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

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

/pdf/reconsideration-of-amyloid-hypothesis-and-tau-hypothesis-in-29t04ypgrw.pdf

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

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

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

Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exact mechanistic link between these two AD lesions remains enigmatic. Through injection of human AD-brain-derived pathological tau (AD-tau) into Aβ plaque-bearing mouse models that do not overexpress tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) and neuropil threads (NTs). These distinct tau pathologies have different temporal onsets and functional consequences on neural activity and behavior. Notably, we found that Aβ plaques created a unique environment that facilitated the rapid amplification of proteopathic AD-tau seeds into large tau aggregates, initially appearing as NP tau, which was followed by the formation and spread of NFTs and NTs, likely through secondary seeding events. Our study provides insights into a new multistep mechanism underlying Aβ plaque-associated tau pathogenesis.

Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation.

The accumulation of pathological misfolded tau is a feature common to a collective of neurodegenerative disorders known as tauopathies, of which Alzheimer’s disease (AD) is the most common. Related tauopathies include progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), Down’s syndrome (DS), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). Investigation of the role of tau pathology in the onset and progression of these disorders is now possible due the recent advent of tau-specific ligands for use with positron emission tomography (PET), including first- (e.g., [18F]THK5317, [18F]THK5351, [18F]AV1451, and [11C]PBB3) and second-generation compounds [namely [18F]MK-6240, [18F]RO-948 (previously referred to as [18F]RO69558948), [18F]PI-2620, [18F]GTP1, [18F]PM-PBB3, and [18F]JNJ64349311 ([18F]JNJ311) and its derivative [18F]JNJ-067)]. In this review we describe and discuss findings from in vitro and in vivo studies using both initial and new tau ligands, including their relation to biomarkers for amyloid-β and neurodegeneration, and cognitive findings. Lastly, methodological considerations for the quantification of in vivo ligand binding are addressed, along with potential future applications of tau PET, including therapeutic trials.

Tau PET imaging in neurodegenerative tauopathies—still a challenge

SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition. In vivo (18)F-AV-1451 positron emission tomography images across the Alzheimer's disease spectrum could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology.

/pdf/regional-profiles-of-the-candidate-tau-pet-ligand-18f-av-uq460wi0kx.pdf

Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages.

cingulum, cingulum-hippocampal and superior longitudinal fasciculus (plus temporal branch). To identify areas of significant FC within the DMN, independent component analysis (ICA) was applied to the resting state fMRI scans. FC ROI was defined as the overlap between the grey matter area surrounding the specific DMN fiber tract terminal and the ICA-DMNmap. In a linear regression analysis, tract specificWMH ratio was tested as a predictor of the tract’s FC ROI value, controlled for age, global AV45-PET, diagnosis and education in the pooled group.Results:Higher WMH ratio in the IFOF was associated with decreased FC in the medial prefrontal cortex and the angular gyrus ROIs (t(73) 1⁄4 -2.295, p 1⁄4 .02) across all subjects. The WMH ratios in other tracts of the DMN were not associated with FC. Conclusions: The results suggest that WMH disrupt functional connectivity in a fiber-tract specific way, independent from beta-amyloid. Future research needs to address whether WMH in particular neural networks are associated with specific cognitive deficits.

Test-retest data for the tau pet imaging agent 18f-av-1451 (previously, 18f-t807)

Number (%) 70 (19.4) 66 (183) 165 (45.7) 60 (16.6) Age (years) 67.2 (6.6) 70.9 (8.0) 73.8(6.5) 73.3(7.7) Sex (% men) 47.1 57.6 57.6 51.7 APOE-74 (%) 23.2 59.1 67.9 16.7 AD after 24 months (%) 1.8 4.3 42.4 2.3 CSF Abeta pg/mL 233 (26) 146 (25) 137 (26) 232 (28) Florbetapir (SUVR) 1.02 (0.07) 1.29 (0.21) 1.34 (0.20) 1.00 (0.06) CSF tau pg/mL 54 (26) 93 (48) 112 (58) 60 (28) CSF p-tau pg/mL 28 (14) 48 (29) 51(24) 28 (15) WMH (z-score) 0.07 (0.93) -0.31(1.25) -0.71 (1.06) -0.46 (1.12) MMSE 28.9 (1.1) 28.6 (16) 27.5 (1-8) 28.1 (18) Immediate memory (z-score) -0.17 (0.75) -0.57 (0.67) -0.88 (0.61) -0.67 (0.65) Delayed memory (z-score) -0.24 (0.97) a,b,c -0.71 (0.82) -1.53 (0.85) -0.96 (0.90) Recognition memory (z-score) -0.22 (0.81) a,b,c -0.58(1.06) -1.21 (0.93) -0.78 (101) Verbal fluency (z-score) -0.26 (0.91) a,b,c -0.56 (1.42) -0.93 (0.90) -0.75 (0.87) Trail A (z-score) -0.17 (1.18) -0.58 (1.00) -130 (2.02) -0.72 (139) Trail B (z-score) -0.17 (0.85) -0.54 (1.18) -129 (1.73) -0.70 (123)

James Dickson

Papers

Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages.

Test-retest data for the tau pet imaging agent 18f-av-1451 (previously, 18f-t807)

Hippocampal sparing and limbic predominant tau subtypes of Alzheimer’s disease determined in vivo using [18F]-AV-1451 PET imaging