The biochemical parameters of tau pathology

5) the spatiotemporal progression of tau pathology, which is extremely well correlated with cognitive impairment; 

The mapping of the spatiotemporal distribution of tau pathology in the different brain areas is important to understand how the disease spreads in the brain. Indeed, there is a precise biochemical pathway of tau pathology in aging and in AD. The progression of tau pathology is sequential, invariable, hierarchical, predictable. 10 stages (S1 to S10) were defined, corresponding to 10 brain areas sequentially affected. The degenerating process always starts in the hippocampal region (S1: transentorhinal cortex; S2: entorhinal cortex; S3: CA1 region of the hippocampus), followed by the temporal cortex (S4: temporal pole; S4: inferior temporal cortex; S6: mid temporal cortex), then the polymodal association brain areas (S7-S8), and finally the primary regions ( motor cortex and/or the occipital cortex) as well as many subcortical nuclei (S9-S10) (Delacourte et al. 1999).

These data show that tau pathology is systematically observed in the normal population aged over 75 years. They also demonstrate that tau pathology sometimes occurs independently of amyloid deposits and that the hippocampal area is the most vulnerable area of the human brain. The hippocampal vulnerability is probably a springboard for Alzheimer pathology, namely amyloid precursor protein dysfunction, which will exacerbate and extend tau pathology in other brain areas (Figure 3). Together, neuropathological and biochemical data concur to indicate that tau pathology is instrumental in AD.

From these data, it is now possible to precisely quantify tau pathology and amyloid deposition at the biochemical level and to determine the Criteria to Establish a Biochemical Diagnosis of AD (CEBDAD), that separate aging from preclinical AD, and preclinical AD from clinical AD (Delacourte et al. 1999). In that respect, it should be pointed out that recent criteria for the neuropathological diagnosis have rehabilitated tau pathology, in good agreement with Aloïs Alzheimer observations and the natural history of AD (WorkingGroup 1997).

The 10 stages of Tau pathology in Alzheimer's disease

The pathway of tau pathology in PSP is different from the one in AD, and roughly the opposite, emerging from subcortical nuclei toward the neocortex, and especially the frontal motor cortex. The specific pattern of tau pathology in PSP, with the upper tau doublet (tau 64, tau 69), is observed in all brain areas affected, from subcortical nuclei to frontal neocortical regions (Vermersch et al. 1994), (Buee Scherrer et al. 1996).

In all types of neurodegenerative disorders, the spreading of tau pathology follows specific neuronal connections, like a precise neuronal chain reaction. There is also likely a "dynamic" of spreading, fuelled by different factors, each of them being a lead for neuroprotection (Delacourte 2000).

Six main features define tau pathology: 

• 1) the quantitative aspects, using western blots ; 

• 2) the different biochemical signatures observed in AD, PSP, CBD, PiD, MyoD (one to four immunodetected electrophoretic bands); 

• 3) the specific tau isoforms content of brain lesions. Indeed, "disease-specific" sets of tau isoforms aggregate to constitute 4 main categories of tau lesions: class 1: AD (all 6 isoforms), class 2: PSP/CBD (3 Exon10+ isoforms), class 3: PiD (3 Exon10- isoforms) and class 4: MyoD (mainly and sometimes exclusively the shortest tau isoform); 

• 4) the different states of phosphorylation of tau, with hyper and abnormal phosphorylation, as well as disease-specific sites of phosphorylation (ex: ser262); 

• 5) the spatiotemporal progression of tau pathology, which is extremely well correlated with cognitive impairment; 

• 6) the genetic aspects, with pathogenic tau mutations in FTDP-17 or characteristic polymorphisms in PSP.