Shahim Pashtun, AlQahtani Abdullah, Kokkinis Angela D, Kazmi Narjis, Ezuma-Ngwu Marie, Misra Jahan, Harmison George, Benoit Nicole, Jones Melina, Howe Elizabeth, Schindler Alice B, Joe Galen O, Grunseich Christopher
Neurogenetics Branch, National Institutes of Neurological Disorders and Stroke, NIH, 35 Convent Drive, Bethesda, MD 20814, USA.
Department of Neurology, MedStar Georgetown University Hospital, Washington, DC 20007, USA.
Brain Commun. 2025 Jul 30;7(4):fcaf275. doi: 10.1093/braincomms/fcaf275. eCollection 2025.
Spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis 4 (ALS4) are two forms of motor neuron disease characterized by clinically slow disease progression. Based on the current limited human studies, the contribution of central nervous neurodegeneration to these diseases and the rate of clinical progression is unclear. Neuronal proteins glial fibrillary acidic protein (GFAP), neurofilament light (NfL) chain, or Total-tau measured in either cerebrospinal fluid or blood could serve as sensitive markers of neurodegeneration. We studied 56 adult participants (32 SBMA, 7 ALS4, and 17 controls) who were enrolled at the National Institutes of Health, of whom 22 (10 SBMA, 7 ALS4, and 5 controls) underwent paired CSF and serum sampling, and of whom 6 participants were assessed longitudinally up to 24 months from initial visit. An additional 7 controls completed CSF sampling only. CSF GFAP, NfL chain, and Total-tau correlated with corresponding levels in serum ( = 0.74, = 0.47, and = 0.70, respectively). CSF GFAP was increased in patients with SBMA (median, 8840 pg/mL, interquartile range (IQR) 5780-10489) as compared to controls (median, 5315 pg/mL, IQR 1822-6657; = 0.029) but not compared with ALS4 (median, 5015 pg/mL, IQR 3172-9803; = 0.31). Patients with SBMA had increased concentrations of CSF NfL chain (median, 719 pg/mL, IQR 483-773) as compared to ALS4 (median, 307 pg/mL, IQR 187-629; = 0.034) or controls (median, 395 pg/mL, IQR 307-497; = 0.024). In contrast, serum concentrations of either biomarker did not differ significantly between SBMA, ALS4, or controls. Higher CSF GFAP and NfL chain levels were associated with lower SBMA Functional Rating Scale scores ( = -0.49 and = -0.42, respectively). Over the course of 24 months, the average change in SBMA Functional Rating Scale was -0.83 points, while the changes in CSF GFAP and NfL chain were progressive (increased 1.4-fold and 1.3-fold, respectively). Our data suggest that SBMA patients have increased concentrations of CSF GFAP and NfL chain as compared to ALS4 and controls, and higher levels of these biomarkers are associated with disease severity. Importantly, these results indicate that SBMA is associated with progressive neurodegeneration and that either CSF GFAP or NfL chain may be useful for patient stratification and monitoring treatment effects in clinical trials.
脊髓延髓肌肉萎缩症（SBMA）和肌萎缩侧索硬化症4型（ALS4）是运动神经元疾病的两种形式，其临床特征为疾病进展缓慢。基于目前有限的人体研究，中枢神经退行性变对这些疾病的影响以及临床进展速度尚不清楚。在脑脊液或血液中检测到的神经元蛋白胶质纤维酸性蛋白（GFAP）、神经丝轻链（NfL）或总tau蛋白可作为神经退行性变的敏感标志物。我们研究了56名成年参与者（32例SBMA、7例ALS4和17名对照），他们均在美国国立卫生研究院登记入组，其中22名（10例SBMA、7例ALS4和5名对照）接受了脑脊液和血清配对采样，6名参与者从初次就诊起接受了长达24个月的纵向评估。另外7名对照仅完成了脑脊液采样。脑脊液GFAP、NfL链和总tau蛋白与血清中的相应水平相关（分别为r = 0.74、r = 0.47和r = 0.70）。与对照组（中位数为5315 pg/mL，四分位间距（IQR）为1822 - 6657；P = 0.029）相比，SBMA患者的脑脊液GFAP升高（中位数为8840 pg/mL，IQR为5780 - 10489），但与ALS4患者（中位数为5015 pg/mL，IQR为3172 - 9803；P = 0.31）相比无差异。与ALS4患者（中位数为307 pg/mL，IQR为187 - 629；P = 0.034）或对照组（中位数为395 pg/mL，IQR为307 - 497；P = 0.024）相比，SBMA患者脑脊液NfL链浓度升高（中位数为719 pg/mL，IQR为483 - 773）。相比之下，SBMA、ALS4或对照组之间这两种生物标志物的血清浓度无显著差异。脑脊液GFAP和NfL链水平较高与较低的SBMA功能评定量表评分相关（分别为r = -0.49和r = -0.42）。在24个月的过程中，SBMA功能评定量表的平均变化为-0.83分，而脑脊液GFAP和NfL链的变化是渐进性的（分别增加了1.4倍和1.3倍）。我们的数据表明，与ALS4和对照组相比，SBMA患者脑脊液GFAP和NfL链浓度升高，这些生物标志物的较高水平与疾病严重程度相关。重要的是，这些结果表明SBMA与进行性神经退行性变相关，脑脊液GFAP或NfL链可能有助于临床试验中的患者分层和监测治疗效果。
