is associated with anosognosia in prodromal AD.

Executive Summary of the 2019 International Conference of Korean Dementia Association: Exploring the Novel Concept of Alzheimer's Disease and Other Dementia: a Report from the Academic Committee of the Korean Dementia Association.

Because of repeated failures of clinical trials, the concept of Alzheimer's disease (AD) has been changing rapidly in recent years. As suggested by the National Institute on Aging and the Alzheimer's Association Research Framework, the diagnosis and classification of AD is now based on biomarkers rather than on symptoms, allowing more accurate identification of proper candidates for clinical trials by pathogenesis and disease stage. Recent development in neuroimaging has provided a way to reveal the complex dynamics of amyloid and tau in the brain in vivo, and studies of blood biomarkers are taking another leap forward in diagnosis and treatment of AD. In the field of basic and translational research, the development of animal models and a deeper understanding of the role of neuroinflammation are taking a step closer to clarifying the pathogenesis of AD. Development of big data and the Internet of Things is also incorporating dementia care and research into other aspects. Large-scale genetic research has identified genetic abnormalities that can provide a foundation for precision medicine along with the aforementioned digital technologies. Through the first international conference of the Korean Dementia Association, experts from all over the world gathered to exchange opinions with association members on these topics. The Academic Committee of the Korean Dementia Association briefly summarizes the contents of the lectures to convey the depth of the conference and discussions. This will be an important milestone in understanding the latest trends in AD's pathogenesis, diagnostic and therapeutic research and in establishing a future direction.

Comparison of variables associated with cerebrospinal fluid neurofilament, total-tau, and neurogranin

IntroductionThree cerebrospinal fluid (CSF) markers of neurodegeneration (N) (neurofilament light [NfL], total-tau [T-tau], and neurogranin [Ng]) have been proposed under the AT(N) scheme of the National Institute on Aging–Alzheimer's Association Research Framework. MethodsWe examined, in a community-based population (N = 777, aged 50–95) (1) what variables were associated with each of the CSF (N) markers, and (2) whether the variables associated with each marker differed by increased brain amyloid. CSF T-tau was measured with an automated electrochemiluminescence Elecsys immunoassay; NfL and Ng were measured with in-house enzyme-linked immunosorbent assays. ResultsMultiple variables were differentially associated with CSF NfL and T-tau levels, but not Ng. Most associations were attenuated after adjustment for age and sex. T-tau had the strongest association with cognition in the presence of amyloidosis, followed by Ng. Variables associations with NfL did not differ by amyloid status. DiscussionUnderstanding factors that influence CSF (N) markers will assist in the interpretation and utility of these markers in clinical practice.

Biomarker-based prognosis for people with mild cognitive impairment (ABIDE): a modelling study

Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become available. We aimed to establish robust prediction models of disease progression in people at risk of dementia. In this modelling study, we included people with mild cognitive impairment (MCI) from single-centre and multicentre cohorts in Europe and North America: the European Medical Information Framework for Alzheimer's Disease (EMIF-AD; n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI; n=829), Amsterdam Dementia Cohort (ADC; n=666), and the Swedish BioFINDER study (n=233). Inclusion criteria were a baseline diagnosis of MCI, at least 6 months of follow-up, and availability of a baseline Mini-Mental State Examination (MMSE) and MRI or CSF biomarker assessment. The primary endpoint was clinical progression to any type of dementia. We evaluated performance of previously developed risk prediction models-a demographics model, a hippocampal volume model, and a CSF biomarkers model-by evaluating them across cohorts, incorporating different biomarker measurement methods, and determining prognostic performance with Harrell's C statistic. We then updated the models by re-estimating parameters with and without centre-specific effects and evaluated model calibration by comparing observed and expected survival. Finally, we constructed a model combining markers for amyloid deposition, tauopathy, and neurodegeneration (ATN), in accordance with the National Institute on Aging and Alzheimer's Association research framework. We included all 2611 individuals with MCI in the four cohorts, 1007 (39%) of whom progressed to dementia. The validated demographics model (Harrell's C 0·62, 95% CI 0·59-0·65), validated hippocampal volume model (0·67, 0·62-0·72), and updated CSF biomarkers model (0·72, 0·68-0·74) had adequate prognostic performance across cohorts and were well calibrated. The newly constructed ATN model had the highest performance (0·74, 0·71-0·76). We generated risk models that are robust across cohorts, which adds to their potential clinical applicability. The models could aid clinicians in the interpretation of CSF biomarker and hippocampal volume results in individuals with MCI, and help research and clinical settings to prepare for a future of precision medicine in Alzheimer's disease. Future research should focus on the clinical utility of the models, particularly if their use affects participants' understanding, emotional wellbeing, and behaviour. ZonMW-Memorabel.

Staging the cognitive continuum in prodromal Alzheimer's disease with episodic memory

It is unclear whether episodic memory is an appropriate descriptor of the cognitive continuum in mild cognitive impairment (MCI). Here, we investigated the ability of episodic memory to track cognitive changes in patients with MCI with biomarker evidence of Alzheimer's disease (AD). We examined 387 MCI amyloid-positive subjects, cognitively staged as “early” or “late” on the basis of episodic memory impairment. Cross-sectional and longitudinal comparisons between these 2 groups were performed for each amyloid, tau, and neurodegeneration (AT(N)) profile. Cross-sectional analyses indicate that “early” MCI represents a transitional phase between normal cognition and “late” MCI in the AD biomarker pathway. After adjusting by confounders and levels of A, T, and (N), “late” MCI progressed significantly faster than “early” MCI only in profiles with both abnormal amyloid and tau markers (A+T+(N)− p < 0.05, A+T+(N)+ p < 0.001). Episodic memory staging is useful for describing symptoms in prodromal AD and complements the AT(N) profiles. Our findings might have implications for the Numeric Clinical staging scheme of the National Institute on Aging and Alzheimer's Association research framework.

A systems-based model of Alzheimer's disease

The new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease has been developed to accelerate drug discovery and offer a common structure and language to construct new Alzheimer's disease conceptual models. However, as a “complex” disease, a model based on systems-level understanding is needed to accommodate the complex, interacting etiologic pathways and the system-level changes associated with Alzheimer's disease pathogenesis and interventions that are currently known and which will be identified in the future. To accomplish this, the evolution of the structure of the research framework itself should be encouraged.

Biomarkers of agitation and aggression in Alzheimer's disease: A systematic review

IntroductionAgitation is one of the most challenging neuropsychiatric symptoms to treat in Alzheimer's disease and has significant implications for patient and caregiver. A major source of difficulty in identifying safe and effective treatments for agitation is the lack of validated biomarkers. As such, patients may not be appropriately targeted, and biological response to pharmacotherapy cannot be adequately monitored. MethodsThis systematic review aimed to summarize evidence on the association between biomarkers and agitation/aggression in patients with Alzheimer's disease, utilizing the National Institute on Aging–Alzheimer's Association Research Framework and the Biomarkers, EndpointS, and other Tools Resource of the Food and Drug Association-National Institutes of Health Biomarker Working Group. ResultsThis review identified six classes of biomarkers (neuropathological, neurotransmitter, neuroimaging, apolipoprotein E (APOE) genotype, inflammatory, and clusterin) associated with agitation/aggression, which were mostly diagnostic in nature. DiscussionFuture studies should investigate the predictive, prognostic, and monitoring capacity of biomarkers to provide insight into the longitudinal course of agitation/aggression, as well as predict and monitor biological response to a pharmacological intervention.

The National Institute on Aging—Alzheimer's Association Framework on Alzheimer's disease: Application to clinical trials

IntroductionThe National Institute on Aging—Alzheimer's Association Research Framework on Alzheimer's disease (AD) represents an important advance in the biological characterization of the AD spectrum. MethodsThe National Institute on Aging—Alzheimer's Association Framework is considered as it applies to clinical trials. ResultsUsing the combination of amyloid (A), tau (T), and neurodegeneration (N) biomarkers, the Framework provides a means of defining the state of patients with regard to Alzheimer pathologic change. The Framework is relevant to clinical trials of disease-modifying agents, allowing participants to be characterized biologically at baseline. The ATN Framework can also inform trial outcomes. The preclinical phase of the disease after amyloid deposition is defined by A+T−N−, and the transition to prodromal disease and dementia is characterized by the addition of T and N. Most symptomatic patients in clinical trials are in the class of A+T+N− and A+T+N+. DiscussionThe National Institute on Aging—Alzheimer's Association Framework on AD represents progress in providing biomarker profiles of participants in the AD spectrum that can be used to help design clinical trials.

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.

National Institute on Aging – Alzheimer's Association Research Framework lays the groundwork for deeper understanding of Alzheimer's disease

National Institute on Aging – Alzheimer's Association Research Framework lays the groundwork for deeper understanding of Alzheimer's disease