Neuropathological features of corticobasal degeneration presenting as corticobasal syndrome or Richardson syndrome

Abstract

Patients with corticobasal degeneration can present with several different clinical syndromes, making ante-mortem diagnosis a challenge. Corticobasal syndrome is the clinical phenotype originally described for corticobasal degeneration, characterized by asymmetric rigidity and apraxia, cortical sensory deficits, dystonia and myoclonus. Some patients do not develop these features, but instead have clinical features consistent with the Richardson syndrome presentation of progressive supranuclear palsy, characterized by postural instability, early unexplained falls, vertical supranuclear gaze palsy, symmetric motor disability and dysphagia. The aim of this study was to identify differences in corticobasal degeneration presenting with corticobasal syndrome (n = 11) or Richardson syndrome (n = 15) with respect to demographic, clinical and neuropathological features. Corticobasal degeneration cases were also compared with patients with pathologically proven progressive supranuclear palsy with Richardson syndrome (n = 15). Cases with corticobasal degeneration, regardless of presentation, shared histopathological and tau biochemical characteristics, but they had differing densities of tau pathology in neuroanatomical regions that correlated with their clinical presentation. In particular, those with corticobasal syndrome had greater tau pathology in the primary motor and somatosensory cortices and putamen, while those with Richardson syndrome had greater tau pathology in limbic and hindbrain structures. Compared with progressive supranuclear palsy, patients with corticobasal degeneration and Richardson syndrome had less neuronal loss in the subthalamic nucleus, but more severe neuronal loss in the medial substantia nigra and greater atrophy of the anterior corpus callosum. Clinically, they had more cognitive impairment and frontal behavioural dysfunction. The results suggest that Richardson syndrome can be a clinicopathological presentation of corticobasal degeneration. Atrophy of anterior corpus callosum may be a potential neuroimaging marker to differentiate corticobasal degeneration from progressive supranuclear palsy in patients with Richardson syndrome.

Figure 1

Semi-quantitative assessment of neuronal loss in the substantia nigra and subthalamic nucleus between CBD-CBS (blue), CBD-RS (purple) and PSP-RS (red). The lateral portion of the substantia nigra refers to the ventrolateral neuronal population (A9) and the medial substantia nigra corresponds to the ventral tegmental area (A10). Pathological scoring scheme: 0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = almost complete; Black line = median pathological score; white line = mean; *P < 0.05; **P < 0.001.

Figure 2

Anterior corpus callosum measurements differentiate corticobasal degeneration and progressive supranuclear palsy. Both CBD-CBS (P = 0.008) and CBD-RS (P = 0.0008) have significantly more callosal atrophy compared with PSP-RS. Measurements were taken on coronal sections immediately adjacent to the cingulate gyrus. Callosal widths are in millimetres; black line = median width.

Figure 3

Tau immunohistochemistry in representative brain regions. CBD-RS has relative sparing of motor and somatosensory cortices (A–C; inset = primary motor cortex) and greater tau pathology in the hippocampus (D–F; inset = CA2) compared with CBD-CBS. CBD-RS tau burden in the cerebellar white matter (G–I) and medulla (J–L; inset = tegmentum) is more comparable with PSP-RS. Bar in panel C represents 3 mm in all the panels and 60 µm in all the insets.

Figure 4

Regional distribution of tau immunoreactivity as assessed by image analysis in CBD-CBS, CBD-RS and PSP-RS. The Mann–Whitney rank sum test was used to compare tau burden in CBD-RS with either CBD-CBS or PSP-RS. NS = not significant.

Figure 5

Immunoblot analysis of the sarkosyl-insoluble fraction from frontal cortex homogenates of CBD-CBS, CBD-RS and PSP-RS. The characteristic doublet at 64 and 68 kDa (asterisks), CBD-CBS and CBD-RS have a lower molecular weight doublet at ∼37 kDa (two arrows, left) and PSP-RS has a single band at ∼33 kDa (arrow, right).