Eaton-Peabody Laboratories, Massachusetts Eye and Ear, Boston, Massachusetts 02114
Department of Otolaryngology-Head & Neck Surgery, Harvard Medical School, Boston, Massachusetts 02115.
J Neurosci. 2023 Dec 13;43(50):8801-8811. doi: 10.1523/JNEUROSCI.1138-23.2023.
Several lines of evidence have suggested that steeply sloping audiometric losses are caused by hair cell degeneration, while flat audiometric losses are caused by strial atrophy, but this concept has never been rigorously tested in human specimens. Here, we systematically compare audiograms and cochlear histopathology in 160 human cases from the archival collection of celloidin-embedded temporal bones at the Massachusetts Eye and Ear. The dataset included 106 cases from a prior study of normal-aging ears, and an additional 54 cases selected by combing the database for flat audiograms. Audiogram shapes were classified algorithmically into five groups according to the relation between flatness (i.e., SD of hearing levels across all frequencies) and low-frequency pure-tone average (i.e., mean at 0.25, 0.5, and 1.0 kHz). Outer and inner hair cell losses, neural degeneration, and strial atrophy were all quantified as a function of cochlear location in each case. Results showed that strial atrophy was worse in the apical than the basal half of the cochlea and was worse in females than in males. The degree of strial atrophy was uncorrelated with audiogram flatness. Apical atrophy was correlated with low-frequency thresholds and basal atrophy with high-frequency thresholds, and the former correlation was higher. However, a multivariable regression with all histopathological measures as predictors and audiometric thresholds as the outcome showed that strial atrophy was a significant predictor of threshold shift only in the low-frequency region, and, even there, the contribution of outer hair cell damage was larger. Cochlear pathology can only be assessed postmortem; thus, human cochlear histopathology is critical to our understanding of the mechanisms of hearing loss. Dogma holds that relative damage to sensory cells, which transduce mechanical vibration into electrical signals, versus the stria vascularis, the cellular battery that powers transduction, can be inferred by the shape of the audiogram, that is, down-sloping (hair cell damage) versus flat (strial atrophy). Here we quantified hair cell and strial atrophy in 160 human specimens to show that it is the degree of low-frequency hearing loss, rather than the audiogram slope, that predicts strial atrophy. Results are critical to the design of clinical trials for hearing-loss therapeutics, as current drugs target only hair cell, not strial, regeneration.
有几条证据表明，陡降型听力损失是由毛细胞变性引起的，而平斜率听力损失是由纹状萎缩引起的，但这一概念从未在人类标本中得到严格验证。在这里，我们系统地比较了马萨诸塞眼耳档案馆中细胞素包埋颞骨存档标本的 160 个人类病例的听力图和耳蜗组织病理学。该数据集包括先前对正常衰老耳朵进行研究的 106 例病例，以及通过数据库搜索平斜率听力图选择的另外 54 例病例。根据平斜率（即所有频率听力水平的标准差）与低频纯音平均（即 0.25、0.5 和 1.0 kHz 处的平均值）之间的关系，通过算法将听力图形状分为五类。在外毛细胞和内毛细胞损失、神经变性和纹状萎缩的情况下，在每个病例中都根据耳蜗位置进行了量化。结果表明，在耳蜗的顶部比底部一半的区域中，纹状萎缩更严重，在女性中比男性中更严重。纹状萎缩的程度与听力图的平斜率无关。顶部萎缩与低频阈值相关，底部萎缩与高频阈值相关，前者相关性更高。然而，一个包含所有组织病理学测量作为预测因子和听力阈值作为结果的多变量回归显示，只有在低频区域，纹状萎缩才是阈值变化的显著预测因子，即使在那里，外毛细胞损伤的贡献也更大。耳蜗病理学只能在死后进行评估；因此，人类耳蜗组织病理学对于我们理解听力损失的机制至关重要。传统观念认为，可以根据听力图的形状，即下斜率（感觉细胞损伤）与平斜率（纹状萎缩），推断出感觉细胞（将机械振动转化为电信号）与纹状血管（为转导提供动力的细胞电池）的相对损伤。在这里，我们量化了 160 个人类标本中的毛细胞和纹状萎缩程度，表明是低频听力损失的程度，而不是听力图的斜率，预测了纹状萎缩。结果对于听力损失治疗的临床试验设计至关重要，因为目前的药物仅针对毛细胞，而不针对纹状血管的再生。
