Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum.
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ABSTRACT: Introduction
We evaluated a new Simoa plasma assay for phosphorylated tau (P-tau) at aa217 enhanced by additional p-tau sites (p217+tau).Methods
Plasma p217+tau levels were compared to 18F-NAV4694 amyloid beta (Aβ) positron emission tomography (PET) and 18F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants.Results
Compared to Aβ- CU, the plasma levels of p217+tau increased 2-fold in Aβ+ CU and 3.5-fold in Aβ+ CI. In Aβ- the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aβ centiloids P = .67 (CI, P = .64; CU, P = .45) and tau SUVRMT P = .63 (CI, P = .69; CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aβ- CU was 0.94, for AD dementia versus other dementia was 0.93, for Aβ+ versus Aβ- PET was 0.89, and for tau+ versus tau- PET was 0.89.Discussion
Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET.
SUBMITTER: Dore V
PROVIDER: S-EPMC8984092 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum.
Doré Vincent V Doecke James D JD Saad Ziad S ZS Triana-Baltzer Gallen G Slemmon Randy R Krishnadas Natasha N Bourgeat Pierrick P Huang Kun K Burnham Samantha S Fowler Christopher C Rainey-Smith Stephanie R SR Bush Ashley I AI Ward Larry L Robertson Jo J Martins Ralph N RN Masters Colin L CL Villemagne Victor L VL Fripp Jurgen J Kolb Hartmuth C HC Rowe Christopher C CC
Alzheimer's & dementia (Amsterdam, Netherlands) 20220405 1
<h4>Introduction</h4>We evaluated a new Simoa plasma assay for phosphorylated tau (P-tau) at aa217 enhanced by additional p-tau sites (p217+tau).<h4>Methods</h4>Plasma p217+tau levels were compared to <sup>18</sup>F-NAV4694 amyloid beta (Aβ) positron emission tomography (PET) and <sup>18</sup>F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants.<h4>Results</h4>Compared to Aβ- CU, the plasma levels of p217+tau increased 2-fold in Aβ+ CU and 3.5-fold i ...[more]
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Project description:BackgroundTau positron emission tomography (PET) imaging enables longitudinal observation of tau accumulation in Alzheimer's disease (AD). 18F-MK6240 is a high affinity tracer for the paired helical filaments of tau in AD, widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the natural history of tau accumulation, and the impact of disease stage and reference region on the magnitude and effect size of regional change.MethodsOne hundred and eighty-four participants: 89 cognitively unimpaired (CU) beta-amyloid negative (Aβ-), 44 CU Aβ+, 51 cognitively impaired Aβ+ (26 with mild cognitive impairment [MCI] and 25 with dementia) had follow-up 18F-MK6240 PET for one to four years (median 1.48). Regional standardised uptake value ratios (SUVR) were generated. Two reference regions were examined: cerebellar cortex and eroded subcortical white matter.FindingsCU Aβ- participants had very low rates of tau accumulation in the mesial temporal lobe (MTL). In CU Aβ+, significantly higher rate of accumulation was seen in the MTL (particularly the amygdala), extending into the inferior temporal lobes. In MCI Aβ+, the rate of accumulation was greatest in the lateral temporal, parietal and lateral occipital cortex, and plateaued in the MTL. Accumulation was global in AD Aβ+, except for a plateau in the MTL. The eroded subcortical white matter reference region showed no significant advantage over the cerebellar cortex and appeared prone to spill-over in AD participants. Data fitting suggested approximately 15-20 years to accumulate tau to typical AD levels.InterpretationTau accumulation occurs slowly. Rates vary according to brain region, disease stage and tend to plateau at high levels. Rates of tau accumulation are best measured in the MTL and inferior temporal cortex in preclinical AD and in large neocortical areas, in MCI and AD.FundingNHMRC; Cerveau Technologies.
| S-EPMC9900352 | biostudies-literature
Project description:PurposeMK6240 is a second-generation tau PET tracer designed to detect the neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). The aim of the study was to characterize 3H-MK6240 in AD and control brain tissue and to compare its binding properties with those of first-generation tau PET tracers.MethodsSaturation binding assays with 3H-MK6240 were carried out in the temporal and parietal cortices of AD brains to determine the maximum number of binding sites (Bmax) and the dissociation constants (Kd) at these sites. Competitive binding assays were carried out between 3H-MK6240 and unlabelled MK6240, AV-1451 (aka T807, flortaucipir) and THK5117, and between 3H-THK5351 and unlabelled MK6240. Regional binding studies with 3H-MK6240 were carried out in homogenates from six AD and seven control brains and, using autoradiography, on large frozen sections from two AD brains and one control brain.ResultsThe saturation binding assays gave Bmax and Kd values of 59.2 fmol/mg and 0.32 nM in the temporal cortex and 154.7 fmol/mg and 0.15 nM in the parietal cortex. The competitive binding assays revealed two binding sites with affinities in the picomolar and nanomolar range shared by 3H-MK6240 and all the tested unlabelled compounds. There were no binding sites in common between 3H-THK5351 and unlabelled MK6240. Regional binding of 3H-MK6240 was significantly higher in AD brain tissue than in controls. Binding in brain tissue from AD patients with early-onset AD was significantly higher than in brain tissue from patients with late-onset AD. Binding of 3H-MK6240 was not observed in off-target regions. Autoradiography showed high regional cortical binding in the two AD brains and very low binding in the control brain.Conclusions3H-MK6240 has a high binding affinity for tau deposits in AD brain tissue but also has different binding characteristics from those of the first-generation tau tracers. This confirms the complexity of tau tracer binding on tau deposits with different binding affinities for different binding sites.
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Project description:The amyloid cascade model of Alzheimer's disease posits the primacy of amyloid beta deposition preceding tau-mediated neurofibrillary tangle formation. The amyloid-tau-neurodegeneration biomarker-only diagnostic framework similarly requires the presence of amyloid beta for a diagnosis on the Alzheimer's continuum. However, medial temporal lobe tau pathology in the absence of amyloid beta is frequently observed at autopsy in cognitively normal individuals, a phenomenon that may reflect a consequence of aging and has been labelled 'primary age-related tauopathy'. Alternatively, others argue that this tauopathy reflects an early stage of the developmental continuum leading to Alzheimer's disease. We used positron emission tomography imaging to investigate amyloid beta and tau positivity and associations with cognition to better inform the conceptualization of biomarker changes in Alzheimer's pathogenesis. Five hundred twenty-three individuals from the Alzheimer's Disease Neuroimaging Initiative who had undergone flortaucipir positron emission tomography imaging were selected to derive positron emission tomography positivity thresholds using conditional inference decision tree regression. A subsample of 301 individuals without dementia (i.e. those with normal cognition or mild cognitive impairment) had also undergone florbetapir positron emission tomography imaging within 12 months and were categorized into one of the four groups based on cortical amyloid and Braak stage I/II tau positivity: A-/T-, A+/T-, A-/T+, or A+/T+. Tau positivity in the absence of amyloid beta positivity (i.e. A-/T+) comprised the largest group, representing 45% of the sample. In contrast, only 6% of the sample was identified as A+/T-, and the remainder of the sample fell into A-/T- (22%) or A+/T+ (27%) categories. A-/T- and A+/T- groups had the best cognitive performances across memory, language and executive function; the A-/T+ group showed small-to-moderate relative decreases in cognition; and the A+/T+ group had the worst cognitive performances. Furthermore, there were negative associations between Braak stage I/II tau values and all cognitive domains only in the A-/T+ and A+/T+ groups, with strongest associations for the A+/T+ group. Among our sample of older adults across the Alzheimer's pathological spectrum, 7-fold fewer individuals have positron emission tomography evidence of amyloid beta pathology in the absence of tau pathology than the converse, challenging prevailing models of amyloid beta's primacy in Alzheimer's pathogenesis. Given that cognitive performance in the A-/T+ group was poorer than in individuals without either pathology, our results suggest that medial temporal lobe tau without cortical amyloid beta may reflect an early stage on the Alzheimer's pathological continuum.
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Project description:Staging the severity of Alzheimer's disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid and tau PET has face validity; however, this would be more practical with plasma biomarkers. Our objectives were, first, to examine approaches for staging amyloid and tau PET and, second, to examine prediction of amyloid and tau PET stages using plasma biomarkers. Participants (n = 1136) were enrolled in either the Mayo Clinic Study of Aging or the Alzheimer's Disease Research Center; had a concurrent amyloid PET, tau PET and blood draw; and met clinical criteria for cognitively unimpaired (n = 864), mild cognitive impairment (n = 148) or Alzheimer's clinical syndrome with dementia (n = 124). The latter two groups were combined into a cognitively impaired group (n = 272). We used multinomial regression models to estimate discrimination [concordance (C) statistics] among three amyloid PET stages (low, intermediate, high), four tau PET stages (Braak 0, 1-2, 3-4, 5-6) and a combined amyloid and tau PET stage (none/low versus intermediate/high severity) using plasma biomarkers as predictors separately within unimpaired and impaired individuals. Plasma analytes, p-tau181, Aβ1-42 and Aβ1-40 (analysed as the Aβ42/Aβ40 ratio), glial fibrillary acidic protein and neurofilament light chain were measured on the HD-X Simoa Quanterix platform. Plasma p-tau217 was also measured in a subset (n = 355) of cognitively unimpaired participants using the Lilly Meso Scale Discovery assay. Models with all Quanterix plasma analytes along with risk factors (age, sex and APOE) most often provided the best discrimination among amyloid PET stages (C = 0.78-0.82). Models with p-tau181 provided similar discrimination of tau PET stages to models with all four plasma analytes (C = 0.72-0.85 versus C = 0.73-0.86). Discriminating a PET proxy of intermediate/high from none/low Alzheimer's disease neuropathological change with all four Quanterix plasma analytes was excellent but not better than p-tau181 only (C = 0.88 versus 0.87 for unimpaired and C = 0.91 versus 0.90 for impaired). Lilly p-tau217 outperformed the Quanterix p-tau181 assay for discriminating high versus intermediate amyloid (C = 0.85 versus 0.74) but did not improve over a model with all Quanterix plasma analytes and risk factors (C = 0.85 versus 0.83). Plasma analytes along with risk factors can discriminate between amyloid and tau PET stages and between a PET surrogate for intermediate/high versus none/low neuropathological change with accuracy in the acceptable to excellent range. Combinations of plasma analytes are better than single analytes for many staging predictions with the exception that Quanterix p-tau181 alone usually performed equivalently to combinations of Quanterix analytes for tau PET discrimination.
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Project description:Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([18F]MK6240), beta-amyloid (Aβ)-PET ([18F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aβ and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aβ+> Aβ- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.
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Project description:Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer's diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer's pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer's pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P < 0.0001), tau (0.25, P = 0.0003), and FDG PET uptakes (-0.37, P < 0.0001), and increased along the Alzheimer's continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level (>18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32-4.08) and FDG PET (3.21, 95%CI 2.06-5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer's pathophysiology.
| S-EPMC8590691 | biostudies-literature
Project description:Recent mechanistic and structural studies have challenged the classical tauopathy classification approach and revealed the complexity and heterogeneity of tau pathology in Alzheimer's disease (AD) and primary tauopathies such as corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), progressing beyond distinct tau isoforms. In this multi-tau tracer study, we focused on the new second-generation tau PET tracers PI2620, MK6240 and RO948 to investigate this tau complexity in AD, CBD, and PSP brains using post-mortem radioligand binding studies and autoradiography of large and small frozen brain sections. Saturation binding studies indicated multiple binding sites for 3H-PI2620 in AD, CBD and PSP brains with different binding affinities (Kd ranging from 0.2 to 0.7 nM) and binding site densities (following the order: BmaxAD > BmaxCBD > BmaxPSP). Competitive binding studies complemented these findings, demonstrating the presence of two binding sites [super-high affinity (SHA): IC50(1) = 8.1 pM; and high affinity (HA): IC50(2) = 4.9 nM] in AD brains. Regional binding distribution studies showed that 3H-PI2620 could discriminate between AD (n = 6) and control cases (n = 9), especially in frontal cortex and temporal cortex tissue (p < 0.001) as well as in the hippocampal region (p = 0.02). 3H-PI2620, 3H-MK6240 and 3H-RO948 displayed similar binding behaviour in AD brains (in both homogenate competitive studies and one large frozen hemispherical brain section autoradiography studies) in terms of binding affinities, number of sites and regional patterns. Our small section autoradiography studies in the frontal cortex of CBD (n = 3) and PSP brains (n = 2) showed high specificity for 3H-PI2620 but not for 3H-MK6240 or 3H-RO948. Our findings clearly demonstrate different binding properties among the second-generation tau PET tracers, which may assist in further understanding of tau heterogeneity in AD versus non-AD tauopathies and suggests potential for development of pure selective 4R tau PET tracers.
| S-EPMC10005967 | biostudies-literature
Project description:Alzheimer's disease (AD) patients are known to have heterogeneous clinical presentation and pathologic patterns. We hypothesize that AD dementia can be categorized into subtypes based on multimodal imaging biomarkers such as magnetic resonance imaging (MRI), tau positron emission tomography (PET), and amyloid PET. We collected 3T MRI, 18F-THK5351 PET, and 18F-flutemetamol (FLUTE) PET data from 83 patients with AD dementia [Clinical Dementia Rating (CDR) ≤1] and 60 normal controls (NC), and applied surface-based analyses to measure cortical thickness, THK5351 standardized uptake value ratio (SUVR) and FLUTE SUVR for each participant. For the patient group, we performed an agglomerative hierarchical clustering analysis using the three multimodal imaging features on the vertices (n = 3 × 79,950). The identified AD subtypes were compared to NC using general linear models adjusting for age, sex, and years of education. We mapped the effect size within significant cortical regions reaching a corrected p-vertex <0.05 (random field theory). Our surface-based multimodal framework has revealed three distinct subtypes among AD patients: medial temporal-dominant subtype (MT, n = 44), parietal-dominant subtype (P, n = 19), and diffuse atrophy subtype (D, n = 20). The topography of cortical atrophy and THK5351 retention differentiates between the three subtypes. In the case of FLUTE, three subtypes did not show distinct topographical differences, although cortical composite retention was significantly higher in the P type than in the MT type. These three subtypes also differed in demographic and clinical features. In conclusion, AD patients may be clustered into three subtypes with distinct topographical features of cortical atrophy and tau deposition, although amyloid deposition may not differ across the subtypes in terms of topography.
| S-EPMC6710378 | biostudies-literature
Project description:BackgroundWe aimed to investigate the tau biomarker discrepancies of Alzheimer's disease (AD) using plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and AV1451 positron emission tomography (PET).MethodsIn the Alzheimer's Disease Neuroimaging Initiative, 724 non-demented participants were categorized into plasma/CSF and plasma/PET groups. Demographic and clinical variables, amyloid-β (Aβ) burden, flortaucipir-PET binding in Braak regions of interest (ROIs), longitudinal changes in clinical outcomes, and conversion risk were compared.ResultsAcross different tau biomarker groups, the proportion of participants with a discordant profile varied (plasma+/CSF- 15.6%, plasma-/CSF+ 15.3%, plasma+/PET- 22.4%, and plasma-/PET+ 6.1%). Within the plasma/CSF categories, we found an increase from concordant-negative to discordant to concordant-positive in the frequency of Aβ pathology or cognitive impairment, rates of cognitive decline, and risk of cognitive conversion. However, the two discordant categories (plasma+/CSF- and plasma-/CSF+) showed comparable performances, resulting in similarly reduced cognitive capacities. Regarding plasma/PET categories, as expected, PET-positive individuals had increased Aβ burden, elevated flortaucipir retention in Braak ROIs, and accelerated cognitive deterioration than concordant-negative persons. Noteworthy, discordant participants with normal PET exhibited reduced flortaucipir uptake in Braak stage ROIs and slower rates of cognitive decline, relative to those PET-positive. Therefore, individuals with PET abnormality appeared to have advanced tau pathological changes and poorer cognitive function, regardless of the plasma status. Furthermore, these results were found only in individuals with Aβ pathology.ConclusionsOur results indicate that plasma and CSF p-tau181 abnormalities associated with amyloidosis occur simultaneously in the progression of AD pathogenesis and related cognitive decline, before tau-PET turns positive.
| S-EPMC8094494 | biostudies-literature
Project description:IntroductionThe timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co-evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers.MethodsWe included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aβ) PET, tau PET, plasma p-tau217, p-tau181, and glial fibrillary acidic protein (GFAP) as endpoints.ResultsIndividual timing of plasma p-tau progression was strongly associated with Aβ PET and GFAP progression. In the population, GFAP became abnormal first, then Aβ PET, plasma p-tau, and tau PET temporal meta-regions of interest when applying cut points based on young, cognitively unimpaired participants.DiscussionPlasma p-tau is a stronger indicator of a temporally linked response to elevated brain Aβ than of tau pathology. While Aβ deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p-tau and Aβ PET was the strongest.HighlightsPlasma p-tau progression was more strongly associated with Aβ than tau PET. Progression on plasma p-tau was associated with Aβ PET and GFAP progression. P-tau181 and p-tau217 become abnormal after Aβ PET and before tau PET. GFAP became abnormal first, before plasma p-tau and Aβ PET.
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