Neuropathology of cervical dystonia

Abstract

The aim of this study was to search for neuropathological changes in postmortem brain tissue of individuals with cervical dystonia (CD). Multiple regions of formalin-preserved brains were collected from patients with CD and controls and examined with an extensive battery of histopathological stains in a two-stage study design. In stage one, 4 CD brains underwent a broad screening neuropathological examination. In stage two, these 4 CD brains were combined with 2 additional CD brains, and the subjective findings were quantified and compared to 16 age-matched controls. The initial subjective neuropathological assessment revealed only two regions with relatively consistent changes. The substantia nigra had frequent ubiquitin-positive intranuclear inclusions known as Marinesco bodies. Additionally, the cerebellum showed patchy loss of Purkinje cells, areas of focal gliosis and torpedo bodies. Other brain regions showed minor or inconsistent changes. In the second stage of the analysis, quantitative studies failed to reveal significant differences in the numbers of Marinesco bodies in CD versus controls, but confirmed a significantly lower Purkinje cell density in CD. Molecular investigations revealed 4 of the CD cases and 2 controls to harbor sequence variants in non-coding regions of THAP1, and these cases had lower Purkinje cell densities regardless of whether they had CD. The findings suggest that subtle neuropathological changes such as lower Purkinje cell density may be found in primary CD when relevant brain regions are investigated with appropriate methods.

Figure 1

Histopathology in the midbrain. Panels A-B show typical ubiquitin-positive inclusions in the substantia nigra (Marinesco bodies). Nigral neurons with one or multiple inclusions were observed (black arrows). Panel C shows an example of satellitosis (arrow) around a dopaminergic neuron in the substantia nigra. Panel D shows increased number and activation of astrocytes (gliosis, arrows) in a midbrain section of a cervical dystonia case. Panels A-B: ubiquitin immunostaining; Panel C: hematoxylin and eosin; Panel D: glial fibrillary acidic protein.

Figure 2

Histopathology in the cerebellum. Panels A-B shows areas with patchy loss of Purkinje cells, as indicated by the black arrows. Torpedo bodies (white arrows) can be identified in Panels B-C. Panel D shows a typical Purkinje cell layer with morphologically normal cell bodies. Panels A-D: silver impregnation.

Figure 3

Box and whisker plot comparing Purkinje cell linear density in 6 cervical dystonia (CD) cases and 13 controls. In this type of plot, the upper and lower limits of the box show the upper and lower quartiles of the data, with the horizontal line in between showing the median. The whiskers show the entire data range, and circles depict each data point. Two independent sections for each subject were analyzed, and all 12 points for the CD group and 26 for the controls are shown. Regression analysis indicated that CD was significantly associated with lower density of Purkinje cells at p<0.05 (A). Regression analysis also revealed that cases with a THAP1 sequence variant (THAP1 sv+) had a significantly lower linear density of Purkinje cells compared to THAP1 negative cases at p<0.05 (THAP1 sv-) (B). In A, open and closed circles represent the data for THAP1 positive and negative cases within each group. In B, open and closed circles represent the data for CD and controls within each THAP1 group.