{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T09:11:29Z","timestamp":1784970689096,"version":"3.55.0"},"reference-count":90,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T00:00:00Z","timestamp":1722384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish MCIN\/AEI\/10.13039\/501100011033","award":["PID2021-126600OB-I00"],"award-info":[{"award-number":["PID2021-126600OB-I00"]}]},{"name":"\u201cERDF A way of making Europe\u201d","award":["PID2021-126600OB-I00"],"award-info":[{"award-number":["PID2021-126600OB-I00"]}]},{"name":"\u201cEuropean Union\u201d","award":["PID2021-126600OB-I00"],"award-info":[{"award-number":["PID2021-126600OB-I00"]}]},{"name":"\u201cEuropean Union Next Generation EU\/PRTR\u201d","award":["PID2021-126600OB-I00"],"award-info":[{"award-number":["PID2021-126600OB-I00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The first objective is to highlight the lack of tools to measure whether a given intervention affords neuroprotection in patients with Alzheimer\u2019s or Parkinson\u2019s diseases. A second aim is to present the primary outcome measures used in clinical trials in cohorts of patients with neurodegenerative diseases. The final aim is to discuss whether metabolomics using body fluids may lead to the discovery of biomarkers of neuroprotection. Information on the primary outcome measures in clinical trials related to Alzheimer\u2019s and Parkinson\u2019s disease registered since 2018 was collected. We analysed the type of measures selected to assess efficacy, not in terms of neuroprotection since, as stated in the aims, there is not yet any marker of neuroprotection. Proteomic approaches using plasma or CSF have been proposed. PET could estimate the extent of lesions, but disease progression does not necessarily correlate with a change in tracer uptake. We propose some alternatives based on considering the metabolome. A new opportunity opens with metabolomics because there have been impressive technological advances that allow the detection, among others, of metabolites related to mitochondrial function and mitochondrial structure in serum and\/or cerebrospinal fluid; some of the differentially concentrated metabolites can become reliable biomarkers of neuroprotection.<\/jats:p>","DOI":"10.3390\/cells13151288","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T17:16:49Z","timestamp":1722446209000},"page":"1288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Potential of Metabolomics to Find Proper Biomarkers for Addressing the Neuroprotective Efficacy of Drugs Aimed at Delaying Parkinson\u2019s and Alzheimer\u2019s Disease Progression"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2549-4919","authenticated-orcid":false,"given":"Rafael","family":"Franco","sequence":"first","affiliation":[{"name":"Molecular Neurobiology Laboratory, Departament de Bioquimica i Biomedicina Molecular, Universitat de Barcelona, Diagonal 643, 08028 Barcelona, Spain"},{"name":"Network Center Neurodegenerative Diseases, CiberNed, Spanish National Health Center Carlos iii, Monforte de Lemos 3, 28029 Madrid, Spain"},{"name":"School of Chemistry, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7296-949X","authenticated-orcid":false,"given":"Claudia","family":"Garrig\u00f3s","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Laboratory, Departament de Bioquimica i Biomedicina Molecular, Universitat de Barcelona, Diagonal 643, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaume","family":"Lillo","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Laboratory, Departament de Bioquimica i Biomedicina Molecular, Universitat de Barcelona, Diagonal 643, 08028 Barcelona, Spain"},{"name":"Network Center Neurodegenerative Diseases, CiberNed, Spanish National Health Center Carlos iii, Monforte de Lemos 3, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2078-6819","authenticated-orcid":false,"given":"Rafael","family":"Rivas-Santisteban","sequence":"additional","affiliation":[{"name":"Network Center Neurodegenerative Diseases, CiberNed, Spanish National Health Center Carlos iii, Monforte de Lemos 3, 28029 Madrid, Spain"},{"name":"Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Campus Bellaterra, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a009399","DOI":"10.1101\/cshperspect.a009399","article-title":"\u03b1-Synuclein in Parkinson\u2019s Disease","volume":"2","author":"Stefanis","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1002\/mds.26424","article-title":"MDS clinical diagnostic criteria for Parkinson\u2019s disease","volume":"30","author":"Postuma","year":"2015","journal-title":"Mov. Disord."},{"key":"ref_3","first-page":"CD012558","article-title":"Clinical judgement by primary care physicians for the diagnosis of all-cause dementia or cognitive impairment in symptomatic people","volume":"6","author":"Creavin","year":"2022","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1515\/dx-2015-0031","article-title":"Evaluation of DSM-5 and IWG-2 criteria for the diagnosis of Alzheimer\u2019s disease and dementia with Lewy bodies","volume":"3","author":"Baker","year":"2016","journal-title":"Diagnosis"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Franco, R., and Cedazo-Minguez, A. (2014). Successful therapies for Alzheimer\u2019s disease: Why so many in animal models and none in humans?. Front. Pharmacol., 5.","DOI":"10.3389\/fphar.2014.00146"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.biopsych.2017.08.010","article-title":"Anti-Amyloid-\u00df Monoclonal Antibodies for Alzheimer\u2019s Disease: Pitfalls and Promise","volume":"83","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1056\/NEJMoa1705971","article-title":"Trial of Solanezumab for Mild Dementia Due to Alzheimer\u2019s Disease","volume":"378","author":"Honig","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/BF00341704","article-title":"Additional experimental studies on L-DOPA in Parkinson\u2019s syndrome and reserpine parkinsonism","volume":"206","author":"Birkmayer","year":"1964","journal-title":"Arch. Psychiatr. Nervenkr."},{"key":"ref_9","first-page":"9","article-title":"The discovery of dopamine deficiency in the parkinsonian brain","volume":"70","author":"Hornykiewicz","year":"2006","journal-title":"J. Neural Transm. Suppl."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1007\/s40265-016-0566-3","article-title":"Drug-Induced Dyskinesia, Part 1: Treatment of Levodopa-Induced Dyskinesia","volume":"76","author":"Vijayakumar","year":"2016","journal-title":"Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1080\/01616412.2000.11740667","article-title":"Advances in neurostimulation for movement disorders","volume":"22","author":"Gross","year":"2000","journal-title":"Neurol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S0301-0082(99)00015-5","article-title":"From experimentation to the surgical treatment of Parkinson\u2019s disease: Prelude or suite in basal ganglia research?","volume":"59","author":"Gross","year":"1999","journal-title":"Prog. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"337","DOI":"10.2165\/00002512-199914050-00002","article-title":"Treating and preventing levodopa-induced dyskinesias: Current and future strategies","volume":"14","author":"Durif","year":"1999","journal-title":"Drugs Aging"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1136\/jnnp.56.3.268","article-title":"Chronic thalamic stimulation improves tremor and levodopa induced dyskinesias in Parkinson\u2019s disease","volume":"56","author":"Blond","year":"1993","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1111\/joim.13541","article-title":"Deep brain stimulation for Parkinson\u2019s disease","volume":"292","author":"Hariz","year":"2022","journal-title":"J. Intern. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2118818119","DOI":"10.1073\/pnas.2118818119","article-title":"Kurarinone alleviated Parkinson\u2019s disease via stabilization of epoxyeicosatrienoic acids in animal model","volume":"119","author":"Sun","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s40035-022-00307-z","article-title":"Tauroursodeoxycholic acid: A potential therapeutic tool in neurodegenerative diseases","volume":"11","author":"Khalaf","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhang, C., Zhao, M., Wang, B., Su, Z., Guo, B., Qin, L., Zhang, W., and Zheng, R. (2021). The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson\u2019s disease. Redox Biol., 47.","DOI":"10.1016\/j.redox.2021.102134"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cui, C., Han, Y., Li, H., Yu, H., Zhang, B., and Li, G. (2022). Curcumin-driven reprogramming of the gut microbiota and metabolome ameliorates motor deficits and neuroinflammation in a mouse model of Parkinson\u2019s disease. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.887407"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"108963","DOI":"10.1016\/j.neuropharm.2022.108963","article-title":"Urolithin A promotes mitophagy and suppresses NLRP3 inflammasome activation in lipopolysaccharide-induced BV2 microglial cells and MPTP-induced Parkinson\u2019s disease model","volume":"207","author":"Qiu","year":"2022","journal-title":"Neuropharmacology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Park, J.S., Choe, K., Lee, H.J., Park, T.J., and Kim, M.O. (2023). Neuroprotective effects of osmotin in Parkinson\u2019s disease-associated pathology via the AdipoR1\/MAPK\/AMPK\/mTOR signaling pathways. J. Biomed. Sci., 30.","DOI":"10.1186\/s12929-023-00961-z"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1038\/s41418-021-00767-2","article-title":"The DJ1-Nrf2-STING axis mediates the neuroprotective effects of Withaferin A in Parkinson\u2019s disease","volume":"28","author":"Zhao","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9424582","DOI":"10.1155\/2021\/9424582","article-title":"Neuroprotective Effect of Ceftriaxone on MPTP-Induced Parkinson\u2019s Disease Mouse Model by Regulating Inflammation and Intestinal Microbiota","volume":"2021","author":"Zhou","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Que, R., Zheng, J., Chang, Z., Zhang, W., Li, H., Xie, Z., Huang, Z., Wang, H.T., Xu, J., and Jin, D. (2021). Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson\u2019s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.794770"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8783","DOI":"10.1038\/s41598-023-35975-y","article-title":"Necrosulfonamide exerts neuroprotective effect by inhibiting necroptosis, neuroinflammation, and \u03b1-synuclein oligomerization in a subacute MPTP mouse model of Parkinson\u2019s disease","volume":"13","author":"Leem","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_26","first-page":"1","article-title":"GlyT1 Inhibition by NFPS Promotes Neuroprotection in Amyloid-\u00df-Induced Alzheimer\u2019s Disease Animal Model","volume":"49","author":"Ulrich","year":"2024","journal-title":"Neurochem. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"118498","DOI":"10.1016\/j.jep.2024.118498","article-title":"Norboldine improves cognitive impairment and pathological features in Alzheimer\u2019s disease by activating AMPK\/GSK3\u00df\/Nrf2 signaling pathway","volume":"333","author":"Zeng","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_28","first-page":"1","article-title":"Neuroprotective Effect of Chlorogenic Acid in an Animal Model of Sporadic Alzheimer\u2019s Disease Induced by Streptozotocin","volume":"61","author":"Bezerra","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e14814","DOI":"10.1111\/cns.14814","article-title":"The selective butyrylcholinesterase inhibitor UW-MD-95 shows symptomatic and neuroprotective effects in a pharmacological mouse model of Alzheimer\u2019s disease","volume":"30","author":"Carles","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ndukwe, K., Serrano, P.A., Rockwell, P., Xie, L., and Figueiredo-Pereira, M. (2023). Histone deacetylase inhibitor RG2833 has therapeutic potential for Alzheimer\u2019s disease in females. bioRxiv.","DOI":"10.1101\/2023.12.26.573348"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lu, Z., Fu, J., Wu, G., Yang, Z., Wu, X., Wang, D., You, Z., Nie, Z., and Sheng, Q. (2023). Neuroprotection and Mechanism of Gas-miR36-5p from Gastrodia elata in an Alzheimer\u2019s Disease Model by Regulating Glycogen Synthase Kinase-3\u00df. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242417295"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s13024-023-00692-7","article-title":"Amyloid-\u00df specific regulatory T cells attenuate Alzheimer\u2019s disease pathobiology in APP\/PS1 mice","volume":"18","author":"Yeapuri","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kolonics, A., Bori, Z., Torma, F., Abraham, D., Feh\u00e9r, J., and Radak, Z. (2023). Exercise combined with postbiotics treatment results in synergistic improvement of mitochondrial function in the brain of male transgenic mice for Alzheimer\u2019s disease. BMC Neurosci., 24.","DOI":"10.1186\/s12868-023-00836-x"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.1021\/acs.jnatprod.3c00894","article-title":"Isolinderalactone Ameliorates the Pathology of Alzheimer\u2019s Disease by Inhibiting the JNK Signaling Pathway","volume":"86","author":"Xiong","year":"2023","journal-title":"J. Nat. Prod."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ali, J., Khan, A., Park, J.S., Tahir, M., Ahmad, W., Choe, K., and Kim, M.O. (2023). Neuroprotective Effects of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) against Amyloid-\u00df-Induced Alzheimer\u2019s Disease Mouse Model. Nutrients, 15.","DOI":"10.3390\/nu15234986"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"111312","DOI":"10.1016\/j.intimp.2023.111312","article-title":"Attenuated memory impairment and neuroinflammation in Alzheimer\u2019s disease by aucubin via the inhibition of ERK-FOS axis","volume":"126","author":"Wang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Xi, Y., Zhang, Y., Zhou, Y., Liu, Q., Chen, X., Liu, X., Grune, T., Shi, L., Hou, M., and Liu, Z. (2023). Effects of methionine intake on cognitive function in mild cognitive impairment patients and APP\/PS1 Alzheimer\u2019s Disease model mice: Role of the cystathionine-\u00df-synthase\/H2S pathway. Redox Biol., 59.","DOI":"10.1016\/j.redox.2022.102595"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"85","DOI":"10.2174\/1871527320666210303111537","article-title":"Conifer Essential Oils Reversed Amyloid Beta1-42 Action by ModulatingBDNF and ARC Expression in The Rat Hippocampus","volume":"21","author":"Postu","year":"2021","journal-title":"CNS Neurol. Disord.-Drug Targets"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.brainresbull.2021.11.004","article-title":"TO901317 activation of LXR-dependent pathways mitigate amyloid-beta peptide-induced neurotoxicity in 3D human neural stem cell culture scaffolds and AD mice","volume":"178","author":"Chiang","year":"2022","journal-title":"Brain Res. Bull."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"111473","DOI":"10.1016\/j.nut.2021.111473","article-title":"Anthocyanin-rich blueberry extracts and anthocyanin metabolite protocatechuic acid promote autophagy-lysosomal pathway and alleviate neurons damage in in vivo and in vitro models of Alzheimer\u2019s disease","volume":"93","author":"Li","year":"2022","journal-title":"Nutrition"},{"key":"ref_41","first-page":"158","article-title":"Geniposidic Acid Confers Neuroprotective Effects in a Mouse Model of Alzheimer\u2019s Disease through Activation of a PI3K\/AKT\/GAP43 Regulatory Axis","volume":"9","author":"Chen","year":"2022","journal-title":"J. Prev. Alzheimer\u2019s Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3233\/JAD-215370","article-title":"JOTROL, a Novel Formulation of Resveratrol, Shows Beneficial Effects in the 3xTg-AD Mouse Model","volume":"86","author":"Dennison","year":"2022","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.jare.2021.03.012","article-title":"Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer\u2019s disease via inhibiting neuropathology and modulating gut microbiota","volume":"35","author":"Qu","year":"2022","journal-title":"J. Adv. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1111\/ene.15635","article-title":"Efficacy and safety of non-ergot dopamine-receptor agonists as an adjunct to levodopa in advanced Parkinson\u2019s disease: A network meta-analysis","volume":"30","author":"Chen","year":"2023","journal-title":"Eur. J. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S1474-4422(18)30405-8","article-title":"Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson\u2019s disease: A randomised, double-blind, placebo-controlled phase 3 trial","volume":"18","author":"LeWitt","year":"2019","journal-title":"Lancet. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Brown, S.D., Fiedler, J.D., and Finn, M.G. (2009). Assembly of Hybrid Bacteriophage Q\u00df Virus-Like Particles. Biochemistry, 48.","DOI":"10.1021\/bi901306p"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S1474-4422(12)70140-0","article-title":"Safety, tolerability, and antibody response of active A\u00df immunotherapy with CAD106 in patients with Alzheimer\u2019s disease: Randomised, double-blind, placebo-controlled, first-in-human study","volume":"11","author":"Winblad","year":"2012","journal-title":"Lancet. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1001\/jamaneurol.2020.5505","article-title":"Aggregated Tau Measured by Visual Interpretation of Flortaucipir Positron Emission Tomography and the Associated Risk of Clinical Progression of Mild Cognitive Impairment and Alzheimer Disease: Results From 2 Phase III Clinical Trials","volume":"78","author":"Lu","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s13550-020-00653-x","article-title":"Comparison of regional flortaucipir PET with quantitative tau immunohistochemistry in three subjects with Alzheimer\u2019s disease pathology: A clinicopathological study","volume":"10","author":"Pontecorvo","year":"2020","journal-title":"EJNMMI Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1038\/nrd.2017.155","article-title":"Tau-based therapies in neurodegeneration: Opportunities and challenges","volume":"16","author":"Li","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev-neuro-072116-031153","article-title":"Propagation of Tau Aggregates and Neurodegeneration","volume":"40","author":"Goedert","year":"2017","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1073\/pnas.84.7.2073","article-title":"Amyloid of neurofibrillary tangles of Guamanian parkinsonism-dementia and Alzheimer disease share identical amino acid sequence","volume":"84","author":"Guiroy","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1073\/pnas.82.12.4245","article-title":"Amyloid plaque core protein in Alzheimer disease and Down syndrome","volume":"82","author":"Masters","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Furcila, D., Dom\u00ednguez-\u00c1lvaro, M., DeFelipe, J., and Alonso-Nanclares, L. (2019). Subregional Density of Neurons, Neurofibrillary Tangles and Amyloid Plaques in the Hippocampus of Patients With Alzheimer\u2019s Disease. Front. Neuroanat., 13.","DOI":"10.3389\/fnana.2019.00099"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Murphy, M.P., Buzinova, V.A., and Johnson, C.E. (2024). The amyloid-\u00df peptide: Guilty as charged?. Biochim. Biophys. Acta. Mol. Basis Dis., 1870.","DOI":"10.1016\/j.bbadis.2023.166945"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"311","DOI":"10.3233\/JAD-2010-1221","article-title":"Alzheimer\u2019s Disease and the \u00df-Amyloid Peptide","volume":"19","author":"Murphy","year":"2010","journal-title":"J. Alzheimers. Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","article-title":"Toward defining the preclinical stages of Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Sperling","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/ana.22248","article-title":"Longitudinal assessment of AB and cognition in aging and Alzheimer disease","volume":"69","author":"Hyman","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_59","first-page":"326","article-title":"Blood Based Biomarker for Optimization of Early and Differential Diagnosis of Alzheimer\u2019s Dementia","volume":"90","author":"Hansen","year":"2022","journal-title":"Fortschr. Neurol. Psychiatr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"957","DOI":"10.4155\/bio-2018-0061","article-title":"Clinical biomarker validation","volume":"10","author":"Allinson","year":"2018","journal-title":"Bioanalysis"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kwon, E.H., Tennagels, S., Gold, R., Gerwert, K., Beyer, L., and T\u00f6nges, L. (2022). Update on CSF Biomarkers in Parkinson\u2019s Disease. Biomolecules, 12.","DOI":"10.3390\/biom12020329"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1001\/jamaneurol.2023.5319","article-title":"Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology","volume":"81","author":"Ashton","year":"2024","journal-title":"JAMA Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S1474-4422(23)00109-6","article-title":"Assessment of heterogeneity among participants in the Parkinson\u2019s Progression Markers Initiative cohort using \u03b1-synuclein seed amplification: A cross-sectional study","volume":"22","author":"Siderowf","year":"2023","journal-title":"Lancet. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1093\/clinchem\/hvad111","article-title":"Early and Accurate Diagnosis of Parkinson Disease May Be Rooted in Seed Amplification Assays","volume":"69","author":"Tropea","year":"2023","journal-title":"Clin. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Ikram, M., Park, T.J., Ali, T., and Kim, M.O. (2020). Antioxidant and neuroprotective effects of caffeine against Alzheimer\u2019s and parkinson\u2019s disease: Insight into the role of Nrf-2 and A2AR signaling. Antioxidants, 9.","DOI":"10.3390\/antiox9090902"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0165-0173(98)00004-6","article-title":"The role of neuronal growth factors in neurodegenerative disorders of the human brain","volume":"27","author":"Connor","year":"1998","journal-title":"Brain Res. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0165-0173(00)00030-8","article-title":"Neurotrophic factors in Alzheimer\u2019s and Parkinson\u2019s disease brain","volume":"33","author":"Siegel","year":"2000","journal-title":"Brain Res. Rev."},{"key":"ref_68","first-page":"597","article-title":"GDNF delivery for Parkinson\u2019s disease","volume":"97","author":"Patel","year":"2007","journal-title":"Diagn. Manag. Park. Dis. Neurosci. Park. Dis. Vol. 1"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S0166-2236(00)01899-3","article-title":"Recombinant proteins for neurodegenerative diseases: The delivery issue","volume":"24","author":"Aebischer","year":"2001","journal-title":"Trends Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1023\/A:1011911912174","article-title":"Localized Delivery of Proteins in the Brain: Can Transport Be Customized?","volume":"15","author":"Haller","year":"1998","journal-title":"Pharm. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1001\/archneur.2008.65.6.nct70003","article-title":"Serum urate as a predictor of clinical and radiographic progression in Parkinson disease","volume":"65","author":"Schwarzschild","year":"2008","journal-title":"Arch. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1001\/archneurol.2009.247","article-title":"Urate as a predictor of the rate of clinical decline in Parkinson disease","volume":"66","author":"Ascherio","year":"2009","journal-title":"Arch. Neurol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/ene.12533","article-title":"Presence and progression of non-motor symptoms in relation to uric acid in de novo Parkinson\u2019s disease","volume":"22","author":"Moccia","year":"2015","journal-title":"Eur. J. Neurol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1097\/NEN.0000000000000091","article-title":"Metabolomics of Human Brain Aging and Age-Related Neurodegenerative Diseases","volume":"73","author":"Ferrer","year":"2014","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_75","first-page":"28","article-title":"Comparing metabolomic and pathologic biomarkers alone and in combination for discriminating Alzheimer\u2019s disease from normal cognitive aging","volume":"2","author":"Zhu","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"10802","DOI":"10.1021\/ac3028307","article-title":"Development of isotope labeling LC-MS for human salivary metabolomics and application to profiling metabolome changes associated with mild cognitive impairment","volume":"84","author":"Zheng","year":"2012","journal-title":"Anal. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1002\/elps.201300019","article-title":"Capillary electrophoresis-mass spectrometry-based metabolome analysis of serum and saliva from neurodegenerative dementia patients","volume":"34","author":"Tsuruoka","year":"2013","journal-title":"Electrophoresis"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.3233\/JAD-142319","article-title":"Sphingomyelin SM(d18:1\/18:0) is Significantly Enhanced in Cerebrospinal Fluid Samples Dichotomized by Pathological Amyloid-\u00df 42, Tau, and Phospho-Tau-181 Levels","volume":"44","author":"Koal","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.jalz.2017.01.020","article-title":"Metabolic network failures in Alzheimer\u2019s disease: A biochemical road map","volume":"13","author":"Toledo","year":"2017","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.neurobiolaging.2016.11.007","article-title":"What success can teach us about failure: The plasma metabolome of older adults with superior memory and lessons for Alzheimer\u2019s disease","volume":"51","author":"Mapstone","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Fiandaca, M.S., Zhong, X., Cheema, A.K., Orquiza, M.H., Chidambaram, S., Tan, M.T., Gresenz, C.R., FitzGerald, K.T., Nalls, M.A., and Singleton, A.B. (2015). Plasma 24-metabolite panel predicts preclinical transition to clinical stages of Alzheimer\u2019s disease. Front. Neurol., 6.","DOI":"10.3389\/fneur.2015.00237"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Wilkins, J.M., and Trushina, E. (2018). Application of metabolomics in Alzheimer\u2019s disease. Front. Neurol., 8.","DOI":"10.3389\/fneur.2017.00719"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Dom\u00ednguez, R., Gonz\u00e1lez-Dom\u00ednguez, \u00c1., Sayago, A., Gonz\u00e1lez-Sanz, J.D., Lechuga-Sancho, A.M., and Fern\u00e1ndez-Recamales, \u00c1. (2021). Mechanistic Insights into Alzheimer\u2019s Disease Unveiled through the Investigation of Disturbances in Central Metabolites and Metabolic Pathways. Biomedicines, 9.","DOI":"10.3390\/biomedicines9030298"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Trushina, E., Nemutlu, E., Zhang, S., Christensen, T., Camp, J., Mesa, J., Siddiqui, A., Tamura, Y., Sesaki, H., and Wengenack, T.M. (2012). Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer\u2019s Disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032737"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Bernal-Casas, D., Serrano-Mar\u00edn, J., S\u00e1nchez-Nav\u00e9s, J., Oller, J.M., and Franco, R. (2024). Advancing Personalized Medicine by Analytical Means: Selection of Three Metabolites That Allows Discrimination between Glaucoma, Diabetes, and Controls. Metabolites, 14.","DOI":"10.3390\/metabo14030149"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.jpha.2023.06.011","article-title":"Integrative multi-omics and systems bioinformatics in translational neuroscience: A data mining perspective","volume":"13","author":"Lim","year":"2023","journal-title":"J. Pharm. Anal."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"O\u2019Connor, L.M., O\u2019Connor, B.A., Zeng, J., and Lo, C.H. (2023). Data Mining of Microarray Datasets in Translational Neuroscience. Brain Sci., 13.","DOI":"10.3390\/brainsci13091318"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Nzoughet, J.K., Guehlouz, K., Leruez, S., Gohier, P., Bocca, C., Muller, J., Blanchet, O., Bonneau, D., Simard, G., and Milea, D. (2020). A Data Mining Metabolomics Exploration of Glaucoma. Metabolites, 10.","DOI":"10.3390\/metabo10020049"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Kr\u00f3l-Grzyma\u0142a, A., Sienkiewicz-Sz\u0142apka, E., Fiedorowicz, E., Rozmus, D., Cie\u015bli\u0144ska, A., and Grzybowski, A. (2022). Tear Biomarkers in Alzheimer\u2019s and Parkinson\u2019s Diseases, and Multiple Sclerosis: Implications for Diagnosis (Systematic Review). Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231710123"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1021\/acscentsci.2c01468","article-title":"Interpretable Machine Learning on Metabolomics Data Reveals Biomarkers for Parkinson\u2019s Disease","volume":"9","author":"Zhang","year":"2023","journal-title":"ACS Cent. Sci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/15\/1288\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:27:17Z","timestamp":1760110037000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/15\/1288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,31]]},"references-count":90,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["cells13151288"],"URL":"https:\/\/doi.org\/10.3390\/cells13151288","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,31]]}}}