Plasma Tau Research Articles

A head‐to‐head comparison of plasma phosphorylated tau assays in the real‐world memory clinic

AbstractBackgroundSeveral blood phosphorylated tau (P‐tau) species (P‐tau181, P‐tau217, and P‐tau231) have shown high accuracy to detect AD pathology, but a direct comparison of the main blood P‐tau assays in a real‐world memory clinic is needed. The main aim of this study is to perform a head‐to‐head comparison of 9 plasma Tau assays and determine their accuracy to discriminate between symptomatic AD from non‐AD.MethodThis is an observational and cross‐sectional study in the BIODEGMAR cohort, which includes patients presenting with cognitive complaints at the Cognitive Decline and Movement Disorders Unit of Hospital del Mar (Barcelona, Spain). Patients were classified into an AD CSF profile group or a non‐AD CSF profile group according to their CSF Aβ42/P‐tau181 ratio (Lumipulse, Fujirebio), and the discrimination accuracy of 9 plasma Tau assays was tested. All plasma samples were treated identically and measurements were performed in a blinded fashion.ResultA total of 197 participants (109 women [55.3%]; mean [SD] age, 72.3 [5.83] years), were investigated. All plasma Tau biomarkers were significantly higher in the AD CSF profile group than in the non‐AD CSF profile group. For plasma Tau biomarkers, the largest effect sizes were found in plasma Janssen P‐tau217 (r = 0.76), Lilly P‐tau217 (r = 0.73), ADx P‐tau181 (r = 0.73), Lilly P‐tau181 (r = 0.68), and UGot P‐tau231 (r = 0.63). All plasma Tau biomarkers significantly discriminated between patients with an AD CSF profile group from those with a non‐AD CSF profile. The AUC of plasma Tau biomarkers were the following (from highest to lower): Janssen P‐tau217 (0.96; 95% CI, 0.93‐0.99), ADx P‐tau181 (0.94; 95% CI, 0.91‐0.97) and Lilly P‐tau217 (0.94; 95% CI, 0.90‐0.98), Lilly P‐tau181 (0.91; 95% CI, 0.87‐0.96), UGot P‐tau231 (0.88; 95% CI, 0.83‐0.93), Quanterix P‐tau181 (0.80; 95% CI, 0.73‐0.87), UGot P‐tau181 (0.80; 95% CI, 0.73‐0.87), Lilly Total‐tau (0.73; 95% CI, 0.65‐0.81), and ADx P‐tau231 (0.66; 95% CI, 0.58‐0.74).ConclusionThe findings indicate that there are several plasma P‐tau biomarkers that can be used in a memory clinic setting as a stand‐alone biomarker to detect AD pathology in a diverse group of patients presenting with cognitive complaints.

Associations among plasma ptau181, tau PET, and amyloid PET in a community‐based study during midlife

AbstractBackgroundThe amyloid‐tau‐neurodegeneration (AT(N)) research framework uses a biomarker definition of Alzheimer’s disease (AD); neuroimaging has been the in vivo gold standard, but plasma‐based measures are becoming more widely available yet need to be characterized earlier in the life course and AD continuum, as well as in representative samples. Our objective was to understand how plasma measures of ptau181 correspond with PET‐derived measures of amyloid and tau in middle age.MethodsIn the ongoing Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease, participants (n=61; 61±6, 52‐79 years old, 67% women, 14±4 years of education, 10% Non‐Latinx White/25% Non‐Latinx Black/65% Latinx) underwent measures of amyloid (weighted average Florbetaben SUVR in Thaal phase regions) and tau (average MK‐6240 SUVR in Braak stage I; SIMOA‐based plasma ptau181). Amyloid‐positivity was determined at >1.25 SUVR and tau‐positivity was determined at >2 SD above the mean SUVR in an independent sample of cognitively unimpaired individuals. General linear models tested associations among plasma ptau181, tau PET, and amyloid PET.ResultsFifteen percent were amyloid‐positive while five percent were tau‐positive. Ptau181 was not associated with PET‐based tau burden (R=‐0.18, p=0.17). Amyloid burden increased with age (R=0.37, p=0.003). PET‐based tau burden increased with amyloid (R=0.29, p=0.02), but not with age (R=0.16, p=0.22). Conversely, ptau181 increased with amyloid (R=0.26, p=0.04) and with age (R=0.25, p=0.05).ConclusionsA temporal discrepancy between plasma and PET‐based tau, particularly in a sample of mostly amyloid‐ and tau‐negative middle‐aged adults, may explain the lack of association between ptau181 and tau PET. However, both plasma and PET‐based tau were associated with elevated amyloid burden, which is thought to be necessary for the spreading of pathological tau in AD. Prior studies suggest that associations between plasma ptau181 and tau PET are stronger and shift from early Braak stage regions to late Braak stage regions further along the AD continuum. Therefore, it is important to understand the utility of plasma ptau181 in the context of age and disease stage.

The effects of age and sex on plasma p‐tau181 concentrations in Alzheimer’s Disease

AbstractBackgroundQuantifying levels of phosphorylated tau in plasma is a highly promising and specific marker for Alzheimer’s disease (AD), but limited data are available on the effect of age on plasma p‐tau181 concentrations in specific clinical groups and especially control subjects. Similarly, the effect of sex on concentration of plasma ptau‐181 levels are unclear.MethodA total of 343 samples of EDTA plasma from patients examined at the UBC Hospital Alzheimer Clinic between 2008 – 2018 included.The patients had been referred with complaint of cognitive impairment and were assessed for dementia and they sorted into four diagnostic groups: Non‐Cognitive Impairment (NCI), non‐ AD neurodegenerative diseases, possible AD, and probable AD, according to US National Institute on Aging (NIA) and the Alzheimer’s Association (AA) criteria diagnosis. The concentrations of their plasma p‐tau181 was measured by a homebrew ADX assay on SIMOA HD‐X platform. We analysed the effect of age and sex on the concentrations of plasma p‐tau181 among and within clinically defined groups. We also assessed p‐tau181 levels in a separate group of healthy individuals (n=60).ResultThere was no significant sex difference in p‐tau181 levels across and between the diagnostic categories (p=0.426). We also confirmed there was not any correlation between age and p‐tau181 levels in healthy controls. Moreover, we did not find any correlation between the age and plasma concentrations of p‐tau181 within each diagnostic group separately. Further with two model linear regression, age was not found to be a significant contributor of plasma p‐tau181 variations (F (3, 429) = 109.04, B=.16, t= 1.42, p<0.16).Interestingly, there was a correlation between average of plasma p‐tau181 with age among the spectrum from NCI to AD.ConclusionWe did not detect any sex difference in plasma p‐tau181 levels. Our findings about the age‐effect of plasma p‐tau181 levels especially within and among diagnostic groups might be described by the intricate dynamics, and kinetics of p‐tau181 in brain and plasma and it needs to investigate with larger healthy control population and multicenter clinical studies.

Alzheimer‐like biomarker heterogeneity in a preclinical elderly birth cohort: Insight46

AbstractBackgroundTwo main complexities of Alzheimer’s Disease (AD) arise from pathological changes (such as amyloid accumulation) occurring a decade or more before symptom onset, and AD being a highly heterogeneous disease with various clinical subtypes. Subtype and Stage Inference (SuStaIn), a data‐driven modelling technique, has been previously applied to ADNI to better understand AD. Here we apply SuStaIn to Insight46, a sub‐study of the British 1946 Birth Cohort to detect different trajectories of preclinical neurodegeneration.MethodSuStaIn was applied to cross‐sectional MRI, amyloid PET, plasma biomarkers, and cognition (Preclinical Alzheimer Cognitive Composite [PACC]) from 466 study members (Table 1). 376 Amyloid‐negative individuals (computed as Lane et al. 2019) were designated as controls. SuStaIn subtypes were also estimated in ADNI (N=789; Tables 1 and 2) for comparison. T‐tests and Chi‐squared tests were used to assess subtype differences in baseline APOE, amyloid status, white matter hyperintensity volume (WMHV), and rates of change in whole brain, ventricular and hippocampal volume calculated using the boundary shift integral.ResultFigure 1 shows three subtypes uncovered by SuStaIn: ‘Typical’, ‘Subcortical’ and ‘Cortical’. The ‘Typical’ subtype appears to reflect a typical AD progression pattern, with early involvement of Aβ40/42 ratio and Neurofilament light (NFL), followed by the PACC and finally, plasma tau. MRI volumetric changes appear later. Both ‘Subcortical’ and ‘Cortical’ subtypes are characterised by earlier abnormality in MRI volumes.Figure 2 shows that subjects assigned to the ‘Cortical’ subtype had significantly higher WMHV than the other two subtypes (p‐value < 0.002). No other significant differences in baseline characteristics were found.Figure 3 shows ‘Typical’ subtype has significantly higher rates of ventricular expansion and whole brain atrophy compared with ‘Subcortical’ subtype (p‐values = 0.001).ConclusionThis study reveals three different subtypes (‘Typical’, ‘Subcortical’ and ‘Cortical’) of presumed neurodegeneration in an elderly, preclinical cohort; these are consistent with those found in AD patient cohorts, e.g. ADNI, meaning that these methods may have utility in population based cohorts. These results suggest that SuStaIn may be helpful in determining different subtypes of neurodegeneration at a very early stage with implications for recruitment to, and powering of, clinical trials.

Association between recollection and familiarity‐based memory measures and plasma biomarkers for Alzheimer’s disease

AbstractBackgroundNormal aging and preclinical Alzheimer’s Disease (AD) share common features, such as structural changes to medial temporal lobe regions and declining episodic memory. However, prior work suggests qualitative differences between AD‐related memory changes and those due to aging. Specifically, recollection‐based, or contextual, memory declines with both normal aging and AD. Alternatively, familiarity‐based, or item, memory is more specific to preclinical AD and atrophy in the perirhinal cortex. In the current analysis, we examined the relationship between these forms of memory with plasma biomarkers associated with AD and neurodegeneration.MethodAt the Penn Alzheimer’s Disease Research Center, 127 cognitively‐normal participants (age=73.12±6.62, 59% female, years of education=16.40±2.62, 80% Caucasian) completed an experimental memory paradigm assessing recollection and familiarity along with standard neuropsychological testing. In this paradigm, pictures of common objects were presented in 80 pairs at study and participants were told to pick the object they preferred. At test, 40 intact, 40 re‐arranged, and 40 novel object pairs were presented. Recollection was defined as the probability(intact)–probability(rearranged), while familiarity was defined as the probability(rearranged)/(1‐R). To account for differences in base rates of false alarms (‘‘old’’ responses to novel pairs), familiarity was calculated using a measure of discrimination (d’) derived from signal detection theory. Whole blood samples were collected in EDTA‐tubes, spun‐down, and stored at ‐80°C. Measures of glial fibrillary acidic protein (GFAP), neurofilament light chain (Nfl), and plasma tau (p‐Tau181) were generated with the Simoa HD‐X analyzer system.ResultFamiliarity correlated with GFAP (r(125) =‐0.24, p<0.05) (Figure 1) and NfL (r(125) =‐0.23, p<0.05) (Figure 2). Further, a partial correlation controlling for age and days between the experimental and plasma measure remained significant for GFAP (r(125)=‐0.25, p<0.05). Additionally, recollection correlated with Nfl (r(125) =‐0.25, p<0.05) (Figure 3). Correlations with standard neuropsychological tests revealed no significant results.ConclusionThis study reveals that within the normal aging spectrum, familiarity‐based memory correlates with molecular measures that have been associated with amyloid (GFAP), while both measures correlated with a non‐specific measure of neurodegeneration (NfL). This supports the notion that familiarity may be sensitive to preclinical AD.

Investigation of relationship between tau PET SUVR and an indicator of post‐translational modification of tau in human blood plasma using electrochemical assay

AbstractBackgroundHuman tau protein is a well‐known biomarker to predict and diagnose the progress of Alzheimer’s disease [1]. The tau protein undergoes various post‐translational modificiation (PTM) of tau such as phosphorylation, O‐glycosylation, nitration, and glycation. Recently, abnormal phosphorylation of tau protein is observed in AD patients, while the level of O‐GlcNAcylation on tau protein is relatively elevated in brains of normal controls [2]. Reference: [1] L.M. Ittner et al. Nature Reviews Neuroscience, 12 (2011) 67. [2] C. Alquezar et al. Frontiers in Neurology, 11 (2021) 595532:Method(Figure 1) To investigate tau protein in human blood plasma and its PTM, a novel type of electrochemical sensor demonstrated and obtained Taumeter, an indicator as relative impedance changes of phosphorylated tau and O‐glycosylated tau, using secondary antibodies Finally, the as‐obtained Taumeter and PET SUVR were investigated for a relationship.ResultWe investigated the clinical relationship between Taumeters for AT8 and AT270 and tau PET SUVR, respectively, obtained from human blood plasma from normal control (NC, n=9), mild cognitive impairment (MCI, n=14), and Alzheimer’s disease (AD, n=13). In the case of AT8, it was observed that average Taumeters in MCI and AD were 2.86 and 4.73 times higher than those in NC (p=0.078 between NC and AD) (Figure 2a). In the case of AT270, average Taumeters in MCI and AD were 1.84 and 4.24 times higher than those in NC (p=0.057 between NC and AD) (Figure 2b). In further study, Taumeters for AT8 and AT270 correlated with tau PET SUVR (r=0.151, p=0.384 and r=0.575, p<0.001) (Figure 2c‐d).ConclusionIn this study, we investigated Taumeter reflecting PTM of tau proteins using secondary antibodies (O‐GlcNAc antibody, AT8, and AT270) in human blood and tau PET scan to investigate the relationship of Taumeter and tau PET SUVR in NC, MCI, and AD. As a result, it can be carefully implied that Taumeter has the relationship with the progress of AD.

Biomarker modelling of Alzheimer's disease using in vivo Braak staging

AbstractBackgroundGold standard diagnostic methods for AD rely on staging systems to measure disease severity, which have not yet been incorporated into the in vivo biological research framework for AD. The topographical information conferred by tau‐PET offers the potential to translate the gold standard histopathological Braak staging system to living individuals.MethodUsing the topographical information from [18F]MK6240 tau‐PET, we applied the Braak tau staging system to 324 living individuals. We used PET‐based Braak stage to model the trajectories of amyloid‐b, phosphorylated tau in cerebrospinal fluid (pTau181, pTau217, pTau231, pTau235) and plasma (pTau181, pTau231), neurodegeneration and cognitive symptoms.ResultPET‐based Braak stages were We identified nonlinear AD biomarker trajectories corresponding to the spatial extent of tau‐PET, with modest biomarker changes detectable by Braak stage II and significant changes occurring at stages III‐IV, followed by plateaus. Early Braak stages were associated with isolated memory impairment, while Braak stages V‐VI were incompatible with normal cognition. Follow up tau‐PET scans indicated sequential progression of in vivo Braak stages over time, with progression beyond Braak stage III requiring the presence of amyloid‐beta abnormality.ConclusionOur results support PET‐based Braak staging as a framework to model the natural history of AD, as well as monitor AD severity from presymptomatic to clinical dementia phases.

Comparison of plasma amyloid, tau, and astrocyte biomarkers to identify AD pathophysiology

AbstractBackgroundAlthough it has been alredy demonstrated that plasma amyloid‐β (Aβ), phosphorylated tau (p‐tau), and glial fibrillar protein (GFAP) can predict with high accuracy Alzheimer's disease (AD) pathophysiology, no previous study has compared their performance in the same set of individuals. Here, we compare the performance of plasma Aβ42/40, p‐tau, GFAP, and NfL against Aβ and tau PET across the AD spectrum.MethodWe used the ROC curve to test the predictive performance of Simoa plasma Aβ42/40, p‐tau (at threonine 181 and 231), NfL, and GFAP to identify Aβ and Pau PET positivity in 138 cognitive unimpaired (CU) and 87 cognitive impaired (CI) from the McGill TRIAD cohort. Pearson correlation and linear regression tested the association between markers.ResultWe showed that plasma p‐tau231, p‐tau181, GFAP, and NfL correlated with each other (Figure 1), while Aβ42/40 did not. In CU, voxel‐wise linear regressions (Figure 2A) showed that p‐tau231, p‐tau181, and GFAP concentrations were significantly associated with Aβ‐PET (Figure 2A). While for Tau‐PET (Figure 2B), there was a significant association only with p‐tau231 and p‐tau181 (Figure 2B). P‐tau231 outperformed the other plasma biomarkers to identify both Aβ‐ and Tau‐PET positivity (AUC 0.877 and 0.796, respectively) in CU individuals. In CI, Aβ‐ and Tau‐PET were significantly associated with p‐tau231, p‐tau181, and GFAP, whereas NfL was only associated with Tau‐PET. The discriminative accuracy of GFAP in identifying both Aβ‐PET and Tau positivity (AUC 0.936 and 0.944, respectively) outperformed the other plasma biomarkers in CI individuals (Figure 3, Table 1).ConclusionWe showed that plasma p‐tau231, a novel biomarker of early AD, best depicted AD pathophysiology in CU individuals. Interestingly, GFAP, an astrocyte reactivity marker, was better associated with brain Aβ and tau pathologies than plasma p‐tau and Aβ markers in CI individuals. Our results highlight that the performance of the novel plasma biomarkers of amyloid, tau and neuroinflammation to detect brain AD pathophysiology is disease stage specific.

Plasma phospho‐tau predicts differences in white matter microstructural complexity and cognition in non‐demented older adults

AbstractBackgroundWhite matter (WM) measures from diffusion magnetic resonance imaging (dMRI) are sensitive to Alzheimer’s disease (AD) pathology and cognitive impairment. Whereas most extant dMRI studies focused on uniformly‐oriented WM fiber tracts, variations in crossing fiber regions also show sensitivity to mild cognitive impairment (MCI) and AD diagnoses. Such crossing fiber alterations may reflect differential disease effects on constituent fibers, suggesting that quantifying crossing fibers may provide unique markers of early WM changes and neurocognitive risk in AD and MCI. Although few methods exist for quantifying crossing fibers, recent findings show older age is associated with increased microstructural complexity (CX) a novel method to characterize in crossing fibers. The present study evaluated CX in relation to variation in plasma AD biomarkers and cognitive performance in older adults without dementia.MethodData from 48 participants included clinical evaluation, neuropsychological assessment, dMRI neuroimaging and venipuncture. SIMOA assays quantified the AD plasma biomarkers Aβ42, Aβ40, and tau phosphorylated at threonine181 (pTau‐181). Participants were clinically characterized as cognitively normal (n=19) or with MCI (amnestic: n=18; non‐amnestic: n=11). Diagnostic groups did not differ with respect to years of age and education, systolic and diastolic blood pressure, proportions of men and women, proportions of APOE ε4 allele carriers, or plasma biomarker levels. Processing of dMRI data followed the MRtrix fixel‐based analysis (FBA) framework to estimate voxelwise CX data for all participants.ResultVoxelwise regression of whole‐brain CX on pTau‐181 levels revealed a significant positive effect in the dorsal cingulum bundle and adjacent corpus callosum. Post hoc regression of mean CX sampled from significant voxels on pTau‐181 showed greater pTau‐181 level strongly predicts higher CX in this region (partial‐R=0.579, p<0.001), even while controlling for age, education, and Montreal Cognitive Assessment (MoCA) score. Path analysis linking pTau‐181 and cognition showed elevated circulating pTau‐181 levels strongly predict increased white matter complexity in mid‐cingulum bundle, which in turn predicts reduced cognitive performance on measures of working memory, list learning, and semantic fluency.ConclusionMicrostructural complexity in crossing fiber WM regions provides a sensitive marker of early WM alterations associated with elevated plasma phospho‐tau and cognitive decrements in non‐demented older adults.

Comparison of plasma amyloid, tau, and astrocyte biomarkers to identify AD pathophysiology

AbstractBackgroundAlthough it has been already demonstrated that plasma amyloid‐β (Aβ), phosphorylated tau (p‐tau), and glial fibrillar protein (GFAP) can predict with high accuracy Alzheimer's disease (AD) pathophysiology, no previous study has compared their performance in the same set of individuals. Here, we compare the performance of plasma Aβ42/40, p‐tau, GFAP, and NfL against Aβ and tau PET across the AD spectrum.MethodWe used the ROC curve to test the predictive performance of Simoa plasma Aβ42/40, p‐tau (at threonine 181 and 231), NfL, and GFAP to identify Aβ and Pau PET positivity in 138 cognitive unimpaired (CU) and 87 cognitive impaired (CI) from the McGill TRIAD cohort. Pearson correlation and linear regression tested the association between markers.ResultWe showed that plasma p‐tau231, p‐tau181, GFAP, and NfL correlated with each other (Figure 1), while Aβ42/40 did not. In CU, voxel‐wise linear regressions (Figure 2A) showed that p‐tau231, p‐tau181, and GFAP concentrations were significantly associated with Aβ‐PET (Figure 2A). While for Tau‐PET (Figure 2B), there was a significant association only with p‐tau231 and p‐tau181 (Figure 2B). P‐tau231 outperformed the other plasma biomarkers to identify both Aβ‐ and Tau‐PET positivity (AUC 0.877 and 0.796, respectively) in CU individuals. In CI, Aβ‐ and Tau‐PET were significantly associated with p‐tau231, p‐tau181, and GFAP, whereas NfL was only associated with Tau‐PET. The discriminative accuracy of GFAP in identifying both Aβ‐PET and Tau positivity (AUC 0.936 and 0.944, respectively) outperformed the other plasma biomarkers in CI individuals (Figure 3, Table 1).ConclusionWe showed that plasma p‐tau231, a novel biomarker of early AD, best depicted AD pathophysiology in CU individuals. Interestingly, GFAP, an astrocyte reactivity marker, was better associated with brain Aβ and tau pathologies than plasma p‐tau and Aβ markers in CI individuals. Our results highlight that the performance of the novel plasma biomarkers of amyloid, tau and neuroinflammation to detect brain AD pathophysiology is disease stage specific.

Plasma levels of an N‐terminal tau fragment predict core AD and neurodegenerative biomarkers in autosomal dominant Alzheimer’s disease: Findings from DIAN

AbstractBackgroundBlood based biomarkers that predict cognitive decline and Alzheimer’s disease (AD) pathology have the potential to accelerate AD therapeutic development and improve clinical care. Prior work suggests that plasma biomarkers of tau pathology (particularly post‐translational modifications of tau) may be highly useful in diagnosis and risk stratification for AD‐related neurodegeneration and cognitive decline. Levels of tau species lacking truncation of the N‐terminal region, particularly plasma and cerebrospinal fluid (CSF) levels of N‐terminal tau fragment 1 (NT1), have previously been shown to predict cognitive decline, neurodegeneration, and tau pathology in preclinical and symptomatic late‐onset AD. Here we examined plasma NT1 as a possible predictor of cognitive, clinical, pathologic, and neurodegenerative trajectories in autosomal dominant AD (ADAD) using data from the Dominantly Inherited Alzheimer Network Observational Study (DIAN‐Obs).MethodsAssociations between plasma NT1 levels and Mini‐Mental State Exam (MMSE), Clinical Dementia Rating SumBox® (CDR‐SB), hippocampal volume (HV), estimated years to symptom onset (EYO), Pittsburgh‐Compound‐B PET, and CSF Aβ42, and p‐tau181 were assessed using linear regression (150 pathogenic variant carriers, 81 non‐carriers; mean[SD] carrier age = 40.1 [10.4] years and EYO = ‐5.4 [10.4]). Plasma NT1 was measured using the Quanterix HD‐X platform. PET, MRI, clinical, and biofluid measures were derived using previously described procedures in DIAN‐Obs.ResultsCross‐sectional plasma NT1 levels in ADAD carriers were significantly associated with MMSE, CDR‐SB, HV, and p‐tau181 even after adjusting for EYO (Table 1; Figure 1). NT1 levels statistically diverged between carriers and non‐carriers 6.8 years before estimated symptom onset (Figure 2). In contrast, plasma NT1 levels were not significantly correlated with measures of β‐amyloid pathology after adjusting for EYO.ConclusionPlasma NT1 levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with CSF measures of tau pathology, but NT1 levels were not strongly associated with CSF or PET measures of β‐amyloid pathology, unlike some previously‐studied plasma tau measures. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1 may be a useful biomarker of AD‐related tau pathology and neurodegeneration across a broad spectrum of disease.

18F]RO‐948 Tau PET Retention and Correlation with Fluid Tau Biomarkers in the Early AD Continuum

AbstractBackgroundTau positron emission tomography (PET) imaging enables the in vivo visualization of tau aggregates occurring during the progression of Alzheimer’s disease (AD). Tau PET imaging is a promising biomarker for clinical diagnosis and tracking of disease progression. However, the sensitivity of tau PET in detecting early tau pathology within the early AD continuum and its association with fluid tau biomarkers remains to be established.MethodForty‐seven cognitively unimpaired individuals from the ALFA+ cohort had [18F]RO‐948 and [18F]flutemetamol PET, T1‐weighted magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and plasma tau biomarkers available (Table1). CSF amyloid(A) and tau(T) positivity were defined using CSF Aß42/40 ratio and ptau181 measured by the exploratory NeuroToolKit and Elecsys® immunoassays, respectively, according to pre‐established thresholds (Milà‐Alomà et al., 2020). Centiloid (CL) values were obtained from [18F]flutemetamol PET scans using a validated pipeline. [18F]RO‐948 uptake was measured in entorhinal (BraakI/II), limbic (BraakIII/IV), and neocortical (BraakV/VI) regions and normalized to the inferior cerebellum to render SUVR values. Regional positivity thresholds per Braak stage were calculated as the median plus two robust standard deviations. Associations between [18F]RO‐948 SUVRs and fluid tau biomarkers were evaluated using Spearman’s rho correlations. P‐values<0.05 were considered statistically significant. [18F]RO‐948 SUVRs were modeled against CL values using the data‐driven robust LOWESS method.ResultIn BraakI/II, 5 cases were considered to be positive, 3 in BraakIII/IV and 2 in BraakV/VI (see Table2 for thresholds), all of them being A+T+. Significant correlations with fluid biomarkers were observed in all Braak stages (Table3, Figure1). [18F]RO‐948 SUVR in BraakI/II showed a linear trend with CL values and inflection points between 20 and 30 CLs were observed for all Braak stages (Figure2).ConclusionA progressively lower number of [18F]RO‐948 PET‐positive cases were detected for more advanced Braak stages as expected from neuropathological studies. [18F]RO‐948 uptake started increasing around 20‐30 CLs and correlated with wet tau biomarkers in cognitively unimpaired individuals, suggesting that [18F]RO‐948 PET can be more sensitive to initial tau pathology than previously thought. These preliminary findings demonstrate that the ALFA+ cohort is well‐suited to study early pathophysiological alterations in preclinical AD stages.

Simultaneous Mass Spectrometric quantification of multiple p‐tau species in plasma – findings along the Alzheimer´s disease continuum

AbstractBackgroundBlood phosphorylated tau (p‐tau) species at positions 181, 217 and 231 have been demonstrated accurate biomarkers of Alzheimer´s disease pathology. Comparisons to assess the performance of each phosphorylation along the Alzheimer´s disease (AD) continuum rely on the use of different immunoassays. In the current study, we simultaneously quantified the plasma concentration of six different phosphorylated (p‐tau 181, 199, 202, 205, 217 and 231), and two non‐phosphorylated, tau peptides using a targeted Mass Spectrometric (MS) method.MethodWe analysed a total of 224 samples from two centres, the TRIAD cohort (Canada) and the BioCogBank Paris Lariboisière cohort (France). Tau enrichment prior to MS analysis was performed by immunoprecipitation, using a combination of several non‐phospho‐tau antibodies, followed by tryptic digestion. A parallel reaction monitoring method with Orbitrap MS was used to measure the levels of targeted peptides. Group‐level comparisons were carried with non‐parametric tests. Cross‐sectional associations between plasma tau biomarkers and Aβ and tau PET were investigated using the locally estimated scatterplot smoothing (LOESS) method for local polynomial regression. Voxel‐wise correlations were performed between plasma and PET biomarkers using Rminc.ResultP‐tau231 levels were significantly increased in amyloid positive and tau negative (A+T‐) individuals compared to A‐T‐ (stratified by CSF biomarkers). Increases in p‐tau217 and p‐tau205 emerged later in the AD continuum, only when tau pathology was present (A+T+). Plasma p‐tau217, p‐tau231 and p‐tau205 were the site‐specific phosphorylations that showed higher correlations with Tau PET (Braak I‐VI) (R=0.7 p<0.0001; R=0.53 p<0.0001; and R=0.53 p<0.0001; respectively) and with Aβ PET (R=0.66 p<0.0001; R=0.56 p<0.0001; R=0.45 p<0.0001, respectively). LOESS analysis revealed that plasma p‐tau231 increases earlier in the disease progression, followed by p‐tau217 and p‐tau205, which showed a progressive increase along Braak stages and amyloid centiloid. Voxel‐wise analysis for tau PET were highest with p‐tau205 with associations in in the inferior, medial, and lateral temporal regions. For Aβ PET, p‐tau217 and p‐tau205 showed the highest associations with frontal, precuneus, posterior cingulate and temporal cortices.ConclusionOur results indicate that plasma p‐tau217, p‐tau231 and p‐tau205 are the site‐specific phosphorylations that better reflect amyloid and tau pathologies, although with different emergence along the AD continuum.

Plasma Leptin Is Associated With Amyloid CSF Biomarkers and Alzheimer's Disease Diagnosis in Cognitively Impaired Patients.

Metabolic dysfunction and dysregulation of leptin signaling have been linked to Alzheimer's disease (AD)'s pathophysiology. The objectives of this study were to examine the associations between plasma leptin, cerebrospinal fluid (CSF), beta-amyloid (Aβ), and tau biomarkers (AT[N] status) and with the stage of cognitive impairment. Cross-sectional analysis of data from cognitively impaired patients from a tertiary memory clinic. Plasma leptin levels were compared according to the stage of cognitive impairment and biomarker profiles, using the AT(N) classification. Linear regression models were performed to examine the relationship between leptin and CSF biomarkers. Results were adjusted for age, gender, body mass index (BMI), and APOE ε4. In a subgroup of A+T+ individuals, we compared the 2-year evolution of Mini-Mental State Examination scores, according to the participants' tertile of plasma leptin levels. We included 1 036 participants (age 68.7 ± 9.1, females = 54.1%). A+T+ and A+T- patients had significantly lower plasma leptin levels than amyloid negative participants (p < .01). CSF Aβ concentration was significantly associated with lower plasma leptin β = -4.3 (1.5), p = .005 unadjusted; and β = -3.4 (1.6), p = .03 after adjustment for age, female gender, BMI, and APOE ε4. Patients with major neurocognitive disorder due to AD had a difference of leptin of -7.3 ng/mL 95% confidence interval (CI; -11.8; -2.8), p = .0002, compared to individuals with other causes of cognitive impairment. Leptin was not associated with the slope of cognitive decline. Plasma leptin levels were associated with CSF Aβ and with the diagnosis of AD confirmed by CSF biomarkers, suggesting a molecular interplay between leptin metabolism and brain amyloid deposition.

Plasma p-tau181, neurofilament light chain and association with cognition in Parkinson’s disease

Early identification of cognitive impairment in Parkinson’s disease (PD) has important clinical and research implications. The aim of our study was to investigate the role of plasma tau phosphorylated at amino acid 181 (p-tau181) and plasma neurofilament light chain (NfL) as biomarkers of cognition in PD. Baseline concentrations of plasma p-tau181 and NfL were measured in a cohort of 136 patients with PD and 63 healthy controls (HC). Forty-seven PD patients were followed up for up to 2 years. Cross-sectional and longitudinal associations between baseline plasma biomarkers and cognitive progression were investigated using linear regression and linear mixed effects models. At baseline, plasma p-tau181 concentration was significantly higher in PD subjects compared with HC (p = 0.026). In PD patients, higher plasma NfL was associated with lower MMSE score at baseline, after adjusting for age, sex and education (p = 0.027). Baseline plasma NfL also predicted MMSE decline over time in the PD group (p = 0.020). No significant association between plasma p-tau181 concentration and baseline or longitudinal cognitive performance was found. While the role of p-tau181 as a diagnostic biomarker for PD and its relationship with cognition need further elucidation, plasma NfL may serve as a feasible, non-invasive biomarker of cognitive progression in PD.

Plasma and CSF biomarkers in a memory clinic: Head-to-head comparison of phosphorylated tau immunoassays.

Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aβ42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aβ42/p-tau ratio. All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF Aβ42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r=0.76; area under the curve [AUC]=0.96), ADx p-tau181 (r=0.73; AUC=0.94), and Lilly p-tau217 (r=0.73; AUC=0.94). Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD. Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts.

A Head-to-Head Comparison Between Plasma pTau181 and Tau PET Along the Alzheimer's Disease Continuum.

Both plasma tau phosphorylated at threonine-181 (pTau181) and tau PET show potential for detecting Alzheimer's disease (AD) pathology and predicting clinical progression. In this study, we performed a head-to-head comparison between plasma pTau181 and tau PET along the AD continuum. Methods: We included participants from the Amsterdam Dementia Cohort who underwent 18F-flortaucipir (tau) PET and had a plasma sample biobanked within 12 mo from tau PET. Fifty subjective cognitive decline (SCD) participants (31 Aβ-negative and 19 Aβ-positive) and 60 Aβ-positive participants with mild cognitive impairment (MCI) or dementia due to AD were included. A subset had 2-y longitudinal plasma pTau181 and tau PET available (n = 40). Longitudinal neuropsychological test data covering 3.2 ± 2.7 y from both before and after tau PET were available. Plasma pTau181 and tau PET were compared in their accuracies in discriminating between cognitive stage (MCI/AD vs. SCD) and preclinical Aβ status (SCD Aβ-positive vs. SCD Aβ-negative), their associations with cross-sectional and longitudinal neuropsychological test performance, and their longitudinal changes over time. Results: When discriminating between preclinical Aβ status, the area under the curve (AUC) for plasma pTau181 (0.83) and tau PET (entorhinal, 0.87; temporal, 0.85; neocortical, 0.67) were equally high (all DeLong P > 0.05), but tau PET outperformed plasma pTau181 in discriminating MCI/AD from SCD (AUC for plasma pTau181: 0.74; AUCs for tau PET: entorhinal, 0.89; temporal, 0.92; neocortical, 0.89) (all P < 0.01). Overall, tau PET showed stronger associations with cognitive decline and was associated with a wider variety of cognitive tests than plasma pTau181 (plasma pTau181, -0.02 > β < -0.12; tau PET, -0.01 > β < -0.22). Both plasma pTau181 and tau PET increased more steeply over time in MCI/AD than in SCD (P < 0.05), but only tau PET annual changes were associated with cognitive decline. Conclusion: Our results suggest that plasma pTau181 and tau PET perform equally well in identifying Aβ pathology but that tau PET better monitors disease stage and clinical progression.

Comparing the effects of olfactory-based sensory stimulation and board game training on cognition, emotion, and blood biomarkers among individuals with dementia: A pilot randomized controlled trial.

Olfactory dysfunction can indicate early cognitive decline and is associated with dementia symptoms. We developed an olfactory-based sensory stimulation program and investigated its effects on cognition and emotion, and board game training were used as a comparison. In this parallel design pilot study, 30 participants with mild to moderate dementia were equal randomly assigned to the control (CONT), olfactory stimulation with cognitive training (OS), and board game (BG) groups. Two participants were withdrawn from CONT and OS groups, respectively. The intervention was a 12-week program with one 30-min session twice a week. We employed a blood-based biomarker technique and several cognitive and psychological tests to measure basal and after-intervention values. No significant differences were observed between the groups after intervention, as measured using the Mini-Mental State Examination, Loewenstein Occupational Therapy Cognitive Assessment (LOTCA), Top International Biotech Smell Identification Test, and Geriatric Depression Scale (GDS). The results showed that the OS group had a lower plasma Tau level than the other groups following intervention, whereas the CONT group had a significantly increased plasma amyloid ß1-42 level. OS participants had a lower concentration ratio of plasma Tau and amyloid Aß1-42 and showed more stable or improved cognition, olfactory function, and mood state. Both the OS and BG groups had a higher percentage of participants with stable or improved cognition and emotion. Taken together, these results suggest that olfactory-based sensory stimulation can be a beneficial intervention for patients with dementia.Clinical trial registration[Clinicaltrials.gov], identifier [NCT05168098].

Plasma tau, NfL, GFAP and UCHL1 as candidate biomarkers of alcohol withdrawal-associated brain damage: A pilot study.

In this translational study, we investigated the plasma tau protein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), which are established biomarkers of neurological injury, as predictive biomarkers of alcohol withdrawal-associated brain toxicity. In the clinical study, patients with severe alcohol use disorder (AUD) on D1 of hospitalization for alcohol cessation (AC) (N = 36) were compared to severe AUD patients with at least 3 months of abstinence (N = 16). Overall, patients were 40 men (76.9%), aged 49.8 years [SD ±9.9]. Tau, NfL, GFAP and UCHL1 levels were measured using SIMOA and analysed with a quasipoisson regression model adjusted for age and sex. The NfL level was higher in the AC group (p = 0.013). In the AC group, the tau (p = 0.021) and UCHL1 (p = 0.021) levels were positively associated with the dose of diazepam per weight, and the tau (p = 0.045), NfL (p = 4.9 × 10-3 ) and UCHL1 (p = 0.036) levels were higher in the presence of signs of Wernicke's encephalopathy (n = 9). In the preclinical study, NfL and GFAP levels were assessed in the alcohol deprivation effect (ADE) procedure (N = 17) and control Wistar rats (N = 15). Furthermore, ADE rats were prospectively assessed: after 24 h (T1) and 3 weeks of AC (T2) (paired-samples Wilcoxon and Mann-Whitney tests). The NfL level was higher in the ADE model than in the control rats at both T1 and T2 (p = 0.033 and p = 1.3 × 10-3 ) and higher at T2 than at T1 (p = 0.040). Plasma tau, NfL and UCHL1 are potential biomarkers of brain suffering during alcohol withdrawal.

P02-04 Performance of NF-L, GFAP, NSE and TAU in Rat Plasma and CSF as Translational Biomarkers of Nervous System Toxicity

P02-04 Performance of NF-L, GFAP, NSE and TAU in Rat Plasma and CSF as Translational Biomarkers of Nervous System Toxicity