**3.2. P-tau**

While t-tau reflects axonal degeneration, p-tau levels reflect the phosphorylation state of tau in the brain tissue. This idea is supported by the absence of alterations in p-tau in neurological diseases presenting neuronal damage but no p-tau pathology in the brain tissue, such as in acute stroke [69].

Contrary to t-tau, elevated CSF p-tau levels seem to be more restricted to AD cases [83]. This is an interesting recurrent observation as aberrant tau phosphorylation also occurs in the brain tissue of tauopathies such as FTD with Parkinsonism linked to chromosome 17 (FTDP-17), Pick disease (PiD), CBD and PSP leading to aggregation into neurofibrillary tangles (NFT) and axonal transport dysfunction [84–86].

In corticobasal degeneration (CBD), initial reports suggested the presence of elevated t-tau levels [60, 61], but decreased or non-altered levels were later reported in other studies [62, 63]. Similarly, patients with progressive supranuclear palsy (PSP) showed total-tau levels compa-

Increased CSF t-tau levels in normal pressure hydrocephalus (NPH) patients compared to controls have also been reported [64]. Interestingly, t-tau levels correlated with the severity of dementia, urinary incontinence, and gait disturbance. However, further studies have not been

In Huntington's disease (HD), a recent study reported elevated levels of CSF t-tau in gene expansion carriers compared with their control subjects. Additionally, t-tau concentrations were associated with phenotypic variability, thus a role for t-tau as a biomarker of disease progression was proposed [67]. However, a diagnostic role for t-tau in HD is excluded as no differences between HD patients compared with pre-manifest gene expansion carriers have

As a marker of neuronal damage, elevated t-tau levels have been reported in acute stroke [69] and head trauma [70]. CSF t-tau levels in acute brain injury present a transitory peak. For instance in traumatic brain injury (TBI), t-tau levels increased shortly after contusion, peaking in the second week post-trauma, slowly decreasing after this period and reaching basal values at 43 days [70]. Instead, in Olympic boxers subjected to repetitive trauma t-tau levels increased after boxing and remained elevated after a rest period of at least 14 days [71]. In acute stroke, t-tau levels are associated to disease severity and long-term outcome [72]. The sizes and localization of the lesion generally affects the profile of CSF t-tau levels after stroke which vary to a great extent, generally reaching maximum levels after 3 weeks to 1 month and returning to normal levels after 3–5 months [69, 73]. Other neurological conditions with transiently elevated t-tau levels include acute Wernicke's disease [74, 75], after chemotherapy treatment for hematologic malignancies [76], and patients with temporary neurologic dysfunction after aortic surgery [77]. Altogether, these studies support the idea of CSF t-tau reflects the degree of brain injury and harbors a prognostic value in transient acute neuronal damage syndromes. An important confounding factor in the biomarker field is the age of subjects in the study. In this regard, the discriminative power of CSF t-tau is higher in young old (<70 years) than in old (≥70 years) control and AD cases, indicating that CSF t-tau loses its discriminative power along the aging process [78]. Therefore, the age effect should be considered when establishing the diagnostic parameters of t-tau quantification as CSF biomarker. Increased t-tau levels during aging in healthy individuals have been validated in several independent cohorts [79], which in turn were associated to ApoE genotype [80, 81]. Consequently, age-dependent t-tau cut-off values in neurologically and psychiatrically healthy individuals have been established [82].

While t-tau reflects axonal degeneration, p-tau levels reflect the phosphorylation state of tau in the brain tissue. This idea is supported by the absence of alterations in p-tau in neurological diseases presenting neuronal damage but no p-tau pathology in the brain tissue, such as

able to replicate the presence of elevated t-tau in NPH patients [65, 66].

rable to those detected in controls [61, 63].

been reported [68].

70 Cognitive Disorders

**3.2. P-tau**

in acute stroke [69].

Neurofibrillary changes are composed of hyper-phosphorylated tau forms that correlate with disease duration and severity [87]. Indeed, the severity of cognitive impairment correlates better with the burden of neocortical neurofibrillary tangles than with amyloid pathology [87–89]. While meta-analysis studies indicate that CSF p-tau levels are a moderate prognostic marker in AD [90], longitudinal studies show that p-tau-181 levels correlated with the progression of cognitive decline [91]. Additionally, a low p-tau-181/tau ratio has also been reported as a strong predictor of cognitive decline [92]. In contrast, p-tau-231 levels correlate with the rate of hippocampal atrophy in AD cases, which are independent of disease duration and severity [93] as well as with a reduction hippocampal volume detected by magnetic resonance imaging (MRI) [94]. Since rates of hippocampal atrophy are suggested to reflect reduction of neuronal density, these observations suggest that p-tau231 is directly associated to extensive neuronal damage but not to disease stage. Additionally, p-tau-199 levels have been shown to be useful in the discrimination of AD patients from non-AD-related dementia and non-demented patients in a large-scale multicenter study [95].

A comparative study on p-tau231, p-tau181 and p-tau199 performance showed that the three p-tau forms were significantly elevated in patients with AD compared with FTD, DLB, VaD and control cases [96]. This study also indicated that p-tau231 and p-tau181 assays performed similarly in the discrimination of AD from non-demented controls, whereas the p-tau199 assay showed a weaker discriminatory value. However, the combinations of the three measurements did not add discriminative power compared to single measurements. Although alternative p-tau epitopes have been studied in the context of AD pathogenesis, it is generally considered that p-tau181, 199 and 231 are those more characteristic to AD. Indeed, most studies have focused on p-tau231 and p-tau181 [14], which in turn, are the most standardized assays for p-tau quantification.

For p-tau-181, a cut-off of >60 pg/mL is generally used to define pathological levels due to AD pathogenesis [97].

While other p-tau species have also been measured such as p-tau199, p-tau199 + 202, as well as p-tau396 + 404, importantly, p-tau levels in AD are increased not only compared to controls, but also compared to other tauopathies and neurodegenerative diseases [98]. Measurement of them becomes a useful marker in the differentiation of AD from its most relevant differential diagnoses. Phosphorylation at Thr-231 is helpful in the discrimination of AD from FTD, and its levels are correlated with disease progression, whereas p-tau-181 (the most established p-tau assay [99]) improves the differentiation between AD and DLB [96, 100, 101]. Additionally, p-tau, when used in combination with amyloid beta-42 (p-tau/amyloid beta-42 ratio), shows the best diagnostic performance in the discrimination of AD from FTLD [102]. This meta-analysis study also reports that p-tau alone would be more useful for high Mini-Mental-State-Examination (MMSE scores), while p-tau/amyloid beta-42 would be preferable for low MMSE scores and younger patients.

Several explanations have been postulated for the specific preserve of high CSF p-tau concentrations in AD. First, it could be that primary tauopathies may present different phosphorylation profiles than those observed in AD. While the complete differential phosphorylation signatures in the spectrum of tauopathies is still not completely defined, in AD, tau is hyperphosphorylated at multiple sites (>30 sites). However, presence of tau hyper-phosphorylation at several epitopes such as 181, 199, 231,396 and 404 is a common hallmark in tauopathies [103].

superficial layers in the neocortex, whereas in AD they predominate in the deep layers [115, 116]. Additionally, in mouse model of repeated TBI, elevated p-tau without NFT formation was observed in aged mice overexpressing human tau [117]. Finally, the absence of altered p-tau levels in the CSF of acute brain damage could also be explained by the presence of different isoforms of aggregated tau. Indeed, this might also explain the unaltered CSF p-tau

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

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

73

As described above, the partial overlap on t-tau levels observed in sCJD and AD cases decreases the specificity of tau quantification in the differential diagnostic context of both diseases. An interesting addition to the biomarker field was the observation that p-tau/t-tau ratio greatly improved the discrimination of sCJD cases, not only from AD, but also from other tauopathies showing increased t-tau levels. This finding was initially reported by Riemenschneider and colleagues in a small cohort of sCJD cases (n = 20) [119] and further validated by many independent studies in large sample populations [16, 120, 121]. Diagnostic parameters and cut-off values were calculated in a cohort of more than 1000 sCJD cases [22]. For the discrimination of sCJD from neurological controls and AD the area under the curves were from 0.996 and 0.990 respectively, indicating that p-tau/t-tau ratio is able to almost fully discriminate sCJD

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

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

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)

presence of increased t-tau concentrations in MCI [43, 46, 125].

levels in tauopathies showing NFL pathology such as PSP [118].

**3.3. P-tau/t-tau - (t-tau/p-tau) ratio**

from non-CJD cases.

**3.4. Non-p-tau**

and FTDP-TDP pathologies [124].

A decrease on CSF t-tau in non-AD tauopathies could compensate the absence of elevated p-tau levels. However, t-tau levels are altered neither in the brain, nor in the brain tissue of non-AD tauopathies. Another aspect to be considered is the differential susceptibilities to clearance between tau forms. While tau turnover is delayed for insoluble forms, it is accelerated for soluble and phosphorylated tau [104]. Therefore, it is tempting to speculate that the combination of some or all these factors may have an influence in the differential CSF t-tau and p-tau profiles observed between tauopathies and AD.

CSF p-tau levels (p-tau-181) have also been reported to be moderately increased in CJD [17, 105]. Although p-tau values in sCJD are only from marginal to slightly elevated, most likely reflecting basal phosphorylation of tau molecules released into the CSF as a consequence of neuronal damage, these alterations are subtype-dependent. In fact, sCJD subtypes VV2 and MV2K showed the highest p-tau levels positively correlating with the amount of tiny tau deposits in brain areas showing spongiform change [24]. In agreement with these observations higher p-tau levels were detected in PRNP codon 129 VV cases compared to MM and MV cases where prion type was unknown [27].

Compared to controls, slightly increased p-tau concentrations have been reported in DLB [17], an observation supported by meta-analysis studies [52]. However, a large amount of studies report normal p-tau concentrations [106–109]. While several studies detected similar concentrations between DLB, PD, and PDD groups [22, 110], other reports suggest that among the group of α-synuclein aggregation disorders, DLB patients show the highest levels of p-tau [59].

Although it is broadly accepted that p-tau levels in FTLD are lower than those reported in AD and similar to controls [111], it has been recently shown that CSF p-tau levels are positively correlated with postmortem tau pathology (cerebral tau burden) [112]. Another interesting finding of this study was the observation that CSF p-tau levels in FTLD-TDP were lower than those detected in FTLD-tau.

In contrast to t-tau, p-tau levels are not elevated in acute brain injury or in TBI [69, 71, 73]. These results support the idea that CSF t-tau and p-tau reflect different pathogenic processes occurring in the brain tissue. While t-tau would be associated to the degree of neuro-axonal damage, p-tau would mirror the presence of hyper-phosphorylated tau forms, and therefore, the presence of neurofibrillary tangles.

Interestingly, a straightforward association has been suggested between ischemic events, tau hyper-phosphorylation and the formation of NFT. In this regard, hyper-phosphorylated and truncated tau-forms, resembling those detected in AD, accumulate after a transient cerebral ischemia [113, 114]. In humans NFT pathology is detected in TBI, but presenting remarkable differences in terms of temporal and regional affection: in TBI, NFT are concentrated in the superficial layers in the neocortex, whereas in AD they predominate in the deep layers [115, 116]. Additionally, in mouse model of repeated TBI, elevated p-tau without NFT formation was observed in aged mice overexpressing human tau [117]. Finally, the absence of altered p-tau levels in the CSF of acute brain damage could also be explained by the presence of different isoforms of aggregated tau. Indeed, this might also explain the unaltered CSF p-tau levels in tauopathies showing NFL pathology such as PSP [118].
