Molecular correlates of sub-regional thalamic degeneration in multiple sclerosis

摘要 多发性硬化症(MS)是一种免疫介导的中枢神经系统(CNS)疾病 这涉及到白质和灰质的脱髓鞘和变性。深部灰质 像丘脑这样的结构在MS研究中受到了极大的关注，因为它们的早期 体积损失。丘脑远远不只是一个“中继站”；它组织着传入和传出 信息处理，它与多个区域的连接使其与疲劳和运动有关， MS患者的认知和感觉障碍丘脑萎缩是残疾的预测因素 和认知障碍在MS的所有病程中，以及临床转换的预测因子- 分离综合征进入多发性硬化症虽然丘脑萎缩在多发性硬化症建立，其确切的机制 潜在的丘脑退行性变没有得到很好的描述。我们已经组建了一支强大的团队 具有跨学科和互补专业知识的调查人员，以确定分子 多发性硬化症中丘脑变性的相关性最近的数据支持脱髓鞘的假设 丘脑以外，影响功能和解剖连接，可能驱动选择性 丘脑内的神经变性。初步结果确定了丘脑的三个区域：外侧 膝状核(LGN)、枕核(PV)和中央内侧核(CM)具有 优先的容量损失，以及b)与患者更大的神经功能障碍显著相关 对于进展性多发性硬化症，我们因此假设，某些丘脑亚区的优先体积损失 这些区域可能是由于其神经元/神经胶质细胞群体的选择性脆弱性。使用尸检核磁共振， 我们确定了一组死后多发性硬化症的大脑，这些大脑有轻度或严重的体积损失， 丘脑脱髓鞘。此外，我们还包括最近发现的一个新的MS组 无任何白质损害但类似的丘脑萎缩的患者(称为脊髓皮质多发性硬化症)。 因此，这个探索性提案的主要目标是生成、识别和验证分子 应用单细胞RNA测序(sc-RNA seq)检测多发性硬化症患者丘脑体积减少的模式。 拟议的研究将为目标1a)sc-rna序列；目标1b)空间使用特征良好的样本。 转录分析；以及目标1c)验证新的细胞团以研究分子 MS患者丘脑萎缩的潜在改变这些研究将揭示基因特征 与多发性硬化症患者易受攻击的丘脑区域相关，并导致体积减少。 本研究的圆满完成将为今后的研究向前迈出重要的一步 监测并最终预防多发性硬化症患者的丘脑萎缩和神经变性。

ABSTRACT Multiple sclerosis (MS) is an immune-mediated disease of the human central nervous system (CNS) that involves demyelination and degeneration of both white matter and gray matter. Deep grey-matter structures such as the thalamus have received significant attention in MS research due to their early volume loss. The thalamus is far more than just a “relay station”; organizing afferent and efferent information processing, its connectivity to multiple regions implicates it in fatigue as well as motor, cognitive, and sensory impairments in individuals with MS. Thalamic atrophy is a predictor of disability and cognitive impairment in all disease courses of MS, as well as a predictor for conversion of clinically- isolated syndrome into MS. While thalamic atrophy is established in MS, the exact mechanisms underlying thalamic degeneration are not well-characterized. We have assembled a strong team of investigators with interdisciplinary and complementary expertise in order to identify the molecular correlates of the thalamic degeneration in MS. Recent data support the hypothesis that demyelination outside the thalamus, affecting the functional and anatomic connections, may drive selective neurodegeneration within the thalamus. Preliminary results have identified three thalamic regions: lateral geniculate nucleus (LGN), pulvinar (PV) nucleus, and centro-medial (CM) nucleus as a) having preferential volume loss, and b) significantly correlating with greater neurological disability in patients with progressive MS. We therefore hypothesize that preferential volume loss of certain thalamic sub- regions may be due selective vulnerability of their neuronal/glial populations. Using postmortem MRI, we identified cohorts of postmortem MS brains with mild or severe volume loss and minimal demyelination in the thalamus. In addition, we also include a recently-identified novel group of MS patients (termed myelocortical MS) without any white-matter lesions, but comparable thalamic atrophy. The main goal of this exploratory proposal is therefore to generate, identify, and validate a molecular pattern representative of thalamic volume loss in MS using single-cell RNA sequencing (sc-RNA seq). The proposed study will use well-characterized samples for Aim 1a) sc-RNA seq; Aim 1b) spatial transcriptomic assays; and Aim 1c) validation of novel cell clusters to investigate the molecular alterations underlying thalamic atrophy in MS. These studies will reveal the genetic signatures associated with thalamic regions that are vulnerable and contribute to volume loss in MS patients. Successful completion of the current study will provide a significant step forward towards future research in monitoring and eventually preventing thalamic atrophy and neurodegeneration in MS patients.