Corticobasal degeneration with olivopontocerebellar atrophy and TDP-43 pathology: an unusual clinicopathologic variant of CBD

Abstract

Corticobasal degeneration (CBD) is a disorder affecting cognition and movement due to a progressive neurodegeneration associated with distinctive neuropathologic features, including abnormal phosphorylated tau protein in neurons and glia in cortex, basal ganglia, diencephalon, and brainstem, as well as ballooned neurons and astrocytic plaques. We identified three cases of CBD with olivopontocerebellar atrophy (CBD-OPCA) that did not have α-synuclein-positive glial cytoplasmic inclusions of multiple system atrophy (MSA). Two patients had clinical features suggestive of progressive supranuclear palsy (PSP), and the third case had cerebellar ataxia thought to be due to idiopathic OPCA. Neuropathologic features of CBD-OPCA are compared to typical CBD, as well as MSA and PSP. CBD-OPCA and MSA had marked neuronal loss in pontine nuclei, inferior olivary nucleus, and Purkinje cell layer. Neuronal loss and grumose degeneration in the cerebellar dentate nucleus were comparable in CBD-OPCA and PSP. Image analysis of tau pathology showed greater infratentorial tau burden, especially in pontine base, in CBD-OPCA compared with typical CBD. In addition, CBD-OPCA had TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions and threads throughout the basal ganglia and in olivopontocerebellar system. CBD-OPCA met neuropathologic research diagnostic criteria for CBD and shared tau biochemical characteristics with typical CBD. These results suggest that CBD-OPCA is a distinct clinicopathologic variant of CBD with olivopontocerebellar TDP-43 pathology.

Fig. 1

CBD-OPCA macroscopic features. The base of the brain shows prominent atrophy of the pons (arrows in a). A transverse section of the mid-pons shows marked atrophy of the pontine base, while the superior cerebellar peduncle is relatively preserved, and the trigeminal nerve (arrow in b) is prominent against the atrophic and has loss of myelin middle cerebellar peduncle (b). Cerebellum sections show marked white matter atrophy compared with normal control (c). Cerebellar white matter has loss of myelin (arrow in d). Luxol fast blue staining (b, d); case 1 (b, c); case 2 (d); case 3 (a)

Fig. 2

Tau and TDP-43 immunohistochemistry in CBD-OPCA. Affected cortical regions show tau-immunoreactive astrocytic plaques (a) and ballooned neurons (b). The substantia nigra has neuronal loss and tau-positive “corticobasal bodies” (c). Abundant TDP-43-positive pathology was seen throughout the olivopontocerebellar system in CBD-OPCA, including neuronal cytoplasmic inclusions in the inferior olivary nucleus (d) and numerous threads and oligodendroglial inclusions in the pontine base (e) and cerebellar white matter (f).

Fig. 3

CBD-OPCA olivopontocerebellar system pathology. The inferior olivary nucleus has neuronal loss with degeneration of olivocerebellar fibers (a), marked degeneration of transverse fibers of the pontine base with preservation of longitudinal fibers (b), cerebellar white matter loss (c, arrowhead) and axonal torpedoes (c, inset arrows).The inferior olivary nucleus has many pretangles and threads (d). Pontine transverse fibers (e) and cerebellar white matter (f) with tau-immunoreactive threads. Luxol fast blue staining (a–c); H&E staining (c inset); tau immunohistochemistry (d–f); bar = 50 μm

Fig 4

Brain magnetic resonance imaging (MRI) from Case 3. (a) T1-weighted mid-sagittal MRI section shows anterior cerebellar (arrow) and brainstem atrophy. (b) T1-weighted coronal section shows bilateral cerebellar atrophy. (c) Axial T2-weighted image and (Dd fluid attenuated inversion recovery MRI showing enlargement of the fourth ventricle and cerebellopontine cisterns (asterisks).

Fig 5

Neuronal loss in CBD-OPCA, CBD, MSA, PSP, and normal controls. Three non-overlapping images were randomly captured from H&E stained sections (1.5 mm × 1.25 mm section for cerebellar Purkinje cell layer in cerebellar hemisphere and vermis; 0.6 mm × 0.5 mm section for inferior olivary nucleus, pontine nuclei and dentate nucleus). Bars represent mean and error bars show the standard error of the mean. CBD-OPCA = corticobasal degeneration with olivopontocerebellar atrophy, MSA = multiple system atrophy, CBD = typical corticobasal degeneration, PSP = progressive supranuclear palsy. * P < 0.001 versus CBD-OPCA and MSA; § P < 0.05 (inferior olivary nucleus) and P < 0.001 (Purkinje and vermis) versus MSA; ^† P < 0.05 versus PSP

Fig. 6

Image analysis tau burden in CBD-OPCA and CBD. The tau burden was quantified for CBD-OPCA (n = 3) and typical CBD (n = 11) on sections of middle frontal gyrus, pontine nuclei, inferior olivary nucleus, and cerebellar dentate nucleus (0.3 mm × 0.25 mm section). Boxes represent the ratio of tau immunoreactive pixels to total pixels as a % tau burden; median = black line; mean = white line; CBD-OPCA = corticobasal degeneration with olivopontocerebellar atrophy, CBD = typical corticobasal degeneration. * P = 0.003

Fig. 7

Biochemical analysis of tau in CBD-OPCA, CBD, and PSP. Proteins were extracted from frontal cortex (F), pons (P), dentate nucleus of the cerebellum (D), and midbrain (M) of CBD-OPCA, CBD, and PSP. Sarkosyl-soluble fractions were separated by SDS-PAGE and immunoblotted (a). Tau was present at the characteristic doublet (~ 64-and 68-kDa, asterisks) for all cases, CBD-OPCA and CBD have a lower molecular weight doublet at ~37-kDa (two arrows, left) and PSP has a single band at ~33-kDa (arrow, right). (b) Densitometric ratio of 37- and 40-kDa to 33-kDa tau. Bar charts show mean and error bars show the standard error of mean. CBD-OPCA = corticobasal degeneration with olivopontocerebellar atrophy, CBD = typical corticobasal degeneration, PSP = progressive supranuclear palsy.