scholarly journals Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest

2019 ◽  
Vol 90 (7) ◽  
pp. 740-746 ◽  
Author(s):  
Martha S Foiani ◽  
Claudia Cicognola ◽  
Natalia Ermann ◽  
Ione O C Woollacott ◽  
Carolin Heller ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Frontotemporal Dementia ◽  
Neurodegenerative Disorder ◽  
The Novel ◽  
Tau Pathology ◽  
Total Tau ◽  
Significant Difference ◽  
T Tau

BackgroundFrontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer’s disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD.Methods86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau(181)). Patients with FTD were grouped based on their Aβ42 level into those likely to have underlying Alzheimer’s disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology.ResultsSignificantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau(181)/T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109.ConclusionsDespite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues.

A new tetra-plex fluorimetric assay for the quantification of cerebrospinal fluid β-amyloid42, total-tau, phospho-tau and α-synuclein in the differential diagnosis of neurodegenerative dementia.

2020 ◽  
Author(s):  
Daniela Diaz Lucena ◽  
Geòrgia Escaramis ◽  
Anna Villar-Piqué ◽  
Peter Hermann ◽  
Matthias Schmitz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Differential Diagnosis ◽  
Discriminant Analysis ◽  
Least Squares ◽  
Total Tau ◽  
Neurodegenerative Dementia ◽  
Jakob Disease ◽  
T Tau

Abstract Background Differential diagnosis of neurodegenerative dementia is currently supported by biomarkers including cerebrospinal fluid (CSF) tests. Among them, CSF total-tau (t-tau), phosphorylated tau (p-tau) and β-amyloid42 (Aβ42) are considered core biomarkers of neurodegeneration. In the present work, we hypothesize that simultaneous assessment of these biomarkers together with CSF α-synuclein (α-syn) will significantly improve the differential diagnostic of Alzheimer’s disease and other dementias. To that aim, we characterized the analytical and clinical performance of a new tetra-plex immunoassay that simultaneously quantifies CSF Aβ42, t-tau, p-tau and α-syn in the differential diagnosis of neurodegenerative dementia. Methods Biomarkers’ concentrations were measured in neurological controls (n=38), Alzheimer’s disease (n=35), Creutzfeldt-Jakob disease (n=37), vascular dementia (n=28), dementia with Lewy bodies/Parkinson’s disease dementia (n=27) and frontotemporal dementia (n=34) using the new tetra-plex assay and established single-plex assays. Biomarker’s performance was evaluated and diagnostic accuracy in the discrimination of diagnostic groups was determined using partial least squares discriminant analysis. Results The tetra-plex assay presented accuracies similar to individual single-plex assays with acceptable analytical performance. Significant correlations were observed between tetra-plex and single-plex assays. Using partial least squares discriminant analysis, Alzheimer’s disease and Creutzfeldt-Jakob disease were well-differentiated, reaching high accuracies in the discrimination from the rest of diagnostic groups. Conclusions The new tetra-plex assay coupled with multivariate analytical approaches becomes a valuable asset for the differential diagnosis of neurodegenerative dementia and related applications.

Cerebrospinal fluid Alzheimer biomarkers can be useful for discriminating dementia with Lewy bodies from Alzheimer’s disease at the prodromal stage

2018 ◽  
Vol 89 (5) ◽  
pp. 467-475 ◽  
Author(s):  
Olivier Bousiges ◽  
Stephanie Bombois ◽  
Susanna Schraen ◽  
David Wallon ◽  
Muriel Muraine Quillard ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Prodromal Stage ◽  
Total Tau ◽  
Prodromal Ad ◽  
And Control ◽  
T Tau

BackgroundDifferential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) is not straightforward, especially in the early stages of disease. We compared AD biomarkers (phospho-Tau181, total-Tau, Aβ42 and Aβ40) in cerebrospinal fluid (CSF) of patients with DLB and AD, focusing especially on the prodromal stage.MethodsA total of 1221 CSF were collected in different memory centres (ePLM network) in France and analysed retrospectively. Samples were obtained from patients with prodromal DLB (pro-DLB; n=57), DLB dementia (DLB-d; n=154), prodromal AD (pro-AD; n=132) and AD dementia (n=783), and control subjects (CS; n=95). These centres use the same diagnostic procedure and criteria to evaluate the patients.ResultsIn patients with pro-DLB, CSF Aβ42 levels appeared much less disrupted than in patients at the demented stage (DLB-d) (P<0.05 CS>pro-DLB; P<0.001 CS>DLB-d). On average, Aβ40 levels in patients with DLB (pro-DLB and DLB-d) were much below those in patients with pro-AD (P<0.001 DLB groups<pro-AD). The Aβ42/Aβ40 ratio in patients with pro-DLB remained close to that of CS. t-Tau and phospho-Tau181 levels were unaltered in patients with DLB (pro-DLB and DLB-d).ConclusionsReduced levels of CSF Aβ42 were found in patients with DLB but rather at a later stage, reaching those of patients with AD, in whom Aβ42 levels were decreased even at the prodromal stage. At the prodromal stage of DLB, the majority of patients presented a normal CSF profile. CSF t-Tau and phospho-Tau181 were the best biomarkers to discriminate between AD and DLB, whatever the stage of disease.

scholarly journals Shared Genetic Background Between Cerebrospinal Fluid Biomarkers and Risk for Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study

2021 ◽  
pp. 1-11
Author(s):  
Soyeon Kim ◽  
Kiwon Kim ◽  
Kwangsik Nho ◽  
Woojae Myung ◽  
Hong-Hee Won
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Genetic Background ◽  
Mendelian Randomization ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
T Tau ◽  
Load Risk ◽  
Shared Genetic

Background: Whether the epidemiological association of amyloid-β (Aβ) and tau pathology in late-onset Alzheimer’s disease (LOAD) is causal remains unclear. Objective: We aimed to investigate the shared genetic background between the cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and the risk of LOAD. Methods: We conducted a two-sample Mendelian randomization (MR) analysis. We used summary statistics of genome-wide association studies for CSF biomarkers (Aβ 1–42 [Aβ], phosphorylated tau181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for LOAD in 21,982 cases and 41,944 controls. We tested the association between changes in the genetically predicted CSF biomarkers and LOAD risk. Results: We found a decrease in LOAD risk per one-standard-deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 2.87×10–3 for AD; 95%confidence interval [CI], 1.54×10–4 –0.05; p = 8.91×10–5). Conversely, we observed an increase in LOAD risk per one-SD increase in the genetically predicted CSF p-tau (OR, 19.46; 95%CI, 1.50–2.52×102; p = 0.02) and t-tau (OR, 33.80; 95%CI, 1.57–7.29×102; p = 0.02). However, only the association between p-tau and the risk for LOAD remained significant after the exclusion of the APOE variant (rs769449). Conclusion: We found the causal association between CSF biomarkers and the risk for LOAD. Our results suggest that the etiology of LOAD involves multiple biological processes, including the pathways of Aβ and tau proteins. Further MR studies using large-scale data of multiple candidate biomarkers are needed to elucidate the pathophysiology of LOAD.

scholarly journals Causal relationship of cerebrospinal fluid biomarkers with the risk of Alzheimer’s disease: A two-sample Mendelian randomization study

2019 ◽  
Author(s):  
Soyeon Kim ◽  
Kiwon Kim ◽  
Kwangsik Nho ◽  
Woojae Myung ◽  
Hong-Hee Won
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Beta ◽  
Mendelian Randomization ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
A Genome ◽  
T Tau ◽  
Load Risk

AbstractWhether the epidemiological association of amyloid beta (Aβ) and tau pathology with Alzheimer’s disease (AD) is causal remains unclear. The recent failures to demonstrate the efficacy of several amyloid beta-modifying drugs may indicate the possibility that the observed association is not causal. These failures also led to efforts to develop tau-directed treatments whose efficacy is still tentative. Herein, we conducted a two-sample Mendelian randomization analysis to determine whether the relationship between the cerebrospinal fluid (CSF) biomarkers for amyloid and tau pathology and the risk of AD is causal. We used the summary statistics of a genome-wide association study (GWAS) for CSF biomarkers (Aβ1-42, phosphorylated tau 181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for late-onset AD (LOAD) in 21,982 LOAD cases and 41,944 cognitively normal controls. We tested the association between the change in the genetically predicted CSF biomarkers and LOAD risk. We found a modest decrease in the LOAD risk per one standard deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 0.63 for AD; 95% confidence interval [CI], 0.38-0.87; P = 0.02). In contrast, we observed a significant increase in the LOAD risk per one SD increase in the genetically predicted CSF p-tau (OR, 2.37; 95% CI, 1.46-3.28; P = 1.09×10−5). However, no causal association was observed of the CSF t-tau with the LOAD risk (OR, 1.15; 95% CI, 0.85-1.45; P = 0.29). Our findings need to be validated in future studies with more genetic variants identified in larger GWASs for CSF biomarkers.

scholarly journals Cerebrospinal fluid biomarkers and cognitive status in differential diagnosis of frontotemporal dementia and Alzheimer’s disease

2019 ◽  
Vol 47 (10) ◽  
pp. 4968-4980 ◽  
Author(s):  
Tiziana Casoli ◽  
Susy Paolini ◽  
Paolo Fabbietti ◽  
Patrizia Fattoretti ◽  
Lucia Paciaroni ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Frontotemporal Dementia ◽  
Primary Progressive Aphasia ◽  
Csf Biomarkers ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
T Tau ◽  
Domain Scores

Objective This study aimed to determine the most appropriate cognitive and cerebrospinal fluid (CSF) biomarker setting to distinguish frontotemporal dementia (FTD) from Alzheimer’s disease (AD). Method Patients with FTD, those with AD, and those without dementia were enrolled in this study. CSF amyloid-ß 42 (Aß42), total (t)-tau, and phosphorylated (p)-tau concentrations were determined by enzyme-linked immunosorbent assays. Cognition was evaluated by the Mini-Mental State Examination (MMSE) and its domain scores. The associations of CSF biomarkers with cognitive measures were examined using regression models and the diagnostic value of CSF biomarkers was determined by receiver operating characteristics curves. Results CSF Aß42 levels were lower, whereas t-tau/Aß42 and p-tau/Aß42 ratios were higher in patients with AD compared with those with FTD. Some MMSE domain scores were different in FTD and AD, but they did not improve the ability to distinguish between the two pathologies. Poor temporal orientation scores were associated with low Aß42 levels only in patients with FTD. The p-tau/Aß42 ratio reached sufficient levels of sensitivity and specificity to discriminate FTD with primary progressive aphasia from AD. Conclusions The ratio of CSF p-tau/Aß42 is a sensitive and specific biomarker for discriminating patients with primary progressive aphasia from those with AD.

scholarly journals Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer’s disease

2020 ◽  
Author(s):  
Pieter Jelle Visser ◽  
Lianne M. Reus ◽  
Johan Gobom ◽  
Iris Jansen ◽  
Ellen Dicks ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Neuronal Plasticity ◽  
Gene Repression ◽  
Barrier Dysfunction ◽  
Total Tau ◽  
Genomic Analyses ◽  
Personalised Treatment ◽  
T Tau

AbstractAlzheimer’s disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.

scholarly journals Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

2015 ◽  
Vol 40 (1-2) ◽  
pp. 54-62 ◽  
Author(s):  
Nina Rostgaard ◽  
Gunhild Waldemar ◽  
Jørgen Erik Nielsen ◽  
Anja Hviid Simonsen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Frontotemporal Dementia ◽  
Core Protein ◽  
Tau Pathology ◽  
Protein Biomarkers ◽  
Cerebrospinal Fluid Biomarkers ◽  
Best Medical Treatment ◽  
New Biomarkers

As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-β42, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.

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.

scholarly journals Cognitive Performance and Cerebrospinal Fluid Markers in Preclinical Alzheimer’s Disease: Results from the Gothenburg H70 Birth Cohort Studies

2021 ◽  
Vol 79 (1) ◽  
pp. 225-235
Author(s):  
Maya Arvidsson Rådestig ◽  
Johan Skoog ◽  
Henrik Zetterberg ◽  
Jürgen Kern ◽  
Anna Zettergren ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cohort Studies ◽  
Cognitive Performance ◽  
Birth Cohort ◽  
Population Based ◽  
Tau Pathology ◽  
Preclinical Alzheimer’S Disease ◽  
Preclinical Ad

Background: We have previously shown that older adults with preclinical Alzheimer’s disease (AD) pathology in cerebrospinal fluid (CSF) had slightly worse performance in Mini-Mental State Examination (MMSE) than participants without preclinical AD pathology. Objective: We therefore aimed to compare performance on neurocognitive tests in a population-based sample of 70-year-olds with and without CSF AD pathology. Methods: The sample was derived from the population-based Gothenburg H70 Birth Cohort Studies in Sweden. Participants (n = 316, 70 years old) underwent comprehensive cognitive examinations, and CSF Aβ-42, Aβ-40, T-tau, and P-tau concentrations were measured. Participants were classified according to the ATN system, and according to their Clinical Dementia Rating (CDR) score. Cognitive performance was examined in the CSF amyloid, tau, and neurodegeneration (ATN) categories. Results: Among participants with CDR 0 (n = 259), those with amyloid (A+) and/or tau pathology (T+, N+) showed similar performance on most cognitive tests compared to participants with A-T-N-. Participants with A-T-N+ performed worse in memory (Supra span (p = 0.003), object Delayed (p = 0.042) and Immediate recall (p = 0.033)). Among participants with CDR 0.5 (n = 57), those with amyloid pathology (A+) scored worse in category fluency (p = 0.003). Conclusion: Cognitively normal participants with amyloid and/or tau pathology performed similarly to those without any biomarker evidence of preclinical AD in most cognitive domains, with the exception of slightly poorer memory performance in A-T-N+. Our study suggests that preclinical AD biomarkers are altered before cognitive decline.

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