scholarly journals Associations between different tau-PET patterns and longitudinal atrophy in the Alzheimer's disease continuum

2021 ◽  
Author(s):  
Rosaleena Mohanty ◽  
Daniel Ferreira ◽  
Agneta Nordberg ◽  
Eric Westman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Structural Mri ◽  
Tau Pathology ◽  
Discrete Subgroups ◽  
Cognitively Normal ◽  
Prodromal Ad ◽  
Tau Pet ◽  
The Relationship

INTRODUCTION: Different subtypes/patterns have been defined using tau-PET and structural-MRI in Alzheimer's disease (AD), but the relationship between tau pathology and atrophy remains unclear. Our goals were twofold: (a) investigate the association between baseline tau-PET patterns and longitudinal atrophy in the AD continuum; (b) characterize heterogeneity as a continuous phenomenon over the conventional notion using discrete subgroups. METHODS: In 366 individuals (amyloid-beta-positive: cognitively normal, prodromal AD, AD dementia; amyloid-beta-negative healthy), we examined the association between tau-PET patterns (operationalized as a continuous phenomenon and a discrete phenomenon) and longitudinal sMRI. RESULTS: We observed a differential association between tau-PET patterns and longitudinal atrophy. Heterogeneity, measured continuously, may offer an alternative characterization, sharing correspondence with the conventional subgrouping. DISCUSSION: Site and the rate of atrophy are modulated differentially by tau-PET patterns in the AD continuum. We postulate that heterogeneity be treated as a continuous phenomenon for greater sensitivity over the current/conventional discrete subgrouping.

scholarly journals The Correlations Between Plasma Fibrinogen With Amyloid-Beta and Tau Levels in Patients With Alzheimer’s Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Dong-Yu Fan ◽  
Hao-Lun Sun ◽  
Pu-Yang Sun ◽  
Jie-Ming Jian ◽  
Wei-Wei Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Fibrinogen ◽  
Cognitively Normal ◽  
Amyloid Aβ ◽  
And Gender ◽  
T Tau ◽  
The Relationship ◽  
Phosphorylated Tau 181 ◽  
Normal Controls

Recent studies show that fibrinogen plays a role in the pathogenesis of Alzheimer’s disease (AD), which may be crucial to neurovascular damage and cognitive impairment. However, there are few clinical studies on the relationship between fibrinogen and AD. 59 11C-PiB-PET diagnosed AD patients and 76 age- and gender-matched cognitively normal controls were included to analyze the correlation between plasma β-amyloid (Aβ) and tau levels with fibrinogen levels. 35 AD patients and 76 controls with cerebrospinal fluid (CSF) samples were included to further analyze the correlation between CSF Aβ and tau levels with fibrinogen levels. In AD patients, plasma fibrinogen levels were positively correlated with plasma Aβ40 and Aβ42 levels, and negatively correlated with CSF Aβ42 levels. Besides, fibrinogen levels were positively correlated with CSF total tau (t-tau), and phosphorylated tau-181 (p-tau) levels and positively correlated with the indicators of Aβ deposition in the brain, such as t-tau/Aβ42, p-tau/Aβ42 levels. In normal people, fibrinogen levels lack correlation with Aβ and tau levels in plasma and CSF. This study suggests that plasma fibrinogen levels are positively correlated with Aβ levels in the plasma and brain in AD patients. Fibrinogen may be involved in the pathogenesis of AD.

scholarly journals Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau

2021 ◽  
Author(s):  
Niklas Mattsson-Carlgren ◽  
Shorena Janelidze ◽  
Randall Bateman ◽  
Ruben Smith ◽  
Erik Stomrud ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medial Temporal Lobe ◽  
Amyloid Plaques ◽  
Amyloid Plaque ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Β Amyloid ◽  
Tau Pet ◽  
Disease Stages

Abstract Alzheimer’s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N=88), both plaque and tangle density contributed independently to higher P-tau217. Several findings were replicated in a cohort with PET imaging (“BioFINDER-2”, N=426), where β-amyloid and tau PET were independently associated to P-tau217. P-tau217 correlated with β-amyloid PET (but not tau PET) in early disease stages, and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.

Predicting diagnosis and cognition with18F-AV-1451 tau PET and structural MRI in Alzheimer's disease

2019 ◽  
Vol 15 (4) ◽  
pp. 570-580 ◽  
Author(s):  
Niklas Mattsson ◽  
Philip S. Insel ◽  
Michael Donohue ◽  
Jonas Jögi ◽  
Rik Ossenkoppele ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structural Mri ◽  
Tau Pet

scholarly journals Co-Localization of Amyloid Beta and Tau Pathology in Alzheimer's Disease Synaptosomes

2008 ◽  
Vol 172 (6) ◽  
pp. 1683-1692 ◽  
Author(s):  
Jeffrey A. Fein ◽  
Sophie Sokolow ◽  
Carol A. Miller ◽  
Harry V. Vinters ◽  
Fusheng Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Tau Pathology

scholarly journals Tau seeding activity anticipates phospho-tau pathology in Alzheimer’s disease

2018 ◽  
Author(s):  
Sarah K. Kaufman ◽  
Kelly Del Tredici ◽  
Talitha L. Thomas ◽  
Heiko Braak ◽  
Marc I. Diamond
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Visual Cortex ◽  
Brain Regions ◽  
Tau Pathology ◽  
Age Related ◽  
Important Addition ◽  
Disease Stages ◽  
Relationship Of ◽  
The Relationship

AbstractAlzheimer’s disease (AD) is characterized by accumulation of tau neurofibrillary tangles (NFTs) and, according to the prion model, transcellular propagation of pathological “seeds” may underlie its progression. Staging of NFT pathology with phospho-tau antibody is useful to classify AD and primary age-related tauopathy (PART) cases. The locus coeruleus (LC) shows the earliest phospho-tau signal, whereas other studies suggest that pathology begins in the transentorhinal/entorhinal cortices (TRE/EC). The relationship of tau seeding activity, phospho-tau pathology, and progression of neurodegeneration remains obscure. Consequently, we employed an established cellular biosensor assay to quantify tau seeding activity in fixed human tissue, in parallel with AT8 phospho-tau staining of immediately adjacent sections. We studied four brain regions from each of n=247 individuals across a range of disease stages. We detected the earliest and most robust seeding activity in the TRE/EC. The LC did not uniformly exhibit seeding activity until later NFT stages. We also detected seeding activity in the first temporal gyrus and visual cortex at stages before NFTs and/or AT8-immunopositivity were detectable. AD and putative PART cases exhibited similar patterns of seeding activity that anticipated histopathology across all NFT stages. Our findings are consistent with the prion model and suggest that pathological seeding activity begins in the TRE/EC rather than in the LC, and may offer an important addition to classical histopathology.

scholarly journals Caspase-6-cleaved tau is relevant in Alzheimer’s disease but not in 4-repeat tauopathies: diagnostic and therapeutic implications

2021 ◽  
Author(s):  
Panos Theofilas ◽  
Antonia M.H. Piergies ◽  
Song Hua Li ◽  
Cathrine Petersen ◽  
Alexander J. Ehrenberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Strategy ◽  
Tau Pathology ◽  
Therapeutic Implications ◽  
Caspase 6 ◽  
Human Brains ◽  
The Relationship ◽  
Self Aggregation ◽  
Active Caspase

AbstractAimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation. Yet, the relationship between aCasp-6, different forms of tr-tau, and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer’s disease (AD) and other tauopathies remains unclear.MethodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used 5-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau, and their co-occurrence in healthy controls, AD, and primary tauopathies.ResultsCasp-6 activation was strong in AD, followed by Pick’s disease (PiD), but almost absent in 4-repeat (4R) tauopathies. Tr-tau neuronal burden was much higher in AD than in 4R tauopathies, and disproportionally higher when normalizing by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, half of the tr-tau positive neurons in AD lacked p-tau aggregates.ConclusionsEarly modulation of aCasp-6 with consequent amortization of tr-tau pathology is a promising therapeutic strategy in AD and possibly PiD, but it is unlikely to benefit 4R tauopathies. The large percentage of tr-tau neurons lacking p-tau suggests that not all tau pathology and vulnerable neurons are detected by conventional p-tau Ser 202 antibody and, that AD, has distinct mechanisms of tangle formation. Therapeutic strategies against tr-tau pathology could modulate tau abnormalities in AD. The disproportional higher burden of tr-tau in AD supports the evaluation of biofluid biomarkers against N-terminus tr-tau to detect AD and differentiate it from 4R tauopathies at a single patient level.

scholarly journals Atrophy of Basal Forebrain Initiates with Tau Pathology in Individuals at Risk for Alzheimer’s Disease

2019 ◽  
Vol 30 (4) ◽  
pp. 2083-2098
Author(s):  
Jose L Cantero ◽  
Mercedes Atienza ◽  
Carmen Lage ◽  
Laszlo Zaborszky ◽  
Eduard Vilaplana ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Nucleus Basalis ◽  
Tau Pathology ◽  
Projection System ◽  
Prodromal Ad

Abstract Evidence suggests that the basal forebrain (BF) cholinergic system degenerates early in the course of Alzheimer’s disease (AD), likely due to the vulnerability of BF cholinergic neurons to tau pathology. However, it remains unclear whether the presence of tauopathy is the only requirement for initiating the BF degeneration in asymptomatic subjects at risk for AD (AR-AD), and how BF structural deficits evolve from normal aging to preclinical and prodromal AD. Here, we provide human in vivo magnetic resonance imaging evidence supporting that abnormal cerebrospinal fluid levels of phosphorylated tau (T+) are selectively associated with bilateral volume loss of the nucleus basalis of Meynert (nbM, Ch4) in AR-AD individuals. Spreading of atrophy to medial septum and vertical limb of diagonal band Broca (Ch1–Ch2) occurred in both preclinical and prodromal AD. With the exception of A+, all groups revealed significant correlations between volume reduction of BF cholinergic compartments and atrophy of their innervated regions. Overall, these results support the central role played by tauopathy in instigating the nbM degeneration in AR-AD individuals and the necessary coexistence of both AD proteinopathies for spreading damage to larger BF territories, thus affecting the core of the BF cholinergic projection system.

scholarly journals Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology

Brain ◽  
2019 ◽  
Vol 143 (2) ◽  
pp. 650-660 ◽  
Author(s):  
Kaj Blennow ◽  
Chun Chen ◽  
Claudia Cicognola ◽  
Kristin R Wildsmith ◽  
Paul T Manser ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Proteolytic Processing ◽  
Tau Pathology ◽  
Strong Negative Correlation ◽  
Drug Candidates ◽  
Tangle Pathology ◽  
Tau Pet ◽  
T Tau ◽  
Fluid Biomarker

Abstract To date, there is no validated fluid biomarker for tau pathology in Alzheimer’s disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer’s disease. We used immunoprecipitation followed by mass spectrometric analyses to evaluate the presence of tau368 species in CSF. A novel Simoa® assay for quantification of tau368 in CSF was developed, while total tau (t-tau) was measured by ELISA and the presence of tau368 in tangles was evaluated using immunohistochemistry. The diagnostic utility of tau368 was first evaluated in a pilot study (Alzheimer’s disease = 20, control = 20), then in a second cohort where the IWG-2 biomarker criteria were applied (Alzheimer’s disease = 37, control = 45), and finally in a third cohort where the correlation with 18F-GTP1 tau PET was evaluated (Alzheimer’s disease = 38, control = 11). The tau368/t-tau ratio was significantly decreased in Alzheimer’s disease (P < 0.001) in all cohorts. Immunohistochemical staining demonstrated that tau fragments ending at 368 are present in tangles. There was a strong negative correlation between the CSF tau368/t-tau ratio and 18F-GTP1 retention. Our data suggest that tau368 is a tangle-enriched fragment and that the CSF ratio tau368/t-tau reflects tangle pathology. This novel tau biomarker could be used to improve diagnosis of Alzheimer’s disease and to facilitate the development of drug candidates targeting tau pathology. Furthermore, future longitudinal studies will increase our understanding of tau pathophysiology in Alzheimer’s disease and other tauopathies.

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