Department of Neurology, Yale School of Medicine, Yale University, 15 York Street, PO Box 208018, New Haven, CT, 06520-8018, USA.
Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, USA.
Acta Neuropathol. 2019 Nov;138(5):859-876. doi: 10.1007/s00401-019-02043-7. Epub 2019 Jul 17.
Several morphological changes, centered in/around Purkinje cells (PCs), have been identified in the cerebellum of essential tremor (ET) patients. These changes have not been contextualized within a broader degenerative disease spectrum, limiting their interpretability. To address this, we compared the severity and patterning of degenerative changes within the cerebellar cortex in patients with ET, other neurodegenerative disorders of the cerebellum (spinocerebellar ataxias (SCAs), multiple system atrophy (MSA)], and other disorders that may involve the cerebellum [Parkinson's disease (PD), dystonia]. Using a postmortem series of 156 brains [50 ET, 23 SCA (6 SCA3; 17 SCA 1, 2 or 6), 15 MSA, 29 PD, 14 dystonia, 25 controls], we generated data on 37 quantitative morphologic metrics, which were grouped into 8 broad categories: (1) PC loss, (2) heterotopic PCs, (3) PC dendritic changes, (4) PC axonal changes (torpedoes), (5) PC axonal changes (other than torpedoes), (6) PC axonal changes (torpedo-associated), (7) basket cell axonal hypertrophy, (8) climbing fiber-PC synaptic changes. Our analyses used z scored raw data for each metric across all diagnoses (5772 total data items). Principal component analysis revealed that diagnostic groups were not uniform with respect to cerebellar pathology. Dystonia and PD each differed from controls in only 2/37 metrics, whereas ET differed in 21, SCA3 in 8, MSA in 19, and SCA1/2/6 in 26 metrics. Comparing ET with primary disorders of cerebellar degeneration (i.e., SCAs), we observed a spectrum of changes reflecting differences of degree, being generally mild in ET and SCA3 and more severe in SCA1/2/6. Comparative analyses across morphologic categories demonstrated differences in relative expression, defining distinctive patterns of changes in these groups. Thus, the degree of cerebellar degeneration in ET aligns it with a milder end in the spectrum of cerebellar degenerative disorders, and a somewhat distinctive signature of degenerative changes marks each of these disorders.
在原发性震颤（essential tremor，ET）患者的小脑内，已经发现了几个以浦肯野细胞（Purkinje cells，PCs）为中心/周围的形态学变化。这些变化在更广泛的退行性疾病谱中尚未得到具体说明，限制了它们的可解释性。为了解决这个问题，我们比较了 ET 患者、小脑退行性疾病（脊髓小脑共济失调（spinocerebellar ataxias，SCAs）、多系统萎缩（multiple system atrophy，MSA））、其他可能涉及小脑的疾病[帕金森病（Parkinson's disease，PD）、肌张力障碍]的小脑皮质内退行性变化的严重程度和模式。我们使用了一组 156 例大脑的死后系列[50 例 ET、23 例 SCA（6 例 SCA3、17 例 SCA1、2 或 6）、15 例 MSA、29 例 PD、14 例肌张力障碍、25 例对照]，生成了 37 个定量形态学指标的数据，这些指标分为 8 个大类：（1）PC 丢失，（2）异位 PC，（3）PC 树突变化，（4）PC 轴突变化（鱼雷），（5）PC 轴突变化（非鱼雷），（6）PC 轴突变化（与鱼雷相关），（7）篮状细胞轴突肥大，（8）攀附纤维-PC 突触变化。我们的分析使用了每个指标的 z 分数原始数据，这些数据横跨所有诊断（5772 个总数据项）。主成分分析显示，诊断组在小脑病理方面并不一致。肌张力障碍和 PD 与对照组的差异仅在 2/37 个指标上，而 ET 在 21 个指标上、SCA3 在 8 个指标上、MSA 在 19 个指标上、SCA1/2/6 在 26 个指标上。将 ET 与小脑退行性变的主要疾病（即 SCAs）进行比较，我们观察到一系列反映程度差异的变化，在 ET 和 SCA3 中通常较为轻微，而在 SCA1/2/6 中则较为严重。对形态学分类的比较分析表明，相对表达的差异定义了这些组中变化的独特模式。因此，ET 的小脑退行性变程度使其与小脑退行性疾病谱的较轻度末端相一致，并且每种疾病的退行性变化都有一个独特的特征。
