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PSP and CBD were initially clinicopathological diagnoses (a typical clinical syndrome was associated with a characteristic neuropathology). Since pathological markers have been used to define them—astrocytic tuft for PSP and astrocytic plaque for DCB—their clinical phenotype has changed ("atypical clinical forms"). PSP and CBD have a common genetic risk factor (tau haplotype HI). In both diseases, it is mainly tau 4-R that accumulates.

PSP and CBD were initially clinicopathological diagnoses (a typical clinical syndrome was associated with a characteristic neuropathology). Since pathological markers have been used to define them—astrocytic tuft for PSP and astrocytic plaque for DCB—their clinical phenotype has changed ("atypical clinical forms"). PSP and CBD have a common genetic risk factor (tau haplotype HI). In both diseases, it is mainly tau 4-R that accumulates.

gested that some type of inclusion could help identifying the disorder: they were basophilic, poorly argyrophilic with Bielschowsky stain, and filled the neuronal cell body (140). But those "corticobasal inclusions" did not survive tau immunohistochemistry, which demonstrated that they were, in fact, true NFTs.

It may be surprising that it took more than 25 yr to realize that a severe cytoskeletal pathology occurred in CBD (141-144). Such a long delay between the initial description of the disease and the elucidation of its typical lesions is probably related to the poor reactivity of CBD alterations to standard silver stain (Gallyas stain, which exquisitely labels them, is an exception) (142). Immunohistochemistry now reveals a whole range of tau accumulations in neurons, glia, and processes. In neurons, it shows inclusions that resemble Pick's bodies, a resemblance that has suggested overlaps between the two disorders (145,146). However, Pick's bodies and neuronal inclusions of CBD may be distinguished (147): one important difference is the low reactivity of Pick's bodies to Gallyas stain in contrast to the neuronal inclusions of CBD. This contrast in staining properties could be due to a difference in the isoforms of the tau protein that accumulates: Pick's bodies are made of 3R-tau whereas neuronal inclusions of CBD contain 4-R tau (148,149). The high density of tau-positive threads in the subcortical white matter and in the deep layers of cortex is quite distinctive of CBD (150,151). As in PSP, these threads appear to be related to the presence of tau in myelin inner and outer loops (104). Another lesion is now considered to be more specific of CBD: the "astrocytic plaque" (or "glial plaque") characterized by "an annulus of tau-positive structures surrounding a clear central core" (144). This lesion has been interpreted as the accumulation of tau in the distal processes of the astrocyte (144,152): this interpretation is based on double-labeling experiments using tau and CD44 antibodies. CD44 is a membrane protein found in leukocytes and activated astroglia. Colocalization is not found with GFAP (144). Astrocytic plaques are particularly abundant in the prefrontal and premotor areas of the cerebral cortex and in the caudate nucleus (114).

Tau-positive threads, coiled bodies, and tangles are shared lesions of CBD and PSP. Thus, although it was, initially, with Pick's disease that the border of CBD was considered difficult to draw, it was, later on, with PSP that the differences seemed to be most elusive. Komori et al. proposed using astrocytic plaques and tufted astrocytes as diagnostic hallmarks, respectively of CBD and PSP (153,154), an opinion that was essentially endorsed by the diagnostic criteria of CBD (155). When these neuropathologic markers are taken as diagnostic tools, the clinical presentation of both diseases appears to be more diverse than initially thought: there are indeed cases of supranuclear gaze palsy (156), progressive aphasia (131,147,157), or frontal dementia (158,159), which exhibit the typical lesions of CBD, whereas some patients who meet the neuropathologic diagnostic criteria of PSP present, as we have seen, with progressive apraxia, reminiscent of CBD.

The use of astrocytic plaques and of tufted astrocytes as the diagnostic markers of CBD and PSP, respectively, modifies the spectrum of the clinical phenotype of both diseases and makes any prediction concerning the pathology, at least presently, particularly difficult. There are distinctive features at neuropathological examination (they are fully reviewed in ref. 160), but even at this stage doubts concerning the diagnosis may remain; cases have been described with neuropathological characteristics of both disorders (161).

Argyrophilic Grain Disease and Neurofibrillary Degeneration of CA2

Argyrophilic grain disease is characterized by the presence of small, spindle-shaped structures loosely scattered in the neuropil of the hippocampus, entorhinal cortex, and amygdala. It was originally found in cases with dementia and was frequently associated with Alzheimer's disease-type pathology. Parkinsonism is not a feature of this disease but since the grains are the focal accumulation of 4R-tau (85) in dendritic spines, it is useful to mention here that association of argyrophilic grain disease and PSP seems particularly frequent (162). Also common to 4R tauopathy is the neurofibrillary degeneration in CA2 sector of the hippocampus, an unusual alteration found in argyro-philic grain disease, PSP, and CBD (163).

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