Plasma T-tau Research Articles

The Association Between Constipation and Positron Emission Tomography and Blood-Based Biomarkers in Older Cognitively Unimpaired Adults with Higher Amyloid-β Burden.

Constipation may be linked to cognitive decline and a higher risk of Alzheimer's disease (AD). We aimed to investigate the association between constipation and positron emission tomography (PET) and blood-based AD biomarkers in older cognitively unimpaired (CU) adults with higher Aβ burden. Constipation was diagnosed according to Rome IV criteria and the severity of constipation was evaluated by using a validated self-reported questionnaire. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET and 18F-MK6240 PET scans; the latter was only performed in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the association between constipation and AD biomarkers. Two cohorts were included in our study. A total of 404 older participants with 126 of whom Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed constipation was associated with plasma t-Tau, p-Tau-181, and neurofilament light chain (NfL) in participants with Aβ-PET (+). Meanwhile, no/mild constipation was associated with lower Aβ-PET standard uptake value ratio. The association between constipation and plasma biomarkers was different in the subgroups stratified by age, sex and APOE ε4 genotype. The above associations were further validated in the validation cohort containing 36 Aβ-PET (+) participants. Importantly, no/mild constipation was associated with lessTau burden evaluated by 18F-MK6240 PET Braak stages. Our data indicate that no/mild constipation may be associated with lower plasma t-Tau, p-Tau-181, and NfL as well as less Aβ and Tau burden in older CU adults with Aβ deposition. Improving constipation and being away from defecation disorders may help reduce the risk of AD development.

Novel β-amyloid PET Imaging Study of [18F]92 in Patients with Cognitive Decline.

[18F]-4-((E)-(((E)-4-(2-(2-(2-Fluoroethoxy)ethoxy)ethoxy)benzylidene)-hydrazono)methyl)-N-methylaniline ([18F]92) is a novel positron emission tomography (PET) tracer previously reported to exhibit high binding affinity to aggregated β-amyloid (Aβ). This study aims to report a fully automated radiosynthesis procedure for [18F]92, explore its radioactive distribution in the brains of healthy subjects, and investigate its potential application value in the early diagnosis of Alzheimer's disease (AD). The fully automated radiosynthesis of [18F]92 was performed on the AllinOne module. Thirty one participants were recruited for this study. Dynamic [18F]92 PET imaging was conducted over 0-90 min period to assess time-activity curves (TAC) and standardized uptake value ratio (SUVR) curves in cognitively normal (CN) subjects. All participants were visually classified as either positive (+) or negative (-). Semiquantitative analyses of [18F]92 were performed by calculating SUVRs in different regions of interest. Furthermore, the study analyzed the relationships between global SUVR and plasma AD biomarkers, including Aβ42, Aβ40, P-tau181, and T-tau. The automated radiosynthesis of [18F]92 was completed within 50 min, yielding a radiochemical purity of greater than 95% and a radiochemical yield of 36 ± 3% (nondecay-corrected). Among the participants, 15 were estimated as Aβ (-) and 16 as Aβ (+). TACs indicated that [18F]92 rapidly crossed the blood-brain barrier within 10 min, followed by a rapid decrease, which then slowed down in the last 50-90 min. SUVR curves revealed that SUVR values stabilized around 60-70 min after injection and reached an equilibrium between 70 and 90 min, primarily in the cerebral cortex. SUVRs of Aβ (+) participants were significantly higher than those of Aβ (-) individuals within the cerebral cortex. In addition, Aβ42 and the Aβ42/Aβ40 ratio exhibited negative correlations with global SUVR, while plasma P-tau181 and the P-tau181/T-tau ratio displayed positive correlations with global SUVR. [18F]92 exhibits excellent pharmacokinetic properties in the human brain and can be synthesized automatically on a large scale. [18F]92 is a promising and reliable radiotracer for estimating Aβ pathology accumulation, providing valuable assistance in AD diagnosis and guiding clinical trials of therapeutic drugs.

Testing the causal impact of amyloidosis on total Tau using a genetically informative sample of adult male twins.

The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers. Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aβs and t-Tau. No clear evidence that Aβ40 or Aβ42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau. In contrast, Aβ aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aβ deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample. Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aβ-PET ([11C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [11C]PiB standardized uptake value ratio was calculated for regions typical for Aβ accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex). Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71ml (0.86) vs. 7.2ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aβ pathology. Plasma t-tau concentration did not associate with any of the measured pathologies. Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.

Longitudinal assessment of plasma biomarkers for early detection of cognitive changes in subjective cognitive decline.

Individuals experiencing subjective cognitive decline (SCD) are at an increased risk of developing mild cognitive impairment and dementia. Early identification of SCD and neurodegenerative diseases using biomarkers may help clinical decision-making and improve prognosis. However, few cross-sectional and longitudinal studies have explored plasma biomarkers in individuals with SCD using immunomagnetic reduction. To identify plasma biomarkers for SCD. Fifty-two participants [38 with SCD, 14 healthy controls (HCs)] underwent baseline assessments, including measurements of plasma Aβ42, Aβ40, t-tau, p-tau, and α-synuclein using immunomagnetic reduction (IMR) assays, cognitive tests and the Mini-Mental State Examination (MMSE). Following initial cross-sectional analysis, 39 individuals (29 with SCD, 10 HCs) entered a longitudinal phase for reassessment of these biomarkers and the MMSE. Biomarker outcomes across different individual categories were primarily assessed using the area under the receiver operating characteristic (ROC) curve. The SCD subgroup with an MMSE decline over one point was compared to those without such a decline. Higher baseline plasma Aβ1-42 levels significantly discriminated participants with SCD from HCs, with an acceptable area under the ROC curve (AUC) of 67.5% [95% confidence interval (CI), 52.7-80.0%]. However, follow-up and changes in MMSE and IMR data did not significantly differ between the SCD and HC groups (p > 0.05). Furthermore, lower baseline plasma Aβ1-42 levels were able to discriminate SCD subgroups with and without cognitive decline with a satisfied performance (AUC, 75.0%; 95% CI, 55.6-89.1%). At last, the changes in t-tau and Aβ42 × t-tau could differentiate between the two SCD subgroups (p < 0.05). Baseline plasma Aβ42 may help identify people with SCD and predict SCD progression. The role of plasma Aβ42 levels as well as their upward trends from baseline in cases of SCD that progress to mild cognitive impairment and Alzheimer's disease require further investigation.

Novel Biomarkers for Alzheimer's Disease: Plasma Neurofilament Light and Cerebrospinal Fluid.

Neurodegenerative disorders such as Alzheimer's disease (AD) represent an increasingly significant public health concern. As clinical diagnosis faces challenges, biomarkers are becoming increasingly important in research, trials, and patient assessments. While biomarkers like amyloid-β peptide, tau proteins, CSF levels (Aβ, tau, and p-tau), and neuroimaging techniques are commonly used in AD diagnosis, they are often limited and invasive in monitoring and diagnosis. For this reason, blood-based biomarkers are the optimal choice for detecting neurodegeneration in brain diseases due to their noninvasiveness, affordability, reliability, and consistency. This literature review focuses on plasma neurofilament light (NfL) and CSF NfL as blood-based biomarkers used in recent AD diagnosis. The findings revealed that the core CSF biomarkers of neurodegeneration (T-tau, P-tau, and Aβ42), CSF NFL, and plasma T-tau were strongly associated with Alzheimer's disease, and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Elevated levels of plasma and cerebrospinal fluid NfL were linked to decreased [18F]FDG uptake in corresponding brain areas. In participants with Aβ positivity (Aβ+), NfL correlated with reduced metabolism in regions susceptible to Alzheimer's disease. In addition, CSF NfL levels correlate with brain atrophy and predict cognitive changes, while plasma total tau does not. Plasma P-tau, especially in combination with Aβ42/Aβ40, is promising for symptomatic AD stages. Though not AD-exclusive, blood NfL holds promise for neurodegeneration detection and assessing treatment efficacy. Given the consistent levels of T-tau, P-tau, Aβ42, and NFL in CSF, their incorporation into both clinical practice and research is highly recommended.

Plasma N-terminal containing tau fragments (NTA-tau): a biomarker of tau deposition in Alzheimer’s Disease

BackgroundNovel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer’s disease (AD), and can track amyloid-β (Aβ) and tau pathology. However, because these biomarkers are strongly associated with the emergence of Aβ pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain.MethodsNTA is a novel ultrasensitive assay targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal fluid (CSF) and plasma, which is elevated in AD. Using two well-characterized research cohorts (BioFINDER-2, n = 1,294, and BioFINDER-1, n = 932), we investigated the association between plasma NTA-tau levels and disease progression in AD, including tau accumulation, brain atrophy and cognitive decline.ResultsWe demonstrate that plasma NTA-tau increases across the AD continuum¸ especially during late stages, and displays a moderate-to-strong association with tau-PET (β = 0.54, p < 0.001) in Aβ-positive participants, while weak with Aβ-PET (β = 0.28, p < 0.001). Unlike plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with tau-PET is the most prominent contributor to NTA-tau variance (52.5% of total R2), while having very low contribution from Aβ pathology measured with CSF Aβ42/40 (4.3%). High baseline NTA-tau levels are predictive of tau-PET accumulation (R2 = 0.27), steeper atrophy (R2 ≥ 0.18) and steeper cognitive decline (R2 ≥ 0.27) in participants within the AD continuum. Plasma NTA-tau levels significantly increase over time in Aβ positive cognitively unimpaired (βstd = 0.16) and impaired (βstd = 0.18) at baseline compared to their Aβ negative counterparts. Finally, longitudinal increases in plasma NTA-tau levels were associated with steeper longitudinal decreases in cortical thickness (R2 = 0.21) and cognition (R2 = 0.20).ConclusionOur results indicate that plasma NTA-tau levels increase across the AD continuum, especially during mid-to-late AD stages, and it is closely associated with in vivo tau tangle deposition in AD and its downstream effects. Moreover, this novel biomarker has potential as a cost-effective and easily accessible tool for monitoring disease progression and cognitive decline in clinical settings, and as an outcome measure in clinical trials which also need to assess the downstream effects of successful Aβ removal.

Plasma Biomarkers of Alzheimer Disease in Women With and Without HIV

Blood-based biomarkers associated with increased risk of Alzheimer disease (AD) are understudied in people living with and without HIV, particularly women. To determine whether baseline or 1-year changes in plasma amyloid-β40 (Aβ40), Aβ42, ratio of Aβ42 to Aβ40, total tau (t-tau), phosphorylated tau 231 (p-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NFL) are associated with neuropsychological performance (NP) among women living with HIV (WLWH) and women living without HIV (WLWOH). This longitudinal, prospective, cohort study with 1-year repeated clinical measures (NP only measured once) and biospecimen collection occurred between 2017 and 2019. Participants were women aged 40 years or older from 10 clinical research sites in cities across the US that were part of the Women's Interagency HIV Study. Data analysis was conducted from April to December 2022. Laboratory-confirmed HIV status and AD biomarkers. Sociodemographically adjusted NP T-scores (attention and working memory, executive function, processing speed, memory, learning, verbal fluency, motor function, and global performance) were the primary outcomes. Baseline and 1-year fasting plasma Aβ40, Aβ42, t-tau, p-tau231, GFAP, and NFL levels were measured and analyzed using multivariable linear regression. The study consisted of 307 participants (294 aged ≥50 years [96%]; 164 African American or Black women [53%]; 214 women with a high school education or higher [70%]; 238 women who were current or former smokers [78%]; and 236 women [77%] who were overweight or obese [body mass index >25]) including 209 WLWH and 98 WLWOH. Compared with WLWOH at baseline, WLWH performed worse on learning (mean [SD] T-score 47.8 [11.3] vs 51.4 [10.5]), memory (mean [SD] T-score 48.3 [11.6] vs 52.4 [10.2]), verbal fluency (mean [SD] T-score 48.3 [9.8] vs 50.7 [8.5]), and global (mean [SD] T-score 49.2 [6.8] vs 51.1 [5.9]) NP assessments. Baseline median Aβ40, GFAP, and NFL levels were higher among WLWH vs WLWOH. There were no differences in 1-year biomarker change by HIV serostatus. Lower learning, memory, and motor NP were associated with 1-year Aβ40 increase; lower learning and motor with Aβ42 increase; lower motor with p-tau231 increase; and lower processing speed, verbal fluency and motor with NFL increase in the entire sample. Among WLWH, a 1-year increase in Aβ40 from baseline to follow-up was associated with worse learning, memory, and global NP; a 1-year increase in t-tau with worse executive function; and a 1-year increase in NFL with worse processing speed. Among WLWOH, a 1-year increase in Aβ40 and Aβ42 were associated with poorer memory performance and NFL was associated with poorer motor performance. These findings suggest that increases in certain plasma AD biomarkers are associated with NP in WLWH and WLWOH and may be associated with later onset of AD, and measuring these biomarkers could be a pivotal advancement in monitoring aging brain health and development of AD among women with and without HIV.

Plasma Amyloid-β, Total Tau, and Neurofilament Light Chain Across the Alzheimer's Disease Clinical Spectrum: A Population-Based Study.

Plasma biomarkers have emerged as a promising approach for characterizing pathophysiology in mild cognitive impairment (MCI) and Alzheimer's disease (AD). We aimed to characterize plasma biomarkers for AD and neurodegeneration across the AD clinical continuum, and to assess their ability to differentiate between AD, MCI, and normal cognition. This population-based study engaged 1,446 rural-dwelling older adults (age ≥60 years, 61.0% women) derived from MIND-China; of these, 402 were defined with MCI and 142 with AD. Plasma amyloid-β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) concentrations were analyzed using the Simoa platform. Data were analyzed using linear and logistic regression models, and receiver operating characteristic (ROC) analysis. Across the AD clinical spectrum, plasma Aβ40 and NfL increased, whereas Aβ42/Aβ40 ratio decreased. Plasma t-tau was higher in people with AD dementia than those with MCI or normal cognition. Plasma NfL outperformed other biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75), but all plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC <0.60). Plasma NfL in combination with age, sex, education, and APOE genotype yielded the AUC of 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition. In this Chinese population, AD plasma biomarkers vary by age, sex, and APOE genotype. Plasma Aβ, t-tau, and NfL differ across the AD clinical spectrum, and plasma NfL appears to be superior to plasma Aβ and t-tau for defining the clinical spectrum.

The heritability of blood-based biomarkers related to risk of Alzheimer's disease in a population-based sample of early old-age men.

Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored. Plasma amyloid beta 40 (Aβ40), Aβ42, the Aβ42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (μ =67.0, SD=2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them. Additive genetics explained 44% to 52% of Aβ42, Aβ40, t-tau, and NfL. The Aβ42/40 ratio was not heritable. Aβ40 and Aβ42 were genetically near identical (rg =0.94). Both Aβ40 and Aβ42 were genetically correlated with NfL (rg =0.35 to 0.38), but genetically unrelated to t-tau. Except for Aβ42/40, plasma biomarkers are heritable. Aβ40 and Aβ42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aβs and t-tau is not consistent with the amyloid cascade hypothesis.

Diffusion and structural MRI as potential biomarkers in people with Parkinson's disease and cognitive impairment.

To explore the neuroimage change in Parkinson's disease (PD) patients with cognitive impairments, this study investigated the correlation between plasma biomarkers and morphological brain changes in patients with normal cognition and mild cognitive impairment. The objective was to identify the potential target deposition regions of the plasma biomarkers and to search for the relevant early neuroimaging biomarkers on the basis of different cognitive domains. Structural brain MRI and diffusion weighted images were analyzed from 49 eligible PD participants (male/female: 27/22; mean age: 73.4 ± 8.5years) from a retrospective analysis. Plasma levels of α-synuclein, amyloid beta peptide, and total tau were collected. A comprehensive neuropsychological assessment of the general and specific cognitive domains was performed. Difference between PD patients with normal cognition and impairment was examined. Regression analysis was performed to evaluate the correlation between image-derived index and plasma biomarkers or neuropsychological assessments. Significant correlation was found between plasma Aβ-42 level and fractional anisotropy of the middle occipital, angular, and middle temporal gyri of the left brain, as well as plasma T-tau level and the surface area of the isthmus or the average thickness of the posterior part of right cingulate gyrus. Visuospatial and executive function is positively correlated with axial diffusivity in bilateral cingulate gyri. In nondemented PD patients, the target regions for plasma deposition might be located in the cingulate, middle occipital, angular, and middle temporal gyri. Changes from multiple brain regions can be correlated to the performance of different cognitive domains. Cognitive impairment in Parkinson's disease is primarily linked to biomarkers associated with Alzheimer's disease rather than those related to Parkinson's disease and resembles the frontal variant of Alzheimer's disease, which may guide management strategies for cognitive impairment in Parkinson's disease. • Fractional anisotropy, surface area, and thickness in the cingulate, middle occipital, angular, and middle temporal gyri can be significantly correlated with plasma Aβ-42 and T-tau level. • Axial diffusivity in the cingulate gyri was correlated with visuospatial and executive function. • The pattern of cognitive impairment in Parkinson's disease can be similar to the frontal variant than typical Alzheimer's disease.

Associations of plasma NfL, GFAP, and t-tau with cerebral small vessel disease and incident dementia: longitudinal data of the AGES-Reykjavik Study

We investigated the associations of plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (t-tau) with markers of cerebral small vessel disease (SVD) and with incident dementia. We also investigated whether associations of NfL, GFAP, and t-tau with incident dementia were explained by SVD. Data are from a random subsample (n = 1069) of the population-based AGES-Reykjavik Study who underwent brain MRI and in whom plasma NfL, GFAP, and t-tau were measured at baseline (76.1 ± 5.4 years/55.9% women/baseline 2002–2006/follow-up until 2015). A composite SVD burden score was calculated using white matter hyperintensity volume (WMHV), subcortical infarcts, cerebral microbleeds, and large perivascular spaces. Dementia was assessed in a 3-step process and adjudicated by specialists. Higher NfL was associated with a higher SVD burden score. Dementia occurred in 225 (21.0%) individuals. The SVD burden score significantly explained part of the association between NfL and incident dementia. WMHV mostly strongly contributed to the explained effect. GFAP was not associated with the SVD burden score, but was associated with WMHV, and WMHV significantly explained part of the association between GFAP and incident dementia. T-tau was associated with WMHV, but not with incident dementia. In conclusion, the marker most strongly related to SVD is plasma NfL, for which the association with WMHV appeared to explain part of its association with incident dementia. This study suggests that plasma NfL may reflect the contribution of co-morbid vascular disease to dementia. However, the magnitude of the explained effect was relatively small, and further research is required to investigate the clinical implications of this finding.

Plasma neurofilament light-chain and phosphorylated tau as biomarkers of disease severity in Huntington's disease: Korean cohort data

ObjectiveTo investigate neurofilament light chain (NfL), phosphorylated tau (p-Tau) and total tau (t-Tau) as plasma markers for clinical severity in Korean Huntington's disease (HD) cohort. MethodsGenetically-confirmed 67 HD patients participated from 13 referral hospitals in South Korea. The subjects were evaluated with the Unified Huntington's Disease Rating Scale (UHDRS), total motor score (TMS) and total functional capacity (TFC), Mini-Mental Status Examination (K-MMSE), Montreal Cognitive Assessment (MoCA-K), and Beck's depression inventory (K-BDI). We measured plasma NfL, p-Tau and t-Tau concentrations using single-molecule array (SIMOA) assays. Stages of HD were classified based on UHDRS-TFC score and plasma markers were analyzed for correlation with clinical severity scales. ResultsPlasma NfL was elevated in both 6 premanifest and 61 full manifest HD patients compared to the reference value, which increased further from premanifest to manifest HD groups. The NfL level was not significantly correlated with UHDRS TMS or TFC scores in manifest HD patients. Plasma p-Tau was also elevated in HD patients (p = 0.038). The level was the highest in stage III-V HD (n = 30) group (post-hoc p < 0.05). The p-Tau was correlated with UHDRS TFC scores (adjusted p = 0.002). Plasma t-Tau neither differed among the groups nor associated with any clinical variables. ConclusionsThis study supports plasma NfL being a biomarker for initial HD manifestation in Korean cohort, and a novel suggestion of plasma p-Tau as a potential biomarker reflecting the clinical severity in full-manifest HD.

Associations of Blood and Cerebrospinal Fluid Aβ and tau Levels with Renal Function.

Amyloid β (Aβ) and tau play pivotal roles in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that brain-derived Aβ and tau can be cleared through transport into the periphery, and the kidneys may be vital organs involved in the clearance of Aβ and tau. However, the effects of deficiency in the clearance of Aβ and tau by the kidneys on brain AD-type pathologies in humans remain largely unknown. In this study, we first recruited 41 patients with chronic kidney disease (CKD) and 40 age- and sex-matched controls with normal renal function to analyze the associations of the estimated glomerular filtration rate (eGFR) with plasma Aβ and tau levels. To analyze the associations of eGFR with cerebrospinal fluid (CSF) AD biomarkers, we recruited 42 cognitively normal CKD patients and 150 cognitively normal controls with CSF samples. Compared with controls with normal renal function, CKD patients had higher plasma levels of Aβ40, Aβ42 and total tau (T-tau), lower CSF levels of Aβ40 and Aβ42 and higher levels of CSF T-tau/Aβ42 and phosphorylated tau (P-tau)/Aβ42. Plasma Aβ40, Aβ42, and T-tau levels were negatively correlated with eGFR. In addition, eGFR was negatively correlated with CSF levels of T-tau, T-tau/Aβ42, and P-tau/Aβ42 but positively correlated with Mini-Mental State Examination (MMSE) scores. Thus, this study showed that the decline in renal function was correlated with abnormal AD biomarkers and cognitive decline, which provides human evidence that renal function may be involved in the pathogenesis of AD.

Reference intervals for plasma amyloid-β, total tau, and phosphorylated tau181 in healthy elderly Chinese individuals without cognitive impairment

BackgroundPlasma amyloid-β (Aβ) peptides and tau proteins are promising biomarkers of Alzheimer’s disease (AD), not only for predicting Aβ and tau pathology but also for differentiating AD from other neurodegenerative diseases. However, reference intervals for plasma biomarkers of AD in healthy elderly Chinese individuals have not yet been established.MethodsBiomarkers of AD were measured using single-molecule array (Simoa) assays in plasma samples from 193 healthy, cognitively unimpaired Chinese individuals aged 50–89 years. The 95% reference intervals for plasma Aβ42, Aβ40, t-tau, p-tau181, and derived ratios were calculated by using log-transformed parametric methods.ResultsPlasma Aβ42, Aβ40, and p-tau181 levels were positively correlated with age, while the Aβ42/Aβ40 ratio was negatively correlated with age. The 95% reference intervals for plasma Aβ42 and Aβ40 were 2.72–11.09 pg/mL and 61.4–303.9 pg/mL, respectively, and the 95% reference intervals for plasma t-tau and p-tau181 were 0.20–3.12 pg/mL and 0.49–3.29 pg/mL, respectively. The 95% reference intervals for the Aβ42/Aβ40 ratio, p-tau181/t-tau ratio, and p-tau181/Aβ42 ratio were 0.022–0.064, 0.38–6.34, and 0.05–0.55, respectively.ConclusionReference intervals for plasma biomarkers of AD may assist clinicians in making accurate clinical decisions.

Integrated algorithm combining plasma biomarkers and cognitive assessments accurately predicts brain β-amyloid pathology

BackgroundAccurate prediction of cerebral amyloidosis with easily available indicators is urgently needed for diagnosis and treatment of Alzheimer’s disease (AD).MethodsWe examined plasma Aβ42, Aβ40, T-tau, P-tau181, and NfL, with APOE genotypes, cognitive test scores and key demographics in a large Chinese cohort (N = 609, aged 40 to 84 years) covering full AD spectrum. Data-driven integrated computational models were developed to predict brain β-amyloid (Aβ) pathology.ResultsOur computational models accurately predict brain Aβ positivity (area under the ROC curves (AUC) = 0.94). The results are validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Particularly, the models have the highest prediction power (AUC = 0.97) in mild cognitive impairment (MCI) participants. Three levels of models are designed with different accuracies and complexities. The model which only consists of plasma biomarkers can predict Aβ positivity in amnestic MCI (aMCI) patients with AUC = 0.89. Generally the models perform better in participants without comorbidities or family histories.ConclusionsThe innovative integrated models provide opportunity to assess Aβ pathology in a non-invasive and cost-effective way, which might facilitate AD-drug development, early screening, clinical diagnosis and prognosis evaluation.

Assessment of Plasma Biomarkers by ImmunoMagnetic Reduction in Parkinson’s Disease Dementia and Dementia with Lewy Bodies (P10-6.008)

<h3>Objective:</h3> To use ImmunoMagnetic Reduction (IMR) assay to assess the diagnostic utility of plasma Aβ42, total Tau (t-Tau), phosphorylated Tau-181 (p-Tau-181) and α-synuclein in identifying and differentiating cases of Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). <h3>Background:</h3> PDD and DLB represent pathological subtypes along a continuum of synucleinopathies. Clinical differentiation is ultimately based on arbitrary and subjectively-reported timing of cognitive and motor symptoms. Ancillary tests are invasive, costly, and exhibit suboptimal sensitivity and specificity. Developments in plasma biomarker assays have increased detection thresholds and provide the opportunity to reassess whether core PDD/DLB plasma biomarkers would be useful for diagnosis. <h3>Design/Methods:</h3> Plasma samples from 61 total subjects (37 normal controls (NC), 12 with PDD, 12 with DLB) and were sent for IMR assay to quantify α-synuclein, Aβ42, t-Tau, and p-Tau-181. To determine discrimination between NC, PDD, and DLB, receiver operating characteristic (ROC) curve analysis was used to obtain sensitivity, specificity, and area under curve (AUC). <h3>Results:</h3> Plasma p-tau levels were significantly higher in DLB compared to NC and PD (p&lt;0.05). Plasma α-synuclein levels were significantly higher in PDD compared to DLB and NC. Plasma t-Tau and Aβ42 levels did not differ between NC, PDD and DLB subjects. When plasma biomarkers were combined, Aβ42 x t-Tau revealed no differences between DLB, PDD and NC. For the α-synuclein x p-Tau-181 combination, both PDD and DLB were greater than NC. <h3>Conclusions:</h3> Investigations into the discrimination of DLB vs. PDD are rare. In this pilot study, we show that IMR assays of plasma for α-synuclein, p-Tau-181, and Aβ42 x t-tau are useful in differentiating PDD from DLB, as well as NC. Thus, our data suggest clinical utility of these novel biomarker modalities and panels. Differentiating DLB from PDD could be consequential in clinical characterization. Future studies will aim to replicate our findings on larger group sizes. <b>Disclosure:</b> Dr. Malaty has nothing to disclose. Dr. Lue has nothing to disclose. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amneal Pharmaceuticals. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine Biosciences. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbive. Dr. Decourt has received personal compensation for serving as an employee of Cleveland Clinic. Dr. Decourt has received personal compensation in the range of $0-$499 for serving as a Reviewer with NIH. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eisai. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genetech=Roche. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Synaptogenix. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Signant Health. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for T3D. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for EIP Pharma. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Quince-Cortexyme. Dr. Sabbagh has stock in Neurotau. Dr. Sabbagh has stock in Seq Biomarque. Dr. Sabbagh has stock in uMethod Health. Dr. Sabbagh has stock in Athira. Dr. Sabbagh has stock in Lighthouse Pharmaceuticals. Dr. Sabbagh has stock in Alzheom. The institution of Dr. Sabbagh has received research support from NIH. The institution of Dr. Sabbagh has received research support from ADDF. Dr. Sabbagh has received publishing royalties from a publication relating to health care.

Correlation of blood-brain barrier leakage with cerebral small vessel disease including cerebral microbleeds in Alzheimer's disease.

Blood-brain barrier (BBB) damage is considered an important part of Alzheimer's disease (AD) progression, and cerebral small-vessel disease (CSVD) is commonly associated with AD. However, the relationship between BBB damage, small cerebrovascular lesions, especially cerebral microbleeds (CMBs), and amyloid and tau biomarkers remains controversial. Therefore, our study aimed to further investigate their association in our cohort of patients with AD. A total of 139 individuals were divided into probable AD (18F-florbetapir PET positive, n = 101) and control group (cognitively normal, n = 38). The levels of cerebrospinal fluid (CSF) and plasma t-tau, p-tau181, Aβ40, Aβ42, and albumin were measured using corresponding commercial assay kits, and the CSF/plasma albumin ratio (Qalb), an indicator of BBB dysfunction, was calculated. CSVD burden and the number of CMBs were defined using magnetic resonance imaging. Patients with AD had higher Qalb (p = 0.0024), higher numbers of CMBs (p = 0.03), and greater CSVD burden (p < 0.0001). In the AD group, CMBs and CSVD correlated with a higher Qalb (p = 0.03), and the numbers of CMBs negatively correlated with CSF Aβ42 (p = 0.02). Blood-brain barrier damage was accompanied by a more severe burden of CSVD, including CMB, in patients with AD.

Transient Changes in the Plasma of Astrocytic and Neuronal Injury Biomarkers in COVID-19 Patients without Neurological Syndromes.

The levels of several glial and neuronal plasma biomarkers have been found to increase during the acute phase in COVID-19 patients with neurological symptoms. However, replications in patients with minor or non-neurological symptoms are needed to understand their potential as indicators of CNS injury or vulnerability. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), and total Tau (T-tau) were determined by Single molecule array (Simoa) immunoassays in 45 samples from COVID-19 patients in the acute phase of infection [moderate (n = 35), or severe (n = 10)] with minor or non-neurological symptoms; in 26 samples from fully recovered patients after ~2 months of clinical follow-up [moderate (n = 23), or severe (n = 3)]; and in 14 non-infected controls. Plasma levels of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), were also determined by Western blot. Patients with COVID-19 without substantial neurological symptoms had significantly higher plasma concentrations of GFAP, a marker of astrocytic activation/injury, and of NfL and T-tau, markers of axonal damage and neuronal degeneration, compared with controls. All these biomarkers were correlated in COVID-19 patients at the acute phase. Plasma GFAP, NfL and T-tau levels were all normalized after recovery. Recovery was also observed in the return to normal values of the quotient between the ACE2 fragment and circulating full-length species, following the change noticed in the acute phase of infection. None of these biomarkers displayed differences in plasma samples at the acute phase or recovery when the COVID-19 subjects were sub-grouped according to occurrence of minor symptoms at re-evaluation 3 months after the acute episode (so called post-COVID or "long COVID"), such as asthenia, myalgia/arthralgia, anosmia/ageusia, vision impairment, headache or memory loss. Our study demonstrated altered plasma GFAP, NfL and T-tau levels in COVID-19 patients without substantial neurological manifestation at the acute phase of the disease, providing a suitable indication of CNS vulnerability; but these biomarkers fail to predict the occurrence of delayed minor neurological symptoms.

Predictive Utility of Plasma Amyloid and Tau for Cognitive Decline in Cognitively Normal Adults.

Alzheimer's disease (AD) is the most common neurodegenerative disease affecting mostly elderly adults. Recent diagnostic criteria for AD recommend the use of imaging and/or cerebrospinal fluid (CSF) biomarkers together with clinical presentation for a more persuasive diagnosis. The invasiveness and expense of such examinations have led to the search for blood-based biomarkers. The plasma levels of amyloid-β (Aβ) protein and tau peptides have been found to correlate with CSF levels and imaging findings in patients with AD. This study was conducted to explore the predictive utility of plasma Aβ1-42 and total tau (t-tau) levels for cognitive decline in healthy adults. In this prospective longitudinal study, we enrolled adults aged ≥ 50 years with normal cognition at Taipei Veterans General Hospital from November 2016 to April 2019. Blood samples were collected on recruitment, and plasma Aβ1-42 and t-tau levels were quantified through immunomagnetic reduction. Thorough neurophysiological assessment was performed at baseline and at the annual follow-up visit. The participants were divided into two groups according to cognitive decline. The predictive utility of Aβ1-42 and t-tau levels was evaluated by receiver operating characteristic curve analysis. Of 60 participants recruited, seven participants progressed to mild cognitive impairment and 53 retained normal cognition on follow-up (average 1.07 ± 0.2 years). The baseline levels of plasma biomarkers (Aβ1-42, t-tau, and Aβ1-42 × t-tau) were significantly higher in the progressive than in the stable group (p = 0.005, p = 0.007, and p = 0.005, respectively). Higher plasma biomarker levels (Aβ1-42 ≥ 16.96 pg/ml and Aβ1-42 × t-tau ≥ 382 pg2/ml2) predicted more cognitive decline on annual follow-up visits. Plasma Aβ1-42 and t-tau levels have predictive utility for cognitive decline, even in subjects with normal cognition. Higher baseline plasma Aβ1-42 and t-tau levels may indicate a higher risk of cognitive decline in cognitively normal adults.