Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, USA.
Department of Neurology, Oregon Health & Science University, Portland, OR, USA; Department of Veterans Affairs MS Center of Excellence-West, Portland, OR, USA.
Mult Scler Relat Disord. 2023 Jun;74:104675. doi: 10.1016/j.msard.2023.104675. Epub 2023 Mar 31.
Vascular disease risk factors (VDRF) such as hypertension, hyperlipidemia, obesity, diabetes and heart disease likely play a role in disease progression in people with multiple sclerosis (PwMS) (Marrie, Rudick et al. 2010). Studies exploring the mechanistic connection between vascular disease and MS disease progression are scant. We hypothesized that phosphate energy metabolism impairment in PwMS with VDRFs (VDRF+) will be greater compared to PwMS without VDRFs (VDRF-) and is related to increased brain atrophy in VDRF+. To test this hypothesis, we planned to study the differences in the high energy phosphate (HEP) metabolites in cerebral gray matter as assessed by P magnetic resonance spectroscopic imaging (MRSI) and MRI brain volumetric in the VDRF+ and VDRF- PwMS at four different timepoints over a 3 yearlong period using a 7T MR system. We present here the results from the cross-sectional evaluation of HEP metabolites and brain volumes. We also evaluated the differences in clinical impairment, blood metabolic biomarkers and quality of life in VDRF+ and VDRF- PwMS in this cohort.
Group differences in high energy phosphate metabolites were assessed from a volume of interest in the occipital region using linear mixed models. Brain parenchymal and white matter lesion volumes were determined from MR anatomic images. We present here the cross-sectional analysis of the baseline data collected as part of a longitudinal 3 yearlong study where we obtained baseline and subsequent 6-monthly clinical and laboratory data and annual 7T MRI volumetric and P MR spectroscopic imaging (MRSI) data on 52 PwMS with and without VDRF. Key clinical and laboratory outcomes included: body mass index (BMI), waist and thigh circumferences and disability [Expanded Disability Status Scale (EDSS)], safety (complete blood count with differential, complete metabolic), lipid panel including total cholesterol and HbA1C. We analyzed clinical and laboratory data for the group differences using student's t or χ2 test. We investigated relationship between phosphate metabolites and VDRF using mixed effect linear regression.
Complete MRI data were available for 29 VDRF+, age 56.3 (6.8) years [mean (SD)] (83% female), and 23 VDRF-, age 52.5 (7.5) years (57% female) individuals with MS. The mean value of normalized adenosine triphosphate (ATP) (calculated as the ratio of ATP to total phosphate signal in a voxel) was decreased by 4.5% (p < .05) in VDRF+ compared to VDRF- MS group. White matter lesion (WML) volume fraction in VDRF+ individuals {0.007 (0.007)} was more than doubled compared to VDRF- participants {0.003 (0.006), p= .02}.
We found significantly lower brain ATP and higher inorganic phosphate (Pi) in those PwMS with VDRFs compared to those without. ATP depletion may reflect mitochondrial dysfunction. Ongoing longitudinal data analysis from this study, not presented here, will evaluate the relationship of phosphate metabolites, brain atrophy and disease progression in PwMS with and without vascular disease.
血管疾病风险因素（VDRF），如高血压、高血脂、肥胖、糖尿病和心脏病，可能在多发性硬化症（MS）患者（PwMS）的疾病进展中起作用（Marrie，Rudick 等人，2010 年）。研究探索血管疾病与 MS 疾病进展之间的机制联系的研究很少。我们假设，患有 VDRF 的 PwMS（VDRF+）的磷酸盐能量代谢受损程度将高于没有 VDRF 的 PwMS（VDRF-），并且与 VDRF+中的脑萎缩增加有关。为了验证这一假设，我们计划在 3 年的时间内，使用 7T MR 系统，在 4 个不同时间点，通过 P 磁共振波谱成像（MRSI）和 MRI 脑容积研究，研究 VDRF+和 VDRF-PwMS 大脑灰质中高能磷酸盐（HEP）代谢物的差异。我们在此介绍 HEP 代谢物和脑容积的横截面评估结果。我们还评估了该队列中 VDRF+和 VDRF-PwMS 之间的临床受损情况、血液代谢生物标志物和生活质量差异。
使用线性混合模型从枕区的感兴趣区域评估高能磷酸盐代谢物的组间差异。脑实质和白质病变体积从 MR 解剖图像中确定。我们在此介绍作为一项为期 3 年的纵向研究的一部分收集的基线数据的横截面分析，我们在该研究中获得了基线和随后的 6 个月临床和实验室数据以及每年的 7T MRI 容积和 P MRSI 数据，共纳入了 52 名有和没有 VDRF 的 PwMS。主要临床和实验室结果包括：体重指数（BMI）、腰围和大腿围以及残疾[扩展残疾状态量表（EDSS）]、安全性（全血细胞计数和差异，全面代谢）、包括总胆固醇和 HbA1C 的血脂谱。我们使用学生 t 检验或 χ2 检验分析组间的临床和实验室数据。我们使用混合效应线性回归研究磷酸盐代谢物与 VDRF 之间的关系。
共有 29 名 VDRF+，年龄 56.3（6.8）岁[平均值（标准差）]（83%为女性）和 23 名 VDRF-，年龄 52.5（7.5）岁（57%为女性）的 MS 患者具有完整的 MRI 数据。与 VDRF- MS 组相比，VDRF+的归一化三磷酸腺苷（ATP）（计算为每个体素中 ATP 与总磷酸盐信号的比值）平均值降低了 4.5%（p<.05）。VDRF+个体的白质病变（WML）体积分数{0.007（0.007）}是 VDRF-参与者的两倍多{0.003（0.006），p=0.02}。
我们发现，与没有 VDRF 的患者相比，患有 VDRF 的 PwMS 大脑中的 ATP 明显较低，无机磷酸盐（Pi）较高。ATP 耗竭可能反映了线粒体功能障碍。本研究正在进行的纵向数据分析（此处未介绍）将评估有和没有血管疾病的 PwMS 中磷酸盐代谢物、脑萎缩和疾病进展之间的关系。
