From the Department of Neuroinflammation (B.S.S., N.A.J., F.D., J.S., F.P., D.P., A.D., D.M., C.A.M.G.W.-K., J.C.), Faculty of Brain Sciences, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology.
From the Department of Neuroinflammation (B.S.S., N.A.J., F.D., J.S., F.P., D.P., A.D., D.M., C.A.M.G.W.-K., J.C.), Faculty of Brain Sciences, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology
AJNR Am J Neuroradiol. 2020 Dec;41(12):2209-2218. doi: 10.3174/ajnr.A6809. Epub 2020 Nov 5.
The secondary progressive phase of multiple sclerosis is characterised by disability progression due to processes that lead to neurodegeneration. Surrogate markers such as those derived from MRI are beneficial in understanding the pathophysiology that drives disease progression and its relationship to clinical disability. We undertook a 1H-MRS imaging study in a large secondary progressive MS (SPMS) cohort, to examine whether metabolic markers of brain injury are associated with measures of disability, both physical and cognitive.
A cross-sectional analysis of individuals with secondary-progressive MS was performed in 119 participants. They underwent H-MR spectroscopy to obtain estimated concentrations and ratios to total Cr for total NAA, mIns, Glx, and total Cho in normal-appearing WM and GM. Clinical outcome measures chosen were the following: Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Nine-Hole Peg Test, Timed 25-foot Walk Test, and the Expanded Disability Status Scale. The relationship between these neurometabolites and clinical disability measures was initially examined using Spearman rank correlations. Significant associations were then further analyzed in multiple regression models adjusting for age, sex, disease duration, T2 lesion load, normalized brain volume, and occurrence of relapses in 2 years preceding study entry.
Significant associations, which were then confirmed by multiple linear regression, were found in normal-appearing WM for total NAA (tNAA)/total Cr (tCr) and the Nine-Hole Peg Test (ρ = 0.23; 95% CI, 0.06-0.40); tNAA and tNAA/tCr and the Paced Auditory Serial Addition Test (ρ = 0.21; 95% CI, 0.03-0.38) (ρ = 0.19; 95% CI, 0.01-0.36); mIns/tCr and the Paced Auditory Serial Addition Test, (ρ = -0.23; 95% CI, -0.39 to -0.05); and in GM for tCho and the Paced Auditory Serial Addition Test (ρ = -0.24; 95% CI, -0.40 to -0.06). No other GM or normal-appearing WM relationships were found with any metabolite, with associations found during initial correlation testing losing significance after multiple linear regression analysis.
This study suggests that metabolic markers of neuroaxonal integrity and astrogliosis in normal-appearing WM and membrane turnover in GM may act as markers of disability in secondary-progressive MS.
多发性硬化症的继发进展期以残疾进展为特征，其原因是导致神经退行性变的过程。磁共振成像（MRI）衍生的替代标志物有助于了解驱动疾病进展及其与临床残疾的关系的病理生理学。我们在一个大型继发进展型多发性硬化症（SPMS）队列中进行了 1H-MRS 成像研究，以检查脑损伤的代谢标志物是否与身体和认知方面的残疾测量值相关。
对 119 名继发进展型 MS 患者进行了横断面分析。他们接受了 H-MRS 光谱检查，以获得正常表现的 WM 和 GM 中总 NAA、mIns、Glx 和总 Cho 的估计浓度和与总 Cr 的比值。选择的临床结果测量指标如下：听觉连续加法测试、符号数字模态测试、九孔钉测试、定时 25 英尺步行测试和扩展残疾状态量表。最初使用 Spearman 等级相关检验检验这些神经代谢物与临床残疾测量值之间的关系。然后，在多变量回归模型中，根据年龄、性别、疾病持续时间、T2 病变负荷、正常化脑体积以及研究前 2 年内的复发情况，对有统计学意义的相关性进行了进一步分析。
在正常表现的 WM 中，总 NAA（tNAA）/总 Cr（tCr）和九孔钉测试（ρ=0.23；95%CI，0.06-0.40），tNAA 和 tNAA/tCr 和听觉连续加法测试（ρ=0.21；95%CI，0.03-0.38）（ρ=0.19；95%CI，0.01-0.36），mIns/tCr 和听觉连续加法测试（ρ=-0.23；95%CI，-0.39 至-0.05）；以及 GM 中的 tCho 和听觉连续加法测试（ρ=-0.24；95%CI，-0.40 至-0.06），存在显著相关性，经多变量线性回归分析后得到确认。在任何代谢物中，GM 中均未发现与任何代谢物相关的其他 GM 或正常表现 WM 关系，在初始相关性检验中发现的相关性在多变量线性回归分析后失去意义。
本研究表明，正常表现 WM 中的神经轴突完整性和星形胶质增生代谢标志物以及 GM 中的膜周转率可能是继发进展型多发性硬化症残疾的标志物。
