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

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

Owing to the lack of high-sensitive techniques and the low amount of tau in blood compared to CSF, the initial measurement of tau in human plasma was technically complicated impeding the detection of this molecule in 80% of samples [154]. However, novel quantification methods were later developed to overcome this limitation. They include immunoassays based on carboxylated microsphere beads [155], digital array technology [156], immunomagnetic reduction assay [157, 158] and ultra-sensitive commercial ELISA kits [159]. This way, in the recent years, plasma tau has arisen as a promising biomarker in neurodegenerative conditions. Importantly, it does not show significant correlation with demographic parameters such as age, sex or educational level [160].

Specific measurement of p-tau in plasma still represents a technical challenge. One of the first attempts to measure p-tau-231 in human plasma was based on a complex immunoassay using multi-arrayed fiber optics coupled to rolling circle amplification (a-EIMAF) [167]. Although the authors only measured 5 sCJD plasma samples and 5 controls, t-tau was increased in all the disease cases. By contrast, no differences between p-tau-231 levels were detected. Interestingly, a similar pattern of t-tau and p-tau-231 was found in the brain tissue. It should be noted that the authors used arbitrary units for p-tau-231 quantification due to technical impediment [167]. Very recently, fine quantification of plasma p-tau-181 has been possible using a novel immunoassay based on digital array technology that has been modified to detect this phosphorylated form. In an exploratory case–control study that included 3 small cohorts (<50 cases per cohort), AD, Down syndrome (DS), neurological controls and healthy controls were analyzed [168]. In general, p-tau-181 was specifically increased in AD and DS patients compared to controls. Correlation between age and p-tau-181 was found in the DS group, supporting the link between this protein and the presence of amyloid pathology. A striking correlation was also found between p-tau-181 levels in plasma and in CSF, in contrast to the weak or no correlation between CSF and plasma t-tau [160]. Therefore, it is possible that phosphorylated tau, in contrast to t-tau in blood, is only

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

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

77

Besides plasma, the levels of t-tau and p-tau-181 have been recently evaluated in the serum of AD cases by real time Surface Plasmon Resonance. Both concentrations were increased in AD compared to controls, with a better performance of tau than p-tau-181. Tau was also significantly elevated in AD compared to MCI. Tau and p-tau-181 in serum appeared strongly correlated, which could mean un-specificity in the CSF-blood filtration of tau species [169]. Similar to plasma, serum tau levels also presented a negative correlation with scores of cogni-

Blood tau levels have also been investigated in rapid progressive dementias. One of the pioneering works reported an increase of t-tau levels in serum in CJD patients compared of those is serum of AD and other non-CJD rapid progressive dementias. In spite of the small number of cases analyzed (<15 per group), it provided a valid proof-of-concept toward measuring t-tau in blood to differentially diagnose CJD [170]. A very recent study has validated these data using a larger and autopsy confirmed cohort. The levels of plasma tau in sporadic CJD appeared more than 2-fold elevated compared to neurological controls and to AD. Genetic CJD cases also presented increased plasma tau compared to AD. Comparison among different subtypes of sCJD also revealed differences in plasma tau, which was higher in MM/MV1 and MM1 + 2 subtypes. On the opposite, the subtype MV2 (kuru plaque) presented the lowest levels of plasma tau among the disease group [161]. These results indicate that plasma t-tau

Several strategies have been considered in order to prevent tau deposition. Compounds inhibiting tau aggregation [171], stimulating immune system against misfolded and

may be also reflecting the subtype-specific hallmarks of sCJD pathology.

**5. Tau in the evaluation of disease-modifying therapies**

originated in the brain.

tive assessment (HMSE and MoCA).

Although a study showed reduced plasma t-tau levels in AD patients compared to normal cognitive individuals [159], the current consensus data point toward the opposite direction. Indeed, in the blood-based diagnostics of AD, t-tau is the only significant biomarker in the discrimination of the disease, displaying an AD/control mean ratio between 1.5 and 4.5 [42, 161]. The use of an assay based on antibodies coupled to magnetic nanoparticles rendered very high values (>90%) of specificity and sensitivity when comparing healthy controls versus AD+MCI cases [157]. This method was subsequently validated in a study enrolling two independent cohorts, where those high levels of specificity and sensitivity were almost reached (>89%) in the combination of cohorts when comparing healthy with AD cases [162]. With these data, the authors concluded that the best performance of plasma t-tau in the AD diagnostics was in combination with plasma Amyloid beta-42 levels, in a similar manner than combination biomarkers increase the diagnostic accuracy of single measurement markers in the CSF [18].

In the differential diagnostic context, plasma t-tau also appeared elevated in AD compared to MCI. However, the overlap between groups hinders the clinical utility of plasma t-tau as a routine biomarker [163]. Plasma t-tau was not found increased in MCI cases that later developed AD compared to controls, neither in cases with pre-MCI stage of subjective cognitive decline (SCD) [164]. These findings suggest that plasma t-tau is a late marker of neuronal damage and cannot be used as a prognostic tool of the likelihood to develop AD-related dementia sensitivity of the methodologies is improved.

Plasma t-tau does not seem to be a good reporter of the tau pathology in AD brain, as no strong correlation between plasma and CSF t-tau could be soundly demonstrated so far in AD [163]. However, plasma and CSF t-tau appeared correlated in a very recent study performed in a cohort with various neurological syndromes [161]. On the other side, mild association of high plasma t-tau with AD-specific pathology cannot be discarded. Within the MCI group, those cases positive for amyloid beta-42 had elevated t-tau compared with those amyloid beta-42 negatives [163]. In addition, high plasma t-tau levels in AD patients are associated to rapid disease progression in late clinical stages, including cognitive impairment and brain dysfunction [163]. The detailed relationship between plasma t-tau and the pathological state of the brain during the course of the disease is not yet clear. The t-tau concentration in plasma has been associated to abnormal cortical thickness and memory performance in a cohort of MCI patients [165]. However, in another cohort of MCI and AD cases, plasma t-tau appeared unrelated to cortical thickness in AD-specific regions [166]. In the same study though, the authors did report a significant association of high plasma t-tau levels and reduced gray matter density.

Specific measurement of p-tau in plasma still represents a technical challenge. One of the first attempts to measure p-tau-231 in human plasma was based on a complex immunoassay using multi-arrayed fiber optics coupled to rolling circle amplification (a-EIMAF) [167]. Although the authors only measured 5 sCJD plasma samples and 5 controls, t-tau was increased in all the disease cases. By contrast, no differences between p-tau-231 levels were detected. Interestingly, a similar pattern of t-tau and p-tau-231 was found in the brain tissue. It should be noted that the authors used arbitrary units for p-tau-231 quantification due to technical impediment [167]. Very recently, fine quantification of plasma p-tau-181 has been possible using a novel immunoassay based on digital array technology that has been modified to detect this phosphorylated form. In an exploratory case–control study that included 3 small cohorts (<50 cases per cohort), AD, Down syndrome (DS), neurological controls and healthy controls were analyzed [168]. In general, p-tau-181 was specifically increased in AD and DS patients compared to controls. Correlation between age and p-tau-181 was found in the DS group, supporting the link between this protein and the presence of amyloid pathology. A striking correlation was also found between p-tau-181 levels in plasma and in CSF, in contrast to the weak or no correlation between CSF and plasma t-tau [160]. Therefore, it is possible that phosphorylated tau, in contrast to t-tau in blood, is only originated in the brain.

Owing to the lack of high-sensitive techniques and the low amount of tau in blood compared to CSF, the initial measurement of tau in human plasma was technically complicated impeding the detection of this molecule in 80% of samples [154]. However, novel quantification methods were later developed to overcome this limitation. They include immunoassays based on carboxylated microsphere beads [155], digital array technology [156], immunomagnetic reduction assay [157, 158] and ultra-sensitive commercial ELISA kits [159]. This way, in the recent years, plasma tau has arisen as a promising biomarker in neurodegenerative conditions. Importantly, it does not show significant correlation with demographic parameters

Although a study showed reduced plasma t-tau levels in AD patients compared to normal cognitive individuals [159], the current consensus data point toward the opposite direction. Indeed, in the blood-based diagnostics of AD, t-tau is the only significant biomarker in the discrimination of the disease, displaying an AD/control mean ratio between 1.5 and 4.5 [42, 161]. The use of an assay based on antibodies coupled to magnetic nanoparticles rendered very high values (>90%) of specificity and sensitivity when comparing healthy controls versus AD+MCI cases [157]. This method was subsequently validated in a study enrolling two independent cohorts, where those high levels of specificity and sensitivity were almost reached (>89%) in the combination of cohorts when comparing healthy with AD cases [162]. With these data, the authors concluded that the best performance of plasma t-tau in the AD diagnostics was in combination with plasma Amyloid beta-42 levels, in a similar manner than combination biomarkers increase the diagnostic accuracy of single measurement markers in the CSF [18]. In the differential diagnostic context, plasma t-tau also appeared elevated in AD compared to MCI. However, the overlap between groups hinders the clinical utility of plasma t-tau as a routine biomarker [163]. Plasma t-tau was not found increased in MCI cases that later developed AD compared to controls, neither in cases with pre-MCI stage of subjective cognitive decline (SCD) [164]. These findings suggest that plasma t-tau is a late marker of neuronal damage and cannot be used as a prognostic tool of the likelihood to develop AD-related

Plasma t-tau does not seem to be a good reporter of the tau pathology in AD brain, as no strong correlation between plasma and CSF t-tau could be soundly demonstrated so far in AD [163]. However, plasma and CSF t-tau appeared correlated in a very recent study performed in a cohort with various neurological syndromes [161]. On the other side, mild association of high plasma t-tau with AD-specific pathology cannot be discarded. Within the MCI group, those cases positive for amyloid beta-42 had elevated t-tau compared with those amyloid beta-42 negatives [163]. In addition, high plasma t-tau levels in AD patients are associated to rapid disease progression in late clinical stages, including cognitive impairment and brain dysfunction [163]. The detailed relationship between plasma t-tau and the pathological state of the brain during the course of the disease is not yet clear. The t-tau concentration in plasma has been associated to abnormal cortical thickness and memory performance in a cohort of MCI patients [165]. However, in another cohort of MCI and AD cases, plasma t-tau appeared unrelated to cortical thickness in AD-specific regions [166]. In the same study though, the authors did report a significant association of high plasma t-tau

such as age, sex or educational level [160].

76 Cognitive Disorders

dementia sensitivity of the methodologies is improved.

levels and reduced gray matter density.

Besides plasma, the levels of t-tau and p-tau-181 have been recently evaluated in the serum of AD cases by real time Surface Plasmon Resonance. Both concentrations were increased in AD compared to controls, with a better performance of tau than p-tau-181. Tau was also significantly elevated in AD compared to MCI. Tau and p-tau-181 in serum appeared strongly correlated, which could mean un-specificity in the CSF-blood filtration of tau species [169]. Similar to plasma, serum tau levels also presented a negative correlation with scores of cognitive assessment (HMSE and MoCA).

Blood tau levels have also been investigated in rapid progressive dementias. One of the pioneering works reported an increase of t-tau levels in serum in CJD patients compared of those is serum of AD and other non-CJD rapid progressive dementias. In spite of the small number of cases analyzed (<15 per group), it provided a valid proof-of-concept toward measuring t-tau in blood to differentially diagnose CJD [170]. A very recent study has validated these data using a larger and autopsy confirmed cohort. The levels of plasma tau in sporadic CJD appeared more than 2-fold elevated compared to neurological controls and to AD. Genetic CJD cases also presented increased plasma tau compared to AD. Comparison among different subtypes of sCJD also revealed differences in plasma tau, which was higher in MM/MV1 and MM1 + 2 subtypes. On the opposite, the subtype MV2 (kuru plaque) presented the lowest levels of plasma tau among the disease group [161]. These results indicate that plasma t-tau may be also reflecting the subtype-specific hallmarks of sCJD pathology.
