scholarly journals Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum

Brain ◽  
2020 ◽  
Author(s):  
Alexis Moscoso ◽  
Michel J Grothe ◽  
Nicholas J Ashton ◽  
Thomas K Karikari ◽  
Juan Lantero Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Longitudinal Data ◽  
Time Course ◽  
Amyloid Β ◽  
Smoothing Splines ◽  
Pet Scan ◽  
Disease Spectrum ◽  
Natural Time ◽  
Tau Aggregation

Abstract Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer’s disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer’s disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer’s disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer’s disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n = 1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-β PET scan at baseline. A subset of participants (n = 864) also had measures of amyloid-β1–42 and p-tau181 levels in CSF, and another subset (n = 298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-β pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer’s disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-β markers reached abnormal levels, with greater rates of change correlating with increased amyloid-β pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-β pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-β were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer’s disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ∼6.5 and 5.7 years after CSF and PET measures of amyloid-β, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-β pathology and with prospective Alzheimer’s disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer’s disease.

scholarly journals Time course of phosphorylated tau181 in blood across the Alzheimer's disease spectrum

2020 ◽  
Author(s):  
Alexis Moscoso ◽  
Michel J. Grothe ◽  
Nicholas J. Ashton ◽  
Thomas K Karikari ◽  
Juan Lantero Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Longitudinal Data ◽  
Time Course ◽  
Temporal Dynamics ◽  
Neurofibrillary Tangle ◽  
Pet Scan ◽  
Disease Spectrum ◽  
Natural Time ◽  
Tau Aggregation

Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer's disease-characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging- and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n=1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an [18F]florbetapir amyloid-β (Aβ) positron emission tomography (PET) scan at baseline. A subset of participants (n=864) also had measures of Aβ1-42 and p-tau181 levels in cerebrospinal fluid (CSF), and another subset (n=298) had undergone an [18F]flortaucipir tau PET scan six years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional Aβ pathology and tau burden six years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's disease biomarkers employing a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Spline regressions demonstrated that earliest plasma p-tau181 changes occurred even before Aβ-markers reached abnormal levels, with greater rates of change correlating with increased Aβ pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with Aβ pathology in early-accumulating brain regions in cognitively healthy individuals, while the strongest associations with Aβ were observed in late-accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation six years later, covering temporo-parietal regions typical for neurofibrillary tangle distribution in Alzheimer's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels approximately 6.5 and 5.7 years after CSF- and PET-measures of Aβ, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical Aβ pathology and with prospective Alzheimer's disease-typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.

scholarly journals Tau and synaptic biomarkers but not amyloid‐β are associated with cerebral perfusion in the Alzheimer’s disease spectrum

2021 ◽  
Vol 17 (S5) ◽  
Author(s):  
Khazar Ahmadi ◽  
Joana B. Pereira ◽  
David Berron ◽  
Jacob W. Vogel ◽  
Silvia Ingala ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Perfusion ◽  
Amyloid Β ◽  
Disease Spectrum

Unravelling the Association Between Amyloid-PET and Cerebrospinal Fluid Biomarkers in the Alzheimer’s Disease Spectrum: Who Really Deserves an A+?

2021 ◽  
pp. 1-12
Author(s):  
Luca Sacchi ◽  
Tiziana Carandini ◽  
Giorgio Giulio Fumagalli ◽  
Anna Margherita Pietroboni ◽  
Valeria Elisa Contarino ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Linear Regression Models ◽  
Csf Analysis ◽  
Disease Spectrum

Background: Association between cerebrospinal fluid (CSF)-amyloid-β (Aβ)42 and amyloid-PET measures is inconstant across the Alzheimer’s disease (AD) spectrum. However, they are considered interchangeable, along with Aβ 42/40 ratio, for defining ‘Alzheimer’s Disease pathologic change’ (A+). Objective: Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients. Methods: We include ed 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aβ 42 within a 365-days interval. Thresholds used for dichotomization were: Aβ 42 <  640 pg/mL (Aβ 42+); pTau >  61 pg/mL (pTau+); and Aβ 42/40 <  0.069 (ADratio+). Amyloid-PET scans were visually assessed and processed by four pipelines (SPMCL, SPMAAL, FSGM, FSWC). Results: Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rho = 0.93–0.99). The most significant findings were: pTau positive correlation with SPMCL SUVR (rho = 0.56, p = 0.0063) and Aβ 42/40 negative correlation with SPMCL and SPMAAL SUVRs (rho = –0.56, p = 0.0058; rho = –0.52, p = 0.0117 respectively). No correlations between CSF-Aβ 42 and global SUVRs were observed. In subregion analysis, both pTau and Aβ 42/40 values significantly correlated with cingulate SUVRs from any pipeline (R2 = 0.55–0.59, p <  0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aβ 42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aβ 42 or using Aβ 42/40, instead of Aβ 42 alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids. Conclusion: We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aβ 42/40 and secondarily pTau rather than Aβ 42 levels.

scholarly journals Relationship between cortical iron and tau aggregation in Alzheimer’s disease

Brain ◽  
2020 ◽  
Vol 143 (5) ◽  
pp. 1341-1349 ◽  
Author(s):  
Nicola Spotorno ◽  
Julio Acosta-Cabronero ◽  
Erik Stomrud ◽  
Björn Lampinen ◽  
Olof T Strandberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Disease Process ◽  
Amyloid Β ◽  
Cortical Atrophy ◽  
Tau Pet ◽  
Tau Aggregation ◽  
The Relationship

Abstract A growing body of evidence suggests that the dysregulation of neuronal iron may play a critical role in Alzheimer’s disease. Recent MRI studies have established a relationship between iron accumulation and amyloid-β aggregation. The present study provides further insight demonstrating a relationship between iron and tau accumulation using magnetic resonance-based quantitative susceptibility mapping and tau-PET in n = 236 subjects with amyloid-β pathology (from the Swedish BioFINDER-2 study). Both voxel-wise and regional analyses showed a consistent association between differences in bulk magnetic susceptibility, which can be primarily ascribed to an increase in iron content, and tau-PET signal in regions known to be affected in Alzheimer’s disease. Subsequent analyses revealed that quantitative susceptibility specifically mediates the relationship between tau-PET and cortical atrophy measures, thus suggesting a modulatory effect of iron burden on the disease process. We also found evidence suggesting the relationship between quantitative susceptibility and tau-PET is stronger in younger participants (age ≤ 65). Together, these results provide in vivo evidence of an association between iron deposition and both tau aggregation and neurodegeneration, which help advance our understanding of the role of iron dysregulation in the Alzheimer’s disease aetiology.

scholarly journals The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2439 ◽  
Author(s):  
Lidia Ciccone ◽  
Chenghui Shi ◽  
Davide di Lorenzo ◽  
Anne-Cécile Van Baelen ◽  
Nicolo Tonali
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Interactions ◽  
Amyloid Β ◽  
Apolipoprotein A1 ◽  
Single Type ◽  
Protein Protein Interactions ◽  
Positive Side ◽  
Amyloid Fibril Formation ◽  
Tau Aggregation

Alzheimer’s disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions.

Yeast Model of Amyloid-β and Tau Aggregation in Alzheimer’s Disease

2015 ◽  
Vol 47 (1) ◽  
pp. 9-16 ◽  
Author(s):  
Behrooz Moosavi ◽  
Bibimaryam Mousavi ◽  
Ian G. Macreadie
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Tau Aggregation ◽  
Yeast Model

scholarly journals Probing the mechanism of inhibition of amyloid-β(1–42)–induced neurotoxicity by the chaperonin GroEL

2018 ◽  
Vol 115 (51) ◽  
pp. E11924-E11932 ◽  
Author(s):  
Marielle A. Wälti ◽  
Joseph Steiner ◽  
Fanjie Meng ◽  
Hoi Sung Chung ◽  
John M. Louis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Molecule ◽  
Time Course ◽  
Global Analysis ◽  
Amyloid Β ◽  
Random Coil ◽  
Neuronal Cultures ◽  
Transverse Relaxation Rate ◽  
Rate Profile

The human chaperonin Hsp60 is thought to play a role in the progression of Alzheimer’s disease by mitigating against intracellular β-amyloid stress. Here, we show that the bacterial homolog GroEL (51% sequence identity) reduces the neurotoxic effects of amyloid-β(1–42) (Aβ42) on human neural stem cell-derived neuronal cultures. To understand the mechanism of GroEL-mediated abrogation of neurotoxicity, we studied the interaction of Aβ42 with GroEL using a variety of biophysical techniques. Aβ42 binds to GroEL as a monomer with a lifetime of ∼1 ms, as determined from global analysis of multiple relaxation-based NMR experiments. Dynamic light scattering demonstrates that GroEL dissolves small amounts of high–molecular-weight polydisperse aggregates present in fresh soluble Aβ42 preparations. The residue-specific transverse relaxation rate profile for GroEL-bound Aβ42 reveals the presence of three anchor-binding regions (residues 16–21, 31–34, and 40–41) located within the hydrophobic GroEL-consensus binding sequences. Single-molecule FRET analysis of Aβ42 binding to GroEL results in no significant change in the FRET efficiency of a doubly labeled Aβ42 construct, indicating that Aβ42 samples a random coil ensemble when bound to GroEL. Finally, GroEL substantially slows down the disappearance of NMR visible Aβ42 species and the appearance of Aβ42 protofibrils and fibrils as monitored by electron and atomic force microscopies. The latter observations correlate with the effect of GroEL on the time course of Aβ42-induced neurotoxicity. These data provide a physical basis for understanding how Hsp60 may serve to slow down the progression of Alzheimer’s disease.

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