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Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease

Nature Medicine volume 27, pages 411–418 (2021)Cite this article

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Abstract

Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease (PD). However, there is no direct evidence in humans to support this role1,2,3,4,5. In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD.

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Fig. 1: Quantitative assessments of mLVs-SSS and mLVs-SS flow by DCE-MRI.
Fig. 2: Quantitative assessment of mLVs drainage by DCE-MRI of dcLNs.
Fig. 3: Impaired meningeal lymphatic drainage with strong meningeal inflammation and loss of meningeal lymphatic endothelial cells in α-syn PFF-injected mice.

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Data availability

Source data underlying all figures and tables are provided with this paper. To respect data protection and privacy of the participants, the remaining data, such as raw MRI images, are not publicly available. These data will be shared on request from qualified investigators for noncommercial research purposes within the limits of participants’ consent and are subject to institutional ethics committee approval and material transfer agreements. Requests will be handled by the corresponding author X.J.W. Source data are provided with this paper.

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Acknowledgements

X.-J.W. was supported by grants from the National Natural Science Foundation of China (no. 81873791, 81471307) and the Natural Science Foundation of Henan Province for Excellent Young Scholars (no. 202300410357). J.-F.T. was supported by grants from the National Natural Science Foundation of China (no. 81671267). B.-S.T. was supported by the National Key Plan for Scientific Research and Development of China (no. 2016YFC1306000). J.-Y.L. was supported by the Swedish Research Council (2019-01551). We thank all our collaborators at the First Affiliated Hospital of Zhengzhou University for their assistance with imaging examinations. Specially, we thank Y. Li for her excellent technical support and we also appreciate Z. Yang and L. Zhou’s assistance with image processing and Euni Wu’s efforts for language editing.

Author information

Author notes

  1. These authors contributed equally: Dan-Hao Xia, Han Liu, Hai-Yan Tian.

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Xue-Bing Ding, Xin-Xin Wang, Dan-Hao Xia, Han Liu, Hai-Yan Tian, Yu Fu, Yong-Kang Chen, Chi Qin, Jiu-Qi Wang, Zhi Xiang, Jun-Fang Teng & Xue-Jing Wang

  2. Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, China

    Xue-Bing Ding, Xin-Xin Wang, Dan-Hao Xia, Han Liu, Hai-Yan Tian, Yu Fu, Yong-Kang Chen, Chi Qin, Jiu-Qi Wang, Zhi Xiang, Jun-Fang Teng & Xue-Jing Wang

  3. National Centre for International Research in Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China

    Zhong-Xian Zhang

  4. Department of Radiation Therapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Qin-Chen Cao

  5. Henan Medical Association, Zhengzhou, China

    Wei Wang

  6. Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden

    Jia-Yi Li

  7. Institute of Health Sciences, China Medical University, Shenyang, China

    Jia-Yi Li

  8. Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, USA

    Erxi Wu

  9. Texas A & M University Colleges of Medicine and Pharmacy, College Station, TX, USA

    Erxi Wu

  10. Livestrong Cancer Institutes and Department of Oncology, Dell Medical School, the University of Texas at Austin, Austin, TX, USA

    Erxi Wu

  11. Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

    Bei-Sha Tang

  12. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

    Bei-Sha Tang

  13. Department of Neurology, Affiliated People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, China

    Ming-Ming Ma

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Contributions

X.-J.W. conceived and designed the experiments; X.-J.W. coordinated the whole project; X.-B.D., M.-M.M., J.-F.T., Y.F. and X.-X.W. were responsible for the initial assessment and diagnosing of patients; X.-B.D., X.-X.W., Y.F. and H.-Y.T. were responsible for assessing and documenting their patients’ health information. X.-X.W., Y.F., Y.-K.C. and Q.-C.C. performed image analysis. D.-H.X., C.Q., J.-Q.W., Z.X. and H.L. conducted modeling surgery and behavioral tests; D.-H.X., H.L., J.-Q.W. and Z.-X.Z. performed immunostaining; E.W., J.-Y.L., B.-S.T., W.W. and X.-B.D. provided statistical analysis and technical support; X.-J.W., X.-B.D., M.-M.M., X.-X.W. and D.-H.X. participated in final data analysis and interpretation; X.-J.W., D.-H.X., X.-X.W., H.L. and X.-B.D. carried out most of the writing with input from other authors. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Ming-Ming Ma, Jun-Fang Teng or Xue-Jing Wang.

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Extended data

Extended Data Fig. 1 CONSORT diagram.

Consolidated Standards of Reporting Trials flow diagram showing study participants screening, eligibility and inclusion.

Extended Data Fig. 2 Patients’ demographics and clinical characteristics.

Demographics and characteristics of DLB, CBD and VP groups who performed DCE-MRI of dcLNs. Mean (standard deviation) and N (%) were reported. Demographic factors and clinical characteristics were compared using chi-square test and two-sided Mann-Whitney tests.

Source data

Extended Data Fig. 3 Demographics and clinical characteristics of iPD patients.

The demographics and clinical characteristics of I-iPD and II-iPD groups who completed the MRI scans. Mean (standard deviation) and N (%) were reported.

Source data

Extended Data Fig. 4 Visualization and measurement of mLVs-SSS and mLVs-SS by high-solution MRI sequences.

a, Visualization of mLVs-SSS in NC (i, v), iPD (ii, vi), MSA (iii, vii) and PSP-RS (iv, viii) groups on 2D T1 black-blood (i-iv) and 3D T2 FLAIR (v-viii) sequences. Visualization of mLVs-SS in NC (ix, xiii), iPD (x, xiv), MSA (xi, xv) and PSP-RS (xii, xvi) groups on 2D T1 black-blood (ix-xii) and 3D T2 FLAIR (xiii-xvi) sequences. The red rectangles represent three mLVs-SSS (L-, R- and Lo-mLVs-SSS) (i-viii) or three mLVs-SS (L-, R- and Lo-mLVs-SS) (ix-xvi), L-, R- and Lo-mLVs-SSS represent the left, right and lower mLVs-SSS, respectively; L-, R- and Lo-mLVs-SS represent the left, right and lower mLVs-SS, respectively. Scale bar, 1 cm. b, Measurement and comparison of the average cross-sectional areas of mLVs-SSS (i) in NC (n = 73), iPD (n = 61), MSA (n = 18) and PSP-RS (n = 19) groups, or mLVs-SS (ii) in NC (n = 47), iPD (n = 46), MSA (n = 18) and PSP-RS (n = 17) groups on 2D T1 black-blood, 3D T1 black-blood and 3D T2 FLAIR sequences (one-way ANOVA with Tukey’s multiple comparison correction, Supplementary Table 3). Measurement and comparison of the average cross-sectional areas of mLVs-SSS (iii) in NC (n = 73), I-iPD (n = 31) and II-iPD (n = 30) groups, or mLVs-SS (iv) in NC (n = 47), I-iPD (n = 23) and II-iPD (n = 23) groups on 2D T1 black-blood, 3D T1 black-blood and 3D T2 FLAIR sequences (one-way ANOVA with Tukey’s multiple comparison correction, Supplementary Table 4). I-iPD group, H&Y stage ≤ 2.5; II-iPD group, H&Y stage > 2.5. c, Correlations between the modified H&Y staging scale scores and the average cross-sectional areas of mLVs-SSS (i-iii) (n = 61) or mLVs-SS (iv-vi) (n = 46) in iPD patients on 2D T1 black-blood (i, iv), 3D T1 black-blood (ii, v) and 3D T2 FLAIR (iii, vi) sequences (two-sided Spearman correlation analysis, Supplementary Table 6). All box-and-whisker plots depict the median, quartiles and range.

Source data

Extended Data Fig. 5 The DCE-MRI parameters of dcLNs in NC, DLB, CBD and VP groups.

Comparison of the average TTP values (a), average wash-in rate values (b) and average AUC values (c) of bilateral dcLNs in NC (n = 95), DLB (n = 8), CBD (n = 4) and VP (n = 19) groups (Kruskal–Wallis test with Dunn’s multiple comparison test). All box-and-whisker plots depict the median, quartiles and range.

Source data

Extended Data Fig. 6 Diagnostic accuracy of the DCE-MRI parameters for distinguishing iPD from AP.

The sensitivity, specificity, threshold, AUROC and 95% CI of the AUROC, sensitivity and specificity were calculated by ROC curve.

Source data

Extended Data Fig. 7 Diagnostic accuracy of the DCE-MRI parameters for distinguishing I-iPD from AP.

The sensitivity, specificity, threshold, AUROC and 95% CI of the AUROC, sensitivity and specificity were calculated by ROC curve.

Source data

Extended Data Fig. 8 PD-like pathology induced by intrastriatal inoculation of α-syn PFFs in mice.

a, Representative transmission electron micrographs of mouse α-syn PFFs before (i) and after (ii) sonication (repeated three times). Scale bar, 100 nm. iii, Distribution of sonicated mouse α-syn PFFs lengths after 500 measurements. b, Representative immunohistochemical results of different segments from α-syn PFFs- (i-iii, v-vii, ix-xi, xiii-xv) and PBS- (iv, viii, xii, xvi) injected mice. Representative images displayed the distribution of pα-syn in the cortex (i-iv), striatum (v-viii), amygdala (ix-xii) and substantia nigra (xiii-xvi) at 1 mpi (i, v, ix, xiii), 3 mpi (ii, vi, x, xiv) and 6 mpi (iii, vii, xi, xv), but not in PBS-injected mice at 6 mpi (iv, viii, xii, xvi). Scale bar, 20 μm. xvii-xx, Quantification of pα-syn immunoreactivity of cortex (xvii), striatum (xviii), amygdala (xix), and substantia nigra (xx) from α-syn PFFs-injected mice at 1, 3 and 6 mpi and PBS-injected mice at 6 mpi; two-sided Student’s t-test. n = 6 mice/age/group. c, Representative immunoblot images of total α-syn (i, ii) or pS129 α-syn (iii, iv) in the soluble (i, iii) and insoluble (ii, iv) fractions of cortex of PBS- and α-syn PFFs-injected mice and quantification (v, vi); two-sided Mann–Whitney test. n = 6 mice/group. The loading controls (GAPDH) were run on different gels in the same experiment. All box-and-whisker plots depict the median, quartiles and range.

Source data

Extended Data Fig. 9 Ligation of the bilateral afferent lymphatics exacerbated PD-like pathology and motor deficits in ligated α-syn PFFs-injected mice.

a, b, Representative images of LYVE-1-positive (green) vessels in the meninges of sham-operated (a1) and ligated (a2) mice and the quantification of diameters (b); two-sided Student’s t-test. n = 6 mice/group. Scale bar, 2 mm. c, d, Representative images of EB (red) draining into the dcLNs (c1-c3, sham-operated; d1-d3, ligated) one hour after injection, stained with LYVE-1 (green) and Hoechst 33258 (blue). Scale bar, 200 µm. e, Quantification of EB percentage area by area in dcLNs of sham-operated and ligated mice; two-sided Mann-Whitney test. n = 6 mice/group. f-i, Representative immunohistochemical results of different segments from ligated α-syn PFFs-injected mice (f1-f3, g1-g3, h1-h3, i1-i3) and ligated PBS-injected mice (f4, g4, h4, i4). The images displayed the distribution of pα-syn in cortex (f1-f3), striatum (g1-g3), amygdala (h1-h3) and substantia nigra (i1-i3) at 1 mpi (f1, g1, h1, i1), 3 mpi (f2, g2, h2, i2) and 6 mpi (f3, g3, h3, i3), but not in ligated PBS-injected mice at 6 mpi (f4, g4, h4, i4). Scale bar, 20 µm. j-m, Quantification of pα-syn immunoreactivity of the cortex (j), striatum (k), amygdala (l) and substantia nigra (m) in non-ligated α-syn PFFs-injected and ligated α-syn PFFs-injected mice (n = 6 mice/age/group); two-sided Student’s t-test. n-p, Representative immunoblot images (n) of total (up) and pS129 (down) α-syn in soluble (left) and insoluble (right) fractions of cortex of non-ligated α-syn PFFs-injected and ligated α-syn PFFs-injected mice and quantification (o, p); two-sided Mann-Whitney test. n = 6 mice/group. The loading controls (GAPDH) were run on different gels in the same experiment. All box-and-whisker plots depict the median, quartiles and range.

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Extended Data Fig. 10 Quantitative assessments of MMA, SSS and ECA flow by DCE-MRI.

a, Representative DCE-MRI scans of MMA (i, ii, vii, viii), SSS (iii, iv, ix, x) and ECA (v, vi, xi, xii) before (i-vi) and after (vii-xii) administration of gadobutrol in NC (i, iii, v, vii, ix, xi) and iPD (ii, iv, vi, viii, x, xii) groups. The red ellipses represent MMA (i, ii, vii, viii), SSS (iii, iv, ix, x) and ECA (v, vi, xi, xii), respectively. Scale bar, 2 cm. b, Representative TICs of MMA (i, iv), SSS (ii, v) and ECA (iii, vi) of NC (i-iii) and iPD groups (iv-vi) obtained by DCE-MRI. L-MMA and R-MMA represent the left and right MMA, respectively. L-ECA and R-ECA represent the left and right ECA, respectively. c, Comparison of the average TTP values (i), average wash-in rate values (iv) and average AUC values (vii) of bilateral MMA in NC (n = 39), iPD (n = 24), MSA (n = 17) and PSP-RS (n = 17) groups (Kruskal–Wallis test with Dunn’s multiple comparison test). Comparison of the TTP values (ii), wash-in rate values (v) and AUC values (viii) of SSS in NC (n = 38), iPD (n = 24), MSA (n = 17) and PSP-RS (n = 18) groups (Kruskal–Wallis test with Dunn’s multiple comparison test). Comparison of the average TTP values (iii), average wash-in rate values (vi) and average AUC values (ix) of bilateral ECA in NC (n = 40), iPD (n = 24), MSA (n = 17) and PSP-RS (n = 18) groups (Kruskal–Wallis test with Dunn’s multiple comparison test). All box-and-whisker plots depict the median, quartiles and range.

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Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2 and Supplementary Tables 1–8.

Reporting Summary

Supplementary Video 1

3D reconstruction of mLVs (red) in a healthy participant from subtracted T1 black-blood images (horizontal view, 360°). The mLVs run alongside the venous sinus, especially the SSS and SS.

Supplementary Video 2

3D reconstruction of mLVs (red) in an iPD patient from subtracted T1 black-blood images (horizontal view, 360°). The mLVs run alongside the venous sinus, especially the SSS and SS.

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Statistical Source Data and unprocessed western blots.

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Ding, XB., Wang, XX., Xia, DH. et al. Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease. Nat Med 27, 411–418 (2021). https://doi.org/10.1038/s41591-020-01198-1

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