Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York Presbyterian Hospital, 630 W 168th Street, New York, NY, 10032, USA.
Acta Neuropathol Commun. 2022 Apr 19;10(1):55. doi: 10.1186/s40478-022-01364-1.
Huntington disease is characterized by progressive neurodegeneration, especially of the striatum, and the presence of polyglutamine huntingtin (HTT) inclusions. Although HTT inclusions are most abundant in the neocortex, their neocortical distribution and density in relation to the extent of CAG repeat expansion in the HTT gene and striatal pathologic grade have yet to be formally established. We immunohistochemically studied 65 brains with a pathologic diagnosis of Huntington disease to investigate the cortical distributions and densities of HTT inclusions within the calcarine (BA17), precuneus (BA7), motor (BA4) and prefrontal (BA9) cortices; in 39 of these brains, a p62 immunostain was used for comparison. HTT inclusions predominate in the infragranular cortical layers (layers V-VI) and layer III, however, the densities of HTT inclusions across the human cerebral cortex are not uniform but are instead regionally contingent. The density of HTT and p62 inclusions (intranuclear and extranuclear) in layers V-VI increases caudally to rostrally (BA17 < BA7 < BA4 < BA9) with the median burden of HTT inclusions being 38-fold greater in the prefrontal cortex (BA9) than in the calcarine cortex (BA17). Conversely, intranuclear HTT inclusions prevail in the calcarine cortex irrespective of HTT CAG length. Neocortical HTT inclusion density correlates with CAG repeat expansion, but not with the neuropathologic grade of striatal degeneration (Vonsattel grade) or with the duration of clinical disease since motor onset. Extrapolation of these findings suggest that HTT inclusions are at a regionally-contingent, CAG-dependent, density during the advanced stages of HD. The distribution and density of HTT inclusions in HD therefore does not provide a measure of pathologic disease stage but rather infers the degree of pathogenic HTT expansion.
亨廷顿病的特征是进行性神经退行性变，特别是纹状体，以及聚谷氨酰胺亨廷顿蛋白（HTT）包涵体的存在。尽管 HTT 包涵体在新皮质中最为丰富，但它们在新皮质中的分布和密度与 HTT 基因中 CAG 重复扩展的程度和纹状体病理分级之间的关系尚未得到正式确立。我们使用免疫组织化学方法研究了 65 例经病理诊断为亨廷顿病的大脑，以研究 HTT 包涵体在距状回（BA17）、楔前叶（BA7）、运动皮质（BA4）和前额叶皮质（BA9）中的皮质分布和密度；在这些大脑中，有 39 例使用了 p62 免疫染色进行比较。HTT 包涵体主要存在于颗粒下皮质层（V-VI 层）和 III 层，但 HTT 包涵体在人类大脑皮质中的密度并不是均匀的，而是区域相关的。HTT 和 p62 包涵体（核内和核外）在 V-VI 层中的密度从尾侧向头侧增加（BA17<BA7<BA4<BA9），前额叶皮质（BA9）中 HTT 包涵体的中位数负担比距状回皮质（BA17）高 38 倍。相反，无论 HTT CAG 长度如何，核内 HTT 包涵体都在距状回皮质中占优势。新皮质 HTT 包涵体密度与 CAG 重复扩展相关，但与纹状体变性的神经病理分级（Vonsattel 分级）或从运动起始到临床疾病的持续时间无关。这些发现的推断表明，在 HD 的晚期阶段，HTT 包涵体的密度与区域相关，CAG 依赖。因此，HD 中 HTT 包涵体的分布和密度不能作为病理疾病阶段的衡量标准，而是推断致病 HTT 扩展的程度。
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