Palpagama Thulani, Mills Aimee Rose, Ferguson Mackenzie Wendy, Vikas Ankeal Praju, Turner Clinton, Tippett Lynette, van der Werf Bert, Waldvogel Henry John, Faull Richard Lewis Maxwell, Kwakowsky Andrea
Centre for Brain Research and Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
MicRoN, Harvard Medical School, Harvard University, Cambridge, MA.
Ann Neurol. 2023 Nov;94(5):895-910. doi: 10.1002/ana.26753. Epub 2023 Aug 16.
Patients with Huntington's disease can present with variable difficulties of motor functioning, mood, and cognition. Neurodegeneration occurs in the anterior cingulate cortex of some patients with Huntington's disease and is linked to the presentation of mood symptomatology. Neuroinflammation, perpetrated by activated microglia and astrocytes, has been reported in Huntington's disease and may contribute to disease progression and presentation. This study sought to quantify the density of mutant huntingtin protein and neuroinflammatory glial changes in the midcingulate cortex of postmortem patients with Huntington's disease and determine if either correlates with the presentation of mood, motor, or mixed symptomatology.
Free-floating immunohistochemistry quantified 1C2 immunolabeling density as an indicative marker of mutant huntingtin protein, and protein and morphological markers of astrocyte (EAAT2, Cx43, and GFAP), and microglial (Iba1 and HLA-DP/DQ/DR) activation. Relationships among the level of microglial activation, mutant huntingtin burden, and case characteristics were explored using correlative analysis.
We report alterations in activated microglia number and morphology in the midcingulate cortex of Huntington's disease cases with predominant mood symptomatology. An increased proportion of activated microglia was observed in the midcingulate of all Huntington's disease cases and positively correlated with 1C2 burden. Alterations in the astrocytic glutamate transporter EAAT2 were observed in the midcingulate cortex of patients associated with mood symptoms.
This study presents pathological changes in microglia and astrocytes in the midcingulate cortex in Huntington's disease, which coincide with mood symptom presentation. These findings further the understanding of neuroinflammation in Huntington's disease, a necessary step for developing inflammation-targeted therapeutics. ANN NEUROL 2023;94:895-910.
亨廷顿舞蹈症患者可能会出现运动功能、情绪和认知方面的各种困难。部分亨廷顿舞蹈症患者的前扣带回皮质会发生神经退行性变，这与情绪症状的表现有关。据报道，亨廷顿舞蹈症存在由活化的小胶质细胞和星形胶质细胞引发的神经炎症，可能会促进疾病进展和症状表现。本研究旨在量化亨廷顿舞蹈症死后患者中扣带回皮质中突变型亨廷顿蛋白的密度以及神经炎症性胶质细胞变化，并确定两者是否与情绪、运动或混合症状的表现相关。
采用游离免疫组化法量化1C2免疫标记密度，作为突变型亨廷顿蛋白的指示性标志物，以及星形胶质细胞（EAAT2、Cx43和GFAP）和小胶质细胞（Iba1和HLA - DP/DQ/DR）活化的蛋白和形态学标志物。使用相关分析探究小胶质细胞活化水平、突变型亨廷顿蛋白负荷与病例特征之间的关系。
我们报告了以情绪症状为主的亨廷顿舞蹈症病例中扣带回皮质活化小胶质细胞数量和形态的改变。在所有亨廷顿舞蹈症病例的中扣带回中均观察到活化小胶质细胞比例增加，且与1C2负荷呈正相关。在伴有情绪症状的患者中扣带回皮质观察到星形胶质细胞谷氨酸转运体EAAT2的改变。
本研究呈现了亨廷顿舞蹈症中扣带回皮质中小胶质细胞和星形胶质细胞的病理变化，这些变化与情绪症状表现一致。这些发现进一步加深了对亨廷顿舞蹈症神经炎症的理解，这是开发针对炎症的治疗方法的必要步骤。《神经病学纪事》2023年；94:895 - 910。
