Ultrasensitive techniques and protein misfolding amplification assays for biomarker-guided reconceptualization of Alzheimer’s and other neurodegenerative diseases

References

• Deuschl G, Beghi E, Fazekas F, et al. The burden of neurological diseases in Europe: an analysis for the global burden of disease study 2017. Lancet Public Health. . 2020;5(10):e551–e567.
   PubMed Web of Science ®Google Scholar
• Marsh AP. Molecular mechanisms of proteinopathies across neurodegenerative disease: a review. Neurol Res Pract. 2019;1: 1–7.
   PubMedGoogle Scholar
• Hermann P, Appleby B, Brandel JP, et al. Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease. Lancet Neurol. 2021;20:235–246.
   PubMed Web of Science ®Google Scholar
• McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia 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;7:263–269.
   PubMed Web of Science ®Google Scholar
• Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014. DOI:https://doi.org/10.1016/S1474-4422(14)70090-0.
   Google Scholar
• Jack CR, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535–562.
   PubMed Web of Science ®Google Scholar
• Baldacci F, Mazzucchi S, della Vecchia A, et al. The path to biomarker-based diagnostic criteria for the spectrum of neurodegenerative diseases. Expert Review of Molecular Diagnostics. Taylor and Francis Ltd, 2020. p. 421–441.
   Google Scholar
• Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16:661–676.
   PubMed Web of Science ®Google Scholar
• Espay AJ, Kalia LV, Gan-Or Z, et al. Disease modification and biomarker development in Parkinson disease: revision or reconstruction?. Neurology. 2020;94(11):481–494.
   PubMed Web of Science ®Google Scholar
• Zetterberg H, Bendlin BB. Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies. Mol Psychiatry. 2021;26(1):296–308.
   PubMed Web of Science ®Google Scholar
• Xia J, Broadhurst DI, Wilson M, et al. Translational biomarker discovery in clinical metabolomics: an introductory tutorial. Metabolomics. 2013;9:280–299.
   PubMed Web of Science ®Google Scholar
• Kovacs GG. Molecular pathological classification of neurodegenerative diseases: turning towards precision medicine. Int J Mol Sci. 2016;17(2):189.
   Web of Science ®Google Scholar
• Jack CR, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of alzheimer’s disease. Alzheimer’s & Dementia. 2018;14:535–562.
   PubMed Web of Science ®Google Scholar
• Rösler TW, Tayaranian Marvian A, Brendel M, et al. Four-repeat tauopathies. Progress in Neurobiology. 2019;180:101644.
   PubMed Web of Science ®Google Scholar
• Elahi FM, Miller BL. A clinicopathological approach to the diagnosis of dementia. Nat Rev Neurol. 2017;13(8):457–476.
   PubMed Web of Science ®Google Scholar
• Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord. 2017;32(6):853–864.
   PubMed Web of Science ®Google Scholar
• Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for parkinson’s disease. Mov Disord. 2015;30:1591–1601.
   PubMed Web of Science ®Google Scholar
• Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal parkinson’s disease. Mov Disord. 2015;30:1600–1611.
   PubMed Web of Science ®Google Scholar
• McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies. Neurology. 2017;89 88–100.
   PubMed Web of Science ®Google Scholar
• McKeith IG, Ferman TJ, Thomas AJ, et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. 2020;94(17):743–755.
   PubMed Web of Science ®Google Scholar
• Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670–676.
   PubMed Web of Science ®Google Scholar
• Ling S-C, Polymenidou M, Cleveland DW, et al. Converging mechanisms in ALS and FTD: disrupted RNA and Protein homeostasis. Neuron. 2013;79(3):416–438.
   PubMed Web of Science ®Google Scholar
• de Carvalho M, Swash M. Awaji diagnostic algorithm increases sensitivity of el escorial criteria for ALS diagnosis. Amyotrophic Lateral Sclerosis. 2009. ;10(1):53–57.
   PubMed Web of Science ®Google Scholar
• Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011. ;76(11):1006–1014.
   PubMed Web of Science ®Google Scholar
• Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011. ;134(9):2456–2477.
   PubMed Web of Science ®Google Scholar
• Ritchie DL, Barria MA. Prion diseases: a unique transmissible agent or a model for neurodegenerative diseases?. Biomolecules. 2021;11(2):1–23.
   Web of Science ®Google Scholar
• Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science. 1982;216(4542):136–144.
   PubMed Web of Science ®Google Scholar
• Alper T, Cramp WA, Haig DA, et al. Does the agent of scrapie replicate without Nucleic Acid ?. Nature. 1967;214(5090):764–766.
   PubMed Web of Science ®Google Scholar
• Alper T. The nature of the scrapie agent. J Clin Pathol. 1972;25(Suppl 6):154–155.
   Google Scholar
• Griffith JS. Nature of the scrapie agent: self-replication and scrapie. Nature. 1967;215(5105):1043–1044.
   PubMed Web of Science ®Google Scholar
• Scheckel C, Aguzzi A. Prions, prionoids and protein misfolding disorders. Nature Reviews Genetics. 2018;19(7):405–418.
   PubMed Web of Science ®Google Scholar
• Orrú CD, Bongianni M, Tonoli G, et al. A test for Creutzfeldt–Jakob disease using nasal brushings. New Engl J Med. 2014;371:519–529.
   PubMed Web of Science ®Google Scholar
• Thompson AGB, Mead SH. Review: fluid biomarkers in the human prion diseases. Molecular and Cellular Neuroscience. 2019;97:81–92.
   PubMed Web of Science ®Google Scholar
• Zanusso G, Monaco S, Pocchiari M, et al. Advanced tests for early and accurate diagnosis of Creutzfeldt–Jakob disease. Nature Reviews Neurology. 2016;12(6):325–333.
   PubMed Web of Science ®Google Scholar
• Hermann P, Appleby B, Brandel JP, et al. Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease. Lancet Neurol. 2021;20:235–246.
   PubMed Web of Science ®Google Scholar
• McGuire LI, Peden AH, Orrú CD, et al. Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 2012;72(2):278–285.
   PubMed Web of Science ®Google Scholar
• Atarashi R, Satoh K, Sano K, et al. Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nature Medicine. 2011;17(2):175–178.
   PubMed Web of Science ®Google Scholar
• Foutz A, Appleby BS, Hamlin C, et al. Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann Neurol. 2017;81 79–92.
   PubMed Web of Science ®Google Scholar
• Orrú CD, Groveman BR, Hughson AG, Zanusso G, Coulthart MB, Caughey B. Rapid and sensitive RT-QuIC detection of human Creutzfeldt-Jakob disease using cerebrospinal fluid. mBio. 2015 Jan 20;6(1):e02451–14https://doi.org/10.1128/mBio.02451-14. PMID: 25604790; PMCID: PMC4313917
   Google Scholar
• Bongianni M, Orrù C, Groveman BR, et al. Diagnosis of human prion disease using real-time quaking-induced conversion testing of olfactory mucosa and cerebrospinal fluid samples. JAMA Neurol. 2017;74(2):155–162.
   PubMed Web of Science ®Google Scholar
• Orrú CD, Groveman BR, Foutz A, et al. Ring trial of 2nd generation RT-QuIC diagnostic tests for sporadic CJD. Ann Clin Transl Neurol. 2020;7(11):2262–2271.
   PubMed Web of Science ®Google Scholar
• Orrú CD, Yuan J, Appleby BS, et al. Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease. Sci Transl Med. 2017;9(417):1–11.
   Web of Science ®Google Scholar
• Goedert M, Clavaguera F, Tolnay M, et al. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends in Neurosciences. 2010;33(7):317–325.
   PubMed Web of Science ®Google Scholar
• Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013;5017465:45–51.
   PubMed Web of Science ®Google Scholar
• Aguzzi A. Beyond the prion principle. Nature. 2009;459(7249):924–925.
   PubMed Web of Science ®Google Scholar
• del Prete E, Beatino MF, Campese N, et al. Fluid candidate biomarkers for alzheimer’s disease: a precision medicine approach. J Pers Med. 2020;10(4):1–34.
   Web of Science ®Google Scholar
• Steinacker P, Anderl-Straub S, Diehl-Schmid J, et al. Serum neurofilament light chain in behavioral variant frontotemporal dementia. Neurology. 2018;91(15):E1390–E1401.
   PubMed Web of Science ®Google Scholar
• Chen Z, Mengel D, Keshavan A, et al. Learnings about the complexity of extracellular tau aid development of a blood-based screen for alzheimer’s disease. Alzheimer’s and Dementia. 2019;15:487–496.
   PubMed Web of Science ®Google Scholar
• Campese N, Palermo G, Del Gamba C, et al. Progress regarding the context-of-use of tau as biomarker of alzheimer’s disease and other neurodegenerative diseases. Expert Review of Proteomics. 2021;18:27–48.
   PubMed Web of Science ®Google Scholar
• Yang SY, Chiu MJ, Chen TF, et al. Detection of plasma biomarkers using immunomagnetic reduction: a promising method for the early diagnosis of Alzheimer’s disease [internet]. Neurol Ther. Springer Healthcare, 2017. p. 37–56.
   Google Scholar
• Nabers A, Perna L, Lange J, et al. Amyloid blood biomarker detects Alzheimer’s disease. EMBO Mol Med. 2018. ; 10.
   Google Scholar
• Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 2018;554(7691):249–254.
   PubMed Web of Science ®Google Scholar
• Palmqvist S, Janelidze S, Stomrud E, et al. Performance of fully automated plasma assays as screening tests for Alzheimer disease-related β-amyloid status. JAMA Neurol. 2019. ;76:1060–1069.
   PubMed Web of Science ®Google Scholar
• Lue LF, Sabbagh MN, Chiu MJ, et al. Plasma levels of Aβ42 and tau identified probable alzheimer’s dementia: findings in two cohorts. Frontiers in Aging Neuroscience. 2017. ; 9.
   Google Scholar
• Vergallo A, Mégret L, Lista S, et al. Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer’s disease. Alzheimers Dement. 2019. ;15:764–775.
   PubMed Web of Science ®Google Scholar
• Chatterjee P, Elmi M, Goozee K, et al. Ultrasensitive detection of plasma Amyloid-β as a biomarker for cognitively normal elderly individuals at risk ofAlzheimer’s disease. J Alzheimer’s Dis. 2019. ;71:775–783.
   PubMed Web of Science ®Google Scholar
• Schindler SE, Bollinger JG, Ovod V, et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019.;93:E1647–E1659.
   PubMed Web of Science ®Google Scholar
• Verberk IMW, Slot RE, Verfaillie SCJ, et al. Plasma amyloid as prescreener for the earliest Alzheimer pathological changes. Ann Neurol. 2018. ;84:648–658.
   PubMed Web of Science ®Google Scholar
• De Wolf F, Ghanbari M, Licher S, et al. Plasma tau, neurofilament light chain and amyloid-b levels and risk of dementia; a population-based cohort study. Brain. 2020.;143:1220–1232.
   PubMed Web of Science ®Google Scholar
• Stocker H, Nabers A, Perna L, et al. Prediction of alzheimer’s disease diagnosis within 14 years through Aβ misfolding in blood plasma compared to APOE4 status, and other risk factors. Alzheimers Dement [Internet]. 2020. ;16:283–291.
   PubMed Web of Science ®Google Scholar
• Stockmann J, Verberk IMW, Timmesfeld N, et al. Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical alzheimer’s disease in individuals with subjective cognitive decline. Alzheimer’s Research and Therapy. 2020.; 12.
   Google Scholar
• Chen Z, Mengel D, Keshavan A, et al. Learnings about the complexity of extracellular tau aid development of a blood-based screen for Alzheimer’s disease. Alzheimers and Dement. 2019. ;15:487–496.
   PubMed Web of Science ®Google Scholar
• Mielke MM, Hagen CE, Wennberg AMV, et al. Association of plasma total tau level with cognitive decline and risk of mild cognitive impairment or dementia in the mayo clinic study on aging. JAMA Neurol. 2017. ;74:1073–1080.
   PubMed Web of Science ®Google Scholar
• Pase MP, Beiser AS, Himali JJ, et al. Assessment of plasma total tau level as a predictive biomarker for dementia and related endophenotypes. JAMA Neurol. 2019. ;76(5):598–606.
   PubMed Web of Science ®Google Scholar
• Karikari TK, Benedet AL, Ashton NJ, et al. Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s disease neuroimaging initiative. Mol Psychiatry. 2021;26:429–442.
   PubMed Web of Science ®Google Scholar
• Karikari TK, Pascoal TA, Ashton NJ, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020;19:422–433.
   PubMed Web of Science ®Google Scholar
• 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. Alzheimer’s and Dementia. 2018;14:989–997.
   PubMed Web of Science ®Google Scholar
• Janelidze S, Mattsson N, Palmqvist S, et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020;26:379–386.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathologica. 2021. ; 141.
   Google Scholar
• Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2020. DOI:https://doi.org/10.1001/jama.2020.12134.
   Google Scholar
• Barthélemy NR, Horie K, Sato C, et al. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease. J ExpMed. 2020. ;217.
   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. Molecular Neurobiology. Springer, 2020. . p. 4667–4691.
   Google Scholar
• Hansson O, Janelidze S, Hall S, et al. Blood-based NfL: a biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017. ;88(10):930–937.
   PubMed Web of Science ®Google Scholar
• Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2019. ;90(2):157–164.
   PubMed Web of Science ®Google Scholar
• Thouvenot E, Demattei C, Lehmann S, et al. Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis. Eur J Neurol. 2020. ;27(2):251–257.
   PubMed Web of Science ®Google Scholar
• Gille B, De Schaepdryver M, Goossens J, et al. Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2019.;45(3):291–304.
   PubMed Web of Science ®Google Scholar
• Mustapic M, Eitan E, Werner JK, et al. Plasma extracellular vesicles enriched for neuronal origin: a potential window into brain pathologic processes. Front Neurosci. 2017. ; 11.
   Google Scholar
• 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. Alzheimer’s and Dementia. 2015. ;11:600–607. e1.
   PubMed Web of Science ®Google Scholar
• Hill AF. Extracellular vesicles and neurodegenerative diseases [internet]. J Neurosci. NLM (Medline). 2019. ; 9269–9273. DOI:https://doi.org/10.1523/JNEUROSCI.0147-18.2019.
   Google Scholar
• Vassileff N, Cheng L, Hill AF, et al. Extracellular vesicles - propagators of neuropathology and sources of potential biomarkers and therapeutics for neurodegenerative diseases. J Cell Sci. Company of Biologists Ltd. 2020.DOI:https://doi.org/10.1242/jcs.243139.
   Google Scholar
• Hornung S, Dutta S, Bitan G, et al. CNS-derived blood exosomes as a promising source of biomarkers: opportunities and challenges. Front Mol Neurosci. Frontiers Media S.A, 2020.
   Google Scholar
• Bahlakeh G, Gorji A, Soltani H, et al. MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: lessons from animal models. J Cell Physiol. Wiley-Liss Inc. 2021. ; 806–823. DOI:https://doi.org/10.1002/jcp.29908.
   Google Scholar
• Zhao Y, Jaber V, Alexandrov PN, et al. microRNA-based biomarkers in Alzheimer’s disease (AD) [internet]. Front Neurosci. Frontiers Media S.A, 2020.
   Google Scholar
• Pegtel DM, Gould SJ. Exosomes. Ann Rev Biochem. 2019. 88(1):487–514.
   PubMed Web of Science ®Google Scholar
• Wang L, Zhang L Circulating exosomal miRNA as diagnostic biomarkers of neurodegenerative diseases. Front Mol Neurosci. Frontiers Media S.A, 2020.
   Google Scholar
• Dong X, Zheng D, Nao J, et al. Circulating exosome microRNAs as diagnostic biomarkers of dementia. Front Aging Neurosci. Frontiers Media S.A, 2020.
   Google Scholar
• Hampel H, Goetzl EJ, Kapogiannis D, et al. Biomarker-drug and liquid biopsy co-development for disease staging and targeted therapy: cornerstones for Alzheimer’s precision medicine and pharmacology. Front Pharmacol. 2019. ; 10.
   Google Scholar
• Goetzl EJ, Schwartz JB, Abner EL, et al. High complement levels in astrocyte-derived exosomes of Alzheimer disease. Ann Neurol.2018. cited 2021 Apr 26;83(3):544–552
   PubMed Web of Science ®Google Scholar
• Cai ZY, Xiao M, Quazi S, et al. Exosomes: a novel therapeutic target for Alzheimer’s disease? [internet]. Neural Regeneration Research. Medknow Publications, 2018. p. 930–935.
   Google Scholar
• Luo S, Du L, Cui Y, et al. Potential therapeutic applications and developments of exosomes in Parkinson’s disease. Mol Pharm. 2020.;17(5):1447–1457.
   PubMed Web of Science ®Google Scholar
• Green AJE, Zanusso G Prion protein amplification techniques. Handbook ofClinical Neurology, Vol 153 2018. p. 357–370.
   Google Scholar
• Saborio GP, Permanne B, Soto C, et al. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature. 2001;411(6839):810–813.
   PubMed Web of Science ®Google Scholar
• Paciotti S, Bellomo G, Gatticchi L, et al. Are we ready for detecting α-synuclein prone to aggregation in patients? The case of “Protein-Misfolding cyclic amplification” and “real-time quaking-induced conversion” as diagnostic tools. Front Neurol. 2018;9:415.
   PubMed Web of Science ®Google Scholar
• Candelise N, Baiardi S, Franceschini A, et al. Towards an improved early diagnosis of neurodegenerative diseases: the emerging role of in vitro conversion assays for protein amyloids. Acta Neuropathol Commun. 2020;8(1):1–16.
   PubMed Web of Science ®Google Scholar
• Ferreira NDC, Caughey B. Proteopathic seed amplification assays for neurodegenerative disorders. Clin Lab Med. 2020;40:257–270.
   PubMed Web of Science ®Google Scholar
• Atarashi R, Sano K, Satoh K, et al. Real-time quaking-induced conversion: a highly sensitive assay for prion detection. Prion. 2011;5(3):150–153.
   PubMed Web of Science ®Google Scholar
• Franceschini A, Baiardi S, Hughson AG, et al. High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions. Sci Rep. 2017;7:3–10.
   PubMed Web of Science ®Google Scholar
• Raymond GJ, Race B, Orrú CD, et al. Transmission of CJD from nasal brushings but not spinal fluid or RT-QuIC product. Ann Clin Transl Neurol. 2020;7(6):932–944.
   PubMed Web of Science ®Google Scholar
• Gao L, Tang H, Nie K, et al. Cerebrospinal fluid alpha-synuclein as a biomarker for Parkinson’s disease diagnosis: a systematic review and meta-analysis. Int JNeurosci. 2015;125:645–654.
   PubMed Web of Science ®Google Scholar
• Van Rumund A, Green AJE, Fairfoul G, et al. α‐Synuclein real‐time quaking‐induced conversion in the cerebrospinal fluid of uncertain cases of parkinsonism. Ann Neurol. 2019;85:777–781.
   PubMed Web of Science ®Google Scholar
• Bongianni M, Ladogana A, Capaldi S, et al. α‐Synuclein RT‐QuIC assay in cerebrospinal fluid of patients with dementia with Lewy bodies. Ann Clin Transl Neurol. 2019;6:2120–2126.
   PubMed Web of Science ®Google Scholar
• Groveman BR, Orrù CD, Hughson AG, et al. Rapid and ultra-sensitive quantitation of disease-associated α-synuclein seeds in brain and cerebrospinal fluid by αSyn RT-QuIC. Acta Neuropathol Commun. 2018;6(1):1–10.
   PubMed Web of Science ®Google Scholar
• Rossi M, Candelise N, Baiardi S, et al. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol []. 2020;140(1):49–62.
   PubMed Web of Science ®Google Scholar
• Orrù CD, Ma TC, Hughson AG, et al. A rapid α-synuclein seed assay of parkinson’s disease CSF panel shows high diagnostic accuracy. Ann Clin Transl Neurol. 2021;8(2):374–384.
   PubMed Web of Science ®Google Scholar
• Kang UJ, Boehme AK, Fairfoul G, et al. Comparative study of cerebrospinal fluid α-synuclein seeding aggregation assays for diagnosis of parkinson’s disease. Mov Disord. 2019;34:536–544.
   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 alpha‐synucleinopathies. Ann Clin Transl Neurol. 2016;3:812–818.
   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.
   PubMed Web of Science ®Google Scholar
• Ning H, Wu Q, Han D, et al. Baseline concentration of misfolded α‐synuclein aggregates in cerebrospinal fluid predicts risk of cognitive decline in Parkinson’s disease. Neuropathol Appl Neurobiol. 2019;45:398–409.
   PubMed Web of Science ®Google Scholar
• Orrù CD, Ma TC, Hughson AG, et al. A rapid α-synuclein seed assay of parkinson’s disease CSF panel shows high diagnostic accuracy. Ann Clin Transl Neurol. 2021;8(2):374–384.
   PubMed Web of Science ®Google Scholar
• Kalia LV, Lang AE, Hazrati L-N, et al. Clinical correlations with Lewy body pathology in LRRK2 -related Parkinson disease. JAMA Neurology. 2015;72:100.
   PubMed Web of Science ®Google Scholar
• Garrido A, Fairfoul G, Tolosa ES, et al. α ‐synuclein RT‐QuIC in cerebrospinal fluid of LRRK 2‐linked Parkinson’s disease. Ann Clin Translation Neuro. 2019;6:1024–1032.
   PubMed Web of Science ®Google Scholar
• Shahnawaz M, Tokuda T, Waraga M, et al. Development of a biochemical diagnosis of Parkinson disease by detection of α-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol. 2017;74(2):163–172.
   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.
   PubMed Web of Science ®Google Scholar
• Singer W, Schmeichel AM, Shahnawaz M, et al., Alpha-Synuclein oligomers and neurofilament light chain in spinal fluid differentiate multiple system atrophy from Lewy body synucleinopathies. Ann Neurol. 2020;88(3): 503–512.
   PubMed Web of Science ®Google Scholar
• Peng C, Gathagan RJ, Lee VMY, et al. Distinct α-synuclein strains and implications for heterogeneity among α-synucleinopathies. Neurobiol Dis. 2018;109:209–218.
   PubMed Web of Science ®Google Scholar
• Rossi M, Candelise N, Baiardi S, et al., Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol. 2020;140(1): 49–62.
   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 alpha‐synucleinopathies. Ann Clin Transl Neurol. 2016;3:812–818.
   PubMed Web of Science ®Google Scholar
• Iranzo A, Fairfoul G, Ayudhaya ACN, et al. Detection of α-synuclein in CSF by RT-QuIC in patients with isolated rapid-eye-movement sleep behaviour disorder: a longitudinal observational study. The Lancet Neurology. 2021;20:203–212.
   PubMed Web of Science ®Google Scholar
• Singer W, Schmeichel AM, Shahnawaz M, et al. Alpha-Synuclein oligomers and neurofilament light chain predict phenoconversion of pure autonomic failure. Ann Neurol. 2021;89:1212–1220.
   PubMed Web of Science ®Google Scholar
• Saijo E, Ghetti B, Zanusso G, et al. Ultrasensitive and selective detection of 3-repeat tau seeding activity in pick disease brain and cerebrospinal fluid. Acta Neuropathol. 2017;133:751–765.
   PubMed Web of Science ®Google Scholar
• Saijo E, Metrick MA, Koga S, et al. 4-repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration. Acta Neuropathol. 2020;139:63–77.
   PubMed Web of Science ®Google Scholar
• Scialò C, Tran TH, Salzano G, et al., TDP-43 real-time quaking induced conversion reaction optimization and detection of seeding activity in CSF of amyotrophic lateral sclerosis and frontotemporal dementia patients. Brain Comm. 2020;2(2): 1–14.
   Google Scholar
• Molinuevo JL, Ayton S, Batrla R, et al. Current state of Alzheimer’s fluid biomarkers. Acta Neuropathol. 2018.
   PubMed Web of Science ®Google Scholar
• del Prete E, Beatino MF, Campese N, et al. Fluid candidate biomarkers for Alzheimer’s disease: a precision medicine approach. J Pers Med. 2020;10(4):1–34.
   Web of Science ®Google Scholar
• Salvadores N, Shahnawaz M, Scarpini E, et al. Detection of misfolded Aβ oligomers for sensitive biochemical diagnosis of Alzheimer’s disease. Cell Reports. 2014;7(1):261–268. .
   PubMed Web of Science ®Google Scholar
• Ausó E, Gómez-Vicente V, Esquiva G, et al. Biomarkers for Alzheimer’s disease early diagnosis. J Pers Med. 2020;10(3):1–27.
   Web of Science ®Google Scholar
• Tvarijonaviciute A, Zamora C, Ceron JJ, et al. Salivary biomarkers in alzheimer’s disease. Clin Oral Investig. 2020;24(10):3437–3444.
   PubMed Web of Science ®Google Scholar
• Pekeles H, Qureshi HY, Paudel HK, et al. Development and validation of a salivary tau biomarker in alzheimer’s disease. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2018;10:53–60.
   Google Scholar
• Rani K, Rastogi S, Vishwakarma P, et al. A novel approach to correlate the salivary exosomes and their protein cargo in the progression of cognitive impairment into alzheimer’s disease. Journal of Neuroscience Methods. 2021;347:108980.
   PubMed Web of Science ®Google Scholar
• Vivacqua G, Suppa A, Mancinelli R, et al. Salivary alpha-synuclein in the diagnosis of parkinson’s disease and progressive supranuclear palsy. Parkinsonism Related Disord. 2019;63:143–148.
   PubMed Web of Science ®Google Scholar
• Cao Z, Wu Y, Liu G, et al. α-Synuclein in salivary extracellular vesicles as a potential biomarker of Parkinson’s disease. Neurosci Lett. 2019;696:114–120.
   PubMed Web of Science ®Google Scholar
• Sun R, Wang H, Shi Y, et al. A pilot study of urinary exosomes in Alzheimer’s disease. Neurodegenerative Diseases. 2019;19(5–6):184–191.
   PubMed Web of Science ®Google Scholar
• Nam D, Kim A, Han SJ, et al. Analysis of α-synuclein levels related to LRRK2 kinase activity: from substantia nigra to urine of patients with parkinson’s disease. Animal Cells and Systems. 2021;25:28–36.
   PubMed Web of Science ®Google Scholar
• Donadio V, Incensi A, Leta V, et al. Skin nerve a-synuclein deposits a biomarker for idiopathic Parkinson disease. Neurology. 2014;82:1362–1369.
   PubMed Web of Science ®Google Scholar
• Donadio V, Incensi A, Rizzo G, et al. Skin biopsy may help to distinguish multiple system Atrophy–Parkinsonism from parkinson’s disease with orthostatic hypotension. Mov Disord. 2020;35:1649–1657.
   PubMed Web of Science ®Google Scholar
• Mammana A, Baiardi S, Quadalti C, Rossi M, Donadio V, Capellari S, Liguori R, Parchi P. RT-QuIC Detection of Pathological α-Synuclein in Skin Punches of Patients with Lewy Body Disease. Mov Disord. 2021 May 18. https://doi.org/10.1002/mds.28651. Epub ahead of print. PMID: 34002890
   Google Scholar
• Wang Z, Becker K, Donadio V, et al. Skin α-Synuclein aggregation seeding activity as a novel biomarker for Parkinson disease. JAMA Neurol. 2021;78(1):30–40.
   Web of Science ®Google Scholar
• Donadio V, Wang Z, Incensi A, et al. In vivo diagnosis of synucleinopathies: a comparative study of skin biopsy and RT-QuIC. Neurology. 2021;96(20):e2513–e2524.
   PubMed Web of Science ®Google Scholar
• CMG DL, Elia AE, Portaleone SM, et al. Efficient RT-QuIC seeding activity for α-synuclein in olfactory mucosa samples of patients with Parkinson’s disease and multiple system atrophy. Transl Neurodegener. 2019;8:1–14.
   PubMed Web of Science ®Google Scholar
• Perra D, Bongianni M, Novi G, et al. Alpha-synuclein seeds in olfactory mucosa and cerebrospinal fluid of patients with dementia with Lewy bodies. Brain Comm. 2021;3(2):1–11.
   Google Scholar
• Stefani A, Iranzo A, Holzknecht E, et al., Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder. Brain. 2021;144(4): 1118–1126.
   PubMed Web of Science ®Google Scholar
• Ashton NJ, Leuzy A, Karikari TK, et al. The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers. Eur J Nucl Med Mol Imaging. 2021. DOI:https://doi.org/10.1007/s00259-021-05253-y.
   Google Scholar
• Schmitz M, Cramm M, Llorens F, et al. The real-time quaking-induced conversion assay for detection of human prion disease and study of other protein misfolding diseases. Nat Protoc. 2016;11(11):2233–2242.
   PubMed Web of Science ®Google Scholar
• Groveman BR, Orrù CD, Hughson AG, et al. Rapid and ultra-sensitive quantitation of disease-associated α-synuclein seeds in brain and cerebrospinal fluid by αSyn RT-QuIC. Acta Neuropathol Commun. 2018;6(1):1–10.
   PubMed Web of Science ®Google Scholar
• Zerr I. RT-QuIC for detection of prodromal α-synucleinopathies. Lancet Neurol]. 2021;20(3):165–166.
   PubMed Web of Science ®Google Scholar
• Badhwar AP, Peggy Mcfall G, Sapkota S, et al. A multiomics approach to heterogeneity in alzheimer’s disease: focused review and roadmap. Brain. Oxford University Press, 2020. p. 1315–1331.
   Google Scholar
• Andreasson U, Perret-Liaudet A, van Waalwijk van Doorn LJC, et al. A practical guide to immunoassay method validation. Frontiers in Neurology [Internet]. 2015. [ cited 2021 Apr 26]; 6.
   Google Scholar
• Hampel H, Lista S, Neri C, et al. Time for the systems-level integration of aging: resilience enhancing strategies to prevent alzheimer’s disease. Progress in Neurobiology. Elsevier Ltd, 2019.
   Google Scholar
• Luckett PH, McCullough A, Gordon BA, et al. Modeling autosomal dominant alzheimer’s disease with machine learning. Alzheimer’s and Dementia. 2021.
   Google Scholar
• Siravegna G, Marsoni S, Siena S, et al. Integrating liquid biopsies into the management of cancer. Nature Reviews Clinical Oncology. Nature Publishing Group, 2017. . p. 531–548.
   Google Scholar
• Kang UJ, Boehme AK, Fairfoul G, et al. Comparative study of cerebrospinal fluid α-synuclein seeding aggregation assays for diagnosis of Parkinsons disease. Movement Disorders. ;34:536544.2019
   Google Scholar