Gutierrez Ashley, Corey-Bloom Jody, Thomas Elizabeth A, Desplats Paula
Department of Neuroscience, School of Medicine, University of California, San Diego, San Diego, CA, United States.
Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, United States.
Front Mol Neurosci. 2020 Jan 23;12:335. doi: 10.3389/fnmol.2019.00335. eCollection 2019.
Huntington's disease (HD) is an autosomal-dominant neurodegenerative movement disorder that presents with prominent cognitive and psychiatric dysfunction. Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of HD, as well as other neurodegenerative and psychiatric disorders, and epigenetic alterations in the complex BDNF promoter have been associated with its deregulation in pathological conditions. BDNF has gained increased attention as a potential biomarker of disease; but currently, the conflicting results from measurements of BDNF in different biofluids difficult the assessment of its utility as a biomarker for HD. Here, we measured BDNF protein levels in plasma ( = 85) and saliva ( = 81) samples from premanifest and manifest HD patients and normal controls using ELISA assays. We further examined DNA methylation levels of promoter IV using DNA derived from whole blood of HD patients and healthy controls ( = 40) using pyrosequencing. BDNF protein levels were not significantly different in plasma samples across diagnostic groups. Plasma BDNF was significantly correlated with age in control subjects but not in HD patients, nor were significant gender effects observed. Similar to plasma, salivary BDNF was correlated with age only in control subjects, with no gender effects observed. Importantly, we detected significantly lower levels of salivary BDNF in premanifest and manifest HD patients compared to control subjects, with lower BDNF levels being observed in premanifest patients within a predicted 10 years to disease onset. Salivary and plasma BDNF levels were not significantly correlated with one another, suggesting different origins. DNA methylation at four out of the 12 CpG sites studied in promoter IV were significantly altered in HD patients in comparison to controls. Interestingly, methylation at three of these CpG sites was inversely correlated to the Hospital Anxiety and Depression Scale (HADS) scores. promoter methylation was not correlated with motor or cognitive scores in HD patients, and was not associated with sex or age in neither disease nor control groups. Conclusion: Our studies show that BDNF protein levels are decreased in saliva; and promoter methylation increased in blood in HD subjects when compared to controls. These findings suggest that salivary BDNF measures may represent an early marker of disease onset and DNA methylation at the promoter IV, could represent a biomarker of psychiatric symptoms in HD patients.
亨廷顿舞蹈病（HD）是一种常染色体显性神经退行性运动障碍疾病，伴有明显的认知和精神功能障碍。脑源性神经营养因子（BDNF）在HD的病理生理学以及其他神经退行性和精神疾病中发挥重要作用，复杂的BDNF启动子中的表观遗传改变与其在病理状态下的失调有关。BDNF作为一种潜在的疾病生物标志物受到了越来越多的关注；但目前，在不同生物流体中测量BDNF得到的相互矛盾的结果，使得评估其作为HD生物标志物的效用变得困难。在此，我们使用酶联免疫吸附测定（ELISA）法测量了临床前和临床期HD患者及正常对照者血浆（n = 85）和唾液（n = 81）样本中的BDNF蛋白水平。我们还使用焦磷酸测序法，检测了HD患者和健康对照者（n = 40）全血DNA中启动子IV的DNA甲基化水平。不同诊断组的血浆样本中BDNF蛋白水平无显著差异。血浆BDNF仅在对照者中与年龄显著相关，在HD患者中则不然，也未观察到显著的性别效应。与血浆类似，唾液BDNF也仅在对照者中与年龄相关，未观察到性别效应。重要的是，我们检测到临床前和临床期HD患者的唾液BDNF水平显著低于对照者，在预计发病前10年内的临床前患者中观察到更低的BDNF水平。唾液和血浆BDNF水平彼此之间无显著相关性，表明其来源不同。与对照者相比，HD患者中研究的12个CpG位点中的4个位点的DNA甲基化发生了显著改变。有趣的是，其中3个CpG位点的甲基化与医院焦虑抑郁量表（HADS）评分呈负相关。启动子甲基化与HD患者的运动或认知评分无关，在疾病组和对照组中均与性别或年龄无关。结论：我们的研究表明，与对照者相比，HD患者唾液中的BDNF蛋白水平降低，血液中启动子甲基化增加。这些发现表明，唾液BDNF测量可能代表疾病发作的早期标志物，而启动子IV的DNA甲基化可能代表HD患者精神症状的生物标志物。
