P-tau Concentrations Research Articles

Differentiation of Alzheimer's disease from other neurodegenerative disorders using chemiluminescence immunoassays measuring cerebrospinal fluid biomarkers.

Prior research identified four neurochemical cerebrospinal fluid (CSF) biomarkers, Aβ1-42, Aβ1-40, tTau, and pTau(181), as core diagnostic markers for Alzheimer's disease (AD). Determination of AD biomarkers using immunoassays can support differential diagnosis of AD vs. several neuropsychiatric disorders, which is important because the respective treatment regimens differ. Results of biomarker determination can be classified according to the Amyloid/Tau/Neurodegeneration (ATN) system into profiles. Less is known about the clinical performance of chemiluminescence immunoassays (ChLIA) measuring specific biomarkers in CSF samples from patients suffering from neuropsychiatric impairments with various underlying causes. Chemiluminescence immunoassays (ChLIAs, EUROIMMUN) were used to determine Beta-Amyloid (1-40), Beta-Amyloid (1-42), Total-Tau, and pTau(181) concentrations in precharacterized cerebrospinal fluid (CSF) samples from 219 AD patients, 74 patients with mild cognitive impairment (MCI), and 220 disease control (DC) patients. 83.0% of AD patients had ATN profiles consistent with AD, whereas 85.5% of DC patients and 77.0% of MCI patients had profiles inconsistent with AD. AD patients showed significantly lower amyloid ratio Aβ1-42/Aβ1-40 (mean: 0.07) and significantly higher concentrations of tTau (mean: 901.6 pg/ml) and pTau(181) (mean: 129 pg/ml) compared to DC and MCI patients (all p values < 0.0071). The ChLIAs effectively determined specific biomarkers and can support differential diagnostics of AD. Their quality was demonstrated in samples from 513 patients with cognitive impairments, representing a realistic mix of underlying causes for seeking treatment at a memory clinic.

ATN blood biomarkers are related to digital cognitive assessment in type 1 diabetes.

Associations between amyloid-tau-neurodegeneration (ATN) plasma biomarkers and cognition have not been characterized in adults with type 1 diabetes (T1D). Using data from participants in the Glycemic Variability and Fluctuations in Cognitive Status in Adults with T1D (GluCog) study (N=114), we evaluated associations between phosphorylated tau (pTau)181, pTau217, β-amyloid 42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) and self-administered digital cognitive tests, adjusting for age, sex, education, comorbidities (e.g., kidney disease), and glycemic indices. Higher concentrations of pTau181 and GFAP were associated with slower responses on working memory tasks (pTau181: β=0.261; p=0.007; GFAP: β=0.175, p=0.036), and higher β-amyloid 42/40 ratio was associated with better vocabulary (β=0.260, p=0.009). Digital cognitive performance was associated with several ATN plasma biomarkers in T1D adults. Prospective studies are needed to understand the utility of these biomarkers in T1D. There is an increase in life expectancy for individuals with type 1 diabetes (T1D).Few studies investigate the relationship between T1D and neurodegeneration.We characterize the relation between ATN plasma biomarkers and cognitive function.Digital cognitive performance was associated with plasma biomarkers in T1D adults.

Plasma biomarkers in chronic single moderate-severe traumatic brain injury.

Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate-severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10-33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = -2.17, SE = 1.06, P = 0.043, 95% CI [-4.28, -0.07]; long delay: bP-tau = -2.56, SE = 1.08, P = 0.020, 95% CI [-4.71, -0.41]}, tau {immediate memory: bTau = -6.22, SE = 2.47, P = 0.014, 95% CI [-11.14, -1.30]} and UCH-L1 {immediate memory: bUCH-L1 = -2.14, SE = 1.07, P = 0.048, 95% CI [-4.26, -0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate-severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI.

Association between blood-based protein biomarkers and brain MRI in the Alzheimer's disease continuum: a systematic review.

Blood-based biomarkers (BBM) are becoming easily detectable tools to reveal pathological changes in Alzheimer's disease (AD). A comprehensive and up-to-date overview of the association between BBM and brain MRI parameters is not available. This systematic review aimed to summarize the literature on the associations between the main BBM and MRI markers across the clinical AD continuum. A systematic literature search was carried out on PubMed and Web of Science and a total of 33 articles were included. Hippocampal volume was positively correlated with Aβ42 and Aβ42/Aβ40 and negatively with Aβ40 plasma levels. P-tau181 and p-tau217 concentrations were negatively correlated with temporal grey matter volume and cortical thickness. NfL levels were negatively correlated with white matter microstructural integrity, whereas GFAP levels were positively correlated with myo-inositol values in the posterior cingulate cortex/precuneus. These findings highlight consistent associations between various BBM and brain MRI markers even in the pre-clinical and prodromal stages of AD. This suggests a possible advantage in combining multiple AD-related markers to improve accuracy of early diagnosis, prognosis, progression monitoring and treatment response.

Neurodegenerative Plasma Biomarkers for Prediction of Hippocampal Atrophy in Older Adults with Suspected Alzheimer's Disease in Kinshasa, Democratic Republic of Congo.

The hippocampus is one of the first brain structures affected by Alzheimer's disease (AD), and its atrophy is a strong indicator of the disease. This study investigates the ability of plasma biomarkers of AD and AD-related dementias-amyloid-β (Aβ42/40), phosphorylated tau-181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)-to predict hippocampal atrophy in adult individuals in Kinshasa, Democratic Republic of Congo (DRC). Eighty-five adult individuals (40 healthy and 45 suspected AD) over 65 years old were evaluated using the Community Screening Instrument for Dementia and Alzheimer's Questionnaire (AQ). Core AD biomarkers (Aβ42/40 and p-tau181) and non-specific neurodegeneration biomarkers (NfL, GFAP) were measured in blood samples collected at the study visit. Hippocampal volumes were measured using magnetic resonance imaging (MRI). General linear regression was used to evaluate differences in biomarker concentrations by neurological status. Logistic regression models were used to create receiver operating characteristic curves and calculate areas under the curve (AUCs) with and without clinical covariates to determine the ability of biomarker concentrations to predict hippocampal atrophy. Plasma biomarkers were used either individually or in combination in the models. Elevated p-tau181 was associated with left hippocampal (LH) atrophy p= 0.020). Only higher p-tau181 concentrations were significantly associated with 4.2-fold increased odds [OR=4.2 (1.5-18.4)] of hippocampal atrophy per standard deviation. The AUC of plasma biomarkers without clinical covariates to discriminate LH, RH, and total hippocampal (TH) or both hippocampi atrophy ranged between 90% to 94%, 76% to 82%, and 85% to 87%, respectively. The AUC of models including clinical covariates and AD biomarkers used in combination to discriminate LH, RH, and TH ranged between 94%-96%, 81%-84%, and 88%-90%, respectively. These results indicate that, consistent with studies in other settings, core AD plasma biomarkers can predict hippocampal atrophy in a population in Sub-Saharan Africa.

Biomarkers and genotypes in patients with Central nervous system infection caused by enterovirus

Purpose Enteroviruses (EV) comprises many different types and are the most common cause of aseptic meningitis. How the virus affects the brain including potential differences between types are largely unknown. Measuring biomarkers in CSF is a tool to estimate brain damage caused by CNS infections. Methods A retrospective study was performed in samples from 38 patients with acute neurological manifestations and positive CSF-EV RNA (n = 37) or serum-IgM (n = 1). The EV in 17 samples were typed by sequencing. The biomarkers neurofilament light (NFL), glial fibrillary acidic protein (GFAP), S-100B protein, amyloid-β (Aβ) 40 and Aβ42, total-tau (T-tau) and phosphorylated tau (P-tau) were measured and compared with data derived from a control group (n = 19). Results There were no increased levels of GFAP (p ≤ 0.1) nor NFL (p ≤ 0.1) in the CSF of patients with EV meningitis (n = 38) compared with controls. However, we found decreased levels of Aβ42 (p < 0.001), Aβ40 (p < 0.001), T-tau (p ≥ 0.01), P-tau (p ≤ 0.001) and S-100B (p ≤ 0.001). E30 (n = 9) and CVB5 (n = 6) were the most frequent EV-types identified, but no differences in biomarker levels or other clinical parameters were found between the infecting virus type. Seven patients who were followed for longer than one month reported remaining cognitive impairment, although no correlations with biomarker concentrations were observed. Conclusion There are no indication of neuronal or astrocyte damage in patients with EV meningitis. Yet, decreased concentrations of Aβ40, Aβ42, P-tau and T-tau were shown, a finding of unknown importance. Cognitive impairment after acute disease occurs, but with only a limited number of patients analysed, no conclusion can be drawn concerning any association with biomarker levels or EV types.

Neurodegenerative biomarkers in different chambers of the eye relative to plasma: an agreement validation study

BackgroundProtein biomarkers have been broadly investigated in cerebrospinal fluid and blood for the detection of neurodegenerative diseases, yet a clinically useful diagnostic test to detect early, pre-symptomatic Alzheimer’s disease (AD) remains elusive. We conducted this study to quantify Aβ40, Aβ42, total Tau (t-Tau), hyperphosphorylated Tau (ptau181), glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) in eye fluids relative to blood.MethodsIn this cross-sectional study we collected vitreous humor, aqueous humor, tear fluid and plasma in patients undergoing surgery for eye disease. All six biomarkers were quantitatively measured by digital immunoassay. Spearman and Bland–Altman correlation analyses were performed to assess the agreement of levels between ocular fluids and plasma.ResultsSeventy-nine adults underwent pars-plana vitrectomy in at least one eye. Of the 79, there were 77 vitreous, 67 blood, 56 tear fluid, and 51 aqueous samples. All six biomarkers were quantified in each bio-sample, except GFAP and NfL in tear fluid due to low sample volume. All six biomarkers were elevated in vitreous humor compared to plasma samples. T-Tau, ptau181, GFAP and NfL were higher in aqueous than in plasma, and t-Tau and ptau181 concentrations were higher in tear fluid than in plasma. Significant correlations were found between Aβ40 in plasma and tears (r = 0.5; p = 0.019), t-Tau in plasma and vitreous (r = 0.4; p = 0.004), NfL in plasma and vitreous (r = 0.3; p = 0.006) and plasma and aqueous (r = 0.5; p = 0.004). No significant associations were found for Aβ42, ptau181 and GFAP among ocular fluids relative to plasma. Bland–Altman analysis showed aqueous humor had the closest agreement to plasma across all biomarkers. Biomarker levels in ocular fluids revealed statistically significant associations between vitreous and aqueous for t-Tau (r = 0.5; p = 0.001), GFAP (r = 0.6; p < 0.001) and NfL (r = 0.7; p < 0.001).ConclusionAD biomarkers are detectable in greater quantities in eye fluids than in plasma and show correlations with levels in plasma. Future studies are needed to assess the utility of ocular fluid biomarkers as diagnostic and prognostic markers for AD, especially in those at risk with eye disease.

High-intensity body weight interval training modifies neurochemistry in AD disease: Preliminary data from a randomized control trial

BackgroundAlzheimer's disease (AD) is an incurable condition characterized by cognitive and neurochemical impairments, necessitating the exploration of alternative interventions. Physical exercise shows promise, but the effects of high-intensity protocols on the neurochemical aspects of AD-related neurodegeneration remain poorly explored. ObjectiveThis study examines the effects of high-intensity body weight interval training (PMED) on brain-derived neurotrophic factor (BDNF) and phosphorylated-TAU protein (p-TAU) in AD disease. MethodsThirty-four elderly individuals diagnosed with AD disease were divided into two groups of 17 subjects: GCP, which participated in PMED (30 min at 80–90 % of maximal cardiac frequency three times per week), and GCS, which had no interventions. Pre- and post-measurements of BDNF and p-TAU were conducted. ResultsThe GCS group showed no changes in his neurochemical factors (p > 0.05). In contrast, the GCP group experienced increased BDNF levels and decreased p-TAU blood concentrations (p < 0.0001 for both). ConclusionsPMED increased BDNF and reduced p-TAU concentrations, improving neurochemistry in AD disease. This can open an avenue of new interventions using high-intensity body weight interval training, including, in home base programs, which can be an advantage to engagement.

Phosphorylated tau 181 (p-tau181) as an innovative, fast and robust biomarker for cerebrospinal fluid leaks.

Cerebrospinal fluid (CSF) leaks can lead to serious complications if left untreated, making rapid and accurate diagnosis essential. Biomarkers such as β2-transferrin (B2TRF) and β-trace protein are used to detect CSF leaks, but their limitations warrant the exploration of alternative markers. This study investigates the potential of phosphorylated tau at threonine 181 (p-tau181) as a biomarker for CSF leaks. Samples from 56 subjects were analyzed for B2TRF and p-tau181 using immunoaffinity blotting and chemiluminescent enzyme immunoassay, respectively. Data analysis included Mann-Whitney test to assess the overall difference in median p-tau181 concentrations between B2TRF positive and negative patients and a receiver operating characteristic (ROC) curve analysis to determine optimal p-tau181 cutoff values for predicting B2TRF positivity. p-tau181 levels were significantly higher in B2TRF positive samples compared to negative samples (p < 0.001). ROC analysis showed high diagnostic performance for p-tau181, with an optimal cutoff of 13.22 pg/mL providing 92.0% sensitivity and 93.1% specificity. Excluding hemolyzed samples improved further the diagnostic performances, maintaining high sensitivity (90.9%) and achieving perfect specificity (100.0%). This study highlights the potential of p-tau181 as a valuable biomarker for the detection of CSF leaks due to its high diagnostic accuracy and practical advantages over the current biomarkers. The characteristics of p-tau181 assay being both quantitative and rapid, with high diagnostic accuracy, suggest that it could be a valuable tool for the detection of CSF leaks. Further research are now needed to validate these findings.

Predicting Cognitive Decline in Amyloid-Positive Patients With Mild Cognitive Impairment or Mild Dementia.

Cognitive decline rates in Alzheimer disease (AD) vary greatly. Disease-modifying treatments may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid-positive patients with mild cognitive impairment (MCI) or mild dementia. From the Amsterdam Dementia Cohort, we selected amyloid-positive participants with MCI or mild dementia and at least 2 longitudinal Mini-Mental State Examination (MMSE) measurements. Amyloid positivity was based on CSF AD biomarker concentrations or amyloid PET. We used linear mixed modeling to predict MMSE over time, describing trajectories using a cubic time curve and interactions between linear time and the baseline predictors age, sex, baseline MMSE, APOE ε4 dose, CSF β-amyloid (Aβ) 1-42 and pTau, and MRI total brain and hippocampal volume. Backward selection was used to reduce model complexity. These models can predict MMSE over follow-up or the time to an MMSE value. MCI and mild dementia were modeled separately. Internal 5-fold cross-validation was performed to calculate the explained variance (R2). In total, 961 participants were included (age 65 ± 7 years, 49% female), 310 had MCI (MMSE 26 ± 2) and 651 had mild dementia (MMSE 22 ± 4), with 4 ± 2 measurements over 2 (interquartile range 1-4) years. Cognitive decline rates increased over time for both MCI and mild dementia (model comparisons linear vs squared vs cubic time fit; p < 0.05 favoring a cubic fit). For MCI, backward selection retained age, sex, and CSF Aβ1-42 and pTau concentrations as time-varying effects altering the MMSE trajectory. For mild dementia, retained time-varying effects were Aβ1-42, age, APOE ε4, and baseline MMSE. R2 was 0.15 for the MCI model and 0.26 for mild dementia in internal cross-validation. A hypothetical patient with MCI, baseline MMSE 28, and CSF Aβ1-42 of 925 pg/mL was predicted to reach an MMSE of 20 after 6.0 years (95% CI 5.4-6.7) and after 8.6 years with a hypothetical treatment reducing decline by 30%. We constructed models for MCI and mild dementia that predict MMSE over time. These models could inform patients about their potential cognitive trajectory and the remaining uncertainty and aid in conversations about individualized potential treatment effects.

Real-world performance of plasma p-tau181 in a heterogeneous memory clinic cohort.

In light of clinical trials and disease-modifying therapies, an early identification of patients at-risk of developing Alzheimer's disease (AD) is crucial. Blood-based biomarkers have shown promising results regarding the in vivo detection of the earliest neuropathological changes in AD. Herein, we investigated the ability of plasma p-tau181 to act as a prescreening marker for amyloid positivity in a heterogeneous memory clinic-based cohort. In this retrospective cross-sectional study, we included a total of 115 patients along the clinical AD continuum (mild cognitive impairment [MCI] due to AD, n = 62, probable AD dementia, n = 53). Based on their biomarker status, they were stratified into an amyloid-positive (Aβ+, n = 88) or amyloid-negative cohort (Aβ-, n = 27). Plasma and CSF p-tau181 concentrations were quantified using an ultrasensitive single-molecule array (SIMOA©). Furthermore, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong's test for correlated AUC curves. The median (interquartile range [IQR]) concentration of plasma p-tau181 was significantly higher in Aβ+ patients (3.6 pg/mL [2.5-4.6]), compared with Aβ- patients (1.7 pg/mL [1.2-1.9], p < 0.001). Regarding the distinction between Aβ+ and Aβ- patients and the prediction of amyloid positivity, a high diagnostic accuracy for plasma p-tau181 with an AUC of 0.89 (95% CI = 0.82-0.95) was calculated. Adding the risk factors, age and APOE4, to the model did not significantly improve its performance. Our findings demonstrate that plasma p-tau181 could be a noninvasive and feasible prescreening marker for amyloid positivity in a heterogeneous clinical AD cohort and therefore help in identifying those who would benefit from more invasive assessment of amyloid pathology.

Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer’s disease

BackgroundIt is not fully established whether plasma β-amyloid(Aβ)42/Aβ40 and phosphorylated Tau181 (p-Tau181) can effectively detect Alzheimer’s disease (AD) pathophysiology in older Chinese adults and how these biomarkers correlate with astrocyte reactivity, Aβ plaque deposition, tau tangle aggregation, and neurodegeneration.MethodsWe recruited 470 older adults and analyzed plasma Aβ42/Aβ40, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. Among them, 301, 195, and 70 underwent magnetic resonance imaging, Aβ and tau positron emission tomography imaging. The plasma Aβ42/Aβ40 and p-Tau181 thresholds were defined as ≤0.0609 and ≥2.418 based on the receiver operating characteristic curve analysis using the Youden index by comparing Aβ-PET negative cognitively unimpaired individuals and Aβ-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma Aβ42/Aβ40 (A) and p-Tau181 (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, Aβ plaque, tau tangle, plasma NfL, hippocampal volume, and temporal-metaROI cortical thickness between different plasma A/T profiles and explored their relations with each other using general linear models, including age, sex, APOE-ε4, and diagnosis as covariates.ResultsPlasma A+/T + individuals showed the highest levels of astrocyte reactivity, Aβ plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 were independently and synergistically correlated with higher plasma GFAP and Aβ plaque. Elevated plasma p-Tau181 and GFAP concentrations were directly and interactively associated with more tau tangle formation. Regarding neurodegeneration, higher plasma p-Tau181 and GFAP concentrations strongly correlated with more axonal degeneration, as measured by plasma NfL, and lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 were related to greater hippocampal atrophy. Higher plasma GFAP levels were associated with thinner cortical thickness and significantly interacted with lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings.DiscussionThis study provides a valuable reference for using plasma biomarkers to detect AD in the Chinese community population and offers novel insights into how astrocyte reactivity contributes to AD progression, highlighting the importance of targeting reactive astrogliosis to prevent AD.

Hormone therapy is associated with lower Alzheimer’s disease tau biomarkers in post-menopausal females -evidence from two independent cohorts

BackgroundFemales represent approximately 70% of the Alzheimer’s disease (AD) cases and the literature has proposed a connection between the decreased estrogen levels during menopause and an increased AD risk. Previous investigations have predominantly focused on assessing how hormone therapy (HT) affects the likelihood of AD development and cognitive deterioration. However, as the research framework has shifted toward a biomarker-defined AD and alterations in specific biomarkers could take place years before cognitive decline becomes discernible, it is crucial to examine how HT influences AD biomarkers. The main goal of this study was to evaluate the impact of HT on AD biomarker-informed pathophysiology in both cognitively unimpaired (CU) and cognitively impaired (CI) post-menopausal females across the aging and AD spectrum.MethodsThis cross-sectional study included post-menopausal females without HT history (HT-) and with HT (HT+) at the time of PET imaging assessment from two cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants underwent magnetic resonance imaging (MRI), positron emission tomography (PET) and biofluid collection. Voxel-based t-tests were performed to assess the differences in amyloid-β (Aβ) and tau neurofibrillary tangles (NFTs) loads between HT- and HT + females. Linear regression models with interaction terms were also conducted to examine the interactive effects of HT and Aβ-PET on regional tau-PET.ResultsHT + females demonstrated significantly lower tau-PET standardized uptake value ratio (SUVR) in Braak I-II ROIs (P < 0.05, Hedges’ g = 0.73), Braak III-IV ROIs (P < 0.0001, Hedges’ g = 0.74) and Braak V-VI ROIs (P < 0.0001, Hedges’ g = 0.69) compared to HT- females. HT + females also showed significantly lower CSF p-tau181 (P < 0.001) and plasma p-tau181 (P < 0.0001) concentrations. Additionally, results from multivariate linear regression models indicated that HT interacts with cortical Aβ and is associated with lower regional NFT load.ConclusionsOverall, findings from this observational study suggest that HT is associated with lower tau neuroimaging and fluid biomarkers in postmenopausal females. Due to the close link between tau and cognition, this study highlights the need for large randomized controlled trials designed to systemically study the influences of HT on AD biomarkers and disease progression.

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients.

The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

Diagnostic performance of plasma pTau217, pTau181, Aβ1-42 and Aβ1-40 in the LUMIPULSE automated platform for the detection of Alzheimer disease

BackgroundRecently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories, and their performance in clinical practice is unknown.MethodsWe analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A +) or negative (A-) according to CSF Aβ1–42/Aβ1–40 ratio. Plasma pTau217, pTau181, Aβ1–42 and Aβ1–40 were measured in the fully-automated LUMIPULSE platform. We used linear regression to compare plasma biomarkers concentrations between A + and A- groups, evaluated Spearman’s correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect brain amyloidosis as determined by CSF Aβ1–42/Aβ1–40 ratio. We analyzed the concordance of pTau217 with CSF amyloidosis.ResultsPlasma pTau217 and pTau181 concentration were higher in A + than A- while the plasma Aβ1–42/Aβ1–40 ratio was lower in A + compared to A-. pTau181 and the Aβ1–42/Aβ1–40 ratio showed moderate correlation between plasma and CSF (Rho = 0.66 and 0.69, respectively). The areas under the ROC curve to discriminate A + from A- participants were 0.94 (95% CI 0.92–0.97) for pTau217, and 0.88 (95% CI 0.84–0.92) for both pTau181 and Aβ1–42/Aβ1–40. Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were less affected. Plasma pTau217 had the highest fold change (× 3.2) and showed high predictive capability in discriminating A + from A-, having 4–7% misclassification rate. The global accuracy of plasma pTau217 using a two-threshold approach was robust in symptomatic groups, exceeding 90%.ConclusionThe evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau217 showed excellent diagnostic accuracy to identify participants with AD in a consecutive sample representing the routine clinical practice in a specialized memory unit.

Aqueous and Plasma Levels of Phosphorylated Tau 181 in Individuals with Normal Cognition.

Plasma and cerebrospinal fluid (CSF) levels of p-tau181 have been associated with Alzheimer's disease (AD). The retina and vitreous have shown measurable quantities of phosphorylated tau 181 (p-tau181). The aqueous humor, which can be collected during cataract surgery, may have measurable concentrations of p-tau181. To determine whether p-tau181 is detectable in the aqueous humor and if so, whether it is associated with other measures that might be consistent with AD such as higher plasma p-tau181 concentration and lower Montreal Cognitive Assessment (MoCA-BLIND version 7.1) score. Aqueous humor samples, blood samples, and MoCA-BLIND scores were collected from patients who did not carry a clinical diagnosis of cognitive impairment at the time of cataract surgery. Aqueous p-tau181 concentrations and plasma p-tau181 concentrations were then measured using ultra-sensitive single-molecule assay ELISA technology. A rank-transformed mixed-effects multivariate regression model was used to determine associations between aqueous concentrations, plasma concentrations, and MoCA-BLIND scores. 16 eyes of 16 participants were enrolled with an average age of 71.6. Average MoCA-BLIND score was 20.6/22, average aqueous p-tau181 concentration was 6.4 pg/mL, and average plasma p-tau181 concentration was 3.1 pg/mL. Higher plasma p-tau181 was significantly associated with higher aqueous p-tau181 (p = 0.02). Aqueous p-tau181 and plasma p-tau181 were negatively associated with MoCA-BLIND scores (p = 0.005 and p = 0.001 respectively) in these patients. Aqueous p-tau181 is positively correlated with plasma p-tau181 and is negatively correlated with MoCA-BLIND scores. Further study in individuals with mild cognitive impairment or AD characterized by cerebrospinal fluid and volumetric MRI metrics may yield further insights.

Association of Plasma Amyloid, P-Tau, GFAP, and NfL With CSF, Clinical, and Cognitive Features in Patients With Dementia With Lewy Bodies.

Plasma β-amyloid-1-42/1-40 (Aβ42/40), phosphorylated-tau (P-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) have been widely examined in Alzheimer disease (AD), but little is known about their reflection of copathologies, clinical importance, and predictive value in dementia with Lewy bodies (DLB). We aimed to evaluate associations of these biomarkers with CSF amyloid, cognition, and core features in DLB. This cross-sectional multicenter cohort study with prospective component included individuals with DLB, AD, and healthy controls (HCs), recruited from 2002 to 2020 with an annual follow-up of up to 5 years, from the European-Dementia With Lewy Bodies consortium. Plasma biomarkers were measured by single-molecule array (Neurology 4-Plex E kit). Amyloid status was determined by CSF Aβ42 concentrations, and cognition was assessed by Mini-Mental State Examination (MMSE). Biomarker differences across groups, associations with amyloid status, and clinical core features were assessed by analysis of covariance. Associations with cognitive impairment and decline were assessed by linear regression and linear mixed-effects models. In our cohort consisting of 562 individuals (HC n = 89, DLB n = 342, AD n = 131; 250 women [44.5%], mean [SD] age of 71 [8] years), sex distribution did not differ between groups. Patients with DLB were significantly older, and had less years of education and worse baseline cognition than HC, but not AD. DLB participants stratified for amyloid status differed significantly in plasma Aβ42/40 ratio (decreased in amyloid abnormal: β = -0.008, 95% CI -0.016 to -0.0003, p = 0.01) and P-tau (increased in amyloid abnormal, P-tau181: β = 0.246, 95% CI 0.011-0.481; P-tau231: β = 0.227, 95% CI 0.035-0.419, both p < 0.05), but not in GFAP (β = 0.068, 95% CI -0.018 to 0.153, p = 0.119), and NfL (β = 0.004, 95% CI -0.087 to 0.096, p = 0.923) concentrations. Higher baseline GFAP, NfL, and P-tau concentrations were associated with lower MMSE scores in DLB, and GFAP and NfL were associated with a faster cognitive decline (GFAP: annual change of -2.11 MMSE points, 95% CI -2.88 to -1.35 MMSE points, p < 0.001; NfL: annual change of -2.13 MMSE points, 95% CI -2.97 to -1.29 MMSE points, p < 0.001). DLB participants with parkinsonism had higher concentrations of NfL (β = 0.08, 95% CI 0.02-0.14, p = 0.006) than those without. Our study suggests a possible utility of plasma Aβ42/40, P-tau181, and P-tau231 as a noninvasive biomarkers to assess amyloid copathology in DLB, and plasma GFAP and NfL as monitoring biomarkers for cognitive symptoms in DLB.

Serum Oligomeric α-Synuclein and p-tau181 in Progressive Supranuclear Palsy and Parkinson's Disease.

Clinical differentiation of progressive supranuclear palsy (PSP) from Parkinson's disease (PD) is challenging due to overlapping phenotypes and the late onset of specific atypical signs. Therefore, easily assessable diagnostic biomarkers are highly needed. Since PD is a synucleopathy while PSP is a tauopathy, here, we investigated the clinical usefulness of serum oligomeric-α-synuclein (o-α-synuclein) and 181Thr-phosphorylated tau (p-tau181), which are considered as the most important pathological protein forms in distinguishing between these two parkinsonisms. We assessed serum o-α-synuclein and p-tau181 by ELISA and SIMOA, respectively, in 27 PSP patients, 43 PD patients, and 39 healthy controls (HC). Moreover, we evaluated the correlation between serum biomarkers and biological and clinical features of these subjects. We did not find any difference in serum concentrations of p-tau181 and o-α-synuclein nor in the o-α-synuclein/p-tau181 ratio between groups. However, we observed that serum p-tau181 positively correlated with age in HC and PD, while serum o-α-synuclein correlated positively with disease severity in PD and negatively with age in PSP. Finally, the o-α-synuclein/p-tau181 ratio showed a negative correlation with age in PD.

Relationships between PET and blood plasma biomarkers in corticobasal syndrome.

Corticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker-confirmed AD in CBS. A cohort of eighteen CBS patients (8amyloid beta [Aβ]+; 10Aβ-) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal-Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake. CBS Aβ+ group showed a reduced Aβ42/40 ratio, with elevated phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aβ- group only showed elevated NfL concentration compared to CU. Both p-tau181 and GFAP were able to differentiate CBS Aβ- from CBS Aβ+ and showed positive associations with Aβ and tau PET uptake. This study supports use of plasma p-tau181 and GFAP to detect AD in CBS. NfL shows potential as a non-specific disease biomarker of CBS regardless of underlying pathology. Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aβ)- from CBS Aβ+. Plasma neurofilament light concentrations are elevated in CBS Aβ- and Aβ+ compared to controls. Plasma p-tau181 and GFAP concentrations were associated with Aβ and tau positron emission tomography (PET) uptake. Aβ42/40 ratio showed a negative correlation with Aβ PET uptake.

APOE ε4 carrier status modifies plasma p-tau181 concentrations in cognitively healthy super-seniors.

This study investigates the effect of apolipoprotein E (APOE) genotype on neurology plasma biomarkers in cognitively healthy Super-Seniors. Three hundred seventy plasma specimens from Super-Senior participants ≥ 85 years old, who have never been diagnosed with dementia, cancer, diabetes, cardiovascular, or major pulmonary disease, were analyzed on the Quanterix Simoa HD-X analyzer using commercial Neurology 4-plex E and phosphorylated tau (p-tau)181 assays. Eighty (22%) participants were APOE ε4 carriers and 290 (73%) were non-carriers. No significant differences were found between APOE ε4 carriers and non-carriers regarding age, sex, or Mini-Mental State Examination scores. In APOE ε4 carriers, plasma amyloid beta 42/40 was lower and p-tau181 and glial fibrillary acidic protein were higher compared to non-APOE ε4 carriers. After adjusting for demographic variables, p-tau181 was the only biomarker to remain significantly associated with APOE ε4 carrier status. APOE ε4 genotype modifies plasma p-tau181 concentration in seniors resilient to age-related clinical disease, suggesting that some Super-Seniors may have Alzheimer's disease pathology without progressing to cognitive decline. Healthy seniors enable identification of associations that may be masked by disease. Plasma phosphorylated tau (p-tau)181 concentrations associate with apolipoprotein E (APOE) ε4 carriership in healthy seniors. APOE should be accounted for when interpreting p-tau181, regardless of disease.