Neurology Section, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom.
Ann Clin Transl Neurol. 2021 Mar;8(3):534-547. doi: 10.1002/acn3.51298. Epub 2021 Jan 23.
In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS-specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post-mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf-L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 naïve MS patients and in 32 controls at time of diagnosis.
PVALB gene expression was downregulated in MS (fold change = 3.7 ± 1.2, P < 0.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, P < 0.001). Likewise, post-mortem CSF-PVALB levels were higher in MS compared to controls (fold change = 196 ± 36, P < 0.001) and correlated with decreased PVALB+ cell density (r = -0.64, P < 0.001) and increased MHC-II+ microglia density (r = 0.74, P < 0.01), as well as with early age of onset (r = -0.69, P < 0.05), shorter time to wheelchair (r = -0.49, P < 0.05) and early age of death (r = -0.65, P < 0.01). Increased CSF-PVALB levels were detected in MS patients at diagnosis compared to controls (P = 0.002). Significant correlation was found between CSF-PVALB levels and cortical lesion number on MRI (R = 0.28, P = 0.006) and global cortical thickness (R = -0.46, P < 0.001), better than Nf-L levels. CSF-PVALB levels increased in MS patients with severe cognitive impairment (mean ± SEM:25.2 ± 7.5 ng/mL) compared to both cognitively normal (10.9 ± 2.4, P = 0.049) and mild cognitive impaired (10.1 ± 2.9, P = 0.024) patients.
CSF-PVALB levels reflect loss of cortical interneurons in MS patients with more severe disease course and might represent an early, new MS-specific biomarker of cortical neurodegeneration, atrophy, and cognitive decline.
为了验证钙结合蛋白（PVALB），一种特定表达于 GABA 能中间神经元的蛋白，是否可以作为灰质神经退行性变的 MS 特异性标志物，我们对 40 例尸检进行了运动皮层的神经病理学/分子学分析。有/无脑膜炎症的进展性 MS 病例，以及 10 例对照病例，结合脑脊液（CSF）评估。在 110 例初诊 MS 患者和 32 例对照患者中，同时进行 CSF PVALB 和神经丝（Nf-L）水平分析，并结合物理/认知/3T MRI 评估。结果：MS 患者的 PVALB 基因表达下调（倍数变化= 3.7±1.2，P<0.001 与对照组相比），反映了皮质病变中 PVALB+细胞密度的显著减少，在脑膜炎症较高的 MS 患者中更为明显（51.8，P<0.001）。同样，死后 CSF-PVALB 水平在 MS 患者中高于对照组（倍数变化= 196±36，P<0.001），与 PVALB+细胞密度降低（r=-0.64，P<0.001）和 MHC-II+小胶质细胞密度增加（r=0.74，P<0.01）以及发病年龄较早（r=-0.69，P<0.05）、从轮椅时间较短（r=-0.49，P<0.05）和早逝（r=-0.65，P<0.01）相关。与对照组相比，MS 患者在诊断时即可检测到 CSF-PVALB 水平升高（P=0.002）。CSF-PVALB 水平与 MRI 上皮质病变数量（R=0.28，P=0.006）和皮质总厚度（R=-0.46，P<0.001）显著相关，优于 Nf-L 水平。与认知正常（10.9±2.4，P=0.049）和轻度认知障碍（10.1±2.9，P=0.024）患者相比，严重认知障碍（平均±SEM：25.2±7.5ng/mL）的 MS 患者 CSF-PVALB 水平升高。结论：CSF-PVALB 水平反映了 MS 患者更严重疾病过程中皮质中间神经元的丧失，可能代表皮质神经退行性变、萎缩和认知能力下降的早期、新的 MS 特异性生物标志物。
