Background
While in healthy conditions, synaptic function is sustained by the interplay between neurons and glial cells. The presence of Alzheimer’s disease (AD) pathophysiology might impose synaptic ...alterations via neuroinflammatory responses from microglia and astrocytes. Imaging and fluid biomarkers allow for testing this conceptual framework in living individuals. Here, we aim at uncovering the associations between neuroinflammatory and synaptic markers in aging and AD.
Method
Participants were recruited from the Translational Biomarker for aging and dementia cohort (TRIAD). We analyzed cognitively unimpaired young (CUY, N = 20), cognitively unimpaired older adults (CU; N = 48) individuals, patients with mild cognitive impairment (MCI; N = 24), AD dementia patients (ADD; N = 16) participants. The endpoints were CSF 14‐3‐3 sigma‐delta (ζδ), CSF Growth Associated Protein 43 (GAP43) and neurogranin as markers of synaptic dysfunction. We modeled associations between these synaptic biomarkers with astrocyte and microglial related inflammatory markers as well as tau, amyloid and neurodegeneration biomarkers.
Result
According to ROC analyses contrasting CSF biomarkers, 14‐3‐3 ζδ was able to discriminate amyloid‐ β pathology in cognitively impaired individuals (AUC = 0.88) (Figure 1). The amyloid‐induced 14‐3‐3 ζδ increase was mediated by inflammatory astrogliosis measured by GFAP, whereas the tau induced 14‐3‐3 ζδ pathology was mediated by anti‐inflammatory cytokines (Figure 2). CSF levels of GAP43 and neurogranin were positively associated with TSPO measured with 11CPBR28(Figure 3.1) and GFAP (Figure 3.2). 11CPBR28 cluster‐based SUVRs was positively correlated to concentrations of (A) Neurogranin (p = 5.8e‐08) and (B) GAP‐43(p = 6.8e‐10).
Conclusion
The present observations support the framework in which glia‐related neuroinflammatory responses contribute to synaptic alterations in carriers of AD pathophysiology. We will discuss the implications and limitations of this framework.
Abstract
Background
Blood biomarkers have gained much attention in recent years given their increasing ability to indicate amyloid pathology and excellent performance in distinguishing diagnostic ...groups in the context of Alzheimer’s disease (AD). Plasma pTau217 has been considered the best candidate biomarker to serve as diagnostic and prognostic tool for clinical trials. However, biomarker assays targeting tau phosphorylation on Thr217 may differ because of their composition (e.g., targeting multiple or single phosphorylation sites) which may lead to distinct associations with pathology. Thus, we aimed to compare two plasma pTau217 immunoassays that differ in regard to their target specificity.
Method
Participants from the TRIAD cohort with available cross‐sectional plasma and imaging data, incorporating within the AD spectrum, were included in this study (Young = 25;CU‐ = 107;CU+ = 32;MCI+ = 42;AD+ = 47;MCI‐ = 19). Plasma pTau was quantified using the assays from Janssen (pTau217+; which exhibits enhanced signal with co‐phosphorylation of pTau212) and from ALZpath (single phosphorylation on pTau217), both performed on the Simoa platform. Amyloid and tau pathologies were indexed by PET using
18
FAZD4694 and
18
FMK6240, respectively. ANCOVA compared biomarker values across groups, Spearman rank tested the correlations between them. Linear regression models (LM) evaluated the association between plasma and PET biomarkers globally and at the voxel level.
Result
Biomarker levels (fold mean of CU‐) were comparable across diagnostic groups, showing the expected increases in amyloid positive groups. Both plasma assays were highly correlated with amyloid (Fig.1), which was also observed on the LM adjusted by age and sex, and on the voxel‐wise analysis (Fig.2). Associations with tau PET SUVR (medial temporal) were also significant and showed similar distribution between the two pTau assays. When neocortical tau was evaluated, however, pTau217+ had a better association as well as higher correlation coefficients within amyloid+ (Fig.3) and neocortical tau+ groups than did ALZpath pTau217.
Conclusion
In general, pTau217 assays with different antibody specificity showed very similar associations with PET. However, pTau217+ achieved a better association with neocortical tau as compared to ALZpath pTau217. A biomarker targeting multiple phosphorylation sites might be a better proxy of advanced tau, therefore may offer improved ability to detect and exclude participants with advanced AD pathology for clinical trials.
Background
To compare the performance of plasma p‐tau181, plasma‐NfL and FDG‐PET in the diagnosis of biological AD.
Method
We included 787 participants (cognitively unimpaired (CU, n = 251), mild ...cognitive impairment (MCI, n = 412), and Alzheimer’s dementia (AD, n = 124) from the ADNI database. Participants underwent measures of plasma p‐tau181, plasma‐NfL, CSF P‐tau181, 18FFDG‐PET, amyloid‐PET and cognitive screening tests. ROC analyses were used to determine diagnostic accuracy of plasma P‐tau181, NfL and 18FFDG‐PET using clinical diagnosis and core AD biomarkers (amyloid‐PET and CSF P‐tau181) as reference standards. We assessed whether plasma P‐tau181 and 18FFDG‐PET diagnostic accuracies were significantly different with a bootstrap‐based test (pROC package in R). Second, correlations of 18FFDG‐PET, plasma‐NfL, plasma P‐tau181 with P‐tau181 CSF, Aβ‐PET, and cognitive performance were evaluated. Correlation coefficients were compared via Cocor package, a statistical framework for comparing associations between intercorrelated measurements.
Result
Across the total sample we observed that plasma P‐tau181, plasma‐NfL, and 18FFDG‐PET were able to identify individuals with CSF evidence of AD as well as participants who are amyloid‐PET+. In the MCI group, plasma P‐tau181 outperformed 18FFDG‐PET and plasma‐NfL in identifying AD pathophysiology measured via CSF P‐tau181 (p = 0.0007), and amyloid‐PET (p = 0.001). We also observed that both plasma P‐tau181, plasma‐NfL and 18FFDG‐PET were associated with AD pathophysiology measured by core AD biomarkers (CSF and amyloid‐PET). However, 18FFDG‐PET was more closely associated with cognitive outcomes than plasma P‐tau181 and plasma NfL (MoCA: p < 0.0001; MMSE: p< 0.0001; CDR‐SB: p < 0.0001)
Conclusion
This study investigated the diagnostic properties of plasma P‐tau181 and two neurodegenerative biomarkers (plasma‐NfL and 18FFDG‐PET) as well as their to identify biological AD. While plasma P‐tau181, plasma‐NfL concentrations and 18FFDG‐PET were associated with AD pathophysiology measured by core AD biomarkers (CSF and amyloid‐PET), plasma P‐tau181 outperformed 18FFDG‐PET and plasma‐NfL in identifying individuals with AD pathophysiology. However, we also observed that 18FFDG‐PET was more strongly associated with neuropsychological assessments than plasma P‐tau181 and plasma‐NfL. Taken together, our study suggests that plasma P‐tau181 may aid in the evaluation of individuals by identifying those with underlying AD pathophysiology.
Background
The high prevalence of Alzheimer’s dementia in females have long puzzled researchers in the field. Despite similar amyloid levels, females show higher load of neurofibrillary tangles ...(NFTs). Previous literature proposed that amyloid‐β (Aβ) and phosphorylated tau (p‐tau) synergism accelerates biomarker abnormalities. However, it remains to be answered whether this synergism is the driving force behind faster tau progression in females. The overarching goal of the study wa to investigate whether amyloid‐β aggregates differentially impose tau hyperphosphorylation and neurofibrillary tangles formation in a sex‐specific manner.
Method
In this longitudinal study, we assessed 287 participants from TRIAD cohort at McGill University Research Centre for Studies in Aging. Cerebral Aβ and tau deposition were assessed with positron emission tomography (PET) radiotracers 18FAZD4694 (18FNAV4694) and 18FMK6240, respectively. Cerebrospinal fluid (CSF) p‐tau181 and p‐tau217 were also measured (analysed at the Clinical Neurochemistry Laboratory at the University of Gothenburg, Sweden). Regression and voxel‐based models with interaction terms were used to evaluate baseline tau load and NFT accumulation rate as a function of sex and baseline biomarkers (Aβ and p‐tau).
Result
We identified sex difference in the relationships between CSF p‐tau, Aβ and NFT (Fig 1). Specifically, voxelwise analyses demonstrated that female presented stronger positive correlations between CSF p‐tau and AD core biomarkers (Aβ and NFT). Furthermore, we discovered that Aβ and CSF ptau181 interactively potentiated tau accumulation in females but not males (Fig 2, Table 1). Together, the present results support that Aβ load imposes higher tau aggregation in females.
Conclusion
Aβ‐dependent tau phosphorylation was the key driver for faster NFT accumulation observed in female.
Highlights • Accelerated HF-rTMS was robustly performed on small animals. • Accelerated HF-rTMS enhances rat motor activity. • Accelerated HF-rTMS reduces the total striatal 5-hydroxyindolacetic acid ...levels.
Background
The natural history of Alzheimer’s disease (AD) comprises a long preclinical stage characterized by pathological changes that start decades before symptoms arise. Despite that AD is ...defined based on the presence of amyloid‐β (Aβ) and tau pathology, increasing evidence supports neuroinflammation as one of the earliest pathomechanistic alterations throughout the AD continuum. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. However, it remains unclear if there are patterns of spatial and temporal susceptibility to neuroinflammatory processes in the brain that may synergize with Aβ and tau accumulation, which drives neurodegeneration in a self‐reinforcing manner.
Method
This was a cross‐sectional study examining a total number of 283 subjects from the TRIAD cohort at McGill University Research Centre for Studies in Aging, Canada. Cerebral amyloid and tau neurofibrillary tangles were assessed using positron emission tomography (PET) radiopharmaceuticals 18FAZD4694 (18FNAV4694) and 18FMK6240 respectively. Cerebrospinal fluid (CSF) biomarkers including Aβ42, Aβ40, phosphorylated tau (p‐tau), total tau (t‐tau), neurofilament light (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), YKL40 and glial fibrillary acidic protein (GFAP) were also measured. Voxelwise analyses were performed to evaluate the relationships between cerebral amyloid load, tau burden and neuroinflammation biomarkers.
Result
We modelled biomarker changes as a function of amyloid PET standardized uptake value ratio (SUVR) and tau PET SUVR as proxies of disease progression. The earliest changes observed in the AD continuum were the decrease in the Aβ42/40 ratio and the increases in astrocytic biomarkers CSF YKL40 and CSF GFAP. This is followed by a steep increase in CSF pTau231 and, to a lesser extent, CSF pTau217 and CSF pTau181. Voxelwise analyses revealed that YKL40 and GFAP are associated with amyloid and tau load in the brain, after accounting for age, sex, education and pathological status.
Conclusion
Neuroinflammation involving astrocytic activation is altered very early in the Alzheimer’s continuum and could be targeted as a promising biomarker.
INTRODUCTION
Fluid biomarkers capable of specifically tracking tau tangle pathology in vivo are greatly needed.
METHODS
We measured cerebrospinal fluid (CSF) and plasma concentrations of N‐terminal ...tau fragments (NTA‐tau), using a novel immunoassay (NTA) in the TRIAD cohort, consisting of 272 individuals assessed with amyloid beta (Aβ) positron emission tomography (PET), tau PET, magnetic resonance imaging (MRI) and cognitive assessments.
RESULTS
CSF and plasma NTA‐tau concentrations were specifically increased in cognitively impaired Aβ‐positive groups. CSF and plasma NTA‐tau concentrations displayed stronger correlations with tau PET than with Aβ PET and MRI, both in global uptake and at the voxel level. Regression models demonstrated that both CSF and plasma NTA‐tau are preferentially associated with tau pathology. Moreover, plasma NTA‐tau was associated with longitudinal tau PET accumulation across the aging and Alzheimer's disease (AD) spectrum.
DISCUSSION
NTA‐tau is a biomarker closely associated with in vivo tau deposition in the AD continuum and has potential as a tau tangle biomarker in clinical settings and trials.
Highlights
An assay for detecting N‐terminal tau fragments (NTA‐tau) in plasma and CSF was evaluated.
NTA‐tau is more closely associated with tau PET than amyloid PET or neurodegeneration.
NTA‐tau can successfully track in vivo tau deposition across the AD continuum.
Plasma NTA‐tau increased over time only in cognitively impaired amyloid‐β positive individuals.
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