van Gool Raquel, Cay Mariesa, Ren Boyu, Brodeur Kailey, Golden Emma, Goodlett Benjamin, Yang Edward, Reilly Tom, Hastings Caroline, Berry-Kravis Elizabeth M, Lee Pui Y, Di Biase Maria, Cropley Vanessa, Pantelis Christos, Velakoulis Dennis, Shinn Ann K, Al-Hertani Walla, Walterfang Mark, Upadhyay Jaymin
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurology, Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, Limburg, the Netherlands.
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Brain Behav Immun. 2025 Feb;124:376-384. doi: 10.1016/j.bbi.2024.12.024. Epub 2024 Dec 15.
Niemann-Pick Disease Type C (NPC) is an ultra-rare disorder characterized by progressive psychiatric and neurologic manifestations, with late infantile, juvenile, and adolescent/adult presentations. We examined morphological properties of the choroid plexus, a protective blood-cerebrospinal fluid barrier, in NPC, and their relationship with neurodegeneration, clinical status, and circulatory markers. This study also determined whether choroid plexus morphology differentiates between NPC and more prevalent illnesses, schizophrenia (SZ) and bipolar disorder (BD), which have overlapping psychiatric symptoms with adolescent and adult-onset NPC and are associated with misdiagnosis.
Patients with NPC were assessed using neuroimaging, clinical instruments, and plasma protein quantification focusing on inflammatory markers. Morphological properties (i.e., choroid plexus volumes) were compared between patients with NPC (n = 17), SZ (n = 20), BD (n = 24), and healthy controls (HCs, n = 106).
Choroid plexus enlargement (p < 0.05) and reduced thalamic volumes (p < 0.05) were observed in NPC patients versus HCs and SZ or BD patients. A logistic regression model with choroid plexus and thalamic volumes as predictors yielded high prediction accuracy for NPC vs. HCs, NPC vs. SZ, and NPC vs. BD (area under the receiver operating characteristics curve [AUROC] of 1). Choroid plexus volumes were negatively correlated with left (p = 0.009-0.012) and right (p = 0.007-0.025) thalamic volumes, left (r = -0.69, p = 0.003) and right (r = -0.71, p = 0.002) crus I of the cerebellum, and greater severity on the NPC-Suspicion Index psychiatric subscale (ρ = 0.72, p = 0.042). Targeted protein expression quantification revealed differential expression of TGFA, HLA-DRA, TNFSF12, EGF, INFG, and IL-18 in NPC patients vs. HCs (p < 0.05), with higher choroid plexus volumes correlating with IL-18 levels (ρ = 0.71, p = 0.047).
The choroid plexus may play a critical role in NPC neuropathogenesis and serve as a novel biomarker for monitoring neurodegenerative and inflammatory processes in NPC.
C型尼曼-匹克病（NPC）是一种极为罕见的疾病，其特征为进行性精神和神经学表现，有晚发性婴儿型、青少年型以及青少年/成人型等表现形式。我们研究了NPC中脉络丛（一种保护性血脑屏障）的形态学特性，及其与神经退行性变、临床状态和循环标志物的关系。本研究还确定了脉络丛形态是否能区分NPC与更为常见的疾病——精神分裂症（SZ）和双相情感障碍（BD），这两种疾病与青少年及成人发病的NPC有重叠的精神症状，且易导致误诊。
使用神经影像学、临床工具以及聚焦于炎症标志物的血浆蛋白定量分析对NPC患者进行评估。比较了NPC患者（n = 17）、SZ患者（n = 20）、BD患者（n = 24）和健康对照者（HCs，n = 106）的形态学特性（即脉络丛体积）。
与HCs以及SZ或BD患者相比，NPC患者出现脉络丛增大（p < 0.05）和丘脑体积减小（p < 0.05）。以脉络丛和丘脑体积作为预测指标的逻辑回归模型对NPC与HCs、NPC与SZ以及NPC与BD的区分具有较高的预测准确性（受试者工作特征曲线下面积[AUROC]为1）。脉络丛体积与左侧（p = 0.009 - 0.012）和右侧（p = 0.007 - 0.025）丘脑体积、左侧（r = -0.69，p = 0.003）和右侧（r = -0.71，p = 0.002）小脑脚I以及NPC-怀疑指数精神亚量表上更严重的症状呈负相关（ρ = 0.72，p = 0.042）。靶向蛋白表达定量分析显示，与HCs相比，NPC患者中TGFA、HLA-DRA、TNFSF12、EGF、INFG和IL-18存在差异表达（p < 0.05），脉络丛体积越大，与IL-18水平越高相关（ρ = 0.71，p = 0.047）。
脉络丛可能在NPC神经发病机制中起关键作用，并可作为监测NPC神经退行性变和炎症过程的新型生物标志物。
