Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients
Abstract
:1. Introduction
2. Results
2.1. Clinical and Demographic Characteristics
2.2. Sex-Related Difference of Biological Features
2.3. Association of QAlb with Clinical and Genetic Parameters
2.4. Association between QAlb at Diagnosis and Disease Outcome
3. Discussion
3.1. Signs of BBB/BSCB Alteration Are Inconsistent in ALS but Are Associated with Survival in Males
3.2. A Gender Effect to Take into Consideration
3.3. C9orf72 Hexanucleotide Expansions Are Not Associated with BBB/BSCB Leakage in ALS
4. Materials and Methods
4.1. Study Design
4.2. Analyte Quantification
4.3. Genetic Analysis
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Feldman, E.L.; Goutman, S.A.; Petri, S.; Mazzini, L.; Savelieff, M.G.; Shaw, P.J.; Sobue, G. Amyotrophic lateral sclerosis. Lancet 2022, 400, 1363–1380. [Google Scholar] [CrossRef] [PubMed]
- Goutman, S.A.; Hardiman, O.; Al-Chalabi, A.; Chió, A.; Savelieff, M.G.; Kiernan, M.C.; Feldman, E.L. Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis. Lancet Neurol. 2022, 21, 465–479. [Google Scholar] [CrossRef] [PubMed]
- Hardiman, O.; Al-Chalabi, A.; Chio, A.; Corr, E.M.; Logroscino, G.; Robberecht, W.; Shaw, P.J.; Simmons, Z.; van den Berg, L.H. Amyotrophic lateral sclerosis. Nat. Rev. Dis. Prim. 2017, 3, 17071. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Neumann, M.; Sampathu, D.M.; Kwong, L.K.; Truax, A.C.; Micsenyi, M.C.; Chou, T.T.; Bruce, J.; Schuck, T.; Grossman, M.; Clark, C.M.; et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006, 314, 130–133. [Google Scholar] [CrossRef] [Green Version]
- Pasquali, L.; Lenzi, P.; Biagioni, F.; Siciliano, G.; Fornai, F. Cell to cell spreading of misfolded proteins as a therapeutic target in motor neuron disease. Curr. Med. Chem. 2014, 21, 3508–3534. [Google Scholar] [CrossRef]
- Shaw, P.J.; Ince, P.G. Glutamate, excitotoxicity and amyotrophic lateral sclerosis. J. Neurol. 1997, 244 (Suppl. 2), S3–S14. [Google Scholar] [CrossRef]
- Robberecht, W. Oxidative stress in amyotrophic lateral sclerosis. J. Neurol. 2000, 247 (Suppl. 1), I1–I6. [Google Scholar] [CrossRef]
- Beers, D.R.; Appel, S.H. Immune dysregulation in amyotrophic lateral sclerosis: Mechanisms and emerging therapies. Lancet Neurol. 2019, 18, 211–220. [Google Scholar] [CrossRef]
- Alarcan, H.; Al Ojaimi, Y.; Lanznaster, D.; Escoffre, J.-M.; Corcia, P.; Vourc’h, P.; Andres, C.R.; Veyrat-Durebex, C.; Blasco, H. Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS? J. Pers. Med. 2022, 12, 1071. [Google Scholar] [CrossRef]
- Abbott, N.J.; Patabendige, A.A.K.; Dolman, D.E.M.; Yusof, S.R.; Begley, D.J. Structure and function of the blood-brain barrier. Neurobiol. Dis. 2010, 37, 13–25. [Google Scholar] [CrossRef]
- Garbuzova-Davis, S.; Hernandez-Ontiveros, D.G.; Rodrigues, M.C.O.; Haller, E.; Frisina-Deyo, A.; Mirtyl, S.; Sallot, S.; Saporta, S.; Borlongan, C.V.; Sanberg, P.R. Impaired blood-brain/spinal cord barrier in ALS patients. Brain Res 2012, 1469, 114–128. [Google Scholar] [CrossRef]
- Garbuzova-Davis, S.; Haller, E.; Saporta, S.; Kolomey, I.; Nicosia, S.V.; Sanberg, P.R. Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modeling ALS. Brain Res. 2007, 1157, 126–137. [Google Scholar] [CrossRef]
- Garbuzova-Davis, S.; Saporta, S.; Haller, E.; Kolomey, I.; Bennett, S.P.; Potter, H.; Sanberg, P.R. Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS ONE 2007, 2, e1205. [Google Scholar] [CrossRef] [Green Version]
- Pan, Y.; Nicolazzo, J.A. Altered blood–brain barrier and blood–spinal cord barrier dynamics in amyotrophic lateral sclerosis: Impact on medication efficacy and safety. Br. J. Pharmacol. 2022, 179, 2577–2588. [Google Scholar] [CrossRef]
- Mirian, A.; Moszczynski, A.; Soleimani, S.; Aubert, I.; Zinman, L.; Abrahao, A. Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis. Front. Cell. Neurosci. 2022, 16, 851563. [Google Scholar] [CrossRef]
- Kadry, H.; Noorani, B.; Cucullo, L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 2020, 17, 69. [Google Scholar] [CrossRef]
- Brettschneider, J.; Petzold, A.; Süssmuth, S.D.; Ludolph, A.C.; Tumani, H. Axonal damage markers in cerebrospinal fluid are increased in ALS. Neurology 2006, 66, 852–856. [Google Scholar] [CrossRef]
- Prell, T.; Vlad, B.; Gaur, N.; Stubendorff, B.; Grosskreutz, J. Blood-Brain Barrier Disruption Is Not Associated With Disease Aggressiveness in Amyotrophic Lateral Sclerosis. Front. Neurosci. 2021, 15, 656456. [Google Scholar] [CrossRef]
- Meucci, G.; Rossi, G.; Bettini, R.; Montanaro, D.; Gironelli, L.; Voci, L.; Bianchi, F. Laser nephelometric evaluation of albumin, IgG and alpha 2-macroglobulin: Applications to the study of alterations of the blood-brain barrier. J. Neurol. Sci. 1993, 118, 73–78. [Google Scholar] [CrossRef]
- Assialioui, A.; Domínguez, R.; Ferrer, I.; Andrés-Benito, P.; Povedano, M. Elevated Cerebrospinal Fluid Proteins and Albumin Determine a Poor Prognosis for Spinal Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2022, 23, 11063. [Google Scholar] [CrossRef]
- Li, J.-Y.; Cai, Z.-Y.; Sun, X.-H.; Shen, D.-C.; Yang, X.-Z.; Liu, M.-S.; Cui, L.-Y. Blood-brain barrier dysfunction and myelin basic protein in survival of amyotrophic lateral sclerosis with or without frontotemporal dementia. Neurol. Sci. 2022, 43, 3201–3210. [Google Scholar] [CrossRef] [PubMed]
- Verde, F.; Ferrari, I.; Maranzano, A.; Ciusani, E.; Torre, S.; Milone, I.; Colombo, E.; Doretti, A.; Peverelli, S.; Ratti, A.; et al. Relationship between cerebrospinal fluid/serum albumin quotient and phenotype in amyotrophic lateral sclerosis: A retrospective study on 328 patients. Neurol. Sci. 2023, 44, 1679–1685. [Google Scholar] [CrossRef] [PubMed]
- Zhong, Z.; Deane, R.; Ali, Z.; Parisi, M.; Shapovalov, Y.; O’Banion, M.K.; Stojanovic, K.; Sagare, A.; Boillee, S.; Cleveland, D.W.; et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat. Neurosci. 2008, 11, 420–422. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pun, P.B.L.; Lu, J.; Moochhala, S. Involvement of ROS in BBB dysfunction. Free Radic. Res. 2009, 43, 348–364. [Google Scholar] [CrossRef] [PubMed]
- Obermeier, B.; Daneman, R.; Ransohoff, R.M. Development, maintenance and disruption of the blood-brain barrier. Nat. Med. 2013, 19, 1584–1596. [Google Scholar] [CrossRef] [Green Version]
- Huang, X.; Hussain, B.; Chang, J. Peripheral inflammation and blood-brain barrier disruption: Effects and mechanisms. CNS Neurosci. Ther. 2021, 27, 36–47. [Google Scholar] [CrossRef]
- Labus, J.; Wöltje, K.; Stolte, K.N.; Häckel, S.; Kim, K.S.; Hildmann, A.; Danker, K. IL-1β promotes transendothelial migration of PBMCs by upregulation of the FN/α5β1 signalling pathway in immortalised human brain microvascular endothelial cells. Exp. Cell Res. 2018, 373, 99–111. [Google Scholar] [CrossRef]
- Zamudio, F.; Loon, A.R.; Smeltzer, S.; Benyamine, K.; Navalpur Shanmugam, N.K.; Stewart, N.J.F.; Lee, D.C.; Nash, K.; Selenica, M.-L.B. TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model. J. Neuroinflamm. 2020, 17, 283. [Google Scholar] [CrossRef]
- Staats, K.A.; Borchelt, D.R.; Tansey, M.G.; Wymer, J. Blood-based biomarkers of inflammation in amyotrophic lateral sclerosis. Mol. Neurodegener. 2022, 17, 11. [Google Scholar] [CrossRef]
- Sweeney, M.D.; Zhao, Z.; Montagne, A.; Nelson, A.R.; Zlokovic, B.V. Blood-Brain Barrier: From Physiology to Disease and Back. Physiol. Rev. 2019, 99, 21–78. [Google Scholar] [CrossRef]
- Sweeney, M.D.; Sagare, A.P.; Zlokovic, B.V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 2018, 14, 133–150. [Google Scholar] [CrossRef]
- Parrado-Fernández, C.; Blennow, K.; Hansson, M.; Leoni, V.; Cedazo-Minguez, A.; Björkhem, I. Evidence for sex difference in the CSF/plasma albumin ratio in ~20 000 patients and 335 healthy volunteers. J. Cell. Mol. Med. 2018, 22, 5151–5154. [Google Scholar] [CrossRef] [Green Version]
- Castellazzi, M.; Morotti, A.; Tamborino, C.; Alessi, F.; Pilotto, S.; Baldi, E.; Caniatti, L.M.; Trentini, A.; Casetta, I.; Granieri, E.; et al. Increased age and male sex are independently associated with higher frequency of blood–cerebrospinal fluid barrier dysfunction using the albumin quotient. Fluids Barriers CNS 2020, 17, 14. [Google Scholar] [CrossRef]
- Yin, H.; Wan, Q.; Tian, Y.; Zhao, B.; Deng, Y. Female Hormone 17β-Estradiol Downregulated MMP-2 Expression and Upregulated A1PI Expression in Human Corneal Stromal Cells. Cell Biochem. Biophys. 2018, 76, 265–271. [Google Scholar] [CrossRef]
- McCombe, P.A.; Henderson, R.D. Effects of gender in amyotrophic lateral sclerosis. Gend. Med. 2010, 7, 557–570. [Google Scholar] [CrossRef]
- Maggioli, E.; McArthur, S.; Mauro, C.; Kieswich, J.; Kusters, D.H.M.; Reutelingsperger, C.P.M.; Yaqoob, M.; Solito, E. Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking. Brain Behav. Immun. 2016, 51, 212–222. [Google Scholar] [CrossRef] [Green Version]
- Ide, T.; Tsutsui, H.; Ohashi, N.; Hayashidani, S.; Suematsu, N.; Tsuchihashi, M.; Tamai, H.; Takeshita, A. Greater Oxidative Stress in Healthy Young Men Compared With Premenopausal Women. Arterioscler. Thromb. Vasc. Biol. 2002, 22, 438–442. [Google Scholar] [CrossRef] [Green Version]
- Mohamed, L.A.; Markandaiah, S.S.; Bonanno, S.; Pasinelli, P.; Trotti, D. Excess glutamate secreted from astrocytes drives upregulation of P-glycoprotein in endothelial cells in amyotrophic lateral sclerosis. Exp. Neurol. 2019, 316, 27–38. [Google Scholar] [CrossRef]
- Pan, Y.; Kagawa, Y.; Sun, J.; Turner, B.J.; Huang, C.; Shah, A.D.; Schittenhelm, R.B.; Nicolazzo, J.A. Altered Blood-Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral Sclerosis. Pharmaceutics 2022, 14, 2803. [Google Scholar] [CrossRef]
- König, T.; Wurm, R.; Parvizi, T.; Silvaieh, S.; Hotzy, C.; Cetin, H.; Klotz, S.; Gelpi, E.; Bancher, C.; Benke, T.; et al. C9orf72 repeat length might influence clinical sub-phenotypes in dementia patients. Neurobiol. Dis. 2022, 175, 105927. [Google Scholar] [CrossRef]
- Brooks, B.R.; Miller, R.G.; Swash, M.; Munsat, T.L. World Federation of Neurology Research Group on Motor Neuron Diseases El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph. Lateral. Scler. Other Motor. Neuron. Disord. 2000, 1, 293–299. [Google Scholar] [CrossRef] [PubMed]
- Brettschneider, J.; Claus, A.; Kassubek, J.; Tumani, H. Isolated blood-cerebrospinal fluid barrier dysfunction: Prevalence and associated diseases. J. Neurol. 2005, 252, 1067–1073. [Google Scholar] [CrossRef] [PubMed]
Variable | All Patients (n = 307) | Male (n = 164) | Female (n = 143) | Adjusted p-Value |
---|---|---|---|---|
Age of onset (years) | 66 (58, 73) | 65 (56, 72) | 67 (61.5, 74) | 0.027 |
Site of onset | 0.027 | |||
Spinal (N, %) | 218 (71%) | 128 (78%) | 90 (62.9%) | |
Bulbar (N, %) | 89 (29%) | 36 (22%) | 53 (37.1%) | |
Diagnostic delay (months) | 9.0 (5.3, 14) | 8.0 (5.0, 13.3) | 8.9 (5.9, 14.0) | 0.77 |
At diagnosis | ||||
FVC (%) | 95.5 (77.1, 111.2) | 94.3 (78.6, 107.6) | 100.7 (76.3, 114) | 0.23 |
Weight (kg) | 68 (59, 78) | 74.5 (67, 81) | 61 (54, 69) | <0.001 |
ALSFRS-r | 40.5 (37, 43) | 41 (37, 44) | 40 (36, 42) | 0.053 |
dALSFRS | 0.30 (0.18, 0.55) | 0.29 (0.17, 0.46) | 0.35 (0.19, 0.59) | 0.076 |
Variation in reference weight (%) | −1.52 (−7.69, 0.00) | −1.20 (−6.14, 0.00) | −2.63 (−8.90, 0.0) | 0.19 |
Variation after a year (%) | ||||
FVC | −18.6 (−32.3, −7.6) | −17.8 (−34.4, −7.4) | −18.7 (−30.4, −9.7) | 0.93 |
Weight | −1.5 (−7.3, 2.5) | −1.9 (−7.0, 1.7) | −0.94 (−8.2, 4.0) | 0.77 |
ALSFRS | −22.9 (−40.7, −12.5) | −21.7 (−39.4, −10.9) | −28.6 (−41.5, −14.3) | 0.47 |
Disease duration before death (months) | 26.3 (18.5–39.4) | 25.8 (18–39) | 28 (18.8–40) | 0.77 |
Variable | Male | Female | ||
---|---|---|---|---|
HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
QAlb | 2.3 (1.2–4.3) | 0.009 | ||
ALSFRS-r | 0.95 (0.89–1.01) | 0.099 | 0.94 (0.87–1.02) | 0.14 |
dALSFRS-r | 4.1 (1.4–11.6) | 0.008 | 1.6 (0.45–5.8) | 0.47 |
FVC | 0.99 (0.98–1.0) | 0.045 | 0.98 (0.97–1.0) | 0.02 |
Variation of reference weight | 1.0 (0.97–1.04) | 0.81 | 0.98 (0.94–1.03) | 0.46 |
Age of onset | 1.0 (0.99–1.03) | 0.57 | ||
Onset site | ||||
Spinal | 0.53 (0.30–0.94) | 0.031 | 0.64 (0.36–1.13) | 0.12 |
Diagnostic delay | 0.92 (0.88–0.97) | 0.002 | 0.89 (0.84–0.95) | 0.0002 |
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Alarcan, H.; Vourc’h, P.; Berton, L.; Benz-De Bretagne, I.; Piver, E.; Andres, C.R.; Corcia, P.; Veyrat-Durebex, C.; Blasco, H. Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients. Int. J. Mol. Sci. 2023, 24, 11196. https://doi.org/10.3390/ijms241311196
Alarcan H, Vourc’h P, Berton L, Benz-De Bretagne I, Piver E, Andres CR, Corcia P, Veyrat-Durebex C, Blasco H. Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients. International Journal of Molecular Sciences. 2023; 24(13):11196. https://doi.org/10.3390/ijms241311196
Chicago/Turabian StyleAlarcan, Hugo, Patrick Vourc’h, Lise Berton, Isabelle Benz-De Bretagne, Eric Piver, Christian R. Andres, Philippe Corcia, Charlotte Veyrat-Durebex, and Hélène Blasco. 2023. "Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients" International Journal of Molecular Sciences 24, no. 13: 11196. https://doi.org/10.3390/ijms241311196