Nanoscale flow cytometry-based quantification of blood-based extracellular vesicle biomarkers distinguishes MCI and Alzheimer's disease.
Alzheimer's disease
biomarker
dementia
extracellular vesicle
mild cognitive impairment
nanoflow cytometry
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
03 Jul 2024
03 Jul 2024
Historique:
revised:
09
05
2024
received:
15
02
2024
accepted:
30
05
2024
medline:
3
7
2024
pubmed:
3
7
2024
entrez:
3
7
2024
Statut:
aheadofprint
Résumé
Accurate testing for Alzheimer's disease (AD) represents a crucial step for therapeutic advancement. Currently, tests are expensive and require invasive sampling or radiation exposure. We developed a nanoscale flow cytometry (nFC)-based assay of extracellular vesicles (EVs) to screen biomarkers in plasma from mild cognitive impairment (MCI), AD, or controls. Circulating amyloid beta (Aβ), tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, p-tauS235, ubiquitin, and lysosomal-associated membrane protein 1-positive EVs distinguished AD samples. p-tau181, p-tau217, p-tauS235, and ubiquitin-positive EVs distinguished MCI samples. The most sensitive marker for AD distinction was p-tau231, with an area under the receiver operating characteristic curve (AUC) of 0.96 (sensitivity 0.95/specificity 1.0) improving to an AUC of 0.989 when combined with p-tauS235. This nFC-based assay accurately distinguishes MCI and AD plasma without EV isolation, offering a rapid approach requiring minute sample volumes. Incorporating nFC-based measurements in larger populations and comparison to "gold standard" biomarkers is an exciting next step for developing AD diagnostic tools. Extracellular vesicles represent promising biomarkers of Alzheimer's disease (AD) that can be measured in the peripheral circulation. This study demonstrates the utility of nanoscale flow cytometry for the measurement of circulating extracellular vesicles (EVs) in AD blood samples. Multiple markers including amyloid beta, tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, and p-tauS235 accurately distinguished AD samples from healthy controls. Future studies should expand blood and cerebrospinal fluid-based EV biomarker development using nanoflow cytometry approaches.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Weston Brain Institute
ID : TR170103
Organisme : New Frontiers in Research Fund
ID : NFRFT-2022-03327
Informations de copyright
© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Références
2021 Alzheimer's disease facts and figures. Alzheimers Dement. 2021;17:327‐406.
Tahami Monfared AA, Ye W, Sardesai A, et al. A path to improved Alzheimer's care: simulating long‐term health outcomes of lecanemab in early Alzheimer's disease from the CLARITY AD trial. Neurol Ther. 2023;12:863‐881.
Shcherbinin S, Evans CD, Lu M, et al. Association of amyloid reduction after donanemab treatment with tau pathology and clinical outcomes: the TRAILBLAZER‐ALZ randomized clinical trial. JAMA Neurol. 2022;79:1015‐1024.
Rashad A, Rasool A, Shaheryar M, et al. Donanemab for Alzheimer's disease: a systematic review of clinical trials. Healthcare. 2023;11:32.
Golde TE, Schneider LS, Koo EH. Anti‐aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron. 2011;69:203‐213.
Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013;369:341‐350.
Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild‐to‐moderate Alzheimer's disease. N Engl J Med. 2014;370:322‐333.
Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab and bapineuzumab for Alzheimer's disease. N Engl J Med. 2014;370:1460.
Becker RE, Greig NH, Giacobini E. Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices? J Alzheimers Dis. 2008;15:303‐325.
Schneider LS. Assessing outcomes in Alzheimer disease. Alzheimer Dis Assoc Disord. 2001;15(1):S8‐18. Suppl.
Gold M. Study design factors and patient demographics and their effect on the decline of placebo‐treated subjects in randomized clinical trials in Alzheimer's disease. J Clin Psychiatry. 2007;68:430‐438.
Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild‐to‐moderate Alzheimer's disease. N Engl J Med. 2014;370:311‐321.
Scott TJ, O'connor AC, Link AN, Beaulieu TJ. Economic analysis of opportunities to accelerate Alzheimer's disease research and development. Ann N Y Acad Sci. 2014;1313:17‐34.
Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p‐tau231: a new biomarker for incipient Alzheimer's disease pathology. Acta Neuropathol. 2021;141:709‐724.
Janelidze S, Teunissen CE, Zetterberg H, et al. Head‐to‐head comparison of 8 plasma amyloid‐β 42/40 assays in Alzheimer disease. JAMA Neurol. 2021;78:1375‐1382.
Lövheim H, Elgh F, Johansson A, et al. Plasma concentrations of free amyloid β cannot predict the development of Alzheimer's disease. Alzheimers Dement. 2017;13:778‐782.
Ashton NJ, Puig‐Pijoan A, Milà‐Alomà M, et al. Plasma and CSF biomarkers in a memory clinic: head‐to‐head comparison of phosphorylated tau immunoassays. Alzheimers Dement. 2023;19:1913‐1924.
De Meyer S, Vanbrabant J, Schaeverbeke JM, et al. Phospho‐specific plasma p‐tau181 assay detects clinical as well as asymptomatic Alzheimer's disease. Ann Clin Transl Neurol. 2022;9:734‐746.
Barthélemy NR, Horie K, Sato C, Bateman RJ. Blood plasma phosphorylated‐tau isoforms track CNS change in Alzheimer's disease. J Exp Med. 2020;217:1‐12.
Brickman AM, Manly JJ, Honig LS, et al. Plasma p‐tau181, p‐tau217, and other blood‐based Alzheimer's disease biomarkers in a multi‐ethnic, community study. Alzheimers Dement. 2021;17:1353‐1364.
Mielke MM, Hagen CE, Xu J, et al. Plasma phospho‐tau181 increases with Alzheimer's disease clinical severity and is associated with tau‐ and amyloid‐positron emission tomography. Alzheimers Dement. 2018;14:989‐997.
Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nat Med. 2020;26:387‐397.
Palmqvist S, Tideman P, Cullen N, et al. Prediction of future Alzheimer's disease dementia using plasma phospho‐tau combined with other accessible measures. Nat Med. 2021;27.
Jin M, Cao Li, Dai Y‐P. Role of neurofilament light chain as a potential biomarker for Alzheimer's disease: a correlative meta‐analysis. Front Aging Neurosci. 2019;11.
Gaetani L, Blennow K, Calabresi P, Di Filippo M, Parnetti L, Zetterberg H. Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry. 2019;90:870LP‐881.
Nestor PJ, Scheltens P, Hodges JR. Advances in the early detection of Alzheimer's disease. Nat Med. 2004;10:S34‐41.
Jack CR, Lowe VJ, Senjem ML, et al. 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. Brain. 2008;131:665‐680.
Lantero‐Rodriguez J, Snellman A, Benedet AL, et al. P‐tau235: a novel biomarker for staging preclinical Alzheimer's disease. EMBO Mol Med. 2021;13:e15098.
Barthélemy NR, Bateman RJ, Hirtz C, et al. Cerebrospinal fluid phospho‐tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid‐positive patient identification. Alzheimers Res Ther. 2020;12:26.
Leuzy A, Janelidze S, Mattsson‐Carlgren N, et al. Comparing the clinical utility and diagnostic performance of CSF P‐Tau181, P‐Tau217, and P‐Tau231 assays. Neurology. 2021;97:e1681‐e1694.
Kanninen KM, Bister N, Koistinaho J, Malm T. Exosomes as new diagnostic tools in CNS diseases. Biochim Biophys Acta. 2016;1862:403‐410.
Badhwar A, Haqqani AS. Biomarker potential of brain‐secreted extracellular vesicles in blood in Alzheimer's disease. Alzheimer's Dement Diagnosis, Assess Dis Monit. 2020;12:e12001.
Ramirez SH, Andrews AM, Paul D, Pachter JS. Extracellular vesicles: mediators and biomarkers of pathology along CNS barriers. Fluids Barriers CNS. 2018;15:1‐21.
Sarko DK, Mckinney CE. Exosomes: origins and therapeutic potential for neurodegenerative disease. Front Neurosci. 2017;11:82.
Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373‐383.
Soares Martins T, Trindade D, Vaz M, et al. Diagnostic and therapeutic potential of exosomes in Alzheimer's disease. J Neurochem. 2021;156:162‐181.
Badhwar AP, Haqqani AS. Biomarker potential of brain‐secreted extracellular vesicles in blood in Alzheimer's disease. Alzheimer's Dement Diagnosis, Assess Dis Monit. 2020;12:1‐14.
Fiandaca MS, Kapogiannis D, Mapstone M, et al. Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case‐control study. Alzheimers Dement. 2015;11:600‐607. e1.
Shi M, Liu C, Cook TJ, et al. Plasma exosomal α‐synuclein is likely CNS‐derived and increased in Parkinson's disease. Acta Neuropathol. 2014;128:639‐650.
Hamlett ED, Goetzl EJ, Ledreux A, et al. Neuronal exosomes reveal Alzheimer's disease biomarkers in Down syndrome. Alzheimers Dement. 2017;13:541‐549.
Winston CN, Goetzl EJ, Akers JC, et al. Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement (Amsterdam, Netherlands). 2016;3:63‐72.
Albert MS, Dekosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging‐Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:270‐279.
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303‐308.
Mckhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS‐ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34:939‐944.
Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS‐ADRDA criteria. Lancet Neurol. 2007;6:734‐746.
Tissot C, Therriault J, Kunach P, et al. Comparing tau status determined via plasma pTau181, pTau231 and [18F]MK6240 tau‐PET. eBioMedicine. 2022;76:103837.
Twohig D, Nielsen HM. α‐synuclein in the pathophysiology of Alzheimer's disease. Mol Neurodegener. 2019;14:23.
Halbgebauer S, Oeckl P, Steinacker P, et al. Beta‐synuclein in cerebrospinal fluid as an early diagnostic marker of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2021;92:349LP‐356.
Youn YC, Lee BS, Kim GJ, et al. Blood amyloid‐β oligomerization as a biomarker of Alzheimer's disease: a blinded validation study. J Alzheimers Dis. 2020;75:493‐499.
Foulds P, Mcauley E, Gibbons L, et al. TDP‐43 protein in plasma may index TDP‐43 brain pathology in Alzheimer's disease and frontotemporal lobar degeneration. Acta Neuropathol. 2008;116:141‐146.
Ali Moussa HY, Manaph N, Ali G, et al. Single extracellular vesicle analysis using flow cytometry for neurological disorder biomarkers. Front Integr Neurosci. 2022;16:879832.
Goetzl EJ, Mustapic M, Kapogiannis D, et al. Cargo proteins of plasma astrocyte‐derived exosomes in Alzheimer's disease. FASEB J. 2016;30:3853‐3859.
Goetzl EJ, Kapogiannis D, Schwartz JB, et al. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease. FASEB J Off Publ Fed Am Soc Exp Biol. 2016;30:4141‐4148.
Gallart‐Palau X, Guo X, Serra A, Sze SK. Alzheimer's disease progression characterized by alterations in the molecular profiles and biogenesis of brain extracellular vesicles. Alzheimers Res Ther. 2020;12:54.
Muraoka S, Deleo AM, Sethi MK, et al. Proteomic and biological profiling of extracellular vesicles from Alzheimer's disease human brain tissues. Alzheimers Dement. 2020;16:896‐907.
Neddens J, Temmel M, Flunkert S, et al. Phosphorylation of different tau sites during progression of Alzheimer's disease. Acta Neuropathol Commun. 2018;6:52.
Gomes J, Lucien F, Cooper TT, et al. Analytical considerations in nanoscale flow cytometry of extracellular vesicles to achieve data linearity. Thromb Haemost. 2018;118:1612‐1624.
Robin X, Turck N, Hainard A, et al. pROC: an open‐source package for R and S+ to analyze and compare ROC curves. BMC Bioinf. 2011;12:77.
Team, Rs. RStudio: Integrated Development for R. 2020.
Ritchie C, Smailagic N, Noel‐Storr AH, Ukoumunne O, Ladds EC, Martin S. CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2017;3:CD010803.
Milà‐Alomà M, Ashton NJ, Shekari M, et al. Plasma p‐tau231 and p‐tau217 as state markers of amyloid‐β pathology in preclinical Alzheimer's disease. Nat Med. 2022;28:1797‐1801.
Ageta H, Tsuchida K. Post‐translational modification and protein sorting to small extracellular vesicles including exosomes by ubiquitin and UBLs. Cell Mol Life Sci. 2019;76:4829‐4848.
Smith VL, Jackson L, Schorey JS. Ubiquitination as a mechanism to transport soluble mycobacterial and eukaryotic proteins to exosomes. J Immunol. 2015;195:2722‐2730.
Humphries WH, Szymanski CJ, Payne CK. Endo‐lysosomal vesicles positive for Rab7 and LAMP1 are terminal vesicles for the transport of dextran. PLoS One. 2011;6:e26626.
Tian C, Stewart T, Hong Z, et al. Blood extracellular vesicles carrying synaptic function‐ and brain‐related proteins as potential biomarkers for Alzheimer's disease. Alzheimers Dement. 2023;19:909‐923.