Fulminant corticobasal degeneration: a distinct variant with predominant neuronal tau aggregates

Abstract

Corticobasal degeneration typically progresses gradually over 5-7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), corticobasal syndrome (N = 2) and Richardson's syndrome (N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p < 0.05). These findings indicated that RP-CBD cases had already developed advanced pathological changes as those observed in End-stage-CBD cases (mean disease duration = 6.7 years), but within a significantly shorter duration (2.5 years; p < 0.001). Subgroup analysis was performed to investigate the cellular patterns of tau aggregates in the anterior frontal cortex and caudate by comparing neuronal-to-astrocytic plaque ratios between six RP-CBD cases, four Intermediate-CBD and 12 age-matched End-stage-CBD. Neuronal-to-astrocytic plaque ratios of Intermediate-CBD and End-stage-CBD, but not RP-CBD, positively correlated with disease duration in both the anterior frontal cortex and caudate (p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p < 0.001, caudate: p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research.

Keywords: Astrocytic plaques; Corticobasal degeneration; Neurofibrillary tangles; Progressive supranuclear palsy; Tau.

Fig. 1

Mean Total, Cortical Grey Matter, Cortical White Matter and Basal Ganglia Tau Load of the Intermediate (Int-CBD), Rapidly Progressive (RP-CBD) and End-Stage (ES-CBD) Groups. All the illustrated tau load measurements of the intermediate group were significantly less than the end-stage group (ANOVA, LSD post-Hoc analysis; p < 0.05). All tau load measurements were the same statistically between the rapidly progressive and end-stage CBD groups, except there was less cortical white matter tau load in the rapidly progressive group than in the end-stage group (ANOVA, LSD post-Hoc analysis; p = 0.04). Error bars represent one standard error of the mean (SEM)

Fig. 2

Mean Regional Tau Load of the Intermediate (Int-CBD), Rapidly Progressive (RP-CBD) and End-Stage (ES-CBD) Groups. Mean regional tau load in the anterior frontal grey and white matter, temporal grey and white matter, caudate, putamen, and subthalamic nucleus were significantly less in the Int-CBD group than in the ES-CBD group (ANOVA, LSD post-Hoc analysis; p < 0.05). Mean regional tau load in the temporal grey and white matter was significantly less in the RP-CBD group when compared with the ES-CBD group (ANOVA, LSD post-Hoc analysis; p < 0.05). *Mean regional tau load in the anterior frontal white matter was the only region showing significant difference between the Int-CBD and ES-CBD group after adjustment for multiple comparisons (p = 0.001). Error bars represent one standard error of the mean (SEM). AFG anterior frontal grey matter, AFW anterior frontal white matter, AMG amygdala, CAU caudate, CDN cerebellar dentate nucleus, CWM cerebellar white matter, GLP globus pallidus, HIP hippocampus, MTC midbrain tectum, MTG midbrain tegmentum, PBS pontine base, PFG posterior frontal grey matter, PFW posterior frontal white matter, PRG parietal grey matter, PRW parietal white matter, PTG pontine tegmentum, PUT putamen, STN subthalamic nucleus, TMG temporal grey matter, TMW temporal white matter

Fig. 3

Proposed Pathological Progression of Different CBD Disease Groups. Top panels illustrate increasing total tau load and severity of nigral cell loss as the disease progresses from preclinical to intermediate, and to end-stage disease. No significant differences in total tau load and severity of nigral cell loss were identified between the rapidly progressive and end-stage groups. The bottom panel illustrates that the preclinical, intermediate and end-stage groups probably follow the same trajectory of disease progression based on our quantitative data above, whereas the rapidly progressive group demonstrates a more aggressive disease course with their pathological changes reaching the same level of severity as the end-stage group within 3 years or less after symptom onset. Notably, the mean disease duration of the Int-CBD and RP-CBD groups did not differ statistically but the severity of pathological changes in the Int-CBD group were significantly milder

Fig. 4

Neuronal-To-Astrocytic Plaque Ratios of the Intermediate (Int-CBD), Rapidly Progressive (RP-CBD) and End-Stage (ES-CBD) Groups of the Anterior Frontal Cortex and Caudate Nucleus. The ratios for both regions in the RP-CBD group were significantly greater than the Int-CBD and ES-CBD groups, indicating proportionally higher number of neuronal lesions (neurofibrillary tangles and pretangles) than astrocytic plaques in RP-CBD cases

Fig. 5

Tau Immunohistochemistry (AT8) Sections of Preclinical (Case 1; Ling et al. Brain 2016), Intermediate and Rapidly Progressive (RP-Case 4) and End-Stage CBD (ES-Case 11) Cases (× 10 objective)