PDF(Pubmed)
Abstract：
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children\'s Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS-derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS-derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ-estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep-related disorders and neurodegenerative conditions associated with glymphatic dysfunction.
摘要：
琥珀酸半醛脱氢酶缺乏症（SSADHD）是一种遗传的γ-氨基丁酸（GABA）分解代谢障碍。沿着淋巴血管周围间隙的脑废物清除取决于水通道蛋白4（AQP4）水通道，其功能被证明受GABA的影响。睡眠障碍与SSADHD和淋巴功能障碍独立相关。这项研究旨在确定SSADHD的高GABA能状态特征指标是否与淋巴功能障碍和睡眠障碍相符，并阐明GABA可能对淋巴系统的调节作用。该研究包括42名个体（21名SSADHD患者；21名健康对照），他们接受了脑MRI和磁共振波谱（MRS）评估淋巴功能障碍和皮质GABA，血浆GABA测量，和生物钟基因表达。SSADHD受试者回答了另一份儿童睡眠习惯问卷(CSHQ)。与对照组相比,SSADHD受试者的性别和年龄没有差异，但在半卵中心血管周围间隙增大的严重程度更高（p<0.001），基底神经节（p=0.01），和中脑（p=0.001），以及较高的MRS衍生的GABA/NAA峰（p<0.001）。在SSADHD小组中，glmphatic功能障碍的严重程度与较低的MRS衍生的GABA/NAA（p=0.04）和较低的血浆GABA（p=0.004）有关。此外,他们的淋巴淋巴功能障碍程度与CSHQ估计的睡眠障碍评分相关(R=5.18,p=0.03).在对照组中，EPVS负荷与年龄或大脑和血浆GABA值无关。GABA可能对类淋巴系统发挥的调节作用对睡眠相关疾病和与类淋巴功能障碍相关的神经退行性疾病具有治疗意义。
