REFERENCES
1. Coleman C, Martin I. Unraveling Parkinson’s disease neurodegeneration: does aging hold the clues? J Parkinsons Dis 2022;12:2321-38.
2. de Rijk MC, Breteler MM, Graveland GA, et al. Prevalence of Parkinson’s disease in the elderly: the Rotterdam Study. Neurology 1995;45:2143-6.
3. Kontis V, Bennett JE, Mathers CD, Li G, Foreman K, Ezzati M. Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble. Lancet 2017;389:1323-35.
4. Rudow G, O’Brien R, Savonenko AV, et al. Morphometry of the human substantia nigra in ageing and Parkinson’s disease. Acta Neuropathol 2008;115:461-70.
5. Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 1991;114:2283-301.
6. Ma SY, Röytt M, Collan Y, Rinne JO. Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol Appl Neurobiol 1999;25:394-9.
7. Buchman AS, Shulman JM, Nag S, et al. Nigral pathology and parkinsonian signs in elders without Parkinson disease. Ann Neurol 2012;71:258-66.
9. Gonzalez-Rodriguez P, Zampese E, Surmeier DJ. Disease mechanisms as subtypes: mitochondrial and bioenergetic dysfunction. Handb Clin Neurol 2023;193:53-66.
10. Gonzalez-Rodriguez P, Zampese E, Surmeier DJ. Selective neuronal vulnerability in Parkinson’s disease. Prog Brain Res 2020;252:61-89.
11. Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 2017;18:101-13.
12. Pandya VA, Patani R. Region-specific vulnerability in neurodegeneration: lessons from normal ageing. Ageing Res Rev 2021;67:101311.
13. Bolam JP, Pissadaki EK. Living on the edge with too many mouths to feed: why dopamine neurons die. Mov Disord 2012;27:1478-83.
14. Pissadaki EK, Bolam JP. The energy cost of action potential propagation in dopamine neurons: clues to susceptibility in Parkinson’s disease. Front Comput Neurosci 2013;7:13.
15. Kowalczyk P, Sulejczak D, Kleczkowska P, et al. Mitochondrial oxidative stress - a causative factor and therapeutic target in many diseases. Int J Mol Sci 2021;22:13384.
16. Guzman JN, Ilijic E, Yang B, et al. Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress. J Clin Invest 2018;128:2266-80.
17. Segura-Aguilar J, Paris I, Muñoz P, Ferrari E, Zecca L, Zucca FA. Protective and toxic roles of dopamine in Parkinson’s disease. J Neurochem 2014;129:898-915.
18. Burbulla LF, Song P, Mazzulli JR, et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 2017;357:1255-61.
19. Vila M. Neuromelanin, aging, and neuronal vulnerability in Parkinson’s disease. Mov Disord 2019;34:1440-51.
20. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013;153:1194-217.
21. Mattson MP, Arumugam TV. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab 2018;27:1176-99.
22. Day JO, Mullin S. The genetics of Parkinson’s disease and implications for clinical practice. Genes 2021;12:1006.
23. Lynch-Day MA, Mao K, Wang K, Zhao M, Klionsky DJ. The role of autophagy in Parkinson’s disease. Cold Spring Harb Perspect Med 2012;2:a009357.
24. Sugiura A, McLelland GL, Fon EA, McBride HM. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. EMBO J 2014;33:2142-56.
25. Smith L, Schapira AHV. GBA variants and Parkinson disease: mechanisms and treatments. Cells 2022;11:1261.
26. Zheng W, Fan D. Glucocerebrosidase mutations cause mitochondrial and lysosomal dysfunction in Parkinson’s disease: pathogenesis and therapeutic implications. Front Aging Neurosci 2022;14:851135.
27. Baden P, Perez MJ, Raji H, et al. Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism. Nat Commun 2023;14:1930.
28. González-Rodríguez P, Zampese E, Stout KA, et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 2021;599:650-6.
29. Que R, Zheng J, Chang Z, et al. Dl-3-n-butylphthalide rescues dopaminergic neurons in Parkinson’s disease models by inhibiting the NLRP3 inflammasome and ameliorating mitochondrial impairment. Front Immunol 2021;12:794770.
30. Kim KH. Intranasal delivery of mitochondrial protein humanin rescues cell death and promotes mitochondrial function in Parkinson’s disease. Theranostics 2023;13:3330-45.
31. Lin MW, Lin CC, Chen YH, Yang HB, Hung SY. Celastrol inhibits dopaminergic neuronal death of Parkinson’s disease through activating mitophagy. Antioxidants 2020;9:37.
32. Gao XY, Yang T, Gu Y, Sun XH. Mitochondrial dysfunction in Parkinson’s disease: from mechanistic insights to therapy. Front Aging Neurosci 2022;14:885500.
33. Prasuhn J, Davis RL, Kumar KR. Targeting mitochondrial impairment in Parkinson’s disease: challenges and opportunities. Front Cell Dev Biol 2021;8:615461.
34. Chang JC, Wu SL, Liu KH, et al. Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson’s disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine-induced neurotoxicity. Transl Res 2016;170:40-56.e3.
35. Chang JC, Chao YC, Chang HS, et al. Intranasal delivery of mitochondria for treatment of Parkinson’s disease model rats lesioned with 6-hydroxydopamine. Sci Rep 2021;11:10597.
36. Shi X, Zhao M, Fu C, Fu A. Intravenous administration of mitochondria for treating experimental Parkinson’s disease. Mitochondrion 2017;34:91-100.
37. Lai JH, Chen KY, Wu JCC, et al. Voluntary exercise delays progressive deterioration of markers of metabolism and behavior in a mouse model of Parkinson’s disease. Brain Res 2019;1720:146301.
38. Zhao Y, Jia M, Chen W, Liu Z. The neuroprotective effects of intermittent fasting on brain aging and neurodegenerative diseases via regulating mitochondrial function. Free Radic Biol Med 2022;182:206-18.
39. Li J, Xu Y, Liu T, Xu Y, Zhao X, Wei J. The role of exercise in maintaining mitochondrial proteostasis in Parkinson’s disease. Int J Mol Sci 2023;24:7994.
40. Falkenburger B, Bernhardt N, Szegö E. Intermittent fasting reduces alpha-synuclein pathology and functional decline in mice. Research Square. [Preprint] July 5, 2023. [accessed on 2024 Mar 19]. Available from: https://www.researchsquare.com/article/rs-3077779/v1.
41. Verschuur CVM, Suwijn SR, Boel JA, et al. Randomized delayed-start trial of levodopa in Parkinson’s disease. N Engl J Med 2019;380:315-24.
42. Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain 2014;137:2731-42.
43. Fedorow H, Halliday GM, Rickert CH, Gerlach M, Piederer P, Double KL. Evidence for specific phases in the development of human neuromelanin. Neurobiol Aging 2006;27:506-12.
44. Nagatsu T, Nakashima A, Watanabe H, Ito S, Wakamatsu K. Neuromelanin in Parkinson’s disease: tyrosine hydroxylase and tyrosinase. Int J Mol Sci 2022;23:4176.
45. Carballo-Carbajal I, Laguna A, Romero-Giménez J, et al. Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis. Nat Commun 2019;10:973.
46. Gonzalez-Sepulveda M, Compte J, Cuadros T, et al. In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease. Brain 2023;146:1040-52.
47. Sulzer D. Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 2007;30:244-50.
48. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997;276:2045-7.
49. Gómez-Benito M, Granado N, García-Sanz P, Michel A, Dumoulin M, Moratalla R. Modeling Parkinson’s disease with the alpha-synuclein protein. Front Pharmacol 2020;11:356.
50. Siderowf A, Concha-Marambio L, Lafontant DE, et al. Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol 2023;22:407-17.
51. Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24:197-211.
52. Angot E, Steiner JA, Lema Tomé CM, et al. Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One 2012;7:e39465.
53. Reish HE, Standaert DG. Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Parkinsons Dis 2015;5:1-19.
54. Sulzer D, Alcalay RN, Garretti F, et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 2017;546:656-61.
57. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-86.
59. Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 2006;24:1159-69.
60. Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease. Nat Rev Immunol 2022;22:657-73.
61. Fulop T, Larbi A, Dupuis G, et al. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol 2017;8:1960.
62. Karrer U, Sierro S, Wagner M, et al. Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. J Immunol 2003;170:2022-9.
63. Chou JP, Effros RB. T cell replicative senescence in human aging. Curr Pharm Des 2013;19:1680-98.
64. Akbar AN, Henson SM, Lanna A. Senescence of T lymphocytes: implications for enhancing human immunity. Trends Immunol 2016;37:866-76.
65. Geginat J, Lanzavecchia A, Sallusto F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 2003;101:4260-6.
66. Lee KA, Flores RR, Jang IH, Saathoff A, Robbins PD. Immune senescence, immunosenescence and aging. Front Aging 2022;3:900028.
67. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 2010;5:99-118.
70. van der Heiden M, van Zelm MC, Bartol SJW, et al. Differential effects of cytomegalovirus carriage on the immune phenotype of middle-aged males and females. Sci Rep 2016;6:26892.
71. Derhovanessian E, Maier AB, Hähnel K, et al. Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans. J Gen Virol 2011;92:2746-56.
72. Khan N, Shariff N, Cobbold M, et al. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 2002;169:1984-92.
73. Hadrup SR, Strindhall J, Køllgaard T, et al. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol 2006;176:2645-53.
74. Brochard V, Combadière B, Prigent A, et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 2009;119:182-92.
75. Sanchez-Guajardo V, Febbraro F, Kirik D, Romero-Ramos M. Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson’s disease. PLoS One 2010;5:e8784.
76. Sommer A, Fadler T, Dorfmeister E, et al. Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model. J Neuroinflammation 2016;13:174.
77. Williams GP, Schonhoff AM, Jurkuvenaite A, Gallups NJ, Standaert DG, Harms AS. CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson’s disease. Brain 2021;144:2047-59.
78. Reynolds AD, Stone DK, Hutter JAL, Benner EJ, Mosley RL, Gendelman HE. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J Immunol 2010;184:2261-71.
79. Sommer A, Marxreiter F, Krach F, et al. Th17 lymphocytes induce neuronal cell death in a human iPSC-based model of Parkinson’s disease. Cell Stem Cell 2018;23:123-31.e6.
80. Galiano-Landeira J, Torra A, Vila M, Bové J. CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson’s disease. Brain 2020;143:3717-33.
81. Lindestam Arlehamn CS, Dhanwani R, Pham J, et al. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nat Commun 2020;11:1875.
82. Kouli A, Williams-Gray CH. Age-related adaptive immune changes in Parkinson’s disease. J Parkinsons Dis 2022;12:S93-104.
83. Moro-García MA, Alonso-Arias R, López-Larrea C. When aging reaches CD4+ T-cells: phenotypic and functional changes. Front Immunol 2013;4:107.
84. Yan Z, Yang W, Wei H, et al. Dysregulation of the adaptive immune system in patients with early-stage Parkinson disease. Neurol Neuroimmunol Neuroinflamm 2021;8:e1036.
85. Baba Y, Kuroiwa A, Uitti RJ, Wszolek ZK, Yamada T. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord 2005;11:493-8.
86. Wang P, Yao L, Luo M, et al. Single-cell transcriptome and TCR profiling reveal activated and expanded T cell populations in Parkinson’s disease. Cell Discov 2021;7:52.
87. Kouli A, Jensen M, Papastavrou V, et al. T lymphocyte senescence is attenuated in Parkinson’s disease. J Neuroinflammation 2021;18:228.
88. Williams-Gray CH, Wijeyekoon RS, Scott KM, Hayat S, Barker RA, Jones JL. Abnormalities of age-related T cell senescence in Parkinson’s disease. J Neuroinflammation 2018;15:166.
89. Vavilova JD, Boyko AA, Ponomareva NV, et al. Reduced immunosenescence of peripheral blood T cells in Parkinson’s disease with CMV infection background. Int J Mol Sci 2021;22:13119.
90. Chen X, Feng W, Ou R, et al. Evidence for peripheral immune activation in Parkinson’s disease. Front Aging Neurosci 2021;13:617370.
91. Chen Y, Qi B, Xu W, et al. Clinical correlation of peripheral CD4+-cell sub-sets, their imbalance and Parkinson’s disease. Mol Med Rep 2015;12:6105-11.
92. Saunders JAH, Estes KA, Kosloski LM, et al. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J Neuroimmune Pharmacol 2012;7:927-38.
93. Markovic M, Yeapuri P, Namminga KL, et al. Interleukin-2 expands neuroprotective regulatory T cells in Parkinson’s disease. NeuroImmune Pharm Ther 2022;1:43-50.
94. Olson KE, Abdelmoaty MM, Namminga KL, et al. An open-label multiyear study of sargramostim-treated Parkinson’s disease patients examining drug safety, tolerability, and immune biomarkers from limited case numbers. Transl Neurodegener 2023;12:26.
95. Olson KE, Namminga KL, Lu Y, et al. Granulocyte-macrophage colony-stimulating factor mRNA and neuroprotective immunity in Parkinson’s disease. Biomaterials 2021;272:120786.
96. Olson KE, Namminga KL, Schwab AD, et al. Neuroprotective activities of long-acting granulocyte-macrophage colony-stimulating factor (mPDM608) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. Neurotherapeutics 2020;17:1861-77.
97. Kosloski LM, Kosmacek EA, Olson KE, Mosley RL, Gendelman HE. GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice. J Neuroimmunol 2013;265:1-10.
98. Hammond TR, Robinton D, Stevens B. Microglia and the brain: complementary partners in development and disease. Annu Rev Cell Dev Biol 2018;34:523-44.
99. McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 1988;38:1285-91.
100. Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol 2003;106:518-26.
101. Bartels AL, Willemsen ATM, Doorduin J, de Vries EF, Dierckx RA, Leenders KL. [11C]-PK11195 PET: quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson’s disease? Parkinsonism Relat Disord 2010;16:57-9.
102. Gerhard A, Pavese N, Hotton G, et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 2006;21:404-12.
103. Stokholm MG, Iranzo A, Østergaard K, et al. Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. Lancet Neurol 2017;16:789-96.
104. Członkowska A, Kohutnicka M, Kurkowska-Jastrzebska I, Członkowski A. Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s disease mice model. Neurodegeneration 1996;5:137-43.
105. Hoenen C, Gustin A, Birck C, et al. Alpha-synuclein proteins promote pro-inflammatory cascades in microglia: stronger effects of the A53T mutant. PLoS One 2016;11:e0162717.
106. Hamza TH, Zabetian CP, Tenesa A, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 2010;42:781-5.
107. Hendrickx DAE, van Eden CG, Schuurman KG, Hamann J, Huitinga I. Staining of HLA-DR, Iba1 and CD68 in human microglia reveals partially overlapping expression depending on cellular morphology and pathology. J Neuroimmunol 2017;309:12-22.
108. Beier EE, Neal M, Alam G, Edler M, Wu LJ, Richardson JR. Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide. Neurobiol Dis 2017;108:115-27.
109. Milde S, van Tartwijk FW, Vilalta A, et al. Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice. J Neuroinflammation 2021;18:225.
110. Greenwood EK, Brown DR. Senescent microglia: the key to the ageing brain? Int J Mol Sci 2021;22:4402.
111. Streit WJ, Sammons NW, Kuhns AJ, Sparks DL. Dystrophic microglia in the aging human brain. Glia 2004;45:208-12.
112. Matsudaira T, Nakano S, Konishi Y, et al. Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype. Commun Biol 2023;6:665.
113. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007;8:57-69.
114. Kannarkat GT, Boss JM, Tansey MG. The role of innate and adaptive immunity in Parkinson’s disease. J Parkinsons Dis 2013;3:493-514.
115. Choi I, Zhang Y, Seegobin SP, et al. Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration. Nat Commun 2020;11:1386.
116. Guo M, Wang J, Zhao Y, et al. Microglial exosomes facilitate α-synuclein transmission in Parkinson’s disease. Brain 2020;143:1476-97.
117. Hong B, Ohtake Y, Itokazu T, Yamashita T. Glial senescence enhances α-synuclein pathology owing to its insufficient clearance caused by autophagy dysfunction. Cell Death Discov 2024;10:50.
118. Dermitzakis I, Theotokis P, Evangelidis P, et al. CNS border-associated macrophages: ontogeny and potential implication in disease. Curr Issues Mol Biol 2023;45:4285-300.
119. Schonhoff AM, Figge DA, Williams GP, et al. Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease. Nat Commun 2023;14:3754.
120. Utz SG, See P, Mildenberger W, et al. Early fate defines microglia and non-parenchymal brain macrophage development. Cell 2020;181:557-73.e18.
121. Silvin A, Uderhardt S, Piot C, et al. Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration. Immunity 2022;55:1448-65.e6.
122. De Maeyer RPH, Chambers ES. The impact of ageing on monocytes and macrophages. Immunol Lett 2021;230:1-10.
123. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 2018;14:576-90.
124. Qin XY, Zhang SP, Cao C, Loh YP, Cheng Y. Aberrations in peripheral inflammatory cytokine levels in Parkinson disease: a systematic review and meta-analysis. JAMA Neurol 2016;73:1316-24.
125. Williams-Gray CH, Wijeyekoon R, Yarnall AJ, et al. ICICLE-PD study group. Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD). Mov Disord 2016;31:995-1003.
126. Lindqvist D, Hall S, Surova Y, et al. Cerebrospinal fluid inflammatory markers in Parkinson’s disease - associations with depression, fatigue, and cognitive impairment. Brain Behav Immun 2013;33:183-9.
127. Lobanova E, Whiten D, Ruggeri FS, et al. Imaging protein aggregates in the serum and cerebrospinal fluid in Parkinson’s disease. Brain 2022;145:632-43.
128. Kouli A, Horne CB, Williams-Gray CH. Toll-like receptors and their therapeutic potential in Parkinson’s disease and α-synucleinopathies. Brain Behav Immun 2019;81:41-51.
129. Williams GP, Muskat K, Frazier A, et al. Unaltered T cell responses to common antigens in individuals with Parkinson’s disease. J Neurol Sci 2023;444:120510.
130. Chen H, Zhang SM, Hernán MA, et al. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol 2003;60:1059-64.
131. Casper D, Yaparpalvi U, Rempel N, Werner P. Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro. Neurosci Lett 2000;289:201-4.
132. Hägg S, Jylhävä J. Sex differences in biological aging with a focus on human studies. Elife 2021;10:e63425.
133. Gillies GE, Pienaar IS, Vohra S, Qamhawi Z. Sex differences in Parkinson’s disease. Front Neuroendocrinol 2014;35:370-84.
134. Gullotta GS, Costantino G, Sortino MA, Spampinato SF. Microglia and the blood-brain barrier: an external player in acute and chronic neuroinflammatory conditions. Int J Mol Sci 2023;24:9144.
135. Wen W, Cheng J, Tang Y. Brain perivascular macrophages: current understanding and future prospects. Brain 2024;147:39-55.
136. Barcia C, Bautista V, Sánchez-Bahillo A, et al. Changes in vascularization in substantia nigra pars compacta of monkeys rendered parkinsonian. J Neural Transm 2005;112:1237-48.
137. Rite I, Machado A, Cano J, Venero JL. Blood-brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons. J Neurochem 2007;101:1567-82.
138. Elabi O, Gaceb A, Carlsson R, et al. Human α-synuclein overexpression in a mouse model of Parkinson’s disease leads to vascular pathology, blood brain barrier leakage and pericyte activation. Sci Rep 2021;11:1120.
139. Al-Bachari S, Naish JH, Parker GJM, Emsley HCA, Parkes LM. Blood-brain barrier leakage is increased in Parkinson’s disease. Front Physiol 2020;11:593026.
140. 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.
142. Olmedo-Díaz S, Estévez-Silva H, Orädd G, Af Bjerkén S, Marcellino D, Virel A. An altered blood-brain barrier contributes to brain iron accumulation and neuroinflammation in the 6-OHDA rat model of Parkinson’s disease. Neuroscience 2017;362:141-51.
143. Zhao C, Ling Z, Newman MB, Bhatia A, Carvey PM. TNF-α knockout and minocycline treatment attenuates blood-brain barrier leakage in MPTP-treated mice. Neurobiol Dis 2007;26:36-46.
144. Toledo JB, Arnold SE, Raible K, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain 2013;136:2697-706.
145. Malek N, Lawton MA, Swallow DM, et al. PRoBaND Clinical Consortium. Vascular disease and vascular risk factors in relation to motor features and cognition in early Parkinson’s disease. Mov Disord 2016;31:1518-26.
146. Verheggen ICM, de Jong JJA, van Boxtel MPJ, et al. Increase in blood-brain barrier leakage in healthy, older adults. Geroscience 2020;42:1183-93.
147. Montagne A, Barnes SR, Sweeney MD, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 2015;85:296-302.
148. Bonte S, Vandemaele P, Verleden S, et al. Healthy brain ageing assessed with 18F-FDG PET and age-dependent recovery factors after partial volume effect correction. Eur J Nucl Med Mol Imaging 2017;44:838-49.
149. Daniel PM, Love ER, Pratt OE. The effect of age upon the influx of glucose into the brain. J Physiol 1978;274:141-8.
150. Mooradian AD, Morin AM, Cipp LJ, Haspel HC. Glucose transport is reduced in the blood-brain barrier of aged rats. Brain Res 1991;551:145-9.
151. Toornvliet R, van Berckel BNM, Luurtsema G, et al. Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-[11C]verapamil and positron emission tomography. Clin Pharmacol Ther 2006;79:540-8.
152. Ceafalan LC, Fertig TE, Gheorghe TC, et al. Age-related ultrastructural changes of the basement membrane in the mouse blood-brain barrier. J Cell Mol Med 2019;23:819-27.
153. Machin DR, Bloom SI, Campbell RA, et al. Advanced age results in a diminished endothelial glycocalyx. Am J Physiol Heart Circ Physiol 2018;315:H531-9.
154. Bell RD, Winkler EA, Sagare AP, et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 2010;68:409-27.
155. Stewart PA, Magliocco M, Hayakawa K, et al. A quantitative analysis of blood-brain barrier ultrastructure in the aging human. Microvasc Res 1987;33:270-82.
156. Banks WA, Reed MJ, Logsdon AF, Rhea EM, Erickson MA. Healthy aging and the blood-brain barrier. Nat Aging 2021;1:243-54.
157. Nikolakopoulou AM, Montagne A, Kisler K, et al. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nat Neurosci 2019;22:1089-98.
159. Li Y, Xie L, Huang T, et al. Aging neurovascular unit and potential role of DNA damage and repair in combating vascular and neurodegenerative disorders. Front Neurosci 2019;13:778.
160. Allahyari RV, Clark KL, Shepard KA, Garcia ADR. Sonic hedgehog signaling is negatively regulated in reactive astrocytes after forebrain stab injury. Sci Rep 2019;9:565.
161. Propson NE, Roy ER, Litvinchuk A, Köhl J, Zheng H. Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging. J Clin Invest 2021;131:140966.
162. Chen MB, Yang AC, Yousef H, et al. Brain endothelial cells are exquisite sensors of age-related circulatory cues. Cell Rep 2020;30:4418-32.e4.
163. Yousef H, Czupalla CJ, Lee D, et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med 2019;25:988-1000.
164. Gemechu JM, Bentivoglio M. T cell recruitment in the brain during normal aging. Front Cell Neurosci 2012;6:38.
165. Zhang X, Wang R, Chen H, et al. Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches. Immun Ageing 2022;19:34.
166. Berry K, Farias-Itao DS, Grinberg LT, et al. B and T lymphocyte densities remain stable with age in human cortex. ASN Neuro 2021;13:17590914211018117.
167. Yang AC, Stevens MY, Chen MB, et al. Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature 2020;583:425-30.
168. Pun PB, Lu J, Moochhala S. Involvement of ROS in BBB dysfunction. Free Radic Res 2009;43:348-64.
169. Ronaldson PT, Davis TP. Regulation of blood-brain barrier integrity by microglia in health and disease: a therapeutic opportunity. J Cereb Blood Flow Metab 2020;40:S6-24.
170. Bisht K, Okojie KA, Sharma K, et al. Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice. Nat Commun 2021;12:5289.
171. Haruwaka K, Ikegami A, Tachibana Y, et al. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nat Commun 2019;10:5816.
172. Huang W, Xia Q, Zheng F, et al. Microglia-mediated neurovascular unit dysfunction in Alzheimer’s disease. J Alzheimers Dis 2023;94:S335-54.
173. Ruan Z, Zhang D, Huang R, et al. Microglial activation damages dopaminergic neurons through MMP-2/-9-mediated increase of blood-brain barrier permeability in a Parkinson’s disease mouse model. Int J Mol Sci 2022;23:2793.
174. Lou N, Takano T, Pei Y, Xavier AL, Goldman SA, Nedergaard M. Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier. Proc Natl Acad Sci U S A 2016;113:1074-9.
175. Zheng L, Guo Y, Zhai X, et al. Perivascular macrophages in the CNS: from health to neurovascular diseases. CNS Neurosci Ther 2022;28:1908-20.
176. Goldmann T, Wieghofer P, Jordão MJ, et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat Immunol 2016;17:797-805.
177. Lee D, Porras C, Spencer C, et al. Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease. medRxiv. [Preprint] Oct 26, 2023. [accessed on 2024 Mar 19]. Available from: https://www.medrxiv.org/content/10.1101/2023.10.25.23297558v1.
178. Drieu A, Du S, Storck SE, et al. Dominantly Inherited Alzheimer Network. Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid. Nature 2022;611:585-93.
179. Van Hove H, Martens L, Scheyltjens I, et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat Neurosci 2019;22:1021-35.
180. Huang X, Hussain B, Chang J. Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms. CNS Neurosci Ther 2021;27:36-47.
181. Wang Y, Liu W, Geng P, et al. Role of crosstalk between glial cells and immune cells in blood-brain barrier damage and protection after acute ischemic stroke. Aging Dis 2023.
182. Galea I. The blood-brain barrier in systemic infection and inflammation. Cell Mol Immunol 2021;18:2489-501.
183. Wang X, Xue GX, Liu WC, et al. Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice. Aging Cell 2017;16:414-21.
184. Gandhi K, Barzegar-Fallah A, Banstola A, Rizwan SB, Reynolds JNJ. Correction: Gandhi et al. Ultrasound-mediated blood-brain barrier disruption for drug delivery: a systematic review of protocols, efficacy, and safety outcomes from preclinical and clinical studies. Pharmaceutics 2022,14,833. Pharmaceutics 2023;15:5.
185. Tung YS, Vlachos F, Feshitan JA, Borden MA, Konofagou EE. The mechanism of interaction between focused ultrasound and microbubbles in blood-brain barrier opening in mice. J Acoust Soc Am 2011;130:3059-67.
186. Lipsman N, Meng Y, Bethune AJ, et al. Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun 2018;9:2336.
187. Pineda-Pardo JA, Gasca-Salas C, Fernández-Rodríguez B, et al. Striatal blood-brain barrier opening in Parkinson’s disease dementia: a pilot exploratory study. Mov Disord 2022;37:2057-65.
