Clinicopathological correlations in corticobasal degeneration

Abstract

Objective: To characterize cognitive and behavioral features, physical findings, and brain atrophy patterns in pathology-proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS) with known histopathology.

Methods: We reviewed clinical and magnetic resonance imaging data in all patients evaluated at our center with either an autopsy diagnosis of CBD (n = 18) or clinical CBS at first presentation with known histopathology (n = 40). Atrophy patterns were compared using voxel-based morphometry.

Results: CBD was associated with 4 clinical syndromes: progressive nonfluent aphasia (n = 5), behavioral variant frontotemporal dementia (n = 5), executive-motor (n = 7), and posterior cortical atrophy (n = 1). Behavioral or cognitive problems were the initial symptoms in 15 of 18 patients; less than half exhibited early motor findings. Compared to controls, CBD patients showed atrophy in dorsal prefrontal and perirolandic cortex, striatum, and brainstem (p < 0.001 uncorrected). The most common pathologic substrates for clinical CBS were CBD (35%), Alzheimer disease (AD, 23%), progressive supranuclear palsy (13%), and frontotemporal lobar degeneration (FTLD) with TDP inclusions (13%). CBS was associated with perirolandic atrophy irrespective of underlying pathology. In CBS due to FTLD (tau or TDP), atrophy extended into prefrontal cortex, striatum, and brainstem, whereas in CBS due to AD, atrophy extended into temporoparietal cortex and precuneus (p < 0.001 uncorrected).

Interpretation: Frontal lobe involvement is characteristic of CBD, and in many patients frontal, not parietal or basal ganglia, symptoms dominate early stage disease. CBS is driven by medial perirolandic dysfunction, but this anatomy is not specific to a single underlying histopathology. Antemortem prediction of CBD will remain challenging until clinical features of CBD are redefined, and sensitive, specific biomarkers are identified.

Figure 1

SPM5 VBM analysis contrasting gray and white matter volume in (a) all patients with corticobasal degeneration (CBD) who had VBM-compatible 1.5T structural T1 scans (N=13) with healthy older controls (NC, N=44) and (b) the three main clinical syndromes seen in CBD compared to NC viewed on a DARTEL-derived template based on 48 healthy controls (voxel resolution: 1 mm). Patients with VBM-compatible scans in the three clinical syndromes included PNFA-CBD (N=4), EM-CBD (N=5), and bvFTD-CBD (N=3).

Figure 2

SPM5 VBM analysis showing the patterns of gray and white matter volume loss in (a) left panel: each CBS subgroup (CBS-AD N=7, CBS-CBD N=11, CBS-PSP N=4, and CBS-TDP N=3) relative to healthy controls (NC, N=44) and (b) right panel: all CBS subgroups relative to NC viewed on a DARTEL-derived template based on 48 healthy controls (voxel resolution: 1 mm).

Figure 3

SPM5 VBM analysis showing the patterns of gray and white matter volume loss in patients with (a) CBS-AD (N=7) and CBS-FTLD (N=18) relative to healthy controls (NC), and (b) CBS-AD relative to CBS-FTLD and CBS-FTLD relative to CBS-AD. All contrasts are displayed on a DARTEL-derived template based on 48 healthy controls (voxel resolution: 1 mm).

Figure 4

Analysis of the degree of (a) frontal (b) superior frontal gyrus, and (c) parietal asymmetry in patients with CBD and CBS with 1.5T MRI scans compatible with Free-surfer-based volumetric analysis with regions of interest as defined in Desikan29. Degree of asymmetry was derived from a right-left ratio for each lobe ([R/L]-1), converted to a percentage. In the CBD analysis (top panel), subjects included healthy older controls (NC, N=34), and patients from the three main clinical syndromes seen in CBD, including PNFA-CBD (N=3), EM-CBD (N=5), and bvFTD-CBD (N=3). In the CBS analysis (bottom panel), subjects included the same healthy older controls (NC, N=34), and patients from the 5 main underlying pathologies seen in CBS, including CBS-AD (N=5), CBS-CBD (N=10), CBS-PSP (N=4), CBS-TDP (n=2), and CBS-mixed (N=3). Dashed lines indicate 2 standard deviations beyond mean asymmetry of normal controls.