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

Alzheimer s & Dementia, Journal Year: 2018, Volume and Issue: 14(4), P. 535 - 562

Published: April 1, 2018

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

Language: Английский

A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers

Neurology, Journal Year: 2016, Volume and Issue: 87(5), P. 539 - 547

Published: July 2, 2016

Biomarkers have become an essential component of Alzheimer disease (AD) research and because the pervasiveness AD pathology in elderly, same biomarkers are used cognitive aging research. A number current issues suggest that unbiased descriptive classification scheme for these would be useful. We propose "A/T/N" system which 7 major divided into 3 binary categories based on nature pathophysiology each measures. "A" refers to value a β-amyloid biomarker (amyloid PET or CSF Aβ42); "T," tau (CSF phospho tau, PET); "N," neurodegeneration neuronal injury ([(18)F]-fluorodeoxyglucose-PET, structural MRI, total tau). Each category is rated as positive negative. An individual score might appear A+/T+/N-, A+/T-/N-, etc. The A/T/N includes new modality PET. It agnostic temporal ordering mechanisms underlying pathogenesis. all individuals any population regardless mix findings therefore suited studies aging. does not specify labels thus diagnostic system. categorizing multidomain at person level format easy understand use. Given present lack consensus among specialists terminology across clinically normal dementia spectrum, will broadest acceptance if it independent from one defined scheme.

Language: Английский

Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts

The Lancet Neurology, Journal Year: 2020, Volume and Issue: 19(5), P. 422 - 433

Published: April 22, 2020

Language: Английский

Neuronal Cell Death

Physiological Reviews, Journal Year: 2018, Volume and Issue: 98(2), P. 813 - 880

Published: Feb. 28, 2018

Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity adult neurons to proliferate or be replaced. The concept used simple as there were just two three types, so we had work out which type was involved in our particular pathology then block it. However, now know that are at least a dozen ways for die, blocking mechanism may not prevent from dying, non-neuronal cells also contribute neuronal death. We review here mechanisms by intrinsic extrinsic apoptosis, oncosis, necroptosis, parthanatos, ferroptosis, sarmoptosis, autophagic death, autosis, autolysis, paraptosis, pyroptosis, phagoptosis, mitochondrial permeability transition. next explore development, those induced axotomy, aberrant cell-cycle reentry, glutamate (excitoxicity oxytosis), loss connected neurons, aggregated proteins unfolded protein response, oxidants, inflammation, microglia. reassess forms occur stroke Alzheimer’s disease, most pathologies involving discuss why has been difficult pinpoint involved, if matters, molecular overlap interplay between subroutines, therapeutic implications these multiple overlapping

Language: Английский

Defining imaging biomarker cut points for brain aging and Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2016, Volume and Issue: 13(3), P. 205 - 216

Published: Sept. 30, 2016

Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) and MRI cortical thickness.We examined five methods determining points.The reliable worsening method produced a point only PET. The specificity, sensitivity, accuracy of cognitively impaired versus young clinically normal (CN) labeled the most people abnormal all gave similar FDG thickness. Cut defined using age-matched CN fewer abnormal.In future, we will use single PET (standardized uptake value ratio, 1.42; centiloid, 19) based on method. We base lenient thickness conservative

Language: Английский

Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease

Frontiers in Neuroscience, Journal Year: 2018, Volume and Issue: 12

Published: Jan. 30, 2018

The so-called amyloid hypothesis, that the accumulation and deposition of oligomeric or fibrillar β (Aβ) peptide is primary cause Alzheimer's disease (AD), has been mainstream concept underlying AD research for over 20 years. However, all attempts to develop Aβ-targeting drugs treat have ended in failure. Here, we review recent findings indicating main factor development progression tau, not Aβ, describe deficiencies hypothesis supported emergence this idea.

Language: Английский

Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease

Brain, Journal Year: 2017, Volume and Issue: 140(12), P. 3286 - 3300

Published: Sept. 5, 2017

Neuropathological and in vivo studies have revealed a tight relationship between tau pathology cognitive impairment across the Alzheimer's disease spectrum. However, is also intimately associated with neurodegeneration amyloid pathology. The aim of present study was therefore to assess whether grey matter atrophy contribute pathology, as measured 18F-AV-1451-PET imaging, deficits disease. We included 40 amyloid-positive patients meeting criteria for mild due (n = 5) or probable dementia 35). Twelve additionally fulfilled diagnostic posterior cortical eight logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance (11C-PiB) positron emission tomography (18F-AV-1451) tomography, episodic semantic memory, language, executive visuospatial functions assessment. Raw scores were converted age-adjusted Z-scores (W-scores) averaged compute composite each domain. Independent regressions performed 18F-AV-1451 binding domain, we used Biological Parametric Mapping toolbox further control local volumes, 11C-PiB uptake, both. Partial correlations causal mediation analyses (mediation R package) then brain regions showing an association cognition both uptake volume. Our results showed that decreased performance domain related increased specific conforming established brain-behaviour relationships (i.e. memory: medial temporal lobe angular gyrus; left anterior regions; language: superior supramarginal functions: bilateral frontoparietal right more than occipitotemporal regions). This pattern regional associations remained essentially unchanged—although less spatially extended—when volume maps added covariates. Mediation direct matter-mediated effects on performance. Together, these show region-specific manner These are weakly burden, but part mediated by volumes. suggests may lead through variety mechanisms, including, not restricted to, loss. might implications future therapeutic trials targeting

Language: Английский

Four distinct trajectories of tau deposition identified in Alzheimer’s disease

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(5), P. 871 - 881

Published: April 29, 2021

Language: Английский

Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5143 - 5169

Published: June 27, 2024

Abstract The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 single 2012 2018 to create recommendations for diagnosis characterization of disease (AD). present document updates research framework response several recent developments. Defining diseases biologically, rather than based syndromic presentation, has long been standard many areas medicine (e.g., oncology), is becoming a unifying concept common all neurodegenerative diseases, not just AD. consistent with this principle. Our intent objective criteria staging AD, incorporating advances biomarkers, serve as bridge between clinical care. These are intended provide step‐by‐step practice guidelines workflow or specific treatment protocols, but general principles inform AD that reflect current science. Highlights We define (AD) be biological process begins appearance neuropathologic change (ADNPC) while people asymptomatic. Progression burden leads later progression symptoms. Early‐changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid accurate plasma [especially phosphorylated tau 217]) map onto either amyloid beta tauopathy pathway; however, these presence ADNPC more generally (i.e., both neuritic plaques tangles). An abnormal biomarker result sufficient establish decision making throughout continuum. Later‐changing 2 (biofluid PET) can prognostic information, when abnormal, will increase confidence contributing integrated scheme described accommodates fact copathologies, cognitive reserve, resistance may modify relationships stages.

Language: Английский

Propagation of Tau Aggregates and Neurodegeneration

Annual Review of Neuroscience, Journal Year: 2017, Volume and Issue: 40(1), P. 189 - 210

Published: July 25, 2017

A pathway from the natively unfolded microtubule-associated protein Tau to a highly structured amyloid fibril underlies human Tauopathies. This ordered assembly causes disease and represents gain of toxic function. In recent years, evidence has accumulated suggest that inclusions form first in small number brain cells, where they propagate other regions, resulting neurodegeneration disease. Propagation pathology is often called prion-like, which refers capacity an assembled induce same abnormal conformation kind, initiating self-amplifying cascade. addition, prion-like encompasses release aggregates cells their uptake by neighboring cells. mice, intracerebral injection induces monomeric Tau, followed its spreading distant regions. Conformational differences between transgenic mouse vitro recombinant account for greater seeding potency aggregates. Short fibrils constitute major species seed-competent brains mice. The existence multiple Tauopathies with distinct morphologies led suggestion different molecular conformers (or strains) aggregated exist.

Language: Английский