Corticobasal degeneration: a pathologically distinct 4R tauopathy

Abstract

Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disorder with onset in the 5(th) to 7(th) decade of life. It is associated with heterogeneous motor, sensory, behavioral and cognitive symptoms, which make its diagnosis difficult in a living patient. The etiology of CBD is unknown; however, neuropathological and genetic evidence supports a pathogenetic role for microtubule-associated protein tau. CBD pathology is characterized by circumscribed cortical atrophy with spongiosis and ballooned neurons; the distribution of these changes dictates the patient's clinical presentation. Neuronal and glial tau pathology is extensive in gray and white matter of the cortex, basal ganglia, diencephalon and rostral brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques. The classic clinical presentation, termed corticobasal syndrome (CBS), comprises asymmetric progressive rigidity and apraxia with limb dystonia and myoclonus. CBS also occurs in conjunction with other diseases, including Alzheimer disease and progressive supranuclear palsy. Moreover, the pathology of CBD is associated with clinical presentations other than CBS, including Richardson syndrome, behavioral variant frontotemporal dementia, primary progressive aphasia and posterior cortical syndrome. Progress in biomarker development to differentiate CBD from other disorders has been slow, but is essential in improving diagnosis and in development of disease-modifying therapies.

Figure 1 |

The distinct histological lesions of CBD and PSP visualized with tau immunohistochemistry. a | The astrocytic plaque is a hallmark of CBD. b | Tufted astrocytes are found in the superior frontal cortex of patients with PSP. c | Numerous neuropil threads in the internal capsule are found in patients with CBD; d | by contrast, those with PSP have sparse neuropil threads with oligodendroglial coiled bodies. e | Western blot of detergent-insoluble tau proteins (P3 fraction) from patients with CBD and PSP. The CBD and PSP samples both exhibit the characteristic major doublet of hyperphosphorylated full-length tau at 64 kDa and 68 kDa (asterisk). Cleaved tau fragments from a patient with CBD migrate as two bands at approximately 37 kDa (small arrow), whereas cleaved fragments from a patient with PSP migrate as a single band at 33 kDa (large arrow). Abbreviations: CBD, corticobasal degeneration; PSP, progressive supranuclear palsy.

Figure 2 |

Patterns of gray matter loss in groups of patients with autopsy-confirmed CBD but different clinical syndromes. The results were generated using voxel-based morphometry and are shown on three-dimensional surface and medial renders of the brain. All clinical groups show gray matter loss as indicated by red coloration in the posterior lateral and medial frontal lobe, suggesting that this is a signature pattern of CBD pathology; however, patterns of gray matter loss that differ between groups extend into other regions of the brain. These differences are thought to cause the various clinical syndromes associated with CBD. Abbreviations: bvFTD, behavioral variant frontotemporal dementia; CBD, corticobasal degeneration; CBS, corticobasal syndrome; PCA, posterior cortical atrophy; PPA, primary progressive aphasia; RS, Richardson syndrome.