Neurometabolite Mapping Highlights Elevated Myo-inositol Profiles within the Developing Brain in Down Syndrome
Neurometabolite Mapping Highlights Elevated Myo-inositol Profiles within the Developing Brain in Down Syndrome
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神经代谢图谱突显唐氏综合症大脑发育中肌醇谱的升高
DOI：
10.1101/2020.07.20.211805
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Patkee P
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文献类型：
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作者：
Patkee P
唐氏综合征（DS）或21三体的神经发育表型是可变的，包括广泛的认知障碍和早发性阿尔茨海默病（AD）的高风险。在DS中，脑内感兴趣的关键代谢物是肌醇（mIns）。NA+/mIns共转运蛋白位于人21号染色体上，在DS中过表达。在DS成人中，脑mIns升高先前与认知障碍相关，并被认为是进展为AD的风险标志物。然而，这是未知的，如果大脑mIns增加在development. This研究的目的是估计mIns浓度水平和关键的脑代谢产物[N-乙酰天冬氨酸（NAA），胆碱（Cho）和肌酸（Cr）]在发育中的大脑DS和年龄匹配的控制。我们对新生儿DS（n= 12）和年龄匹配的对照组（n= 26）在出生后（月经后36-45周）进行活体磁共振波谱（MRS）扫描。此外，我们使用质谱分析了早期（受孕后10-20周）DS（n= 14）和对照（n= 30）病例的离体胎脑组织样本，与年龄匹配的正常发育对照组相比，我们报告了DS新生儿基底神经节/丘脑中相对于[Cho]和[Cr]的体内[mIns]比值升高。甘氨酸浓度比[Gly]/[Cr]和[Cho]/[Cr]也出现升高。我们观察到DS的离体胎脑皮质组织中的[mIns]高于对照组。总之，早在受孕后10周，大脑中的mIns水平就明显升高，并且从月经后36周起就可以在体内测量。未来的工作将确定代谢物的这种早期差异是否与儿童期的认知结果有关，或者是否可作为早期干预的潜在治疗生物标志物。
The neurodevelopmental phenotype in Down Syndrome (DS), or Trisomy 21, is variable including a wide spectrum of cognitive impairment and a high risk of early-onset Alzheimer's disease (AD). A key metabolite of interest within the brain in DS is Myo-inositol (mIns). The NA+/mIns co-transporter is located on human chromosome 21 and is overexpressed in DS. In adults with DS, elevated brain mIns was previously associated with cognitive impairment and proposed as a risk marker for progression to AD. However, it is unknown if brain mIns is increased earlier in development.The aim of this study was to estimate mIns concentration levels and key brain metabolites [N-acetylaspartate (NAA), Choline (Cho) and Creatine (Cr)] in the developing brain in DS and aged-matched controls. We usedin vivomagnetic resonance spectroscopy (MRS) in neonates with DS (n= 12) and age-matched controls (n= 26) scanned just after birth (36–45 weeks postmenstrual age). Moreover, we used Mass Spectrometry in early (10–20 weeks post conception)ex vivofetal brain tissue samples from DS (n= 14) and control (n= 30) cases.Relative to [Cho] and [Cr], we report elevated ratios of [mIns]in vivoin the basal ganglia/thalamus, in neonates with DS, when compared to age-matched typically developing controls. Glycine concentration ratios [Gly]/[Cr] and [Cho]/[Cr] also appear elevated. We observed elevated [mIns] in theex vivofetal cortical brain tissue in DS compared with controls.In conclusion, a higher level of brain mIns was evident as early as 10 weeks post conception and was measurablein vivofrom 36 weeks post-menstrual age. Future work will determine if this early difference in metabolites is linked to cognitive outcomes in childhood or has utility as a potential treatment biomarker for early intervention.