Corticobasal Degeneration

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Corticobasal degeneration (CBD) is only rarely mistaken for PD due to characteristic focal cortical signs that are the clinical hallmark of this disorder. Common clinical presentations include progressive asymmetrical rigidity and apraxia, progressive aphasia, and progressive frontal lobe dementia (43). Most cases also have some degree of parkinsonism, with bradykinesia, rigidity, and dystonia more common than tremor. Given the prominent cortical findings on clinical evaluations, it is not surprising that gross examination of the brain often reveals focal cortical atrophy. The atrophy may be severe and "knife-edge" in some cases or subtle and hardly noticeable in others and it may be asymmetrical. Atrophy is often most marked in the medial superior frontal gyrus, parasagittal pre and postcentral gyri and the superior parietal lobule. The temporal and occipital lobes are usually preserved. The brainstem does not have gross atrophy as in PSP, but pigment loss is common in the substantia nigra. In contrast to PSP, the superior cerebellar peduncle and the sub-thalamic nucleus are grossly normal. The cerebral white matter in affected areas is often attenuated and may have a gray discoloration. The corpus callosum is sometimes thinned, the frontal horn of the lateral ventricle is frequently dilated, the caudate head may have flattening, and the thalamus may be smaller than usual.

Microscopic examination of atrophic cortical sections shows neuronal loss with superficial spongiosis, gliosis, and usually many achromatic or ballooned neurons (44). Ballooned neurons are swollen and vacuolated neurons found in middle and lower cortical layers. They are variably positive with silver stains and tau immuno-histochemistry, but intensely stained with immunohistochemistry for a-B-crystallin, a small heat shock protein, and for neurofilament (Fig. 5).

FIGURE 5 Corticobasal degeneration (CBD): The hallmark lesion in CBD is the astrocytic plaque (asterix), which is a cluster of irregular tau processes around a central astrocyte (A). The white matter and gray matter in CBD has numerous tau-immunoreactive thread-like processes (B). Cortical neurons have swelling characteristic of ballooning degeneration (C) and the ballooned neurons have intense immunoreactivity with the stress protein a-B-crystallin (D). Neurons in the substantia nigra have round inclusions called corticobasal bodies (arrow in E) that are positive for tau (arrow in F). Note also the many thread-like processes in (F).

FIGURE 5 Corticobasal degeneration (CBD): The hallmark lesion in CBD is the astrocytic plaque (asterix), which is a cluster of irregular tau processes around a central astrocyte (A). The white matter and gray matter in CBD has numerous tau-immunoreactive thread-like processes (B). Cortical neurons have swelling characteristic of ballooning degeneration (C) and the ballooned neurons have intense immunoreactivity with the stress protein a-B-crystallin (D). Neurons in the substantia nigra have round inclusions called corticobasal bodies (arrow in E) that are positive for tau (arrow in F). Note also the many thread-like processes in (F).

Cortical neurons in atrophic areas also have tau-immunoreactive lesions. In some neurons, tau is densely packed into a small inclusion body somewhat reminiscent of a Pick body or a small NFT. In other neurons, the filamentous inclusions are more dispersed and diffuse. As in PSP, neurofibrillary lesions in CBD are not detected well with most diagnostic silver stains and thioflavin fluorescent microscopy. Neu-rofibrillary lesions in brainstem monoaminergic nuclei, such as the locus ceruleus and substantia nigra, sometimes resemble globose NFTs. In addition to fibrillary lesions in the perikarya of neurons, the neuropil of CBD invariably contains a large number of thread-like tau-immunoreactive processes. They are usually profuse in both gray and white matter, and this latter feature is an important attribute of CBD and a useful feature in differentiating it from other disorders (44).

The most characteristic tau-immunoreactive lesion in the cortex in CBD is an annular cluster of short, stubby processes with fuzzy outlines that may be highly suggestive of a neuritic plaque of AD (45) (Fig. 5). In contrast to Alzheimer plaques, they do not contain amyloid, but rather tau-positive astrocytes and have been referred to as "astrocytic plaques." Astrocytic plaques differ from the tufted astrocytes seen in PSP, and the two lesions do not co-exist in the same brain (39). The astrocytic plaque may be the most specific histopathologic lesion of CBD (46).

In addition to cortical pathology, deep gray matter is consistently affected in CBD. The globus pallidus and putamen show mild neuronal loss with gliosis. Thal-amic nuclei may also be affected. In the basal ganglia, thread-like processes are often extensive, often in the pencil fibers of the striatum. Tau-positive neurons, but not NFTs, are common in the striatum and globus pallidus. The internal capsule and thalamic fasciculus often have many thread-like processes. The subthalamic nucleus usually has a normal neuronal population, but neurons may have tau inclusions, and there may be many thread-like lesions in the nucleus. Fibrillary gliosis typical of PSP is not seen in the subthalamic nucleus in CBD.

The substantia nigra usually shows moderate-to-severe neuronal loss with extraneuronal neuromelanin and gliosis. Many of the remaining neurons contain NFTs, which have also been termed "corticobasal bodies" (47) (Fig. 5). The locus ceruleus and raphe nuclei have similar inclusions. In contrast to PSP where neurons in the pontine base almost always have at least a few NFTs, the pontine base is largely free of NFTs in CBD. In contrast, tau inclusions in glia and thread-like lesions are frequent in the pontine base. The cerebellum has mild Purkinje cell loss and axonal torpedoes. There is also mild neuronal loss in the dentate nucleus, but grumose degeneration is much less common than in PSP. In CBD, the filaments have a paired helical appearance at the electron microscopic level, but the diameter is wider and the periodicity is longer than the paired helical filaments of AD (45). These structures have been referred to as twisted ribbons. Similar to PSP, abnormal insoluble tau in CBD migrates as two prominent bands (68 and 64 kDa) on western blots (42).

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