Age-Dependency of Total Tau in the Cerebrospinal Fluid Is Corrected by Amyloid-β 1–40: A Correlational Study in Healthy Adults

2021 ◽  
pp. 1-8
Author(s):  
Paul Theo Zebhauser ◽  
Achim Berthele ◽  
Marie-Sophie Franz ◽  
Oliver Goldhardt ◽  
Janine Diehl-Schmid ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Healthy Adults ◽  
Tau Proteins ◽  
Clinical Settings ◽  
Inclusion Criteria ◽  
Total Tau ◽  
Potential Marker ◽  
Wide Range ◽  
The Relationship

Background: Tau proteins are established biomarkers of neuroaxonal damage in a wide range of neurodegenerative conditions. Although measurement of total-Tau in the cerebrospinal fluid is widely used in research and clinical settings, the relationship between age and total-Tau in the cerebrospinal fluid is yet to be fully understood. While past studies reported a correlation between age and total-Tau in the cerebrospinal fluid of healthy adults, in clinical practice the same cut-off value is used independently of patient’s age. Objective: To further explore the relationship between age and total-Tau and to disentangle neurodegenerative from drainage-dependent effects. Methods: We analyzed cerebrospinal fluid samples of 76 carefully selected cognitively healthy adults and included amyloid-β 1–40 as a potential marker of drainage from the brain’s interstitial system. Results: We found a significant correlation of total-Tau and age, which was no longer present when correcting total-Tau for amyloid-β 1–40 concentrations. These findings were replicated under varied inclusion criteria. Conclusion: Results call into question the association of age and total-Tau in the cerebrospinal fluid. Furthermore, they suggest diagnostic utility of amyloid-β 1–40 as a possible proxy for drainage-mechanisms into the cerebrospinal fluid when interpreting biomarker concentrations for neurodegenerative diseases.

scholarly journals On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

2021 ◽  
pp. 174077452110344
Author(s):  
Michelle M Nuño ◽  
Joshua D Grill ◽  
Daniel L Gillen ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cerebrospinal Fluid ◽  
Phosphorylated Tau ◽  
Inclusion Criteria ◽  
Eligibility Criteria ◽  
Total Tau ◽  
Prodromal Alzheimer’S Disease ◽  
Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

Immune modulations and immunotherapies for Alzheimer’s disease: a comprehensive review

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Sara Mahdiabadi ◽  
Sara Momtazmanesh ◽  
George Perry ◽  
Nima Rezaei
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Cognitive Outcomes ◽  
Tau Proteins ◽  
Causal Role ◽  
Wide Range ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Immune Related Genes

Abstract Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive cognitive and memory impairment ensued from neuronal dysfunction and eventual death. Intraneuronal deposition of tau proteins and extracellular senile amyloid-β plaques have ruled as the supreme postulations of AD for a relatively long time, and accordingly, a wide range of therapeutics, especially immunotherapies have been implemented. However, none of them resulted in significant positive cognitive outcomes. Especially, the repetitive failure of anti-amyloid therapies proves the inefficiency of the amyloid cascade hypothesis, suggesting that it is time to reconsider this hypothesis. Thus, for the time being, the focus is being shifted to neuroinflammation as a third core pathology in AD. Neuroinflammation was previously considered a result of the two aforementioned phenomena, but new studies suggest that it might play a causal role in the pathogenesis of AD. Neuroinflammation can act as a double-edged sword in the pathogenesis of AD, and the activation of glial cells is indispensable for mediating such attenuating or detrimental effects. The association of immune-related genes polymorphisms with the clinical phenotype of AD as well as the protective effect of anti-inflammatory drugs like nonsteroidal anti-inflammatory drugs supports the possible causal role of neuroinflammation in AD. Here, we comprehensively review immune-based therapeutic approaches toward AD, including monoclonal antibodies and vaccines. We also discuss their efficacy and underlying reasons for shortcomings. Lastly, we highlight the capacity of modulating the neuroimmune interactions and targeting neuroinflammation as a promising opportunity for finding optimal treatments for AD.

scholarly journals Effect of Sample Collection Tubes on Cerebrospinal Fluid Concentrations of Tau Proteins and Amyloid β Peptides

2006 ◽  
Vol 52 (2) ◽  
pp. 332-334 ◽  
Author(s):  
Piotr Lewczuk ◽  
Georg Beck ◽  
Hermann Esselmann ◽  
Ralf Bruckmoser ◽  
Rüdiger Zimmermann ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Sample Collection

The Head Turning Sign in Dementia and Mild Cognitive Impairment: Its Relationship to Cognition, Behavior, and Cerebrospinal Fluid Biomarkers

2018 ◽  
Vol 46 (1-2) ◽  
pp. 42-49 ◽  
Author(s):  
João Durães ◽  
Miguel Tábuas-Pereira ◽  
Rui Araújo ◽  
Diana Duro ◽  
Inês Baldeiras ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Geriatric Depression Scale ◽  
Depression Scale ◽  
Tau Proteins ◽  
Cognitive Measures ◽  
Head Turning ◽  
Total Tau ◽  
Scale Scores

Background/Aims: The head turning sign (HTS) is frequently noticed in clinical practice, but few studies have investigated its etiological and neuropsychological correlates. Methods: The presence and frequency of the HTS was operationalized and prospectively evaluated in patients with Alzheimer’s disease (AD), amnestic mild cognitive impairment (MCI), and behavioral-variant frontotemporal dementia (bvFTD). Cerebrospinal fluid (CSF) samples for AD biomarkers were collected. Mini-Mental State Examination, Montreal Cognitive Assessment, Geriatric Depression Scale (GDS), and insight scale scores were ascertained. Results: A total of 84 patients were included. The HTS was more prevalent in AD than in MCI or bvFTD. It correlated negatively with cognitive measures and depression. It also had a positive correlation with CSF total tau and hyperphosphorylated tau proteins. Total tau protein and GDS score were the only variables independently associated with the HTS. Conclusions: The presence of the HTS in a cognitively impaired individual suggests a diagnosis of AD. A higher HTS frequency correlates with higher CSF total tau levels, a smaller GDS score, and worse cognitive measures. In the MCI subgroup, the HTS may suggest a higher risk of progression.

scholarly journals The coupling of global brain activity and cerebrospinal fluid inflow is correlated with Alzheimer’s disease related pathology

2020 ◽  
Author(s):  
Feng Han ◽  
Jing Chen ◽  
Aaron Belkin-Rosen ◽  
Yameng Gu ◽  
Liying Luo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Driving Forces ◽  
Brain Activity ◽  
Amyloid Β ◽  
Resting State Fmri ◽  
High Amplitude ◽  
Tau Proteins ◽  
Global Brain

AbstractThe glymphatic system plays an important role in clearing the amyloid-β and tau proteins that are closely linked to Alzheimer’s disease (AD) pathology. Glymphatic clearance, as well as amyloid-β accumulation, is highly dependent on sleep, but the sleep-dependent driving forces behind cerebrospinal fluid (CSF) movements essential to the glymphatic flux remain largely unclear. Recent studies have reported that widespread, high-amplitude spontaneous brain activations in the drowsy state and during sleep, which are shown as large global signal peaks in resting-state fMRI, is coupled with the CSF movements, suggesting their potential link to the glymphatic flux and metabolite clearance. By analyzing multimodal data from the Alzheimer’s Disease Neuroimaging Initiative project, here we showed that the coupling between the global fMRI signal and CSF influx is correlated with AD-related pathology, including various risk factors for AD, the severity of AD-related diseases, the cortical amyloid-β level, and the cognitive decline over a two-year follow-up. These results provide critical initial evidence for involvement of sleep-dependent global brain activity, as well as the associated physiological modulations, in the clearance of AD-related brain waste.

scholarly journals Markers of vitamin B12 status in relation to cerebrospinal fluid biomarkers and cognitive performance

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Babak Hooshmand ◽  
Franziska Koch ◽  
Patrik Fissler ◽  
Markus Otto ◽  
Hayrettin Tumani ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Vitamin B12 ◽  
Cognitive Performance ◽  
Amyloid Β ◽  
Binary Logistic Regression ◽  
Cognitive Status ◽  
University Hospital ◽  
Binary Logistic Regression Analysis ◽  
Csf Biomarkers ◽  
Total Tau

AbstractIntroduction: The association between markers of vitamin B12 status and cerebrospinal fluid (CSF) biomarkers of Alzheimer's type dementia which precede cognitive impairment has been investigated by only a few small studies and the results have been inconsistent.Aim: To investigate the associations of vitamin B12 related markers (vitamin B12, holotranscobalamin (HoloTC), homocysteine (tHcy), and methylmalonic acid (MMA)) with CSF total tau, Amyloid-β 42 (Aβ42) and cognitive performance.Methods: Data included 462 patients aged 40–94 years referred to the Memory Clinic at the Ulm University Hospital, Ulm, Germany between December 2009 and August 2015. Vitamin B12 and HoloTC were measured via chemiluminescence microparticle immunoassay, tHcy via chemiluminescence immunoassay and MMA via liquid chromatography mass specterometry. CERAD battery was used to examine the cognitive status, and different domains were derived. Regression models were used to investigate the associations.Results: After adjusting for age, sex, creatinine levels and APOEε4 status, higher values of vitamin B12 and lower values of MMA were associated with lower concentrations of CSF total-tau: the odds ratios (ORs) (95% confidence intervals (CI)) in a binary logistic regression analysis investigating the associations with total tau cut-off of 400 pg/ml were 0.39 (0.15–0.99) and 5.60 (1.93–16.26) for the highest quartile of B12 and MMA compared to the lowest, respectively. Furthermore, HoloTC, MMA, and tHcy were associated with several cognitive domains such as episodic memory and executive functioning. No relationships were found with Aβ42.Conclusions: Vitamin B12 and its related markers may be independent predictors of CSF biomarkers of Alzheimer's disease and cognitive status. Randomized controlled trials are needed to determine the importance of vitamin B12 supplementation on slowing structural brain changes and cognitive decline in older adults.

Modulation of tau pathology in tau transgenic models

2010 ◽  
Vol 38 (4) ◽  
pp. 996-1000 ◽  
Author(s):  
Jean-Pierre Brion ◽  
Kunie Ando ◽  
Céline Heraud ◽  
Karelle Leroy
Keyword(s):  
Neuronal Death ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Amyloid Β Peptide ◽  
Wild Type ◽  
Tau Pathology ◽  
Amyloid Pathology ◽  
Aβ Amyloid ◽  
Tau Aggregation ◽  
The Relationship

NFTs (neurofibrillary tangles) in Alzheimer's disease and in tauopathies are hallmark neuropathological lesions whose relationship with neuronal dysfunction, neuronal death and with other lesions [such as Aβ (amyloid β-peptide) pathology] are still imperfectly understood. Many transgenic mice overexpressing wild-type or mutant tau proteins have been generated to investigate the physiopathology of tauopathies. Most of the mice overexpressing wild-type tau do not develop NFTs, but can develop a severe axonopathy, whereas overexpression of mutant tau leads to NFT formation, synaptic loss and neuronal death in several models. The association between neuronal death and NFTs has, however, been challenged in some models showing a dissociation between tau aggregation and tau toxicity. Cross-breeding of mice developing NFTs with mice developing Aβ deposits increases NFT pathology, highlighting the relationship between tau and amyloid pathology. On the other hand, tau expression seems to be necessary for expression of a pathological phenotype associated with amyloid pathology. These findings suggest that there is a bilateral cross-talk between Aβ and tau pathology. These observations are discussed by the presentation of some relevant models developed recently.

scholarly journals Influence of File Motion on Shaping, Apical Debris Extrusion and Dentinal Defects: A Critical Review

2018 ◽  
Vol 12 (1) ◽  
pp. 189-201 ◽  
Author(s):  
Victor Feliz Pedrinha ◽  
Juliana Melo da Silva Brandão ◽  
Oscar Faciola Pessoa ◽  
Patrícia de Almeida Rodrigues
Keyword(s):  
Adaptive Systems ◽  
State Of The Art ◽  
Inclusion Criteria ◽  
Human Teeth ◽  
Specific Analysis ◽  
Apical Extrusion ◽  
Wide Range ◽  
The Relationship ◽  
Shaping Ability

Advances in endodontics have enabled the evolution of file manufacturing processes, improving performance beyond that of conventional files. In the present study, systems manufactured using state of the art methods and possessing special properties related to NiTi alloys (i.e., CM-Wire, M-Wire and R-Phase) were selected. The aim of this review was to provide a detailed analysis of the literature about the relationship between recently introduced NiTi files with different movement kinematics and shaping ability, apical extrusion of debris and dentin defects in root canal preparations. From March 2016 to January 2017, electronic searches were conducted in the PubMed and SCOPUS databases for articles published since January 2010. In vitro studies performed on extracted human teeth and published in English were considered for this review. Based on the inclusion criteria, 71 papers were selected for the analysis of full-text copies. Specific analysis was performed on 45 articles describing the effects of reciprocating, continuous and adaptive movements on the WaveOne Gold, Reciproc, HyFlex CM and Twisted File Adaptive systems. A wide range of testing conditions and methodologies have been used to compare the systems. Due the controversies among the results, the characteristics of the files used, such as their design and alloys, appear to be inconsistent to determine the best approach.

BACE1 and Other Alzheimer’s-Related Biomarkers in Cerebrospinal Fluid and Plasma Distinguish Alzheimer’s Disease Patients from Cognitively-Impaired Neurosyphilis Patients

2020 ◽  
Vol 77 (1) ◽  
pp. 313-322 ◽  
Author(s):  
Min Zhang ◽  
Xiaomei Zhong ◽  
Haishan Shi ◽  
Eugeen Vanmechelen ◽  
Ann De Vos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cognitive Function ◽  
Amyloid Β ◽  
Cognitively Impaired ◽  
Protein Levels ◽  
Scale Scores ◽  
Early Biomarker ◽  
The Relationship

Background: Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer’s disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear. Objective: To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI. Methods: Levels of neurogranin (NGRN) and β-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-β 1–40 (Aβ40), Aβ42, and total tau in the CSF of 23 AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment. Results: Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores. Conclusion: GPI and NS patients might have different biomarker level patterns compared to AD patients. While plasma BACE1 could be a promising early biomarker for distinguishing AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations.

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