Progressive Supranuclear Palsy

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In the original description of this disease entity, patients with supranuclear ophthalmoplegia, pseudobulbar palsy, dysarthria, rigidity, and mild cognitive deficits were found to have abundant NFTs in subcortical nuclei (91). The clinical phenotype is now recognized to be much more variable and includes both pure parkinsonism and frontotemporal dementia with no movement abnormality (1,2,4,5,71).

The macroscopic changes are quite variable. The cerebral cortex often appears normal but may show significant frontotemporal atrophy that may be quite circumscribed (Fig. 5A). The midbrain and pontine tegmentum are often atrophic whereas the globus pallidus is the most commonly affected part of the basal ganglia (Fig. 5B). Microscopic degeneration with neuronal loss and gliosis also tends to be more widespread and severe in PSP than CBD, with substantia nigra, locus ceruleus, globus pallidus, subthalamic nucleus, midbrain tegmentum, cerebellar dentate nucleus, and pontine nuclei usually involved.

As with CBD, the histopathology of PSP is characterized by the abnormal accumulation of tau protein, in both neurons and glia, which can be demonstrated with immunohistochemistry or silver methods such as Gallyas (82,83,86,88,90,92). The most characteristic feature is widespread NFT formation (Fig. 5C) (91). Current diagnostic criteria require the presence of numerous NFTs in at least three of the following sites: pallidum, subthalamic nucleus, substantia nigra, or pons, and at least some tangles in three of striatum, oculomotor nucleus, medulla, or dentate (93,94). The tangles in these subcortical regions often have a rounded or globose shape (Fig. 5D) and ultrastructural studies show they are composed predominantly of 12-20 nm straight filaments. NFTs may also be found in cerebral cortex where their morphology more closely resemble those seen in AD, being flame-shaped and composed of paired helical filaments (95-97). Although the number and distribution of cortical NFTs in PSP is usually more restricted than in AD, some studies have shown a correlation with cognitive dysfunction (98). ANs (more characteristic of CBD) may be found in some cases of PSP but tend to be limited to limbic cortex (76).

Several types of argyrophilic, tau-positive glial inclusions occur consistently in PSP. Many of these, such as thorn-shaped astrocytes, coiled bodies, and threadlike lesions, are nonspecific, also being seen in other tauopathies such as CBD and Pick's disease (82,83,88-90). The most diagnostic glial pathology in PSP is the presence of tufted astrocytes, which are most numerous in striatum but that are also found in other subcortical regions and frontal cortex (86,88). Although immunoreactive for tau, the morphology is best appreciated with Gallyas silver method, which shows the filamentous inclusion material surrounding the astrocyte nucleus and extending into a complex collection of long delicate processes, producing a shrublike appearance (Fig. 5E). This is different from thorn-shaped astrocytes where the inclusion material is restricted to more proximal processes (Fig. 4G) and astro-cytic plaques in which only the most distal parts of processes are involved (Fig. 4F).

Finally, a unique pathology, which may be seen in the cerebellar dentate nucleus in PSP, is grumose degeneration in which granular eosinophilic material surrounds neurons, some of which are achromatic (Fig. 5F). Ultrastructural studies have shown the granular material to be degenerating axon terminals of Purkinje cells (99).

Fig. 5. Progressive supranuclear palsy. Gross photographs showing (A) lobar frontal atrophy and (B) atrophy and discoloration of basal ganglia. (C) Multiple neurofibrillary tangles (NFTs) and pretangles in midbrain (tau-immunohistochemistry). (D) Globose NFT (H&E stain). (E) Tufted-astrocyte (Gallyas silver stain). (F) Grumose degeneration (arrows) of neurons in cerebellar dentate nucleus (H&E stain).

Fig. 5. Progressive supranuclear palsy. Gross photographs showing (A) lobar frontal atrophy and (B) atrophy and discoloration of basal ganglia. (C) Multiple neurofibrillary tangles (NFTs) and pretangles in midbrain (tau-immunohistochemistry). (D) Globose NFT (H&E stain). (E) Tufted-astrocyte (Gallyas silver stain). (F) Grumose degeneration (arrows) of neurons in cerebellar dentate nucleus (H&E stain).

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