Objective

To quantify changes in segmented brain volumes over 12 months in children with mucopolysaccharidosis types IIIA and IIIB (MPS IIIA and IIIB).

Methods

In order to establish suitable outcome measures for clinical trials, twenty-five children greater than 2 years of age were enrolled in a prospective natural history study of MPS IIIA and IIIB at Nationwide Children's Hospital. Data from sedated non-contrast brain 3 T MRIs and neuropsychological measures were reviewed from the baseline visit and at 12-month follow-up. No intervention beyond standard clinical care was provided. Age- and sex-matched controls were gathered from the National Institute of Mental Health Data Archive. Automated brain volume segmentation with longitudinal processing was performed using FreeSurfer.

Results

Of the 25 subjects enrolled with MPS III, 17 children (4 females, 13 males) completed at least one MRI with interpretable volumetric data. The ages ranged from 2.8 to 13.7 years old (average 7.2 years old) at enrollment, including 8 with MPS IIIA and 9 with MPS IIIB. At baseline, individuals with MPS III demonstrated reduced cerebral white matter and corpus callosum volumes, but greater volumes of the lateral ventricles, cerebellar cortex, and cerebellar white matter compared to controls. Among the 13 individuals with MPS III with two interpretable MRIs, there were annualized losses or plateaus in supratentorial brain tissue volumes (cerebral cortex −42.10 ± 18.52 cm³/year [mean ± SD], cerebral white matter −4.37 ± 11.82 cm³/year, subcortical gray matter −6.54 ± 3.63 cm³/year, corpus callosum −0.18 ± 0.62 cm³/yr) and in cerebellar cortex (−0.49 ± 12.57 cm³/year), with a compensatory increase in lateral ventricular volume (7.17 ± 6.79 cm³/year). Reductions in the cerebral cortex and subcortical gray matter were more striking in individuals younger than 8 years of age. Greater cerebral cortex volume was associated with higher fine and gross motor functioning on the Mullen Scales of Early Learning, while greater subcortical gray matter volume was associated with higher nonverbal functioning on the Leiter International Performance Scale. Larger cerebellar cortex was associated with higher receptive language performance on the Mullen, but greater cerebellar white matter correlated with worse adaptive functioning on the Vineland Adaptive Behavioral Scales and visual problem-solving on the Mullen.

Conclusions

Loss or plateauing of supratentorial brain tissue volumes may serve as longitudinal biomarkers of MPS III age-related disease progression compared to age-related growth in typically developing controls. Abnormally increased cerebellar white matter in MPS III, and its association with worse performance on neuropsychological measures, suggest the possibility of pathophysiological mechanisms distinct from neurodegeneration-associated atrophy that warrant further investigation.

中文翻译：

---

粘多糖贮积症 IIIA 和 IIIB 型儿童一年内纵向 MRI 脑容量变化

客观的

量化 IIIA 型和 IIIB 型粘多糖贮积症（MPS IIIA 和 IIIB）儿童 12 个月内分段脑容量的变化。

方法

为了为临床试验建立合适的结果衡量标准，25 名 2 岁以上的儿童参加了 Nationwide Children's Hospital 的 MPS IIIA 和 IIIB 前瞻性自然病程研究。从基线访问和 12 个月的随访中审查了镇静非对比脑 3 T MRI 和神经心理学测量的数据。没有提供超出标准临床护理的干预措施。年龄和性别匹配的对照来自美国国家心理健康研究所数据档案馆。使用 FreeSurfer 执行具有纵向处理的自动脑体积分割。

结果

在 MPS III 登记的 25 名受试者中，17 名儿童（4 名女性，13 名男性）完成了至少一项具有可解释体积数据的 MRI。入组年龄为2.8～13.7岁（平均7.2岁），其中MPS IIIA 8人，MPS IIIB 9人。在基线时，与对照组相比，患有 MPS III 的个体表现出大脑白质和胼胝体体积减少，但侧脑室、小脑皮质和小脑白质体积更大。在具有两个可解释 MRI 的 MPS III 的 13 名个体中，幕上脑组织体积（大脑皮层 -42.10 ± 18.52 cm ³ /年 [平均值 ± SD]，脑白质 -4.37 ± 11.82 cm ³ /年，皮层下灰质 -6.54 ± 3.63 cm ³/年，胼胝体 -0.18 ± 0.62 cm ³ /yr）和小脑皮层（-0.49 ± 12.57 cm ³ /年），侧脑室容积代偿性增加（7.17 ± 6.79 cm ^3）/年）。大脑皮层和皮层下灰质的减少在 8 岁以下的个体中更为显着。在马伦早期学习量表上，较大的大脑皮层体积与较高的精细和粗大运动功能相关，而在莱特国际表现量表上，较大的皮质下灰质体积与较高的非语言功能相关。较大的小脑皮层与马伦人更高的语言接受能力相关，但更大的小脑白质与 Vineland 适应性行为量表上较差的适应性功能和马伦人视觉问题解决能力相关。

结论

与典型发育对照的年龄相关生长相比，幕上脑组织体积的丢失或停滞可能作为 MPS III 年龄相关疾病进展的纵向生物标志物。MPS III 中小脑白质异常增加，及其与神经心理学测量表现较差的关联，表明与神经变性相关萎缩不同的病理生理机制的可能性，值得进一步研究。