Cerebrospinal Fluid Biomarkers as a Diagnostic Tool of the Underlying Pathology of Primary Progressive Aphasia

Paraskevas, George P.; Kasselimis, Dimitrios; Kourtidou, Evie; Constantinides, Vasilios C.; Bougea, Anastasia; Potagas, Constantinos; Evdokimidis, Ioannis; Kapaki, Elisabeth

doi:10.3233/jad-160494

Cited by 38 publications

(45 citation statements)

References 18 publications

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“…Finally, p-tau/t-tau ratio has been proved in independent studies to discriminate the two main forms of FTLD; FTLD with TAR DNA-binding protein 43 (TDP-43) inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-tau), with reduced p-tau/t-tau ratio detected in cases with FTLD-TDP pathology [122,123]. This goes in line with the recent observation that patients with primary progressive aphasia with a non-AD profile (presumably FTLD) were stratified in two clusters according to p-tau/t-tau ratio, possibly corresponding to FTDP-tau and FTDP-TDP pathologies [124].…”

Section: P-tau/t-tau -(T-tau/p-tau) Ratiosupporting

confidence: 79%

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

Llorens¹,

Villar‐Piqué²,

Candelise³

et al. 2019

Cognitive Disorders

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Tau is a microtubule-associated protein, whose main function is the modulation of the stability of axonal microtubules. In physiological conditions tau is abundant in neurons while its expression in glial populations is low and restricted to astrocytes and oligodendrocytes. The aggregation of tau in neurofibrillary or gliofibrillary tangles is the main hallmark of tauopathies, a complex group of human neurodegenerative conditions where tau hyper-phosphorylation causes its increased insolubility and aggregation leading to tangle formation and microtubule destabilization. Tau can be detected in biological fluids in physiological and pathological conditions. In several neurodegenerative dementias, either associated or not to a primary tauopathy, tau levels are altered in a diseasespecific pattern, which can be used as a biomarker for disease diagnosis and prognosis. The study of tau levels in biological fluids has been mainly performed in the cerebrospinal fluid (CSF), although the recent development of ultrasensitive techniques allows the robust quantification of tau in blood-based biofluids such as serum and plasma. The presence of elevated total-tau in the CSF is assumed to reflect the degree of axonal damage in the brain tissue. Consequently, highest total-tau CSF levels are found in sporadic Creutzfeldt-Jakob disease, which is characterized by massive neuronal damage and a rapid progressive course. Elevated total-tau is also detected in Alzheimer's disease and dementia with Lewy bodies, while in other dementia conditions such as vascular dementia, frontotemporal dementia and corticobasal degeneration are unchanged, inconclusive or not determined. Additionally, total-tau rises temporarily due to cerebral infarction. In contrast, elevated phospho-tau levels seem to be restricted to Alzheimer's disease pathology, most likely mirroring the presence of the hyper-phosphorylated form in the brain tissue, although phospho-tau levels are mainly unaffected in tauopathies. Additionally, isoforms and different structural and truncated tau forms have also been reported to be altered in neurodegenerative dementias. In this complex scenario the diagnostic accuracy of diverse tau forms as disease-specific biomarkers needs to be established. In this chapter, we summarize the current knowledge on the alterations of diverse tau forms

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Section: P-tau/t-tau -(T-tau/p-tau) Ratiosupporting

confidence: 79%

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

Llorens¹,

Villar‐Piqué²,

Candelise³

et al. 2019

Cognitive Disorders

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“…97,98 The core AD biomarkers are also valuable when differentiating between underlying AD or FTLD pathology in the differential diagnosis of PPA, in which an AD profile is often found in clinically diagnosed lvPPA patients as opposed to svPPA and nfvPPA patients. [99][100][101][102] An AD CSF profile occasionally occurs in FTD cases, even in pathology proven cases; this may partly be explained by the cooccurrence of AD pathology. 103 Moreover, decreased Aβ1-42 levels were found in up to 25% C9orf72 patients in a Finish cohort, but not in GRN patients, and to elucidate its pathophysiological significance, more clinicopathological and genetic studies are required.…”

Section: Csf Amyloid-β and Taumentioning

confidence: 99%

Imaging and fluid biomarkers in frontotemporal dementia

Meeter¹,

et al. 2017

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Frontotemporal dementia (FTD), the second most common type of presenile dementia, is a heterogeneous neurodegenerative disease characterized by progressive behavioural and/or language problems, and includes a range of clinical, genetic and pathological subtypes. The diagnostic process is hampered by this heterogeneity, and correct diagnosis is becoming increasingly important to enable future clinical trials of disease-modifying treatments. Reliable biomarkers will enable us to better discriminate between FTD and other forms of dementia and to predict disease progression in the clinical setting. Given that different underlying pathologies probably require specific pharmacological interventions, robust biomarkers are essential for the selection of patients with specific FTD subtypes. This Review emphasizes the increasing availability and potential applications of structural and functional imaging biomarkers, and cerebrospinal fluid and blood fluid biomarkers in sporadic and genetic FTD. The relevance of new MRI modalities - such as voxel-based morphometry, diffusion tensor imaging and arterial spin labelling - in the early stages of FTD is discussed, together with the ability of these modalities to classify FTD subtypes. We highlight promising new fluid biomarkers for staging and monitoring of FTD, and underline the importance of large, multicentre studies of individuals with presymptomatic FTD. Harmonization in the collection and analysis of data across different centres is crucial for the implementation of new biomarkers in clinical practice, and will become a great challenge in the next few years.

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“…For inclusion in the study, patients had to undoubtedly receive the diagnosis of ALS or FTD according to widely accepted criteria (see below). Exclusion criterion was the presence of an AD CSF biomarker profile, defined according to the cutoff values of our laboratory (Aβ 42 ≤ 580 pg/mL, τ T ≥ 376 pg/mL, and τ P-181 ≥ 62.5 pg/mL, respectively) [15]. …”

Section: Methodsmentioning

confidence: 99%

“…In Alzheimer disease (AD), cerebrospinal fluid (CSF) biomarkers have recently been incorporated in the updated criteria [11] and an “AD biomarker profile” (namely increased total tau protein [τ T ] and tau protein phosphorylated at threonine 181 [τ p-181 ] as well as decreased beta-amyloid peptide with 42 amino acids [Aβ 42 ]) can be helpful in differentiating cases with underlying AD pathology [12,13,14,15]. Such a profile does not currently exist to predict TDP-43 pathology, unless there is a known associated gene mutation.…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders

Bourbouli

Rentzos²,

Bougea³

et al. 2017

Dement Geriatr Cogn Disord

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Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are nowadays recognized as spectrum disorders with a molecular link, the TAR DNA-binding protein 43 (TDP-43), rendering it a surrogate biomarker for these disorders. Methods: We measured cerebrospinal fluid (CSF) levels of TDP-43, beta-amyloid peptide with 42 amino acids (Aβ₄₂), total tau protein (τ_T), and tau protein phosphorylated at threonine 181 (τ_P-181) in 32 patients with ALS, 51 patients with FTD, and 17 healthy controls. Double-sandwich commercial enzyme-linked immunosorbent assays were used for measurements. Results: Both ALS and FTD patients presented with higher TDP-43 and τ_T levels compared to the control group. The combination of biomarkers in the form of the TDP-43 × τ_T / τ_P-181 formula achieved the best discrimination between ALS or FTD and controls, with sensitivities and specificities >0.8. Conclusion: Combined analysis of TDP-43, τ_T, and τ_P-181 in CSF may be useful for the antemortem diagnosis of ALS and FTD.

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Cerebrospinal Fluid Biomarkers as a Diagnostic Tool of the Underlying Pathology of Primary Progressive Aphasia

Abstract: CSF biomarkers may be a valuable tool for the discrimination between PPA patients with AD and non-AD pathophysiology and possibly between FTLD patients with tau and TDP-43 pathology.

Cited by 38 publications

References 18 publications

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

Imaging and fluid biomarkers in frontotemporal dementia

Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders

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