Olfactory dysfunction is common in Parkinson’s disease and is an early symptom, but its pathogenesis remains poorly understood. Hindering progress in our mechanistic understanding of olfactory dysfunction in Parkinson’s disease is the paucity of literature about the human olfactory bulb, both from normal and Parkinson’s disease cases. Qualitatively it is well established that the neat arrangement of the glomerular array seen in the mouse olfactory bulb is missing in humans. But rigorous quantitative approaches to describe and compare the thousands of glomeruli in the human olfactory bulb are not available. Here we report a quantitative approach to describe the glomerular component of the human olfactory bulb, and its application to draw statistical comparisons between olfactory bulbs from normal and Parkinson’s disease cases. We subjected horizontal 10 µm sections of olfactory bulbs from six normal and five Parkinson’s disease cases to fluorescence immunohistochemistry with antibodies against vesicular glutamate transporter-2 and neural cell adhesion molecule. We scanned the immunostained sections with a fluorescence slide scanner, segmented the glomeruli, and generated 3D reconstructions of whole olfactory bulbs. We document the occurrence of atypical glomerular morphologies and glomerular-like structures deep in the olfactory bulb, both in normal and Parkinson’s disease cases. We define a novel and objective parameter: the global glomerular voxel volume, which is the total volume of all voxels that are classified immunohistochemically as glomerular. We find that the global glomerular voxel volume in Parkinson’s disease cases is half that of normal cases. The distribution of glomerular voxels along the dorsal-ventral dimension of the olfactory bulb in these series of horizontal sections is significantly altered in Parkinson’s disease cases: whereas most glomerular voxels reside within the ventral half of olfactory bulbs from normal cases, glomerular voxels are more evenly spread among the ventral and dorsal halves of olfactory bulbs from Parkinson’s disease cases. These quantitative whole-olfactory bulb analyses indicate a predominantly ventral deficit in the glomerular component in Parkinson’s disease, consistent with the olfactory vector hypothesis for the pathogenesis of this neurodegenerative disease. The distribution of serine 129-phosphorylated α-synuclein immunoreactive voxels correlates with that of glomerular voxels. The higher the serine 129-phosphorylated α-synuclein load of an olfactory bulb from a Parkinson’s disease case, the lower the global glomerular voxel volume. Our rigorous quantitative approach to the whole olfactory bulb will help understand the anatomy and histology of the normal human olfactory bulb and its pathological alterations in Parkinson’s disease.

中文翻译：

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整个嗅球重建显示帕金森氏病的腹侧肾小球缺陷

嗅觉功能障碍在帕金森氏病中很常见，是一种早期症状，但其发病机理仍知之甚少。从正常和帕金森氏病的病例来看，关于人类嗅球的文献匮乏，阻碍了我们对帕金森氏病嗅觉功能障碍的机械理解的进展。定性地确定，人类嗅球中看不到的肾小球阵列的整齐排列。但是，无法使用严格的定量方法来描述和比较人类嗅球中的数千个肾小球。在这里，我们报告一种定量的方法来描述人类嗅球的肾小球成分，并将其应用于绘制正常人和帕金森氏病患者的嗅球之间的统计比较。我们对来自6例正常和5例帕金森氏病病例的嗅球的水平10 µm切片进行了荧光免疫组织化学分析，并采用了针对囊泡谷氨酸转运蛋白2和神经细胞粘附分子的抗体。我们用荧光玻片扫描仪扫描了免疫染色的切片，分割了肾小球，并生成了整个嗅球的3D重建。我们记录了在正常和帕金森氏病病例中嗅球深处的非典型肾小球形态和肾小球样结构的发生。我们定义了一个新颖而客观的参数：总体肾小球体素体积，它是被免疫组织化学分类为肾小球的所有体素的总体积。我们发现帕金森氏病病例的总体肾小球体素体积是正常病例的一半。在帕金森氏病病例中，在这一系列水平截面中，沿嗅球的背腹面尺寸的肾小球体素分布发生了明显变化：而正常情况下，大多数肾小球体素位于嗅球的腹侧一半内，而肾小球体素分布更均匀在帕金森氏病病例的嗅球的腹侧和背侧之间扩散。这些定量的全嗅球分析表明，帕金森氏病的肾小球成分主要存在腹侧缺损，这与该神经退行性疾病发病机理的嗅觉载体假说相符。丝氨酸129-磷酸化α-突触核蛋白免疫反应性体素的分布与肾小球体素的分布相关。帕金森氏病病例中嗅球的丝氨酸129-磷酸化α-突触核蛋白负荷越高，总体肾小球体素量越低。我们对整个嗅球的严格定量方法将有助于了解正常人嗅球的解剖结构，组织学及其在帕金森氏病中的病理变化。