Unveiling Parkinson’s disease through biomarker research: current insights and future prospects

References

• Yilmaz R, Hopfner F, van Eimeren T, et al. Biomarkers of parkinson’s disease: 20 years later. J Neural Transm (Vienna). 2019;126(7):803–813. doi: 10.1007/s00702-019-02001-3.
   PubMed Web of Science ®Google Scholar
• Indrieri A, Pizzarelli R, Franco B, et al. Dopamine, alpha-synuclein, and mitochondrial dysfunctions in Parkinsonian eyes. Front Neurosci. 2020;14:567129. doi: 10.3389/fnins.2020.567129.
   PubMed Web of Science ®Google Scholar
• Palermo G, Mazzucchi S, Della Vecchia A, et al. Different clinical contexts of use of blood neurofilament light chain protein in the spectrum of neurodegenerative diseases. Mol Neurobiol. 2020;57(11):4667–4691. doi: 10.1007/s12035-020-02035-9.
   PubMed Web of Science ®Google Scholar
• Compta Y, Revesz T. Neuropathological and biomarker findings in Parkinson’s disease and Alzheimer’s disease: from protein aggregates to synaptic dysfunction. J Parkinsons Dis. 2021;11(1):107–121. doi: 10.3233/JPD-202323.
   PubMedGoogle Scholar
• Paolini Paoletti F, Gaetani L, Parnetti L. The challenge of disease-modifying therapies in Parkinson’s disease: role of CSF biomarkers. Biomolecules. 2020;10(2):335. doi: 10.3390/biom10020335.
   PubMed Web of Science ®Google Scholar
• Ugrumov M. Development of early diagnosis of Parkinson’s disease: illusion or reality? CNS Neurosci Ther. 2020;26(10):997–1009. doi: 10.1111/cns.13429.
   PubMed Web of Science ®Google Scholar
• Bougea A. New markers in Parkinson’s disease. Adv Clin Chem. 2020;96:137–178. doi: 10.1016/bs.acc.2019.12.001.
   PubMed Web of Science ®Google Scholar
• Titova N, Qamar MA, Chaudhuri KR. Biomarkers of Parkinson’s disease: an introduction. Int Rev Neurobiol. 2017;132:183–196. doi: 10.1016/bs.irn.2017.03.003.
   PubMed Web of Science ®Google Scholar
• Khan MA, Haider N, Singh T, et al. Promising biomarkers and therapeutic targets for the management of Parkinson’s disease: recent advancements and contemporary research. Metab Brain Dis. 2023;38(3):873–919. doi: 10.1007/s11011-023-01180-z.
   PubMed Web of Science ®Google Scholar
• Wang J, Hoekstra JG, Zuo C, et al. Biomarkers of Parkinson’s disease: current status and future perspectives. Drug Discov Today. 2013;18(3-4):155–162. doi: 10.1016/j.drudis.2012.09.001.
   PubMed Web of Science ®Google Scholar
• Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197–211. doi: 10.1016/s0197-4580(02)00065-9.
   PubMed Web of Science ®Google Scholar
• Poortvliet PC, O'Maley K, Silburn PA, et al. Perspective: current pitfalls in the search for future treatments and prevention of Parkinson’s disease. Front Neurol. 2020;11:686. doi: 10.3389/fneur.2020.00686.
   PubMed Web of Science ®Google Scholar
• Chang KH, Chen CM. The role of oxidative stress in Parkinson’s disease. Antioxidants (Basel). 2020;9(7):597. doi: 10.3390/antiox9070597.
   PubMedGoogle Scholar
• Garcia Santa Cruz B, Husch A, Hertel F. Machine learning models for diagnosis and prognosis of Parkinson’s disease using brain imaging: general overview, main challenges, and future directions. Front Aging Neurosci. 2023;15:1216163. doi: 10.3389/fnagi.2023.1216163.
   PubMed Web of Science ®Google Scholar
• Shen J, Du T, Wang X, et al. α-synuclein amino terminus regulates mitochondrial membrane permeability. Brain Res. 2014;1591:14–26. doi: 10.1016/j.brainres.2014.09.046.
   PubMed Web of Science ®Google Scholar
• Parihar MS, Parihar A, Fujita M, et al. Alpha-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells. Int J Biochem Cell Biol. 2009;41(10):2015–2024. doi: 10.1016/j.biocel.2009.05.008.
   PubMed Web of Science ®Google Scholar
• Kang UJ, Goldman JG, Alcalay RN, et al. The BioFIND study: characteristics of a clinically typical Parkinson’s disease biomarker cohort. Mov Disord. 2016;31(6):924–932. doi: 10.1002/mds.26613.
   PubMed Web of Science ®Google Scholar
• Shahnawaz M, Mukherjee A, Pritzkow S, et al. Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature. 2020;578(7794):273–277. doi: 10.1038/s41586-020-1984-7.
   PubMed Web of Science ®Google Scholar
• Santaella A, Kuiperij HB, van Rumund A, et al. Inflammation biomarker discovery in Parkinson’s disease and atypical Parkinsonisms. BMC Neurol. 2020;20(1):26. doi: 10.1186/s12883-020-1608-8.
   PubMed Web of Science ®Google Scholar
• Eusebi P, Giannandrea D, Biscetti L, et al. Diagnostic utility of cerebrospinal fluid α-synuclein in Parkinson’s disease: a systematic review and meta-analysis. Mov Disord. 2017;32(10):1389–1400. doi: 10.1002/mds.27110.
   PubMed Web of Science ®Google Scholar
• Førland MG, Öhrfelt A, Dalen I, et al. Evolution of cerebrospinal fluid total α-synuclein in Parkinson’s disease. Parkinsonism Relat Disord. 2018;49:4–8. doi: 10.1016/j.parkreldis.2018.01.018.
   PubMed Web of Science ®Google Scholar
• Fairfoul G, McGuire LI, Pal S, et al. Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol. 2016;3(10):812–818. doi: 10.1002/acn3.338.
   PubMed Web of Science ®Google Scholar
• Manne S, Kondru N, Hepker M, et al. Ultrasensitive detection of aggregated α-synuclein in glial cells, human cerebrospinal fluid, and brain tissue using the RT-QuIC assay: new high-throughput neuroimmune biomarker assay for parkinsonian disorders. J Neuroimmune Pharmacol. 2019;14(3):423–435. doi: 10.1007/s11481-019-09835-4.
   PubMed Web of Science ®Google Scholar
• Poggiolini I, Gupta V, Lawton M, et al. Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies. Brain. 2022;145(2):584–595. doi: 10.1093/brain/awab431.
   PubMed Web of Science ®Google Scholar
• Luan M, Sun Y, Chen J, et al. Diagnostic value of salivary Real-Time Quaking-induced conversion in Parkinson’s disease and multiple system atrophy. Mov Disord. 2022;37(5):1059–1063. doi: 10.1002/mds.28976.
   PubMed Web of Science ®Google Scholar
• Majbour N, Aasly J, Abdi I, et al. Disease-associated α-synuclein aggregates as biomarkers of Parkinson disease clinical stage. Neurology. 2022;99(21):e2417–e2427. doi: 10.1212/WNL.0000000000201199.
   PubMed Web of Science ®Google Scholar
• Zhou B, Wen M, Yu WF, et al. The diagnostic and differential diagnosis utility of cerebrospinal fluid α -synuclein levels in Parkinson’s disease: a meta-analysis. Parkinsons Dis. 2015;2015:567386.
   PubMed Web of Science ®Google Scholar
• Si X, Tian J, Chen Y, et al. Central nervous system-derived exosomal alpha-synuclein in serum may be a biomarker in Parkinson’s disease. Neuroscience. 2019;413:308–316. doi: 10.1016/j.neuroscience.2019.05.015.
   PubMed Web of Science ®Google Scholar
• Cerri S, Ghezzi C, Sampieri M, et al. The exosomal/total α-synuclein ratio in plasma is associated with glucocerebrosidase activity and correlates with measures of disease severity in PD patients. Front Cell Neurosci. 2018;12:125. doi: 10.3389/fncel.2018.00125.
   PubMed Web of Science ®Google Scholar
• Gramotnev DK, Gramotnev G, Gramotnev A, et al. Path analysis of biomarkers for cognitive decline in early Parkinson’s disease. PLoS One. 2022;17(5):e0268379. doi: 10.1371/journal.pone.0268379.
   PubMed Web of Science ®Google Scholar
• Fan Z, Pan Y-T, Zhang Z-Y, et al. Systemic activation of NLRP3 inflammasome and plasma α-synuclein levels are correlated with motor severity and progression in Parkinson’s disease. J Neuroinflammation. 2020;17(1):11. doi: 10.1186/s12974-019-1670-6.
   PubMed Web of Science ®Google Scholar
• Minchev D, Kazakova M, Sarafian V. Neuroinflammation and autophagy in Parkinson’s disease-novel perspectives. Int J Mol Sci. 2022;23(23):14997. doi: 10.3390/ijms232314997.
   PubMed Web of Science ®Google Scholar
• Williams-Gray CH, Wijeyekoon R, Yarnall AJ, ICICLE-PD study group, et al. Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD). Mov Disord. 2016;31(7):995–1003. doi: 10.1002/mds.26563.
   PubMed Web of Science ®Google Scholar
• Scalzo P, Kümmer A, Cardoso F, et al. Serum levels of interleukin-6 are elevated in patients with Parkinson’s disease and correlate with physical performance. Neurosci Lett. 2010;468(1):56–58. doi: 10.1016/j.neulet.2009.10.062.
   PubMed Web of Science ®Google Scholar
• More SV, Kumar H, Kim IS, et al. Cellular and molecular mediators of neuroinflammation in the pathogenesis of Parkinson’s disease. Mediators Inflamm. 2013;2013:952375–952312. doi: 10.1155/2013/952375.
   PubMed Web of Science ®Google Scholar
• Umemura A, Oeda T, Yamamoto K, et al. Baseline plasma C-reactive protein concentrations and motor prognosis in Parkinson disease. PLoS One. 2015;10(8):e0136722. doi: 10.1371/journal.pone.0136722.
   PubMed Web of Science ®Google Scholar
• Yu SY, Zuo LJ, Wang F, et al. Potential biomarkers relating pathological proteins, neuroinflammatory factors and free radicals in PD patients with cognitive impairment: a cross-sectional study. BMC Neurol. 2014;14(1):113. doi: 10.1186/1471-2377-14-113.
   PubMedGoogle Scholar
• Yan Y, Jiang W, Liu L, et al. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell. 2015;160(1-2):62–73. doi: 10.1016/j.cell.2014.11.047.
   PubMed Web of Science ®Google Scholar
• Lee E, Hwang I, Park S, et al. MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration. Cell Death Differ. 2019;26(2):213–228. doi: 10.1038/s41418-018-0124-5.
   PubMed Web of Science ®Google Scholar
• Parnetti L, Paciotti S, Eusebi P, et al. Cerebrospinal fluid β-glucocerebrosidase activity is reduced in Parkinson’s disease patients. Mov Disord. 2017;32(10):1423–1431. doi: 10.1002/mds.27136.
   PubMed Web of Science ®Google Scholar
• Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361(17):1651–1661. doi: 10.1056/NEJMoa0901281.
   PubMed Web of Science ®Google Scholar
• Marques TM, van Rumund A, Oeckl P, et al. Serum NFL discriminates Parkinson disease from atypical Parkinsonisms. Neurology. 2019;92(13):e1479–e1486. doi: 10.1212/WNL.0000000000007179.
   PubMed Web of Science ®Google Scholar
• Aamodt WW, Waligorska T, Shen J, et al. Neurofilament light chain as a biomarker for cognitive decline in Parkinson disease. Mov Disord. 2021;36(12):2945–2950. doi: 10.1002/mds.28779.
   PubMed Web of Science ®Google Scholar
• Vijiaratnam N, Lawton M, Heslegrave AJ, PRoBaND clinical consortium., et al. Combining biomarkers for prognostic modelling of Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2022;93(7):707–715. doi: 10.1136/jnnp-2021-328365.
   PubMed Web of Science ®Google Scholar
• Kinumi T, Kimata J, Taira T, et al. Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxide-mediated oxidation in vivo in human umbilical vein endothelial cells. Biochem Biophys Res Commun. 2004;317(3):722–728. doi: 10.1016/j.bbrc.2004.03.110.
   PubMed Web of Science ®Google Scholar
• Zhao ZH, Chen ZT, Zhou RL, et al. Increased DJ-1 and α-synuclein in plasma neural-derived exosomes as potential markers for Parkinson’s disease. Front Aging Neurosci. 2018;10:438. doi: 10.3389/fnagi.2018.00438.
   PubMed Web of Science ®Google Scholar
• Shi M, Zabetian CP, Hancock AM, et al. Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson’s disease. Neurosci Lett. 2010;480(1):78–82. doi: 10.1016/j.neulet.2010.06.009.
   PubMed Web of Science ®Google Scholar
• Hong Z, Shi M, Chung KA, et al. DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain. 2010;133(Pt 3):713–726. doi: 10.1093/brain/awq008.
   PubMed Web of Science ®Google Scholar
• Shi M, Bradner J, Hancock AM, et al. Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression. Ann Neurol. 2011;69(3):570–580. doi: 10.1002/ana.22311.
   PubMed Web of Science ®Google Scholar
• Salvesen L, Bech S, Lokkegaard A, et al. The DJ-1 concentration in cerebrospinal fluid does not differentiate among Parkinsonian syndromes. Parkinsonism Relat Disord. 2012;18(7):899–901. doi: 10.1016/j.parkreldis.2012.03.013.
   PubMed Web of Science ®Google Scholar
• Gui Y, Liu H, Zhang L, et al. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget. 2015;6(35):37043–37053. doi: 10.18632/oncotarget.6158.
   PubMedGoogle Scholar
• Yalçınkaya N, Haytural H, Bilgiç B, et al. Expression changes of genes associated with apoptosis and survival processes in Parkinson’s disease. Neurosci Lett. 2016;615:72–77. doi: 10.1016/j.neulet.2016.01.029.
   PubMed Web of Science ®Google Scholar
• Kang WY, Yang Q, Jiang XF, et al. Salivary DJ-1 could be an indicator of Parkinson’s disease progression. Front Aging Neurosci. 2014;6:102. doi: 10.3389/fnagi.2014.00102.
   PubMed Web of Science ®Google Scholar
• Masters JM, Noyce AJ, Warner TT, et al. Elevated salivary protein in Parkinson’s disease and salivary DJ-1 as a potential marker of disease severity. Parkinsonism Relat Disord. 2015;21(10):1251–1255. doi: 10.1016/j.parkreldis.2015.07.021.
   PubMed Web of Science ®Google Scholar
• Saito Y, Hamakubo T, Yoshida Y, et al. Preparation and application of monoclonal antibodies against oxidized DJ-1. Significant elevation of oxidized DJ-1 in erythrocytes of early-stage Parkinson disease patients. Neurosci Lett. 2009;465(1):1–5. doi: 10.1016/j.neulet.2009.08.074.
   PubMed Web of Science ®Google Scholar
• Saito Y, Akazawa-Ogawa Y, Matsumura A, et al. Oxidation and interaction of DJ-1 with 20S proteasome in the erythrocytes of early stage Parkinson’s disease patients. Sci Rep. 2016;6(1):30793. doi: 10.1038/srep30793.
   PubMedGoogle Scholar
• Akazawa YO, Saito Y, Hamakubo T, et al. Elevation of oxidized DJ-1 in the brain and erythrocytes of Parkinson disease model animals. Neurosci Lett. 2010;483(3):201–205. doi: 10.1016/j.neulet.2010.08.007.
   PubMed Web of Science ®Google Scholar
• Ragland M, Hutter C, Zabetian C, et al. Association between the ubiquitin carboxyl-terminal esterase L1 gene (UCHL1) S18Y variant and Parkinson’s disease: a HuGE review and meta-analysis. Am J Epidemiol. 2009;170(11):1344–1357. doi: 10.1093/aje/kwp288.
   PubMed Web of Science ®Google Scholar
• Ng ASL, Tan YJ, Lu Z, et al. Plasma ubiquitin C-terminal hydrolase L1 levels reflect disease stage and motor severity in Parkinson’s disease. Aging (Albany NY). 2020;12(2):1488–1495. doi: 10.18632/aging.102695.
   PubMedGoogle Scholar
• Liu C, Xue Y, Liu MF, et al. Orexin and Parkinson’s disease: a protective neuropeptide with therapeutic potential. Neurochem Int. 2020;138:104754. doi: 10.1016/j.neuint.2020.104754.
   PubMed Web of Science ®Google Scholar
• McDowell KA, Hadjimarkou MM, Viechweg S, et al. Sleep alterations in an environmental neurotoxin-induced model of Parkinsonism. Exp Neurol. 2010;226(1):84–89. doi: 10.1016/j.expneurol.2010.08.005.
   PubMed Web of Science ®Google Scholar
• Bubser M, Fadel JR, Jackson LL, et al. Dopaminergic regulation of orexin neurons. Eur J Neurosci. 2005;21(11):2993–3001. doi: 10.1111/j.1460-9568.2005.04121.x.
   PubMed Web of Science ®Google Scholar
• Overeem S, van Hilten JJ, Ripley B, et al. Normal hypocretin-1 levels in Parkinson’s disease patients with excessive daytime sleepiness. Neurology. 2002;58(3):498–499. doi: 10.1212/wnl.58.3.498.
   PubMed Web of Science ®Google Scholar
• Yasui K, Inoue Y, Kanbayashi T, et al. CSF orexin levels of Parkinson’s disease, dementia with lewy bodies, progressive supranuclear palsy and corticobasal degeneration. J Neurol Sci. 2006;250(1-2):120–123. doi: 10.1016/j.jns.2006.08.004.
   PubMed Web of Science ®Google Scholar
• Drouot X, Moutereau S, Nguyen JP, et al. Low levels of ventricular CSF orexin/hypocretin in advanced PD. Neurology. 2003;61(4):540–543. doi: 10.1212/01.wnl.0000078194.53210.48.
   PubMed Web of Science ®Google Scholar
• Weinecki M, Werth E, Poryazova R, et al. Progressive dopamine and hypocretin deficiencies in Parkinson’s disease: is there an impact on sleep and wakefulness? J Sleep Res. 2012;21(6):710–717. doi: 10.1111/j.1365-2869.2012.01027.x.
   PubMed Web of Science ®Google Scholar
• Hirayama M, Nakamura T, Watanabe H, et al. Urinary 8-hydroxydeoxyguanosine correlate with hallucinations rather than motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord. 2011;17(1):46–49. doi: 10.1016/j.parkreldis.2010.11.004.
   PubMed Web of Science ®Google Scholar
• Kikuchi A, Takeda A, Onodera H, et al. Systemic increase of oxidative nucleic acid damage in Parkinson’s disease and multiple system atrophy. Neurobiol Dis. 2002;9(2):244–248. doi: 10.1006/nbdi.2002.0466.
   PubMed Web of Science ®Google Scholar
• Gmitterová K, Heinemann U, Gawinecka J, et al. 8-OHdG in cerebrospinal fluid as a marker of oxidative stress in various neurodegenerative diseases. Neurodegener Dis. 2009;6(5-6):263–269. doi: 10.1159/000237221.
   PubMed Web of Science ®Google Scholar
• Sato S, Mizuno Y, Hattori N. Urinary 8-hydroxyde­oxyguanosine levels as a biomarker for progression of Parkinson disease. Neurology. 2005;64(6):1081–1083. doi: 10.1212/01.WNL.0000154597.24838.6B.
   PubMed Web of Science ®Google Scholar
• Vermeiren Y, De Deyn PP. Targeting the norepinephrinergic system in Parkinson’s disease and related disorders: the locus coeruleus story. Neurochem Int. 2017;102:22–32. doi: 10.1016/j.neuint.2016.11.009.
   PubMed Web of Science ®Google Scholar
• Goldstein DS, Holmes C, Sharabi Y. Cerebrospinal fluid biomarkers of Central catecholamine deficiency in Parkinson’s disease and other synucleinopathies. Brain. 2012;135(Pt 6):1900–1913. doi: 10.1093/brain/aws055.
   PubMed Web of Science ®Google Scholar
• Cerroni R, Liguori C, Stefani A, et al. Increased noradrenaline as an additional cerebrospinal fluid biomarker in PSP-like parkinsonism. Front Aging Neurosci. 2020;12:126. doi: 10.3389/fnagi.2020.00126.
   PubMed Web of Science ®Google Scholar
• Katunina EA, Blokhin V, Nodel MR, et al. Searching for biomarkers in the blood of patients at risk of developing Parkinson’s disease at the prodromal stage. Int J Mol Sci. 2023;24(3):1842. doi: 10.3390/ijms24031842.
   PubMed Web of Science ®Google Scholar
• Wen M, Zhou B, Chen Y-H, et al. Serum uric acid levels in patients with Parkinson’s disease: a meta-analysis. PLoS One. 2017;12(3):e0173731. doi: 10.1371/journal.pone.0173731.
   PubMed Web of Science ®Google Scholar
• de Lau LM, Koudstaal PJ, Hofman A, et al. Serum uric acid levels and the risk of Parkinson disease. Ann Neurol. 2005;58(5):797–800. doi: 10.1002/ana.20663.
   PubMed Web of Science ®Google Scholar
• Pellecchia MT, Savastano R, Moccia M, et al. Lower serum uric acid is associated with mild cognitive impairment in early Parkinson’s disease: a 4-year follow-up study. J Neural Transm (Vienna). 2016;123(12):1399–1402. doi: 10.1007/s00702-016-1622-6.
   PubMed Web of Science ®Google Scholar
• Kobylecki CJ, Nordestgaard BG, Afzal S. Plasma urate and risk of Parkinson’s disease: a mendelian randomization study. Ann Neurol. 2018;84(2):178–190. doi: 10.1002/ana.25292.
   PubMed Web of Science ®Google Scholar
• Chang KH, Cheng ML, Tang HY, et al. Alternations of metabolic profile and kynurenine metabolism in the plasma of Parkinson’s disease. Mol Neurobiol. 2018;55(8):6319–6328. doi: 10.1007/s12035-017-0845-3.
   PubMed Web of Science ®Google Scholar
• Heilman PL, Wang EW, Lewis MM, et al. Tryptophan metabolites are associated with symptoms and nigral pathology in Parkinson’s disease. Mov Disord. 2020;35(11):2028–2037. doi: 10.1002/mds.28202.
   PubMed Web of Science ®Google Scholar
• Lewitt PA, Li J, Lu M, Arizona Parkinson’s Disease Consortium, et al. 3-hydroxykynurenine and other Parkinson’s disease biomarkers discovered by metabolomic analysis. Mov Disord. 2013;28(12):1653–1660. doi: 10.1002/mds.25555.
   PubMed Web of Science ®Google Scholar
• Gjessing LR, Gjesdahl P, Dietrichson P, et al. Free amino acids in the cerebrospinal fluid in old age and in Parkinson’s disease. Eur Neurol. 1974;12(1):33–37. doi: 10.1159/000114602.
   PubMed Web of Science ®Google Scholar
• Havelund JF, Andersen AD, Binzer M, et al. Changes in kynurenine pathway metabolism in Parkinson patients with L-DOPA-induced dyskinesia. J Neurochem. 2017;142(5):756–766. doi: 10.1111/jnc.14104.
   PubMed Web of Science ®Google Scholar
• Giasson BI, Murray IV, Trojanowski JQ, et al. A hydrophobic stretch of 12 amino acid residues in the Middle of alpha-synuclein is essential for filament assembly. J Biol Chem. 2001; 26276(4):2380–2386. doi: 10.1074/jbc.M008919200.
   PubMed Web of Science ®Google Scholar
• Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276(5321):2045–2047. doi: 10.1126/science.276.5321.2045.
   PubMed Web of Science ®Google Scholar
• Surguchov A. Intracellular dynamics of synucleins: “here, there and everywhere.” Int Rev Cell Mol Biol. 2015;320:103–169. doi: 10.1016/bs.ircmb.2015.07.007.
   PubMed Web of Science ®Google Scholar
• Chinta SJ, Mallajosyula JK, Rane A, et al. Mitochondrial α-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett. 2010;486(3):235–239. doi: 10.1016/j.neulet.2010.09.061.
   PubMed Web of Science ®Google Scholar
• Mollenhauer B, Caspell-Garcia CJ, Coffey CS, PPMI study., et al. Longitudinal analyses of cerebrospinal fluid α-synuclein in prodromal and early Parkinson’s disease. Mov Disord. 2019;34(9):1354–1364. doi: 10.1002/mds.27806.
   PubMed Web of Science ®Google Scholar
• Song Z, Shen J, Liu Y, et al. Lower plasma α-synuclein levels are associated with cognitive impairment in Parkinson’s disease. Clin Lab. 2021;67(5):1176–1183. doi: 10.7754/Clin.Lab.2020.200852.
   Web of Science ®Google Scholar
• Gibbons CH, Garcia J, Wang N, et al. The diagnostic discrimination of cutaneous α-synuclein deposition in Parkinson disease. Neurology. 2016;87(5):505–512. doi: 10.1212/WNL.0000000000002919.
   PubMed Web of Science ®Google Scholar
• Shannon KM, Keshavarzian A, Dodiya HB, et al. Is alpha-synuclein in the colon a biomarker for premotor parkinson’s disease? Evidence from 3 cases. Mov Disord. 2012;27(6):716–719. doi: 10.1002/mds.25020.
   PubMed Web of Science ®Google Scholar
• McGeer PL, Itagaki S, Boyes BE, et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 1988;38(8):1285–1291. doi: 10.1212/wnl.38.8.1285.
   PubMed Web of Science ®Google Scholar
• Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21(7):677–687. doi: 10.1038/nm.3893.
   PubMed Web of Science ®Google Scholar
• Lee SJ. Origins and effects of extracellular alpha-synuclein: implications in Parkinson’s disease. J Mol Neurosci. 2008;34(1):17–22. doi: 10.1007/s12031-007-0012-9.
   PubMed Web of Science ®Google Scholar
• Ferrari CC, Pott Godoy MC, Tarelli R, et al. Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1beta in the substantia nigra. Neurobiol Dis. 2006;24(1):183–193. doi: 10.1016/j.nbd.2006.06.013.
   PubMed Web of Science ®Google Scholar
• Codolo G, Plotegher N, Pozzobon T, et al. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS One. 2013;8(1):e55375. doi: 10.1371/journal.pone.0055375.
   PubMed Web of Science ®Google Scholar
• Parnetti L, Gaetani L, Eusebi P, et al. CSF and blood biomarkers for parkinson’s disease. Lancet Neurol. 2019;18(6):573–586. doi: 10.1016/S1474-4422(19)30024-9.
   PubMed Web of Science ®Google Scholar
• Parnetti L, Chiasserini D, Persichetti E, et al. Cerebrospinal fluid lysosomal enzymes and alpha-synuclein in Parkinson’s disease. Mov Disord. 2014;29(8):1019–1027. doi: 10.1002/mds.25772.
   PubMed Web of Science ®Google Scholar
• Cilia R, Tunesi S, Marotta G, et al. Survival and dementia in GBA-associated Parkinson’s disease: the mutation matters. Ann Neurol. 2016;80(5):662–673. doi: 10.1002/ana.24777.
   PubMed Web of Science ®Google Scholar
• Gaetani L, Paolini Paoletti F, Bellomo G, et al. CSF and blood biomarkers in neuroinflammatory and neurodegenerative diseases: implications for treatment. Trends Pharmacol Sci. 2020;41(12):1023–1037. doi: 10.1016/j.tips.2020.09.011.
   PubMed Web of Science ®Google Scholar
• Gaiottino J, Norgren N, Dobson R, et al. Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One. 2013;8(9):e75091. doi: 10.1371/journal.pone.0075091.
   PubMed Web of Science ®Google Scholar
• Mollenhauer B, Dakna M, Kruse N, et al. Validation of serum neurofilament light chain as a biomarker of Parkinson’s disease progression. Mov Disord. 2020;35(11):1999–2008. doi: 10.1002/mds.28206.
   PubMed Web of Science ®Google Scholar
• Repici M, Giorgini F. DJ-1 in Parkinson’s disease: clinical insights and therapeutic perspectives. J Clin Med. 2019; 8(9):1377. doi: 10.3390/jcm8091377.
   PubMed Web of Science ®Google Scholar
• Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism. Science. 2003;299(5604):256–259. doi: 10.1126/science.1077209.
   PubMed Web of Science ®Google Scholar
• Huang M, Chen S. DJ-1 in neurodegenerative diseases: pathogenesis and clinical application. Prog Neurobiol. 2021;204:102114. doi: 10.1016/j.pneurobio.2021.102114.
   PubMed Web of Science ®Google Scholar
• Ishiwatari S, Takahashi M, Yasuda C, et al. The protective role of DJ-1 in ultraviolet-induced damage of human skin: DJ-1 levels in the stratum corneum as an indicator of antioxidative defense. Arch Dermatol Res. 2015;307(10):925–935. doi: 10.1007/s00403-015-1605-8.
   PubMed Web of Science ®Google Scholar
• Kasten M, Hartmann C, Hampf J, et al. Genotype-phenotype relations for the Parkinson’s disease genes parkin, PINK1, DJ1: MDSGene systematic review. Mov Disord. 2018;33(5):730–741. doi: 10.1002/mds.27352.
   PubMed Web of Science ®Google Scholar
• Mondello S, Constantinescu R, Zetterberg H, et al. CSF α-synuclein and UCH-L1 levels in Parkinson’s disease and atypical Parkinsonian disorders. Parkinsonism Relat Disord. 2014;20(4):382–387. doi: 10.1016/j.parkreldis.2014.01.011.
   PubMed Web of Science ®Google Scholar
• Scammell TE, Winrow CJ. Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2011;51(1):243–266. doi: 10.1146/annurev-pharmtox-010510-100528.
   PubMedGoogle Scholar
• van der Zee S, Vermeiren Y, Fransen E, et al. Monoaminergic markers across the cognitive spectrum of lewy body disease. J Parkinsons Dis. 2018;8(1):71–84. doi: 10.3233/JPD-171228.
   PubMedGoogle Scholar
• Hawkes CH, Del Tredici K, Braak H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol. 2007;33(6):599–614. doi: 10.1111/j.1365-2990.2007.00874.x.
   PubMed Web of Science ®Google Scholar
• Scheperjans F, Aho V, Pereira PA, et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord. 2015;30(3):350–358. doi: 10.1002/mds.26069.
   PubMed Web of Science ®Google Scholar
• Nowak JM, Kopczyński M, Friedman A, et al. Microbiota dysbiosis in Parkinson disease-in search of a biomarker. Biomedicines. 2022;10(9):2057. doi: 10.3390/biomedicines10092057.
   PubMed Web of Science ®Google Scholar
• Schönfeld P, Wojtczak L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res. 2016;57(6):943–954. doi: 10.1194/jlr.R067629.
   PubMed Web of Science ®Google Scholar
• Willkommen D, Lucio M, Moritz F, et al. Metabolomic investigations in cerebrospinal fluid of Parkinson’s disease. PLoS One. 2018;13(12):e0208752. doi: 10.1371/journal.pone.0208752.
   PubMed Web of Science ®Google Scholar
• LeWitt PA, Li J, Lu M, Parkinson Study Group–DATATOP Investigators., et al. Metabolomic biomarkers as strong correlates of parkinson disease progression. Neurology. 2017;88(9):862–869. doi: 10.1212/WNL.0000000000003663.
   PubMed Web of Science ®Google Scholar
• He R, Yan X, Guo J, et al. Recent advances in biomarkers for parkinson’s disease. Front Aging Neurosci. 2018;10:305. doi: 10.3389/fnagi.2018.00305.
   PubMed Web of Science ®Google Scholar
• Ascherio A, LeWitt PA, Xu K, Parkinson Study Group DATATOP Investigators., et al. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch Neurol. 2009;66(12):1460–1468. doi: 10.1001/archneurol.2009.247.
   PubMed Web of Science ®Google Scholar
• Sohmiya M, Tanaka M, Tak NW, et al. Redox status of plasma coenzyme Q10 indicates elevated systemic oxidative stress in Parkinson’s disease. J Neurol Sci. 2004;223(2):161–166. doi: 10.1016/j.jns.2004.05.007.
   PubMed Web of Science ®Google Scholar
• Foulds PG, Diggle P, Mitchell JD, et al. A longitudinal study on α-synuclein in blood plasma as a biomarker for Parkinson’s disease. Sci Rep. 2013;3(1):2540. doi: 10.1038/srep02540.
   PubMedGoogle Scholar
• Scalzo P, Kümmer A, Bretas TL, et al. Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson’s disease. J Neurol. 2010;257(4):540–545. doi: 10.1007/s00415-009-5357-2.
   PubMed Web of Science ®Google Scholar
• Fernandez AM, Torres-Alemán I. The many faces of insulin-like peptide signalling in the brainNat. Nat Rev Neurosci. 2012;13(4):225–239. doi: 10.1038/nrn3209.
   PubMed Web of Science ®Google Scholar
• Bernhard FP, Heinzel S, Binder G, et al. Insulin-Like growth factor 1 (IGF-1) in Parkinson’s disease: potential as trait-, progression- and prediction marker and confounding factors. PLoS One. 2016;11(3):e0150552. doi: 10.1371/journal.pone.0150552.
   PubMed Web of Science ®Google Scholar