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

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]. 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

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

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

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,

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

and p-tau profiles observed between tauopathies and AD.

MV cases where prion type was unknown [27].

those detected in FTLD-tau.

72 Cognitive Disorders

the presence of neurofibrillary tangles.

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 from non-CJD cases.

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].
