Altered CSF Albumin Quotient Links Peripheral Inflammation and Brain Damage in MS

(A) Comparison between patients with and without increased Q_Alb of frequencies of Th2-A (CCR6- CCR4+ CRTH2−) in CM CD28⁺ CD27-, EM CD28⁺ CD27-, EM CD28-, and TEMRA CD28⁺ CD27⁺ CD4⁺ CSF-infiltrating T cells. (B) Comparison between patients with IgG(loc) (>10%) and without IgG(loc) (<10%) of frequencies of EM CD28⁺ CD27- CD4⁺ CSF-infiltrating cells with a Th2-A (CCR6- CCR4+ CRTH2−) functional phenotype. Correlation between these frequencies and IgG(loc) expressed as %. (C) Comparison between patients with and without increased Q_Alb of frequencies of Th1 (CCR6- CCR4- CRTH2−) cells in EM CD28- CD4⁺ CSF-infiltrating T cells and amount of IFNγ expressed as pg/mL present in the CSF of 30 patients as well as correlation between the amount of IFNγ and Q_Alb. (D) Comparison of NF-L and CHI3L1 intrathecal concentration between patients with and without increased Q_Alb. (E) Correlation between the intrathecal concentration of these 2 biomarkers and Q_Alb and also between themselves. Graphs (A–C) represent subcohort 1 of 79 patients with MS, and frequencies have been obtained by ex vivo immunophenotyping, and (E–D) represent the main cohort of 121 patients with MS. Each dot in the graphs corresponds to 1 patient, and bars show the mean. Patients with increased Q_Alb are shown in red. T test t test for normally distributed variables and U test (Mann-Whitney) for non-normally distributed variables was used to compared patients. Linear correlation was tested using Pearson for normally distributed and Spearman r for non-normally distributed variables. Statistical significance (*p < 0.05, **p < 0.01) is shown.

(A) Heat map of the 10 statistically most significant altered lipid species between patients with MS with and without increased Q_Alb. The abundance of the lipid species is qualitatively represented by color intensity for each of the 36 patients with MS (subcohort 2). Mean, SD, and p values of the group comparisons are shown. (B) Correlations between Q_Alb and the intrathecal concentration for 6 of the identified lipid species. Linear correlation between variables was tested using Pearson correlation, and p values are shown. (C) Ratios between mean CSF concentration of lipid species in patients with MS and the concentration in plasma from a reference control cohort with 24 healthy controls. Marked in red are the 4 SM and 5 PC species that were significantly more abundant in patients with MS with increased Q_Alb. Ig = immunoglobulin; QAlb = serum albumin quotient.

Comparison, between patients with (red) and without (black) increased Q_Alb, of number of CD8⁺ CM CD28⁺ Th1 (CCR6- CCR4- CRTH2-) and Th1* (CCR6+ CCR4- CRTH2-), CD4⁺ CM CD28⁺ CD27⁺ Th1 (CCR6- CCR4- CRTH2-) and Th1* (CCR6+ CCR4- CRTH2-), CD4⁺ EM CD28⁺ CD27⁺ Th1 (CCR6- CCR4- CRTH2-) and Th1* (CCR6+ CCR4- CRTH2-), and CD4⁺ TEMRA CD28⁺ Th1 (CCR6- CCR4- CRTH2-) and Th1* (CCR6+ CCR4- CRTH2-) in patients with and without increased Q_Alb, as well as the correlation between these cell counts and Q_Alb. All graphs represent subcohort 1 consisting of 79 patients with MS. Each dot in the graph corresponds to a single patient, and bars show the mean. T test t test for normally distributed variables and U test (Mann-Whitney) for non-normally distributed variables was used to compared patients. Linear correlation was tested using Pearson for normally distributed and Spearman r for non-normally distributed variables. Statistical significance (*p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001) is shown. Statistical significance (*p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001) is shown. QAlb = serum albumin quotient.

(A and B) Linear representations of Q_Alb minus Q_Norm values (B) and number of CSF-infiltrating cells per μL (C) over time in a cohort of 33 patients with MS from which CSF samples at different time points were available. X-axis represents time in months, and Y-axis represents Q_Alb-Q_Norm and number of CSF-infiltrating cells per μL. The number of patients in each graph is indicated. The dotted line represents the limit for normal values (0 for QAlb-QNorm and 4 for number of CSF-infiltrating cells). Patients who maintain high levels over time are shown in red, those who maintain low levels in black, and those who change the levels in gray. Fine lines and circles correspond to untreated patients. Patients treated between lumbar punctures are shown with bold lines and squares (dimethyl fumarate), triangles (natalizumab), and diamonds (fingolimod). QAlb = serum albumin quotient; QNorm = normal QAlb.

(A and B) QAlb minus QNorm has been used like in patients with MS to differentiate controls with (in red) and without (in black) increased QAlb. Comparison between controls (ONIND [n = 40] (A) and OIND [n = 21] (B)) with and without increased QAlb of IgA and IgG quotient, CSF-infiltrating cells, and frequency of TH2-A (CCR6- CCR4+ CRTH2-) and TH2-B (CCR6- CCR4+ CRTH2+) in CD4⁺ CM CD28⁺ CD27- and in CD4⁺ EM CD28⁺ CD27- CSF-infiltrating cells. In all graphs, each dot corresponds to 1 patient, and bars show the mean. T test t test for normally distributed variables and U test (Mann-Whitney) for non-normally distributed variables was used to compared patients. Statistical significance (*p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001) is shown. Statistical significance (*p < 0.05, **p < 0.01, and ****p < 0.0001) is shown. QAlb = serum albumin quotient; QNorm = normal QAlb.