**3.4. Non-p-tau**

Recently, an assay able to reliably measure CSF concentrations of non-phosphorylated tau (non-p-tau) has been developed. The assay specifically measures non-p-tau at epitopes 175, 181 or 231 [15]. The non-p-tau CSF levels in AD cases (at MCI or dementia stages) were increased compared to controls. Additionally, the authors did not find differences on non-ptau levels between patients in the MCI and the dementia stages of AD, in agreement with the presence of increased t-tau concentrations in MCI [43, 46, 125].

One of the major handicaps in the use of t-tau and p-tau concentrations in the differential diagnosis of neurodegenerative dementias is the partial overlap on both biomarkers among several conditions [17, 22, 83]. Thus, it could be hypothesized that the comparative study of non-p-tau in diseases with brain injury (elevated t-tau), but differential tau pathology could improve the discrimination achieved by both t-tau and p-tau. In this regard, a recent study investigated if non-p-tau quantification could improve the current diagnostic performance of the AD-associated CSF biomarker panel (amyloid beta-42, t-tau and p-tau-181) in differential diagnosis of four neurodegenerative dementias (AD, FTLD, DLB, CJD) [107]. While the authors concluded that non-p-tau quantification had no added diagnostic value as a CSF biomarker for the differential diagnosis of neurodegenerative dementia, it improved the discrimination of sCJD cases. Unfortunately, as t-tau levels were above the quantification limit in 17 out of 19 CJD cases analyzed in this study, no significant conclusions could be drawn on the differential diagnostic accuracy of both tests.

While no C-terminal tau fragment was detected in CSF, a combination of ELISA and mass spectrometry analysis [145] revealed the presence of a C-terminal tau fragments in serum derived from AD patients. The levels of this fragment inversely correlated with the Mattis Dementia Rating Scale, suggesting that the increase of the fragment in the serum might paral-

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

http://dx.doi.org/10.5772/intechopen.73528

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The development and implementation of seeding-based methodologies for disease diagnostic purposes is an emerging topic with demonstrated clinical applicability in the field of prion diseases due to the real-time quaking-induced conversion assay (RT-QuIC). This assay exploits the self-propagating replication capacity of the abnormally folded and pathogenic PrP (seed), which induce the misfolding of naive PrP molecules (template) into a similar pathogenic structure. This reaction can be amplified to detectable levels and quantified in real-time. Importantly, the use of CSF from prion disease cases as a seeding material in the RT-QuIC assay allows the discrimination of CJD from non-CJD cases with high diagnostic

Although the precise mechanism of neurofibrillary tangle formation in the brain tissue is not fully understood, the observation of tau spreading implicates the presence of a prionlike pathogenesis, where abnormal tau forms may induce the misfolding of non-pathological forms in a regional-dependent manner. Therefore, the principles of the RT-QuIC assay could be applied to the amplification of tau pathological forms in biological tissues. Although, successful cell- and tissue-based tau seeding assays have been recently developed the presence of tau seeding activity in the CSF of a tau-related pathology has been only reported once. Saijo et al. developed a tau RT-QuIC based on the use of a 3-repeat tau fragment as a substrate, a tau isoform that preferentially accumulates in Pick bodies. The authors detected positive tau RT-QUIC signal in the CSF from Pick disease (PiD) cases, suggesting that this assay may be

Although lumbar puncture is a routine technique in the diagnosis of neurological syndromes, it entails important side effects for the patient being headache and cranial nerves dysfunction the most frequent ones [149, 150]. Therefore, many efforts are focused to identify biomarkers in other body fluids. Among them, blood analysis has arisen as a promising and cost-effective tool to identify biomarker molecules out of the CSF. Besides avoiding side-effects associated to lumbar puncture, blood extraction is suitable to be practiced in ambulatory centers or in home visits for first disease screening. However, the blood-CSF barrier imposes a decrease in the concentration of brain-specific molecules in the blood compared to that found in the CSF, which creates the need to develop ultra-sensitive quantification methods [151]. Several works have investigated the use of amyloid-beta peptides levels in plasma as a biomarker candidate

lel the cognitive decline.

**3.6. Tau-seeding-based assays**

accuracy and almost full specificity [146, 147].

helpful in discriminating PiD and non-PiD cases [148].

for AD, but little research is done for other proteins [152, 153].

**4. Tau in blood-based biofluids**

In summary, preliminary observations indicate that the non-p-tau assay may be an interesting additional tool for the study of the dissociation between neuronal damage and tau pathology in the brain and biological fluids of neurodegenerative disorders.
