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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.

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

A comparison of accuracy between Multimodal magnetic resonance imaging (MRI) and Noncontrast computed tomography (CT) for detection of acute intracerebral hemorrhage in patients presenting with acute focal stroke symptoms is described. It is found that MRI is more accurate than CT for detection of chronic intracerebral hemorrhage.

Recent research on finding appropriate composite endpoints for preclinical Alzheimer's disease has focused considerable effort on finding "optimized" weights in the construction of a weighted composite score. In this paper, several proposed methods are reviewed. Our results indicate no evidence that these methods will increase the power of the test statistics, and some of these weights will introduce biases to the study. Our recommendation is to focus on identifying more sensitive items from clinical practice and appropriate statistical analyses of a large Alzheimer's data set. Once a set of items has been selected, there is no evidence that adding weights will generate more sensitive composite endpoints. [ABSTRACT FROM AUTHOR]

The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson's disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1,741 participants had SAA data and of these 1,030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary., Competing Interests: COMPETING INTERESTS TD declares former employment for and employee stock options in Biogen. GP declares employment for F. Hoffmann-La Roche Ltd. and stock ownership for F. Hoffmann-La Roche Ltd., Atea, Novartis and Eli Lilly. MB declares travel grants from The Michael J. Fox Foundation. CG declares employment for The Michael J. Fox Foundation. KP declares consultancies for Curasen; was on a scientific advisory board for Curasen and Amprion; honoraria from invited scientific presentations to universities and professional societies not exceeding $5000 per year from California Congress of Clinical Neurology, California Neurological Society, and Johns Hopkins University; and patents or patent applications numbers 17/314,979 and 63/377,293. KP also declares grants to her institution (Stanford University School of Medicine) from NIH/NINDS NS115114, NS062684, NS075097, NIH/NIA U19 AG065156, P30 AG066515, The Michael J. Fox Foundation, Lewy Body Dementia Association, Alzheimer’s Drug Discovery Foundation, Sue Berghoff LBD Research Fellowship and the Knight Initiative for Brain Resilience. DW declares salary support from The Michael J. Fox Foundation for serving on an Executive Steering Committee for the PPMI and consultancies for Roche Pharma. DW declares membership on the npj Parkinson’s Disease Editorial Board. LC declares grants to her institution from Biogen (clinical trial funding), MJFF, UPMC Competitive Medical Research Fund, National Institutes of Health, and University of Pittsburgh; grant and travel support from MJFF; royalties from Wolters Kluwel (for authorship); and in-kind donation by Advanced Brain Monitoring of equipment for research study to her institution. CC declares grants from The Michael J. Fox Foundation and NIH/NINDS. CT declares consultancies for CNS Ratings, Australian Parkinson’s Mission, Biogen, Evidera, Cadent (data safety monitoring board), Adamas (steering committee), Biogen (via the Parkinson Study Group steering committee), Kyowa Kirin (advisory board), Lundbeck (advisory board), Jazz/Cavion (steering committee), Acorda (advisory board), Bial (DMC) and Genentech. CT also declares grant support to her institution from The Michael J. Fox Foundation, National Institute of Health, Gateway LLC, Department of Defense, Roche Genentech, Biogen, Parkinson Foundation and Marcus Program in Precision Medicine. CT declares membership on the npj Parkinson’s Disease Editorial Board. CK declares employment for The Michael J. Fox Foundation. YX declares employment for and travel grants from The Michael J. Fox Foundation. SC declares employment for and travel grants from The Michael J. Fox Foundation. LC-M declares employment for and employee stock options in Amprion, grants 16712 and 21233 from The Michael J. Fox Foundation to his institution; grant U44NS111672 from NIH to his institution; and patents or patent application numbers US 20210277076A1, US 20210311077A1, US 20190353669A1 and US 20210223268A1. PD has no declarations. TF declares travel grants and grant payments to her institution (Indiana University) from The Michael J. Fox Foundation. MF declares employment for The Michael J. Fox Foundation and an unpaid advisory role at Vaxxinity. DJ declares employment for and employee stock options from Denali Therapeutics. KK declares support to his institution (University of Rochester Medical Center) from The Michael J. Fox Foundation. KMe declares consultancies for The Michael J. Fox Foundation, AcuRx, Caraway, Cerebral Therapeutics, NRG Therapeutics (scientific advisory board), Nitrase Therapeutics (scientific advisory board), Nurabio, Retromer Therapeutics (director on the board, part-time chief scientific officer), Schrodinger, Sinopia Biosciences (scientific advisory board), and Vanqua Biosciences (scientific advisory board); stock ownership for Cognition Therapeutics, Eli Lilly (retiree stock holder), Envisagenics, Nitrase Therapeutics, Sinopia Biosciences and Retromer Therapeutics; honoraria for the University of Utah; patents or patent applications for Retromer Therapeutics (planned patent); research grant from The Michael J. Fox Foundation and travel grants from the University of Utah. BM declares consultancies from Roche and Biogen; grants from The Michael J. Fox Foundation, ASAP and DFG; honoraria for Abbvie and Bial; leadership role for The Michael J. Fox Foundation and travel grants for Abbvie. TM declares support to his institution (Stanford University School of Medicine) from The Michael J. Fox Foundation. KN declares grant to her institution from The Michael J. Fox Foundation. JS declares consultancies from Invicro, Biogen, and Abbvie; and stock ownership from RealmIDX, MNI Holdings, and LikeMinds as well as grants from The Michael J. Fox Foundation. TSh declares employment for The Michael J. Fox Foundation. ASin declares employment for The National Institutes of Health who received grants from The Michael J. Fox Foundation and ASAP. ASin declares Diagnostic for Stroke royalties (unrelated to current work); honoraria from Movement Disorders Society and Nature Publishing Group; travel grants from Chan Zuckerberg Initiative, The Michael J. Fox Foundation and Weill Cornell. ASin’s spouse is an employee of GeneDx. ASin declares being an associate editor for the npj Parkinson’s Disease Editorial Board. DS has no declarations. MS declared consultancies for Mediflix, Inc., Health and Wellness Partners; honoraria from Atria Foundation, International Parkinson and Movement Disorder Society, Neurocrine, Luye Pharma and Acorda. MS serves on advisory board at Neuroderm, Alexza, Alexion and Biogen. CS declares employment for Amprion; stock ownership for Amprion; honoraria (will receive royalties for the sale of seed amplification assay [SAA]) from Amprion; and patents or patent applications, awarded and amplified in conjunction with Amprion for the SAA assay. ET has no declarations. ASid declares consultancies for SPARC Therapeutics, Capsida Therapeutics and Parkinson Study Group; honoraria from Bial; grants from The Michael J. Fox Foundation (member of PPMI Steering Committee); and participation on board at Wave Life Sciences, Inhibikase, Prevail, Huntington Study Group and Massachusetts General Hospital. BD declarations are TBD. TSi declares consultancies for AcureX, Adamas, AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson’s Consortium, Denali, The Michael J. Fox Foundation, Neuroderm, Roche, Sanofi, Sinopia, Takeda, and Vanqua Bio; on advisory boards for AcureX, Adamas, AskBio, Biohaven, Denali, GAIN, Neuron23 and Roche; on scientific advisory boards for Koneksa, Neuroderm, Sanofi and UCB; and received research funding from Amneal, Biogen, Roche, Neuroderm, Sanofi, Prevail and UCB and an investigator for NINDS, MJFF, Parkinson’s Foundation. KMa declares support to his institution (Institute for Neurodegenerative Disorders) from The Michael J. Fox Foundation. KMa also declares consultancies for Invicro, The Michael J. Fox Foundation, Roche, Calico, Coave, Neuron23, Orbimed, Biohaven, Anofi, Koneksa, Merck, Lilly, Inhibikase, Neuramedy, IRLabs and Prothena and participates on DSMB at Biohaven.

Introduction: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis., Methods: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale., Results: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach., Discussion: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification., Highlights: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step-by-step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. HIGHLIGHTS: We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early-changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later-changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)