Journal of Neurodevelopmental Disorders ( IF 4.1 ) Pub Date : 2019-12-16 , DOI: 10.1186/s11689-019-9299-4 Heather Cody Hazlett 1 , Vittorio Gallo 2
Following in the footsteps of the first JND special issue in 2018, highlighting the work of the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers (IDDRCs), this year again showcases the work of the IDDRCs and honors the distinguished career of Dr. Jean de Vellis, world-renowned scientist in the study of white matter pathophysiology and long-standing director of the UCLA IDDRC. As eloquently described in the dedication [1] accompanying this special section of the Journal, Jean de Vellis devoted his life’s work to examining glia biology and the importance of these neural cells in the brain. In this issue, we present cutting-edge, clinical and pre-clinical research and reviews by IDDRC investigators as a fitting tribute to the memory of our colleague.
Much of the promise in studying white matter comes from the potential this neural structure has for developing new treatments. In a review of both mouse models and clinical work [2], the novel approach of targeting glia cells to treat seizures in Tuberous Sclerosis Complex (TSC) may prove to be a successful treatment for these patients. Investigators at the Harvard-Boston Children’s IDDRC have demonstrated reduced white matter integrity in key fiber bundles may help to identify those individuals with TSC who also present with an autism spectrum disorder [3]. These investigators propose that widespread neuropathology of white matter may underlie the presence of autism in TSC. Similar findings of white matter abnormalities have been reported in autism spectrum disorder (ASD). Work at the UC Davis IDDRC suggests that white matter microstructure develops differently in young children with ASD, and in particular sex may play an important role in modulating the ASD neuroanatomical phenotype [4].
In addition to investigations of white matter morphology, a key aspect of thinking about novel treatments has come from thinking about inflammation and the negative impact this may have on neurodevelopment. Investigators at the Children’s Hospital of Philadelphia IDDRC present exciting work demonstrating that inflammation caused by Th2 cytokines during early brain development can be rescued with the application of IL-4 antibody treatment in the newborn rat [5]. This work highlights the importance of the immune system and impact on white matter development. This mechanism may play a role in injury and disorders that damage myelin, such as premature brain injury and cerebral palsy. In Alexander disease, a rare leukodystrophy resulting from demyelination, it is the accumulation of proteins that may first signify white matter abnormalities. The potential to design treatments targeting the accumulations of glial fibrillary acidic proteins (GFAP) is the focus of a review [6] by the investigators at the Waisman IDDRC, who are working to identify the toxicity of GFAP in these patients. Thinking more broadly about leukodystrophies, the team at the Kennedy Krieger IDDRC have sought to characterize a group of patients with a similar etiology [7]. Patients with mt-aaRS mutations have similar neurophenotypes, specifically observable abnormalities in white matter tracts on MRI.
As may be evident by work focusing on these neurodevelopmental disorders, a key benefit of approaching treatment stems from an ability to change developmental trajectories by acting early through specific interventions. In a comprehensive study examining motor neurons in a Down syndrome mouse model (Ts65Dn), the investigators demonstrated clear changes in the spinal white matter composition across the lifespan [8]. This work highlights the fluctuations in cellular properties, depending on developmental stage, which may help inform potential treatment target windows. The prospect of using white matter properties as a biomarker is further explored in a review of literature informed by ongoing work in the field of autism and related neurogenetic disorders such as fragile X syndrome [9]. A study of language disorder suggests where the field could be headed, where white matter biomarkers could be used to help monitor treatment effectiveness. Investigators at the Vanderbilt IDDRC found an important white matter tract known to be associated with language development, the inferior longitudinal fasciculus (ILF), showed differences in language outcomes [10].
The articles included in this special issue highlight the advances made in understanding white matter in neurodevelopmental disorders that investigators across the IDDRCs strive to tackle daily. By approaching these questions from both clinical (human) and basic neuroscience perspectives, both sides gain knowledge and move forward to the goal of better interventions. We hope that the work showcased in this special issue underscores the promise for developing targeted treatments in neurodevelopmental disorders that comes from these investigations. Many of the IDDRCs contain researchers influenced and inspired by the groundbreaking work Jean de Vellis began. We hope that this special issue also serves to honor his legacy to the field.
Not applicable.
- 1.
Bookheimer SY, and Kornblum HI. In Memory of Jean de Vellis (1935-2018). J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9298-5.
- 2.
Wong M. The role of glia in epilepsy, intellectual disability, and other neurodevelopmental disorders in tuberous sclerosis complex. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9289-6.
- 3.
Prohl AK, Scherrer B, Tomas-Fernandez X, Davis PE, Filip-Dhima R, Prabhu SP, et al. Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9293-x.
- 4.
Andrews DS, Lee JK, Solomon M, Rogers SJ, Amaral DG, Nordahl CW. A diffusion-weighted imaging tract-based spatial statistics study of autism spectrum disorder in preschool-aged children. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9291-z.
- 5.
Zanno AE, Romer MA, Fox L, Golden T, Santos LJ, Simmons RA, Grinspan JB. Reducing Th2 inflammation through neutralizing IL-4 antibody rescues myelination in IUGR rat brain. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9297-6.
- 6.
Messing A. Refining the concept of GFAP toxicity in Alexander disease. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9290-0.
- 7.
Fine AS, Nemeth CL, Kaufman ML, Fatemi A. Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9292-y.
- 8.
Aziz NM, Klein JA, Brady MR, Olmos-Serrano JL, Gallo V, Haydar TF. Spatiotemporal development of spinal neuronal and glial populations in the Ts65Dn mouse model of Down syndrome. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9294-9.
- 9.
Swanson MR, Hazlett HC. White matter as a monitoring biomarker for neurodevelopmental disorder intervention studies. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9295-8.
- 10.
Del Tufo SN, Earle FS, Cutting LE. The impact of expressive language development and the left inferior longitudinal fasciculus on listening and reading comprehension. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9296-7.
The authors wish to thank Drs. Susan Bookheimer and Harley Kornblum for writing the dedication to Jean de Vellis, and we thank Dr. Joseph Piven for suggesting this special issue.
Funding
The authors declare that they did not receive any funding for this editorial.
Affiliations
- Department of Psychiatry, School of Medicine, UNC-Chapel Hill and Carolina Institute for Developmental Disabilities, Chapel Hill, NC, USA
- Heather Cody Hazlett
- Center for Neuroscience Research, Children’s National Research Institute, Children’s National Hospital, Washington, DC, USA
- Vittorio Gallo
- Search for Heather Cody Hazlett in:
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Contributions
Both authors contributed equally to writing the editorial and read and approved the manuscript.
Corresponding author
Correspondence to Heather Cody Hazlett.
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Cite this article
Hazlett, H.C., Gallo, V. White matter and neurodevelopmental disorders: honoring Jean De Vellis through the work of the NICHD-funded intellectual and developmental disabilities research centers. J Neurodevelop Disord 11, 38 (2019) doi:10.1186/s11689-019-9299-4
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中文翻译：
白质和神经发育障碍：通过NICHD资助的智力和发育障碍研究中心的工作，向让·德·维利斯致敬。
继2018年首届JND专刊的脚步，着重强调了Eunice Kennedy Shriver智力与发育障碍研究中心（IDDRC）的工作之后，今年再次展示了IDDRC的工作，并表彰了Jean de博士的杰出职业Vellis是研究白质病理生理学的世界著名科学家，也是UCLA IDDRC的长期负责人。正如《华尔街日报》这一特殊部分随附的专着[ 1 ]中雄辩地描述的那样，让·德·维利斯（Jean de Vellis）一生致力于研究神经胶质生物学以及这些神经细胞在大脑中的重要性。在本期中，我们将提供IDDRC研究人员的前沿，临床和临床前研究与评论，以对我们同事的记忆表示敬意。
研究白质的许多希望来自这种神经结构在开发新疗法方面的潜力。在对小鼠模型和临床工作的回顾中[ 2 ]，靶向神经胶质细胞治疗结节性硬化症（TSC）癫痫发作的新方法可能证明对这些患者是成功的治疗方法。哈佛大学波士顿儿童国际研究中心的研究人员表明，关键纤维束中白质完整性的降低可能有助于识别那些患有自闭症谱系障碍的TSC患者[ 3]。这些研究人员提出，广泛的白质神经病理学可能是TSC中自闭症存在的基础。自闭症谱系障碍（ASD）中也有类似的白质异常发现报道。加州大学戴维斯分校IDDRC的工作表明，ASD幼儿的白质微观结构发育不同，特别是性别可能在调节ASD神经解剖表型中起重要作用[ 4 ]。
除了对白质的形态进行研究外，对新疗法的思考的一个关键方面还来自对炎症及其对神经发育可能产生的负面影响的思考。费城儿童医院IDDRC的研究人员进行了激动人心的工作，表明在新生大鼠中应用IL-4抗体可以挽救早期大脑发育过程中由Th2细胞因子引起的炎症[ 5]。这项工作突出了免疫系统的重要性及其对白质发育的影响。此机制可能在损害髓磷脂的损伤和疾病中发挥作用，例如过早的脑损伤和脑瘫。在亚历山大病中，这是由脱髓鞘引起的罕见的白细胞营养不良，蛋白质的积累可能首先表示白质异常。Waisman IDDRC的研究人员正在研究针对胶质纤维酸性蛋白（GFAP）积累的设计治疗方法的潜力[ 6 ]，他们正在努力确定GFAP在这些患者中的毒性。肯尼迪·克里格（Kennedy Krieger）IDDRC小组更广泛地考虑白细胞营养障碍，试图对一组病因相似的患者进行特征分析[ 7]。mt-aaRS突变的患者具有相似的神经表型，特别是在MRI上可观察到的白质道异常。
正如专注于这些神经发育障碍的工作所证明的那样，接近治疗的主要好处来自通过早期采取特定干预措施来改变发育轨迹的能力。在一项检查唐氏综合症小鼠模型（Ts65Dn）中运动神经元的综合研究中，研究人员证明了整个寿命过程中脊髓白质组成的明显变化[ 8 ]。这项工作强调了细胞特性的波动，取决于发育阶段，这可能有助于告知潜在的治疗目标窗口。在自闭症和相关的神经遗传性疾病（如脆性X综合征）领域正在进行的工作为文献提供的文献综述中，进一步探讨了将白质特性用作生物标记物的前景[ 9]。一项对语言障碍的研究表明，该领域可能走向何方，白质生物标志物可用于帮助监测治疗效果。范德比尔特IDDRC的研究人员发现了一个重要的白质束，与语言发展有关，下纵筋膜（ILF）表现出语言结果的差异[ 10 ]。
本期特刊中的文章重点介绍了在神经发育障碍中了解白质方面的进步，各个IDDRC的研究人员每天都在努力解决这些问题。通过从临床（人类）和基本神经科学的角度解决这些问题，双方都将获得知识，并朝着更好的干预目标迈进。我们希望本期特刊中的工作强调这些研究为开发针对神经发育障碍的靶向治疗方法的希望。许多IDDRC的研究人员都受让·德·维利斯（Jean de Vellis）开始的开创性工作的影响和启发。我们希望这个特刊也有助于纪念他在该领域的遗产。
不适用。
- 1。
Bookheimer SY和Kornblum HI。纪念Jean de Vellis（1935-2018）。神经发育紊乱杂志。2019年https://doi.org/10.1186/s11689-019-9298-5。
- 2。
Wong M.神经胶质在结节性硬化症中的癫痫，智力障碍和其他神经发育障碍中的作用。神经发育紊乱杂志。2019.https ： //doi.org/10.1186/s11689-019-9289-6 。
- 3。
Prohl AK，Scherrer B，Tomas-Fernandez X，Davis PE，Filip-Dhima R，Prabhu SP等。在患有自闭症谱系障碍的结节性硬化症复杂患者中，早期白质发育异常。神经发育紊乱杂志。2019年https://doi.org/10.1186/s11689-019-9293-x。
- 4，
Andrews DS，Lee JK，Solomon M，Rogers SJ，Amaral DG，Nordahl CW。基于扩散加权成像道的学龄前儿童自闭症谱系障碍的空间统计研究。神经发育紊乱杂志。2019年https://doi.org/10.1186/s11689-019-9291-z。
- 5，
Zanno AE，Romer MA，Fox L，Golden T，Santos LJ，Simmons RA，Grinspan JB。通过中和IL-4抗体减少Th2炎症，可以挽救IUGR大鼠大脑的髓鞘形成。神经发育紊乱杂志。2019.https ： //doi.org/10.1186/s11689-019-9297-6 。
- 6，
混乱A.完善GFAP在亚历山大病中的毒性概念。神经发育紊乱杂志。2019.https ： //doi.org/10.1186/s11689-019-9290-0 。
- 7。
精细AS，Nemeth CL，Kaufman ML，Fatemi A.线粒体氨酰基-tRNA合成酶疾病：一组新出现的髓鞘发育疾病。神经发育紊乱杂志。2019年https://doi.org/10.1186/s11689-019-9292-y。
- 8。
Aziz NM，Klein JA，Brady MR，Olmos-Serrano JL，Gallo V，Haydar TF。唐氏综合征的Ts65Dn小鼠模型中脊神经和胶质细胞群体的时空发育。神经发育紊乱杂志。2019.https ： //doi.org/10.1186/s11689-019-9294-9 。
- 9。
斯旺森MR，哈兹莱特HC。白质作为神经发育障碍干预研究的监测生物标志物。神经发育紊乱杂志。2019.https ： //doi.org/10.1186/s11689-019-9295-8 。
- 10。
Del Tufo SN，Earle FS，Cutting LE。表达性语言发展和左下纵筋膜对听力和阅读理解的影响。神经发育紊乱杂志。2019.https ： //doi.org/10.1186/s11689-019-9296-7 。
作者要感谢Drs。苏珊·布克海默（Susan Bookheimer）和哈雷·科恩布鲁姆（Harley Kornblum）为让·德·维利斯（Jean de Vellis）写了献词，我们感谢约瑟夫·皮文（Joseph Piven）博士提出了这个特别问题。
资金
作者声明，他们没有获得此社论的任何资金。
隶属关系
- 美国北卡罗来纳州教堂山，UNC教堂山和卡罗来纳州发育障碍研究所医学院精神病学系
- 希瑟·科迪·哈兹莱特（Heather Cody Hazlett）
- 美国华盛顿特区儿童国家医院儿童国家研究所神经科学研究中心
- 维托里奥·加洛（Vittorio Gallo）
会费
两位作者在撰写社论，阅读和批准手稿方面均做出了同等贡献。
通讯作者
对应于希瑟·科迪·哈兹莱特。
道德规范的批准和参与同意
不适用。
同意发表
不适用。
利益争夺
作者宣称他们没有竞争利益。
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引用本文
Hazlett，HC，Gallo，V.白质和神经发育障碍：通过NICHD资助的智力和发育障碍研究中心的工作，向Jean De Vellis致敬。ĴNeurodevelop Disord 11， 38（2019）DOI：10.1186 / s11689-019-9299-4
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