# 神经元坏死（Neuron Necrosis）

- 器官 / 系统：脑 / 神经系统（brain / nervous-system）
- NTP 数据编号：ntp-0389
- 规范 URL：https://www.labsmart.cn/ntp/brain-neuron-necrosis.html
- 中文图谱总页锚点：https://www.labsmart.cn/ntp-atlas.html#brain-neuron-necrosis
- 原始出处：https://ntp.niehs.nih.gov/atlas/nnl/nervous-system/brain/Neuron-Necrosis
- 授权：美国联邦政府作品，公有领域；引用请标注 NTP Nonneoplastic Lesion Atlas
- 适用说明：仅供科研使用，不用于临床诊断

## 一句话结论
这组脑坏死图像旨在使病理学家熟悉神经元细胞死亡的形态学变化，涵盖从急性坏死形态到坏死晚期形态（晚期有时以矿化为显著特征）。

## 病变描述（中文）
这组脑坏死图像旨在使病理学家熟悉神经元细胞死亡的形态学变化，涵盖从急性坏死形态到坏死晚期形态（晚期有时以矿化为显著特征）。Figure 1 展示了早期神经元坏死最常被识别的证据。其特征包括神经元胞质皱缩和强烈的嗜酸性，同时伴有细胞核皱缩和嗜碱性（黑箭头）。神经元坏死通常由缺血或任何损害神经元能量代谢的因素引起。在这种情况下，该变化被称为急性嗜酸性坏死、“急性代谢停滞”、“急性缺血性改变”，或者更通俗地称为“红死”神经元。神经元坏死应通过筛查坏死的各个阶段和/或真正坏死神经元附近是否存在炎性细胞或其他病变，与深染神经元伪影（见 Brain - Introduction）仔细鉴别。在本例中，这些坏死神经元的外观可与相邻浦肯野细胞（红箭头）更正常的形态形成对比。此外，脑组织损伤的重要佐证表现为下方神经毡的水肿性空泡化改变，以及该区域内胶质细胞坏死浓缩（核固缩）的细胞核（箭头）。Figure 2 展示了紫外显微镜图像，显示 Fluoro-Jade B 对坏死海马锥体细胞（蓝箭头）呈阳性绿色荧光经验性染色。使用 Fluoro-Jade 系列经验性神经退行性染色剂对于快速识别即使少量的退行性神经元极具价值，即使在低倍镜下也是如此。尽管已进行了大量研究，但该染色剂对坏死神经元具有这种亲和力的实际机制仍知之甚少。受累细胞的荧光可突出显示损伤的神经元，但使用苏木精和伊红（H&E）也很重要，以识别相关的神经变化，佐证荧光发现并确定病变的时间顺序。Fluoro-Jade C 是 Fluoro-Jade 染色剂系列中最新的一种，已发现其可染色所有退行性神经元，无论具体损伤或细胞死亡机制如何。Fluoro-Jade C 表现出最大的信号背景比以及最高的分辨率，因此对退行性神经元具有最大的对比度和亲和力。该染色剂还可识别退行性远端树突、轴突和终末。该染料抗褪色，并与大多数组织学方法兼容。使用胶质纤维酸性蛋白免疫荧光、Fluoro-Jade C 和 4'',6-二脒基-2-苯基吲哚（DAPI）可分别同时标记活化的星形胶质细胞、退行性神经元和细胞核。在判读时需谨慎，因为 Fluoro-Jade 也会轻度染色伪影性嗜碱性神经元（PB Little，个人观察）。注意正常的红细胞（Figure 2，白箭头）在血管中也呈阳性染色。在 Figure 3 中，梨状皮质内可见坏死神经元（箭头）邻近更正常的神经元。注意有些神经元特别淡染，几乎不可见。该图像展示了较晚期的神经元坏死，由急性嗜酸性神经元坏死（见 Figure 1）演变而来。随着时间顺序的进行性退行性改变，胞质嗜酸性和细胞核嗜碱性出现明显褪色。褪色之后是原神经元轮廓模糊，称为“幽灵形态”，随后任何可观察到的退行性结构消失。邻近区域存在更正常的神经元有助于识别这些形式的退行性细胞，从而将这些变化与自溶区分开来。根据神经毒性作用后观察时间的不同，退行性神经元形态变化的时间顺序连续谱可能较为明显。有些变化，如急性嗜酸性坏死，很容易识别；然而，病理学家必须了解 Figure 3 所示的更细微、常被忽视的变化，即神经元淡染的“幽灵”轮廓。在 Figure 4 中，嗜碱性坏死神经元未经历 Figure 3 所示的较快溶解过程。注意神经元膜细微的点状铁化（营养不良性矿化）（箭头）。退行性神经元原位保留，其表面早期有矿物质积聚（铁化）。该图像展示了多个细小的点状矿物质聚集，其中一些可能代表树突终末扣结的矿化。Figure 5 展示了 CA2 区海马锥体细胞的神经元坏死。注意神经元的铁化（营养不良性矿化）比 Figure 4 所示更显著、更晚期（箭头）。神经元形态的某些方面仍可见，但随着营养不良性矿化过程的进展，核周体更完全地被矿物质灌注。小神经元（如嗅球和齿状回的颗粒细胞以及小脑内颗粒细胞层）的坏死，在 H&E 染色上以嗜碱性核固缩为特征。在 Figure 6 中，小脑内颗粒细胞层的颗粒细胞具有这种嗜碱性核固缩外观，是该类型神经元急性坏死的典型表现（箭头）。尽管存在区域性颗粒细胞坏死，许多浦肯野细胞仍保持正常外观。为便于比较，Figure 7 是小脑颗粒细胞坏死的高倍放大图像。注意核固缩的细胞核（箭头）和相邻的正常细胞核（箭头）。将 Figure 6、Figure 7 所示的颗粒细胞坏死与自溶中所见的形态学变化区分开来很重要。在自溶中，虽然颗粒细胞核皱缩，但组织中还有其他自溶指标，如广泛的组织淡染和神经毡空泡化。相邻正常细胞与坏死细胞之间的显著对比有助于将自溶与神经组织的真实病变区分开来。坏死组织（包括脑细胞）的矿化随时间发生。当矿物质沉积物结壳于可识别的细胞或其树突终末扣结上时，病理学家必须识别脑内退行性细胞的这一时间顺序特征，并将其与可能混淆的酵母或真菌菌丝区分开来。

## 诊断与分级建议（NTP 共识，中文）
在 NTP 研究中，所有形式的神经元坏死均诊断为神经元坏死，并记录病变、解剖亚部位位置和严重程度。严重程度基于受累神经元的数量。当凋亡与坏死同时存在时，在 NTP 研究中诊断记录为坏死。当存在其他并发病变如炎症时，通常诊断严重程度最高的病变。如果严重程度需要，其他并发病变可单独诊断。

## 英文原文 · Comment
This panel of brain necrosis images is intended to familiarize pathologists with the morphologic variations of neuronal cell death ranging from the morphology of acute necrosis to that of late stages of necrosis in which mineralization sometimes is prominent. Figure 1 depicts the most commonly recognized evidence of early neuronal necrosis. Features include neuronal cytoplasmic shrinkage and intense eosinophilia accompanied by shrinkage and basophilia of the nucleus (black arrow). Neuronal necrosis is commonly the result of ischemia, or any influence that impairs neuronal energy metabolism. In this case, the change has been referred to as acute eosinophilic necrosis, “acute metabolic arrest,” “acute ischemic change,” or, more colloquially, “red dead” neurons. Neuronal necrosis should be carefully differentiated from dark neuron artifact (see Brain - Introduction ) by screening for various stages of necrosis and/or the presence of inflammatory cells or other lesions in the vicinity of the truly necrotic neurons. In this case, the appearance of these necrotic neurons can be contrasted with the more normal morphology of an adjacent Purkinje cell (red arrow). Further, important substantiating evidence of brain tissue injury is represented by the edematous vacuolar change of the subjacent neuropil and the presence of necrotic condensed (pyknotic) nuclei of glial cells (arrowhead) within that region. Figure 2 depicts an ultraviolet microscopy image showing the positive green fluorescent, empiric staining by Fluoro-Jade B of necrotic hippocampal pyramidal cells (blue arrow). Use of the Fluoro-Jade family of empiric neurodegenerative stains is extremely valuable in quickly identifying even small numbers of degenerative neurons, even at low magnification. Although given much investigation, the actual mechanism whereby the stain has this affinity for necrotic neurons is still poorly understood. Fluorescence of affected cells highlights the injured neurons, but the use of hematoxylin and eosin is also important to identify associated neural changes corroborating the fluorescent findings and defining the chronology of the lesions. Fluoro-Jade C is the most recent of the Fluoro-Jade stains and has been found to stain all degenerating neurons, regardless of specific insult or mechanism of cell death. Fluoro-Jade C exhibits the greatest signal-to-background ratio, as well as the highest resolution, therefore giving maximal contrast and affinity for degenerating neurons. The stain also identifies degenerated distal dendrites, axons, and terminals. The dye is resistant to fading and is compatible with most histologic methods. Activated astrocytes, degenerating neurons, and cell nuclei can be labeled together using glial fibrillary acidic protein immunofluorescence, Fluoro-Jade C, and 4'',6-diamidino-2-phenylindole (DAPI), respectively. Some care needs to be taken in interpretation, since Fluoro-Jade also lightly stains artifactual basophilic neurons (PB Little, personal observations). Note that normal red blood cells ( Figure 2 , white arrow) also stain positive in the blood vessels. In Figure 3 , necrotic neurons (arrows) are evident adjacent to more normal neurons in the piriform cortex. Note that some are particularly faded and almost invisible. This image depicts neuronal necrosis at a later stage, evolving from that seen with acute eosinophilic neuronal necrosis (see Figure 1 ). With chronologic progressive degenerative change, there is noticeable fading of the eosinophilia of the cytoplasm and basophilia of the nucleus. The fading is followed by vague outlines of the former neurons, referred to as “ghost forms,” followed by the loss of any observable degenerate structure. The presence of more normal neurons in adjacent areas assists with the recognition of these forms of degenerate cells differentiating the changes from that of autolysis. Depending on the time of observation after neurotoxic effects, a chronologic continuum of degenerative neuronal morphologic changes may be apparent. Some, such as acute eosinophilic necrosis, are readily apparent; however, the pathologist must be aware of the more subtle, often overlooked, changes shown in Figure 3 consisting of faded “ghost” profiles of neurons. In Figure 4 , basophilic necrotic neurons have escaped the more rapid process of dissolution shown in Figure 3 . Note the subtle punctate ferrugination (dystrophic mineralization) of neuronal membrane (arrows). The degenerate neurons remain in situ and have early accumulation of mineral (ferrugination) at their surfaces. The image depicts multiple small punctate aggregations of mineral, some of which may represent mineralization of dendritic terminal boutons. Figure 5 depicts neuronal necrosis of hippocampal pyramidal cells in the CA2 region. Note that there is more prominent, advanced ferrugination (dystrophic mineralization) of neurons (arrows) than shown in Figure 4 . Some aspects of neuronal morphology are still apparent, but the perikaryon is more completely infused with mineral as the dystrophic mineralization process proceeds. Necrosis of small neurons, such as the granule cells of the olfactory bulb and dentate gyrus and the internal granule cell layer of the cerebellum, is characterized by basophilic nuclear pyknosis with hematoxylin and eosin staining. In Figure 6 , granule cells of the cerebellar internal granule cell layer have this pyknotic basophilic appearance typical of acute necrosis for this type of neuron (arrow). Many Purkinje cells retain a normal appearance in spite of the regional granule cell necrosis. For comparison, Figure 7 is a higher magnification of the cerebellar granule necrosis. Note the pyknotic nuclei (arrows) and adjacent normal nuclei (arrowheads). It is important to differentiate granule cell necrosis shown in Figure 6 and Figure 7 from the morphologic change seen in autolysis. In autolysis, while granule cell nuclei shrink, there are other indicators of autolysis in the tissue, such as widespread tissue fading and neuropil vacuolation. The marked contrast between adjacent normal and necrotic cells is helpful in differentiation of autolysis from genuine lesions of nervous tissue. Mineralization of necrotic tissue, including brain cells, occurs over time. Where mineral deposits encrust a recognizable cell or its dendritic terminal boutons, it is important for the pathologist to recognize this chronologic feature of degenerated cells in brain and to differentiate it from yeast or mycotic hyphae with which it may be confused.

## 英文原文 · Recommendation
Neuronal necrosis is diagnosed for all forms of neuronal necrosis in NTP studies, and the lesion, anatomic subsite location, and severity are also documented. Severity is based on the number of affected neurons. When apoptosis is noted in conjunction with necrosis, the diagnosis is recorded as necrosis in NTP studies. In the presence of other concurrent lesions such as inflammation, lesions with the most severity are typically diagnosed. Other concurrent lesions may be diagnosed separately, if warranted by the severity.

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