Progressive supranuclear palsy: pathology and genetics

Abstract

Progressive supranuclear palsy (PSP) is an atypical Parkinsonian disorder associated with progressive axial rigidity, vertical gaze palsy, dysarthria and dysphagia. Neuropathologically, the subthalamic nucleus and brainstem, especially the midbrain tectum and the superior cerebellar peduncle, show atrophy. The substantia nigra shows loss of pigment corresponding to nigrostriatal dopaminergic degeneration. Microscopic findings include neuronal loss, gliosis and neurofibrillary tangles in basal ganglia, diencephalon and brainstem. Characteristic tau pathology is also found in glia. The major genetic risk factor for sporadic PSP is a common variant in the gene encoding microtubule-associated protein tau (MAPT) and recent studies have suggested that this may result in the altered expression of specific tau protein isoforms. Imaging studies suggest that there may be sensitive and specific means to differentiate PSP from other parkinsonian disorders, but identification of a diagnostic biomarker is still elusive.

Figure 1

Gross appearance of the brain in progressive supranuclear palsy shows mild frontal atrophy (A) with widening of sulcal spaces (arrows); on medial views (B) the most consistent finding is atrophy of the midbrain with flattening of the tectal plate (arrow).

Figure 2

Gross appearance of the sectioned brain reveals atrophy of the subthalamic nucleus (arrows) in the diencephalon at the level of the mammillothalamic tract (A), loss of pigment in the substantia nigra (arrow) in the midbrain (B), and atrophy of the superior cerebellar peduncle (arrow) in the rostral pons (C).

Figure 3

The major histologic lesions in progressive supranuclear palsy (PSP) are visible with tau immunohistochemistry (A,C,E) or silver stain (Gallyas) (B,D,F). Neurofibrillary tangles (A,B) often have a globose appearance. Tufted astrocytes (C,D) are relatively specific for PSP. Oligodendroglial coiled bodies (E,F) are characteristic, but can also be found in other disorders.

Figure 4

Electron microscopy of neurofibrillary tangle in progressive supranuclear palsy (A) shows a globose tangled mass of filaments that displaces cytosolic elements. The filaments at higher magnification (B) are mostly straight (bars = 1 µm).

Figure 5

Western blot of detergent insoluble tau proteins in Alzheimer’s disease (AD), corticobasal degeneration (CBD) and two cases of progressive supranuclear palsy (PSP). Note that PSP and CBD have two prominent bands (arrowheads) at 64‐kDa and 68‐kDa, while AD has three major bands (arrowheads) at 60‐kDa, 64‐kDa and 68‐kDa. There is a minor higher molecular weight species in AD, CBD and PSP, as well as variable lower molecular weight species due to protein degradation.