18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease
TL;DR: It is concluded that CSF T‐t Tau and P‐tau mainly behave as biomarkers of “disease state”, since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates.
Abstract: To elucidate the relationship between cerebrospinal fluid (CSF) total‐tau (T‐tau) and phosphorylated tau (P‐tau) with the tau PET ligand 18 F‐AV‐1451 in Alzheimer9s disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T‐tau and P‐tau were highly correlated ( R = 0.92, P 18 F‐AV‐1451, and mainly in demented AD patients. 18 F‐AV‐1451, but not CSF T‐tau or P‐tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal 18 F‐AV‐1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though 18 F‐AV‐1451 retention was always increased at this disease stage. We conclude that CSF T‐tau and P‐tau mainly behave as biomarkers of “disease state”, since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, 18 F‐AV‐1451 is a biomarker of “disease stage”, since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.
Citations
More filters
Mayo Clinic1, Rush University2, University of Gothenburg3, Alzheimer's Association4, Silver Spring Networks5, Biogen Idec6, Washington University in St. Louis7, University of California, Berkeley8, University of Cologne9, University of Pennsylvania10, Stanford University11, National Institutes of Health12, University of California, San Francisco13, University of Melbourne14, VU University Medical Center15, Eli Lilly and Company16, Brigham and Women's Hospital17
TL;DR: This research 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 and 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.
Abstract: 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.
5,126 citations
Cites background from "18F-AV-1451 and CSF T-tau and P-tau..."
...Because CSF P-tau and T-tau are highly correlated in AD and are equally correlated with tau PET [124], they do not seem to provide independent information in AD....
[...]
...This may be in part because P-tau seems to plateau later in the disease [14] while the tau PET signal continues to increase [124]....
[...]
TL;DR: Plasma P-tau18 level increased with progression of Alzheimer’s disease (AD) and differentiated AD dementia from other neurodegenerative diseases, supporting its further development as a blood-based biomarker for AD.
Abstract: Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer’s disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87–0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94–0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials. Plasma P-tau18 level increased with progression of Alzheimer’s disease (AD) and differentiated AD dementia from other neurodegenerative diseases, supporting its further development as a blood-based biomarker for AD.
565 citations
TL;DR: Technical developments with ultrasensitive immunoassays and novel mass spectrometry techniques give promise of biomarkers to monitor brain amyloidosis and neurodegeneration in plasma samples and one promising candidate is the synaptic protein neurogranin that seems specific for AD and predicts future rate of cognitive deterioration.
Abstract: Accumulating data from the clinical research support that the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau) reflect key elements of AD pathophysiology. Importantly, a large number of clinical studies very consistently show that these biomarkers contribute with diagnostically relevant information, also in the early disease stages. Recent technical developments have made it possible to measure these biomarkers using fully automated assays with high precision and stability. Standardization efforts have given certified reference materials for CSF Aβ42, with the aim to harmonize results between assay formats that would allow for uniform global reference limits and cut-off values. These encouraging developments have led to that the core AD CSF biomarkers have a central position in the novel diagnostic criteria for the disease and in the recent National Institute on Aging and Alzheimer's Association biological definition of AD. Taken together, this progress will likely serve as the basis for a more general introduction of these diagnostic tests in clinical routine practice. However, the heterogeneity of pathology in late-onset AD calls for an expansion of the AD CSF biomarker toolbox with additional biomarkers reflecting additional aspects of AD pathophysiology. One promising candidate is the synaptic protein neurogranin that seems specific for AD and predicts future rate of cognitive deterioration. Further, recent studies bring hope for easily accessible and cost-effective screening tools in the early diagnostic evaluation of patients with cognitive problems (and suspected AD) in primary care. In this respect, technical developments with ultrasensitive immunoassays and novel mass spectrometry techniques give promise of biomarkers to monitor brain amyloidosis (the Aβ42/40 or APP669-711/Aβ42 ratios) and neurodegeneration (tau and neurofilament light proteins) in plasma samples, but future studies are warranted to validate these promising results further.
454 citations
TL;DR: The findings suggest that plasma NfL can be used as a noninvasive biomarker associated with neurodegeneration in patients with AD and may be useful to monitor effects in trials of disease-modifying drugs.
Abstract: Importance Plasma neurofilament light (NfL) has been suggested as a noninvasive biomarker to monitor neurodegeneration in Alzheimer disease (AD), but studies are lacking. Objective To examine whether longitudinal plasma NfL levels are associated with other hallmarks of AD. Design, Setting, and Participants This North American cohort study used data from 1583 individuals in the multicenter Alzheimer’s Disease Neuroimaging Initiative study from September 7, 2005, through June 16, 2016. Patients were eligible for inclusion if they had NfL measurements. Annual plasma NfL samples were collected for up to 11 years and were analyzed in 2018. Exposures Clinical diagnosis, Aβ and tau cerebrospinal fluid (CSF) biomarkers, imaging measures (magnetic resonance imaging and fluorodeoxyglucose–positron emission tomography), and tests on cognitive scores. Main Outcomes and Measures The primary outcome was the association between baseline exposures (diagnosis, CSF biomarkers, imaging measures, and cognition) and longitudinal plasma NfL levels, analyzed by an ultrasensitive assay. The secondary outcomes were the associations between a multimodal classification scheme with Aβ, tau, and neurodegeneration (ie, the ATN system) and plasma NfL levels and between longitudinal changes in plasma NfL levels and changes in the other measures. Results Of the included 1583 participants, 716 (45.2%) were women, and the mean (SD) age was 72.9 (7.1) years; 401 had no cognitive impairment, 855 had mild cognitive impairment, and 327 had AD dementia. The NfL level was increased at baseline in patients with mild cognitive impairment and AD dementia (mean levels: cognitive unimpairment, 32.1 ng/L; mild cognitive impairment, 37.9 ng/L; and AD dementia, 45.9 ng/L;P Conclusions and Relevance The findings suggest that plasma NfL can be used as a noninvasive biomarker associated with neurodegeneration in patients with AD and may be useful to monitor effects in trials of disease-modifying drugs.
375 citations
TL;DR: Findings from in vitro and in vivo studies using both initial and new tau ligands are described and discussed, including their relation to biomarkers for amyloid-β and neurodegeneration, and cognitive findings.
Abstract: 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.
369 citations
References
More filters
11 Jun 2013
113,134 citations
TL;DR: The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information becomes available.
Abstract: Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
26,847 citations
"18F-AV-1451 and CSF T-tau and P-tau..." refers methods in this paper
...All cases met the DSM-IIIR criteria for dementia (American Psychiatric Association, & American Psychiatric Association, Work Group to Revise DSM-III, 1987) as well as the NINCDSADRDA criteria for AD (McKhann et al, 1984)....
[...]
TL;DR: The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations, permitting the differentiation of six stages.
Abstract: Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.
13,699 citations
"18F-AV-1451 and CSF T-tau and P-tau..." refers methods in this paper
...…a previously described protocol to aggregate FreeSurfer ROIs by their involvement in different stages of tau spread, as determined using 18F-AV-1451 PET in cases with different stages of AD (Cho et al, 2016), and these stages roughly corresponds to the Braak staging approach (Braak & Braak, 1991)....
[...]
TL;DR: A package of computer programs for analysis and visualization of three-dimensional human brain functional magnetic resonance imaging (FMRI) results is described and techniques for automatically generating transformed functional data sets from manually labeled anatomical data sets are described.
10,002 citations
"18F-AV-1451 and CSF T-tau and P-tau..." refers methods in this paper
...The dynamic scans were motion-corrected using AFNI’s 3dvolreg (Cox, 1996), time-averaged and rigidly coregistered to the skull-stripped MRI scan....
[...]
TL;DR: An automated labeling system for subdividing the human cerebral cortex into standard gyral-based neuroanatomical regions is both anatomically valid and reliable and may be useful for both morphometric and functional studies of the cerebral cortex.
9,940 citations