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Cited by 62Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative

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Sanchez, Erlan, Wilkinson, Tim, Coughlan, Gillian, Mirza, Saira, Baril, Andrée‐Ann, Ramirez, Joel, Binns, Malcolm A., Black, Sandra E. +36 more·2024·Alzheimer's & Dementia
DOI 10.1002/alz.13560PMC PMC10984487
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Abstract

Abstract INTRODUCTION We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p‐tau)181 and amyloid beta (Aβ) 42/40 were measured using ultra‐sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS GFAP, NfL, and/or p‐tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p‐tau181 were highly predictive across diseases, p‐tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ 42/40 . DISCUSSION GFAP, NfL, and p‐tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

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  1. [3]Zetterberg H, Blennow K. Moving fluid biomarkers for Alzheimer's disease from research tools to routine clinical diagnostics. Mol Neurodegener. 2021; 16: 10. 33608044 PMC7893769
  2. [5]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. The Lancet Neurology. 2020; 19: 422‐ 433. 32333900
  3. [6]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. 32123386 PMC7101073
  4. [7]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. 32123385
  5. [8]Preische O, Schultz SA, Apel A, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med. 2019; 25: 277‐ 283. 30664784 PMC6367005
  6. [9]Cicognola C, Janelidze S, Hertze J, et al. Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment. Alzheimer's Res Ther. 2021; 13: 68. 33773595 PMC8005231
  7. [10]Chouliaras L, Thomas A, Malpetti M, et al. Differential levels of plasma biomarkers of neurodegeneration in Lewy body dementia, Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 2022; 93: 651‐ 658. 35078917 PMC9148982
  8. [12]Ramirez J, McNeely AA, Scott CJM, Masellis M, Black SE. White matter hyperintensity burden in elderly cohort studies: the Sunnybrook Dementia Study, Alzheimer's Disease Neuroimaging Initiative, and Three‐City Study. Alzheimers Dement. 2016; 12: 203‐ 210. 26208292
  9. [13]Robinson JL, Lee EB, Xie SX, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age‐related and APOE4‐associated. Brain. 2018; 141: 2181‐ 2193. 29878075 PMC6022546
  10. [15]Rahimi J, Kovacs GG. Prevalence of mixed pathologies in the aging brain. Alzheimers Res Ther. 2014; 6: 82. 25419243 PMC4239398
  11. [16]Sunderland KM, Beaton D, Arnott SR, et al. Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort. Alzheimers Dement. 2023; 19: 226‐ 243. 36318754
  12. [17]Farhan SM, Bartha R, Black SE, et al. The Ontario Neurodegenerative Disease Research Initiative (ONDRI). CJNS. 2017; 44: 196‐ 202. 28003035
  13. [18]Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol. 1987; 149: 351‐ 356. 3496763
  14. [19]Wahlund LO, Barkhof F, Fazekas F, et al. A new rating scale for age‐related white matter changes applicable to MRI and CT. Stroke. 2001; 32: 1318‐ 1322. 11387493
  15. [20]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. 21514250 PMC3312024
  16. [21]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. 21514249 PMC3312027
  17. [22]Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011; 134: 2456‐ 2477. 21810890 PMC3170532
  18. [23]Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013; 80: 496‐ 503. 23359374 PMC3590050
  19. [24]Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele‐Richardson‐Olszewski syndrome): report of the NINDS‐SPSP international workshop. Neurology. 1996; 47: 1‐ 9. 8710059
  20. [25]Gorno‐Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011; 76: 1006‐ 1014. 21325651 PMC3059138
  21. [26]Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico‐pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992; 55: 181‐ 184. 1564476 PMC1014720
  22. [28]Litvan I, Goldman JG, Tröster AI, et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: movement Disorder Society Task Force guidelines. Mov Disord. 2012; 27: 349‐ 356. 22275317 PMC3641655
  23. [30]McLaughlin PM, Sunderland KM, Beaton D, et al. The quality assurance and quality control protocol for neuropsychological data collection and curation in the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study. Assessment. 2021; 28: 1267‐ 1286. 32321297
  24. [31]Sunderland KM, Beaton D, Fraser J, et al. The utility of multivariate outlier detection techniques for data quality evaluation in large studies: an application within the ONDRI project. BMC Med Res Methodol. 2019; 19: 102. 31092212 PMC6521365
  25. [32]Farhan SMK, Dilliott AA, Ghani M, et al. The ONDRISeq panel: custom‐designed next‐generation sequencing of genes related to neurodegeneration. NPJ Genom Med. 2016; 1: 16032. 29263818 PMC5685311
  26. [33]Dilliott AA, Evans EC, Farhan SMK, et al. Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative. CJNS. 2019; 46: 491‐ 498. 31217043
  27. [34]Dilliott AA, Abdelhady A, Sunderland KM, et al. Contribution of rare variant associations to neurodegenerative disease presentation. NPJ Genom Med. 2021; 6: 80. 34584092 PMC8478934
  28. [35]Lezak MD, Howieson DB, Loring DW, Hannay HJ, Fischer JS. Neuropsychological Assessment. 4th ed. Oxford University Press; 2004.
  29. [36]Lawton MP, Brody EM. Assessment of older people: self‐maintaining and instrumental activities of daily living. Gerontologist. 1969; 9: 179‐ 186. 5349366
  30. [37]Heller C, Foiani MS, Moore K, et al. Plasma glial fibrillary acidic protein is raised in progranulin‐associated frontotemporal dementia. J Neurol Neurosurg Psychiatry. 2020; 91: 263‐ 270. 31937580
  31. [38]Tang Y, Han L, Li S, et al. Plasma GFAP in Parkinson's disease with cognitive impairment and its potential to predict conversion to dementia. NPJ Parkinsons Dis. 2023; 9: 23. 36759508 PMC9911758
  32. [39]Benedet AL, Milà‐Alomà M, Vrillon A, et al. Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the Alzheimer Disease Continuum. JAMA Neurol. 2021; 78: 1471‐ 1483. 34661615 PMC8524356
  33. [41]Ashton NJ, Janelidze S, Al Khleifat A, et al. A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat Commun. 2021; 12: 3400. 34099648 PMC8185001
  34. [42]Mattsson N, Andreasson U, Zetterberg H, Blennow K. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer Disease. JAMA Neurol. 2017; 74: 557‐ 566. 28346578 PMC5822204
  35. [43]Götze K, Vrillon A, Bouaziz‐Amar E, Mouton‐Liger F, Hugon J, Martinet M, et al. Plasma neurofilament light chain in memory clinic practice: evidence from a real‐life study. Neurobiol Dis. 2023; 176: 105937. 36462720
  36. [44]Pagonabarraga J, Pérez‐González R, Bejr‐Kasem H, et al. Dissociable contribution of plasma NfL and p‐tau181 to cognitive impairment in Parkinson's disease. Parkinsonism Relat Disord. 2022; 105: 132‐ 138. 35752549
  37. [45]Zhu Y, Yang B, Wang F, et al. Association between plasma neurofilament light chain levels and cognitive function in patients with Parkinson's disease. J Neuroimmunol. 2021; 358: 577662. 34311152
  38. [46]Lin CH, Li CH, Yang KC, et al. Blood NfL: a biomarker for disease severity and progression in Parkinson disease. Neurology. 2019; 93: e1104‐ e1111. 31420461
  39. [47]Kivisäkk P, Carlyle BC, Sweeney T, et al. Plasma biomarkers for diagnosis of Alzheimer's disease and prediction of cognitive decline in individuals with mild cognitive impairment. Front Neurol. 2023; 14: 1069411. 36937522 PMC10018178
  40. [48]Zhu N, Santos‐Santos M, Illán‐Gala I, et al. Plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia. Transl Neurodegener. 2021; 10: 50. 34893073 PMC8662866
  41. [49]Donaghy PC, Firbank M, Petrides G, et al. The relationship between plasma biomarkers and amyloid PET in dementia with Lewy bodies. Parkinsonism Relat Disord. 2022; 101: 111‐ 116. 35872565
  42. [50]Lin YS, Lee WJ, Wang SJ, Fuh JL. Levels of plasma neurofilament light chain and cognitive function in patients with Alzheimer or Parkinson disease. Sci Rep. 2018; 8: 17368. 30478269 PMC6255914
  43. [51]Batzu L, Rota S, Hye A, et al. Plasma p‐tau181, neurofilament light chain and association with cognition in Parkinson's disease. NPJ Parkinsons Dis. 2022; 8: 154. 36371469 PMC9653432
  44. [52]Yang X, Li Z, Bai L, et al. Association of plasma and electroencephalography markers with motor subtypes of Parkinson's disease. Front Aging Neurosci. 2022; 14: 911221. 35903537 PMC9314775
  45. [53]Ng ASL, Tan YJ, Yong ACW, et al. Utility of plasma Neurofilament light as a diagnostic and prognostic biomarker of the postural instability gait disorder motor subtype in early Parkinson's disease. Mol Neurodegener. 2020; 15: 33. 32503574 PMC7275464
  46. [54]Gendron TF, Heckman MG, White LJ, et al. Comprehensive cross‐sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders. Cell Rep Med. 2022; 3: 100607. 35492244 PMC9044101
  47. [55]Li Q, Li Z, Han X, et al. A panel of plasma biomarkers for differential diagnosis of parkinsonian syndromes. Front Neurosci. 2022; 16: 805953. 35250451 PMC8891509
  48. [57]Gonzalez‐Ortiz F, Kac PR, Brum WS, Zetterberg H, Blennow K, Karikari TK. Plasma phospho‐tau in Alzheimer's disease: towards diagnostic and therapeutic trial applications. Mol Neurodegener. 2023; 18: 18. 36927491 PMC10022272
  49. [59]Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013; 12: 207‐ 216. 23332364 PMC3622225
  50. [60]Bilgel M, An Y, Walker KA, et al. Longitudinal changes in Alzheimer's‐related plasma biomarkers and brain amyloid. Alzheimers Dement. 2023; 19(10): 4335‐ 4345. 10.1002/alz.13157 37216632 PMC10592628 · DOI
  51. [62]Hirtz C, Busto GU, Bennys K, et al. Comparison of ultrasensitive and mass spectrometry quantification of blood‐based amyloid biomarkers for Alzheimer's disease diagnosis in a memory clinic cohort. Alzheimers Res Ther. 2023; 15: 34. 36800984 PMC9938625
  52. [63]Tsai HH, Tsai LK, Lo YL, Lin CH. Amyloid related cerebral microbleed and plasma Aβ40 are associated with cognitive decline in Parkinson's disease. Sci Rep. 2021; 11: 7115. 33782518 PMC8007804
  53. [64]Keith J, Gao FQ, Noor R, et al. Collagenosis of the deep medullary veins: an underrecognized pathologic correlate of white matter hyperintensities and periventricular infarction? J Neuropathol Exp Neurol. 2017; 76: 299‐ 312. 28431180
  54. [65]Lahna D, Schwartz DL, Woltjer R, et al. Venous collagenosis as pathogenesis of white matter hyperintensity. Ann Neurol. 2022; 92: 992‐ 1000. 36054513 PMC9671829
  55. [67]Wardlaw JM, Valdés Hernández MC, Muñoz‐Maniega S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J Am Heart Assoc. 2015; 4: 001140. 26104658 PMC4599520

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Authors
Sanchez, E., Wilkinson, T., Coughlan, G., Mirza, S., Baril, A., Ramirez, J., Binns, M. A., Black, S. E., Borrie, M., Dilliott, A. A., Dixon, R. A., Dowlatshahi, D., Farhan, S., Finger, E., Fischer, C. E., Frank, A., Freedman, M., Goncalves, R. A., Grimes, D. A., Hassan, A., Hegele, R. A., Kumar, S., Lang, A. E., Marras, C., McLaughlin, P. M., Orange, J. B., Pasternak, S. H., Pollock, B. G., Rajji, T. K., Roberts, A. C., Robinson, J. F., Rogaeva, E., Sahlas, D. J., Saposnik, G., Strong, M. J., Swartz, R. H., Tang‐Wai, D. F., Tartaglia, M. C., Troyer, A. K., Kvartsberg, H., Zetterberg, H., Munoz, D. P., the ONDRI Investigators, & Masellis, M.
Affiliations
  • Sunnybrook Research Institute (CA)
  • Harvard University (US)
  • University of Toronto (CA)
  • Douglas Mental Health University Institute (CA)
  • Western University (CA)
  • Montreal Neurological Institute and Hospital (CA)
  • University of Alberta (CA)
  • University of Ottawa (CA)
  • St. Michael's Hospital (CA)
  • Mount Sinai Hospital (CA)
  • Centre for Neuroscience Studies Queen's University Kingston Ontario Canada
  • Thunder Bay Regional Research Institute (CA)
  • Centre for Addiction and Mental Health (CA)
  • Toronto Western Hospital (CA)
  • Dalhousie University (CA)
  • McMaster University (CA)
  • Sunnybrook Health Science Centre (CA)
  • University Health Network (CA)
  • Sahlgrenska University Hospital (SE)
  • University of Wisconsin–Madison (US)
  • Queen's University (CA)
Corresponding author
Masellis, Mario
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2023-12-17
Volume
20
Issue
3
Pages
1753-1770
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.13560
PMC
PMC10984487
OpenAlex
W4389862492
Cited by
62
References
10
Citations by year
2026: 22 · 2025: 31 · 2024: 8 · 2023: 1
FWCI
12.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion, cc-by)
Funders
  • Ontario Brain Institute
  • Alberta Innovates
  • Canadian Institutes of Health Research (#163902)
  • Vetenskapsrådet (#2022‐01018, #2019‐02397)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
plasma biomarkers, glial fibrillary acidic protein
MeSH terms
Activities of Daily Living, Alzheimer Disease, Cardiovascular Diseases, Cognition, Humans, Ontario, Biomarkers, Amyloid beta-Peptides, tau Proteins, Neurodegenerative Diseases, Frontotemporal Dementia, Cognitive Dysfunction

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