Pathoarchitectonics of the cerebral cortex in chorea-acanthocytosis and Huntington's disease

Abstract

Aims: Quantitative estimation of cortical neurone loss in cases with chorea-acanthocytosis (ChAc) and its impact on laminar composition.

Methods: We used unbiased stereological tools to estimate the degree of cortical pathology in serial gallocyanin-stained brain sections through the complete hemispheres of three subjects with genetically verified ChAc and a range of disease durations. We compared these results with our previous data of five Huntington's disease (HD) and five control cases. Pathoarchitectonic changes were exemplarily documented in TE1 of a 61-year-old female HD-, a 60-year-old female control case, and ChAc3.

Results: Macroscopically, the cortical volume of our ChAc cases (ChAc1-3) remained close to normal. However, the average number of neurones was reduced by 46% in ChAc and by 33% in HD (P = 0.03 for ChAc & HD vs. controls; P = 0.64 for ChAc vs. HD). Terminal HD cases featured selective laminar neurone loss with pallor of layers III, V and VIa, a high density of small, pale, closely packed radial fibres in deep cortical layers VI and V, shrinkage, and chromophilia of subcortical white matter. In ChAc, pronounced diffuse astrogliosis blurred the laminar borders, thus masking the complete and partial loss of pyramidal cells in layer IIIc and of neurones in layers III, V and VI.

Conclusion: ChAc is a neurodegenerative disease with distinct cortical neurodegeneration. The hypertrophy of the peripheral neuropil space of minicolumns with coarse vertical striation was characteristic of ChAc. The role of astroglia in the pathogenesis of this disorder remains to be elucidated.

Keywords: minicolumn; neurodegenerative disease; neurone number; selective vulnerability; stereology.

Figure 1.

The dorsal and ventral bank of the superior temporal sulcus (Brodmann’s [20] areas 22 and 21; von Economo-Koskinas [21] area temporalis propria or TE1) in gallocyanin stained 420 μm coronal sections. (a) 60 year-old female control case. (b) 61 year-old female Huntington’s disease case. The horizontal layers in this polymodal isocortex are designated with Roman numerals I–VI, and their sublayers with a, b and c. IIIc pyramidal cells are characteristic of polymodal association cortices and can be recognized as small dark spots (see also Figure 2b,c). Note the pallor and thinning of layers III, V and VI, and the hyperchromatic central medullary ray in (b). STS superior temporal sulcus. Same magnification in (a,b); white asterisk in (b): grazing section through combined layers IV and Va left to and vertical section right to asterisk. Readers interested in studying delicate details of cytoarchitectonics are recommended to open the electronic version of the article and to view the high-resolution PDF images of panels 1 and 2 in Adobe Reader or Acrobat with 200–400% magnification.

Figure 2.

Low-power macroscopic overview of TE1 of a 54 year-old male chorea-acanthocytosis 3 (ChAc3) case (a) and low-power microscopic aspect of area TE1 of the 60 year-old control case (b), the 61 year-old Huntington’s disease- (HD) (c), and the 54 year-old ChAc-case (d). Blurred laminar boundaries in cortex with an apparently normal thickness (a). The black asterisk in (a) indicates unstained fibre bundles that leave the central medullary ray to pierce the cortex in a fan-like manner (radial fibres). The depth of focus of microscopic lenses is less than that of macroscopic photographic lenses and only few cell-sparse radial fibres were within the focus of (b) through (d). Vertical stacks of pyramidal cells were arranged parallel to the radial fibres and the distance between the parallel neurones gives an impression of the average diameter of radial fibres and the dimensions of minicolumns. Radial fibres or vertical bundles are an integral part of the minicolumnar peripheral neuropil space [42]. Therefore, the average diameter of minicolumns was obviously higher in ChAc than in the control cases, however, due to cell loss and diffuse astrogliosis the borders were less distinct in ChAc compared with controls. Neurone density was apparently higher in HD (c) than in controls (b) and ChAc (d), however, average neurone size was lower, IIIc pyramidal cells were missing or confined to few radial fibres (arrow), whereas the latter outnumbered those in controls and in ChAc. The average diameter of HD radial fibres was only half or less compared with controls. Bar in (a) 100 μm, same magnification in (b–d). Layers IV and V seemed to be fused in HD and ChAc, and the borders of layers Vb, VIa and VIb were difficult to distinguish in terminal stages of both choreatic diseases.

Figure 3.

Astrocytes in the cortex and medullary layer of the medial temporal gyrus in chorea-acanthocytosis (ChAc) (a–c) and Huntington’s disease (HD) (d–f). (a) Glial fibrillary acidic protein (GFAP) immunohistochemistry in ChAc3 shows high signal intensity in the medullary and deep cortical layers (VI and V) (white arrow) and focal intensity in the supragranular layers. (b) Higher magnification view displaying a high density of GFAP-positive astrocytic perikarya and a dense meshwork of fibres in the central medullary ray (b), hypertrophic astrocytic perikarya and long vertically coursing fibres in the supragranular layers of the medial temporal gyrus (c). Autoclaving of paraffin sections for GFAP-immunostaining caused detachment of the sections or considerable artifacts, particularly in the medullary layer (lower part of Figure (d) of our HD cases. Silver impregnation with a modified Gallyas staining (e,f) showed a loose mesh of long thin astrocytic fibres in the cortical medulla. A dense sleeve of fibres and astrocytic perikarya was only present around bigger vessels at the cortical-subcortical border (e black arrows). Few astrocytes were observed in layer VI (e black star). After Gallyas impregnation, the supragranular layers of TE2 (f) were characterized by inconspicuous perikarya of astrocytes (black star) and radially oriented long thin fibres. Same magnification in (c) through (e).