CoChat
Sign Up
Cited by 48Amyotrophic Lateral Sclerosis ResearchDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Biomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis

Open access
Katzeff, Jared S., Bright, Fiona, Phan, Katherine, Kril, Jillian J., Ittner, Lars M., Kassiou, Michael, Hodges, John R., Piguet, Olivier +3 more·2022·Brain
DOI 10.1093/brain/awac077PMC PMC9166557
Open this paper in CoChat — free account

Abstract

Frontotemporal dementia refers to a group of neurodegenerative disorders characterized by behaviour and language alterations and focal brain atrophy. Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by loss of motor neurons resulting in muscle wasting and paralysis. Frontotemporal dementia and amyotrophic lateral sclerosis are considered to exist on a disease spectrum given substantial overlap of genetic and molecular signatures. The predominant genetic abnormality in both frontotemporal dementia and amyotrophic lateral sclerosis is an expanded hexanucleotide repeat sequence in the C9orf72 gene. In terms of brain pathology, abnormal aggregates of TAR-DNA-binding protein-43 are predominantly present in frontotemporal dementia and amyotrophic lateral sclerosis patients. Currently, sensitive and specific diagnostic and disease surveillance biomarkers are lacking for both diseases. This has impeded the capacity to monitor disease progression during life and the development of targeted drug therapies for the two diseases. The purpose of this review is to examine the status of current biofluid biomarker discovery and development in frontotemporal dementia and amyotrophic lateral sclerosis. The major pathogenic proteins implicated in different frontotemporal dementia and amyotrophic lateral sclerosis molecular subtypes and proteins associated with neurodegeneration and the immune system will be discussed. Furthermore, the use of mass spectrometry-based proteomics as an emerging tool to identify new biomarkers in frontotemporal dementia and amyotrophic lateral sclerosis will be summarized.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/brain/awac077

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The significant degree of clinical, pathological and genetic heterogeneity observed in FTD hinders the development of sensitive and specific biomarkers that would allow for targeted recruitment of groups at highest risk for clinical/cognitive decline.

    “the significant degree of clinical, pathological and genetic heterogeneity observed in FTD hinders the development of sensitive and specific biomarkers that would allow for targeted recruitment of groups at highest risk for clinical/cognitive decline (Katzeff et al., 2022).”

    From Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI (2024) · cites this paper as Katzeff et al., 2022

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 140

  1. [1]Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015; 386(10004): 1672– 1682. 26595641 PMC5970949
  2. [2]Lambert MA, Bickel H, Prince M, et al Estimating the burden of early onset dementia; systematic review of disease prevalence. Eur J Neurol. 2014; 21(4): 563– 569. 24418291
  3. [3]Olney NT, Spina S, Miller BL. Frontotemporal dementia. Neurol Clin. 2017; 35(2): 339– 374. 28410663 PMC5472209
  4. [4]Pottier C, Ravenscroft TA, Sanchez-Contreras M, Rademakers R. Genetics of FTLD: Overview and what else we can expect from genetic studies. J Neurochem. 2016; 138(Suppl 1): 32– 53. 27009575
  5. [5]Schroeter ML, Pawelke S, Bisenius S, et al A modified reading the mind in the eyes test predicts behavioral variant frontotemporal dementia better than executive function tests. Front Aging Neurosci. 2018; 10: 11. 29441012 PMC5797534
  6. [6]Marshall CR, Hardy CJD, Volkmer A, et al Primary progressive aphasia: A clinical approach. J Neurol. 2018; 265(6): 1474– 1490. 29392464 PMC5990560
  7. [7]Woollacott IO, Rohrer JD. The clinical spectrum of sporadic and familial forms of frontotemporal dementia. J Neurochem. 2016; 138(Suppl 1): 6– 31. 27144467
  8. [8]Ciervo Y, Ning K, Jun X, Shaw PJ, Mead RJ. Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis. Mol Neurodegener. 2017; 12(1): 85. 29132389 PMC5683324
  9. [9]Taylor JP, Brown RH Jr, Cleveland DW. Decoding ALS: From genes to mechanism. Nature. 2016; 539(7628): 197– 206. 27830784 PMC5585017
  10. [10]Talbott EO, Malek AM, Lacomis D. The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol. 2016; 138: 225– 38. 27637961
  11. [11]van Es MA, Hardiman O, Chio A, et al Amyotrophic lateral sclerosis. Lancet. 2017; 390(10107): 2084– 2098. 28552366
  12. [13]Turner MR. Motor neuron disease: Biomarker development for an expanding cerebral syndrome. Clin Med (Lond). 2016; 16(Suppl 6): s60– s65. 27956443 PMC6329564
  13. [14]Lattante S, Ciura S, Rouleau GA, Kabashi E. Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Trends Genet. 2015; 31(5): 263– 273. 25869998
  14. [16]Tan RH, Ke YD, Ittner LM, Halliday GM. ALS/FTLD: Experimental models and reality. Acta Neuropathol. 2017; 133(2): 177– 196. 28058507
  15. [17]Neumann M, Sampathu DM, Kwong LK, et al Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006; 314(5796): 130– 133. 17023659
  16. [18]DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011; 72(2): 245– 256. 21944778 PMC3202986
  17. [19]Renton AE, Majounie E, Waite A, et al A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 20 2011; 72(2): 257– 268. 21944779 PMC3200438
  18. [20]Borroni B, Archetti S, Del Bo R, et al TARDBP mutations in frontotemporal lobar degeneration: Frequency, clinical features, and disease course. Rejuvenation Res. 2010; 13(5): 509– 517. 20645878
  19. [21]Mackenzie IR, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 2010; 9(10): 995– 1007. 20864052
  20. [22]Buratti E, Baralle FE. Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci. 2008; 13: 867– 878. 17981595
  21. [23]Buratti E, Baralle FE. TDP-43: Gumming up neurons through protein-protein and protein-RNA interactions. Trends Biochem Sci. 2012; 37(6): 237– 247. 22534659
  22. [24]Suarez-Calvet M, Dols-Icardo O, Llado A, et al Plasma phosphorylated TDP-43 levels are elevated in patients with frontotemporal dementia carrying a C9orf72 repeat expansion or a GRN mutation. J Neurol Neurosurg Psychiatry. 2014; 85(6): 684– 691. 24309270
  23. [25]Junttila A, Kuvaja M, Hartikainen P, et al Cerebrospinal fluid TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis patients with and without the C9ORF72 hexanucleotide expansion. Dement Geriatr Cogn Dis Extra. 2016; 6(1): 142– 149. 27195002 PMC4868946
  24. [26]Kasai T, Tokuda T, Ishigami N, et al Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathol. 2009; 117(1): 55– 62. 18989684
  25. [27]Majumder V, Gregory JM, Barria MA, Green A, Pal S. TDP-43 as a potential biomarker for amyotrophic lateral sclerosis: A systematic review and meta-analysis. BMC Neurol. 2018; 18(1): 90. 29954341 PMC6027783
  26. [28]Feneberg E, Gray E, Ansorge O, Talbot K, Turner MR. Towards a TDP-43-based biomarker for ALS and FTLD. Mol Neurobiol. 2018; 55(10): 7789– 7801. 29460270 PMC6132775
  27. [29]Feneberg E, Steinacker P, Lehnert S, et al Limited role of free TDP-43 as a diagnostic tool in neurodegenerative diseases. Amyotroph Lateral Scler Frontotemporal Degener. 2014; 15(5-6): 351– 356. 24834468
  28. [31]Hirokawa N. Microtubule organization and dynamics dependent on microtubule-associated proteins. Curr Opin Cell Biol. 1994; 6(1): 74– 81. 8167029
  29. [32]Poorkaj P, Bird TD, Wijsman E, et al Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998; 43(6): 815– 825. 9629852
  30. [33]Hutton M, Lendon CL, Rizzu P, et al Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998; 393(6686): 702– 705. 9641683
  31. [34]van der Zee J, Van Broeckhoven C. Dementia in 2013: Frontotemporal lobar degeneration—building on breakthroughs. Nat Rev Neurol. 2014; 10(2): 70– 72. 24394289
  32. [35]Borroni B, Benussi A, Archetti S, et al Csf p-tau181/tau ratio as biomarker for TDP pathology in frontotemporal dementia. Amyotroph Lateral Scler Frontotemporal Degener. 2015; 16(1–2): 86– 91. 25352065
  33. [36]Hu WT, Watts K, Grossman M, et al Reduced CSF p-Tau181 to Tau ratio is a biomarker for FTLD-TDP. Neurology. 2013; 81(22): 1945– 1952. 24174584 PMC3843382
  34. [37]Foiani MS, Woollacott IO, Heller C, et al Plasma tau is increased in frontotemporal dementia. J Neurol Neurosurg Psychiatry. 2018; 89(8): 804– 807. 29440230 PMC6204947
  35. [39]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(3): 387– 397. 32123386 PMC7101073
  36. [40]Benussi A, Karikari TK, Ashton N, et al Diagnostic and prognostic value of serum NfL and p-Tau181 in frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry. 2020; 91(9): 960– 967. 32611664
  37. [41]Grossman M, Elman L, McCluskey L, et al Phosphorylated tau as a candidate biomarker for amyotrophic lateral sclerosis. JAMA Neurol. 2014; 71(4): 442– 448. 24492862 PMC3989393
  38. [42]Foiani MS, Cicognola C, Ermann N, et al Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: An elusive quest. J Neurol Neurosurg Psychiatry. 2019; 90: 740– 746. 30981993 PMC6585261
  39. [43]Burrell JR, Halliday GM, Kril JJ, et al The frontotemporal dementia-motor neuron disease continuum. Lancet. 2016; 388(10047): 919– 931. 26987909
  40. [44]Ho WY, Tai YK, Chang JC, et al The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy. Autophagy. 2019; 15(5): 827– 842. 30669939 PMC6526867
  41. [45]Atanasio A, Decman V, White D, et al C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep. 2016; 6: 23204. 26979938 PMC4793236
  42. [46]Burberry A, Suzuki N, Wang JY, et al Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci Transl Med. 2016; 8(347): 347ra93. PMC5024536 27412785
  43. [47]O’Rourke JG, Bogdanik L, Yanez A, et al C9orf72 is required for proper macrophage and microglial function in mice. Science. 2016; 351(6279): 1324– 1329. 26989253 PMC5120541
  44. [48]Xi Z, van Blitterswijk M, Zhang M, et al Jump from pre-mutation to pathologic expansion in C9orf72. Am J Hum Genet. 2015; 96(6): 962– 970. 26004200 PMC4457950
  45. [49]Xi Z, Zhang M, Bruni AC, et al The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients. Acta Neuropathologica. 2015; 129(5): 715– 727. 25716178
  46. [50]Renton AE, Chio A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014; 17(1): 17– 23. 24369373 PMC4544832
  47. [51]Shi Y, Lin S, Staats KA, et al Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med. 2018; 24(3): 313– 325. 29400714 PMC6112156
  48. [52]Gao FB, Almeida S, Lopez-Gonzalez R. Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder. EMBO J. 2017; 36(20): 2931– 2950. 28916614 PMC5641681
  49. [53]Kumar V, Hasan GM, Hassan MI. Unraveling the role of RNA mediated toxicity of C9orf72 repeats in C9-FTD/ALS. Front Neurosci. 2017; 11: 711. 29326544 PMC5736982
  50. [54]Kanekura K, Yagi T, Cammack AJ, et al Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation. Hum Mol Genet. 2016; 25(9): 1803– 1813. 26931465 PMC4986334
  51. [55]Gendron TF, Chew J, Stankowski JN, et al Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci Transl Med. 2017; 9(383):eaai7866. PMC5576451 28356511
  52. [56]Meeter LHH, Gendron TF, Sias AC, et al Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers. Ann Clin Transl Neurol. 2018; 5(5): 583– 597. 29761121 PMC5945959
  53. [57]Lehmer C, Oeckl P, Weishaupt JH, et al Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD. EMBO Mol Med. 2017; 9(7): 859– 868. 28408402 PMC5494528
  54. [58]Bunton-Stasyshyn RK, Saccon RA, Fratta P, Fisher EM. SOD1 function and its implications for amyotrophic lateral sclerosis pathology: New and renascent themes. Neuroscientist. 2015; 21(5): 519– 29. 25492944
  55. [59]Rosen DR, Siddique T, Patterson D, et al Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993; 362(6415): 59– 62. 8446170
  56. [60]Saccon RA, Bunton-Stasyshyn RK, Fisher EM, Fratta P. Is SOD1 loss of function involved in amyotrophic lateral sclerosis? Brain. 2013; 136(Pt 8): 2342– 58. 23687121 PMC3722346
  57. [61]Zetterstrom P, Andersen PM, Brannstrom T, Marklund SL. Misfolded superoxide dismutase-1 in CSF from amyotrophic lateral sclerosis patients. J Neurochem. 2011; 117(1): 91– 99. 21226712
  58. [62]Winer L, Srinivasan D, Chun S, et al SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy. JAMA Neurol. 2013; 70(2): 201– 207. 23147550 PMC3812918
  59. [64]Yuan A, Rao MV, Veeranna, Nixon RA. Neurofilaments at a glance. J Cell Sci. 2012; 125(Pt 14): 3257– 3263. 22956720 PMC3516374
  60. [65]Khalil M, Teunissen CE, Otto M, et al Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018; 14(10): 577– 589. 30171200
  61. [66]Cajanus A, Katisko K, Kontkanen A, et al Serum neurofilament light chain in FTLD: Association with C9orf72, clinical phenotype, and prognosis. Ann Clin Transl Neurol. 2020; 7(6): 903– 910. 32441885 PMC7318100
  62. [67]van der Ende EL, Meeter LH, Poos JM, et al Serum neurofilament light chain in genetic frontotemporal dementia: A longitudinal, multicentre cohort study. Lancet Neurol. 2019; 18(12): 1103– 1111. 31701893
  63. [68]Panman JL, Venkatraghavan V, van der Ende EL, et al Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia. J Neurol Neurosurg Psychiatry. 2021; 92: 494– 501. 33452053 PMC8053353
  64. [69]Rojas JC, Wang P, Staffaroni AM, et al Plasma neurofilament light for prediction of disease progression in familial frontotemporal lobar degeneration. Neurology. 2021; 96: e2296– e2312. 33827960 PMC8166434
  65. [70]Wilke C, Preische O, Deuschle C, et al Neurofilament light chain in FTD is elevated not only in cerebrospinal fluid, but also in serum. J Neurol Neurosurg Psychiatry. 2016; 87(11): 1270– 1272. 27188986
  66. [72]Abu-Rumeileh S, Mometto N, Bartoletti-Stella A, et al Cerebrospinal fluid biomarkers in patients with frontotemporal dementia spectrum: A single-center study. J Alzheimers Dis. 2018; 66(2): 551– 563. 30320576
  67. [73]Abu-Rumeileh S, Vacchiano V, Zenesini C, et al Diagnostic-prognostic value and electrophysiological correlates of CSF biomarkers of neurodegeneration and neuroinflammation in amyotrophic lateral sclerosis. J Neurol. 2020; 267: 1699– 1708. 32100123
  68. [74]Sun Q, Zhao X, Li S, et al CSF neurofilament light chain elevation predicts ALS severity and progression. Front Neurol. 2020; 11: 919. 32982935 PMC7484044
  69. [76]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: 870– 881. 30967444
  70. [77]Skillback T, Mattsson N, Blennow K, Zetterberg H. Cerebrospinal fluid neurofilament light concentration in motor neuron disease and frontotemporal dementia predicts survival. Amyotroph Lateral Scler Frontotemporal Degener. 2017; 18(5–6): 397– 403. 28631955
  71. [78]Brodovitch A, Boucraut J, Delmont E, et al Combination of serum and CSF neurofilament-light and neuroinflammatory biomarkers to evaluate ALS. Sci Rep. 2021; 11(1): 703. 33436881 PMC7803734
  72. [79]van der Ende EL, Bron EE, Poos JM, et al A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia. Brain. 2021; 17: e053497. PMC9166533 34633446
  73. [80]Behzadi A, Pujol-Calderon F, Tjust AE, et al Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics. Sci Rep. 2021; 11(1): 22128. 34764380 PMC8585882
  74. [81]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(2): 277– 283. 30664784 PMC6367005
  75. [82]Sako W, Murakami N, Izumi Y, Kaji R. Neurofilament light chain level in cerebrospinal fluid can differentiate Parkinson's disease from atypical parkinsonism: Evidence from a meta-analysis. J Neurol Sci. 2015; 352(1–2): 84– 87. 25868897
  76. [83]Edwards KR, Garten L, Button J, O’Connor J, Kamath V, Frazier C. Neurofilament light chain as an indicator of exacerbation prior to clinical symptoms in multiple sclerosis. Mult Scler Relat Disord. 2019; 31: 59– 61. 30927733
  77. [84]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(1): 3400. 34099648 PMC8185001
  78. [85]Pijnenburg YA, Janssen JC, Schoonenboom NS, et al CSF neurofilaments in frontotemporal dementia compared with early onset Alzheimer's disease and controls. Dement Geriatr Cogn Disord. 2007; 23(4): 225– 230. 17290105
  79. [86]Boylan KB, Glass JD, Crook JE, et al Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2013; 84(4): 467– 72. 23117489
  80. [87]Benatar M, Wuu J, Lombardi V, et al Neurofilaments in pre-symptomatic ALS and the impact of genotype. Amyotroph Lateral Scler Frontotemporal Degener. 2019; 20(7–8): 538– 548. 31432691 PMC6768722
  81. [88]Remnestal J, Oijerstedt L, Ullgren A, et al Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers. Transl Neurodegener. 2020; 9(1): 27. 32576262 PMC7310563
  82. [89]Haggmark A, Mikus M, Mohsenchian A, et al Plasma profiling reveals three proteins associated to amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 2014; 1(8): 544– 553. 25356426 PMC4184557
  83. [90]Bright F, Werry EL, Dobson-Stone C, et al Neuroinflammation in frontotemporal dementia. Nat Rev Neurol. 2019; 15(9): 540– 555. 31324897
  84. [91]McCauley ME, Baloh RH. Inflammation in ALS/FTD pathogenesis. Acta Neuropathol. 2019; 137(5): 715– 730. 30465257 PMC6482122
  85. [92]Rathcke CN, Vestergaard H. YKL-40–an emerging biomarker in cardiovascular disease and diabetes. Cardiovasc Diabetol. 2009; 8: 61. 19930630 PMC2789050
  86. [93]Nordenbaek C, Johansen JS, Junker P, Borregaard N, Sorensen O, Price PA. YKL-40, a matrix protein of specific granules in neutrophils, is elevated in serum of patients with community-acquired pneumonia requiring hospitalization. J Infect Dis. 1999; 180(5): 1722– 1726. 10515841
  87. [94]Lee CG, Dela Cruz CS, Herzog E, Rosenberg SM, Ahangari F, Elias JA. YKL-40, a chitinase-like protein at the intersection of inflammation and remodeling. Am J Respir Crit Care Med. 2012; 185(7): 692– 694. 22467800
  88. [95]Oeckl P, Weydt P, Steinacker P, et al Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase. J Neurol Neurosurg Psychiatry. 2019; 90: 4– 10. 30224549
  89. [96]Vu L, An J, Kovalik T, Gendron T, Petrucelli L, Bowser R. Cross-sectional and longitudinal measures of chitinase proteins in amyotrophic lateral sclerosis and expression of CHI3L1 in activated astrocytes. J Neurol Neurosurg Psychiatry. 2020; 91: 350– 358. 31937582 PMC7147184
  90. [97]Andres-Benito P, Dominguez R, Colomina MJ, Llorens F, Povedano M, Ferrer I. YKL40 in sporadic amyotrophic lateral sclerosis: Cerebrospinal fluid levels as a prognosis marker of disease progression. Aging. 2018; 10(9): 2367– 2382. 30215603 PMC6188478
  91. [98]Del Campo M, Galimberti D, Elias N, et al Novel CSF biomarkers to discriminate FTLD and its pathological subtypes. Ann Clin Transl Neurol. 2018; 5(10): 1163– 1175. 30349851 PMC6186934
  92. [99]Woollacott IOC, Nicholas JM, Heller C, et al Cerebrospinal fluid YKL-40 and chitotriosidase levels in frontotemporal dementia vary by clinical, genetic and pathological subtype. Dement Geriatr Cogn Disord. 2020; 49(1): 56– 76. 32344399 PMC7513620
  93. [100]Teunissen CE, Elias N, Koel-Simmelink MJ, et al Novel diagnostic cerebrospinal fluid biomarkers for pathologic subtypes of frontotemporal dementia identified by proteomics. Alzheimers Dement (Amst). 2016; 2: 86– 94. 27239539 PMC4879654
  94. [101]Baldacci F, Lista S, Cavedo E, Bonuccelli U, Hampel H. Diagnostic function of the neuroinflammatory biomarker YKL-40 in Alzheimer's disease and other neurodegenerative diseases. Expert Rev Proteomics. 2017; 14(4): 285– 299. 28281838
  95. [104]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(3): 263– 270. 31937580
  96. [106]Benninger F, Glat MJ, Offen D, Steiner I. Glial fibrillary acidic protein as a marker of astrocytic activation in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis. J Clin Neurosci. 2016; 26: 75– 78. 26602604
  97. [107]Nycander M, Estrada S, Mort JS, Abrahamson M, Bjork I. Two-step mechanism of inhibition of cathepsin B by cystatin C due to displacement of the proteinase occluding loop. FEBS Lett. 1998; 422(1): 61– 64. 9475170
  98. [108]George PM, Sheat JM. Cystatin C quantification in CSF. Clin Chem. 1989; 35(1): 179– 180. 2491975
  99. [109]Nagai A, Ryu JK, Terashima M, et al Neuronal cell death induced by cystatin C in vivo and in cultured human CNS neurons is inhibited with cathepsin B. Brain Res. 2005; 1066(1–2): 120– 128. 16325785
  100. [111]Okamoto K, Hirai S, Amari M, Watanabe M, Sakurai A. Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti-cystatin C serum. Neurosci Lett. 1993; 162(1–2): 125– 128. 8121614
  101. [112]Okamoto K, Mizuno Y, Fujita Y. Bunina bodies in amyotrophic lateral sclerosis. Neuropathology. 2008; 28(2): 109– 115. 18069968
  102. [113]Ranganathan S, Williams E, Ganchev P, et al Proteomic profiling of cerebrospinal fluid identifies biomarkers for amyotrophic lateral sclerosis. J Neurochem. 2005; 95(5): 1461– 1471. 16313519 PMC1540444
  103. [114]Tsuji-Akimoto S, Yabe I, Niino M, Kikuchi S, Sasaki H. Cystatin C in cerebrospinal fluid as a biomarker of ALS. Neurosci Lett. 2009; 452(1): 52– 55. 19444952
  104. [115]Ren Y, Zhu W, Cui F, et al Measurement of cystatin C levels in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Int J Clin Exp Pathol. 2015; 8(5): 5419– 5426. 26191245 PMC4503116
  105. [116]Heywood WE, Hallqvist J, Heslegrave AJ, et al CSF pro-orexin and amyloid-beta38 expression in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging. 2018; 72: 171– 176. 30292090 PMC6221294
  106. [117]Zhong XM, Hou L, Luo XN, et al Alterations of CSF cystatin C levels and their correlations with CSF Alphabeta40 and Alphabeta42 levels in patients with Alzheimer's disease, dementia with Lewy bodies and the atrophic form of general paresis. PLoS ONE. 2013; 8(1): e55328. 23383156 PMC3558470
  107. [118]Beers DR, Henkel JS, Zhao W, et al Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011; 134(Pt 5): 1293– 314. 21596768 PMC3097891
  108. [119]Beers DR, Zhao W, Wang J, et al ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight. 2017; 2(5): e89530. 28289705 PMC5333967
  109. [120]Rentzos M, Evangelopoulos E, Sereti E, et al Alterations of T cell subsets in ALS: A systemic immune activation? Acta Neurol Scand. 2012; 125(4): 260– 264. 21651502
  110. [121]Zhao W, Beers DR, Liao B, Henkel JS, Appel SH. Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol Dis. 2012; 48(3): 418– 428. 22820142 PMC3897268
  111. [122]Giovannelli I, Heath P, Shaw PJ, Kirby J. The involvement of regulatory T cells in amyotrophic lateral sclerosis and their therapeutic potential. Amyotroph Lateral Scler Frontotemporal Degener. 2020; 21(5–6): 435– 444. 32484719
  112. [123]Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front Immunol. 2019; 10: 43. 30804926 PMC6371029
  113. [124]Shepheard SR, Chataway T, Schultz DW, Rush RA, Rogers ML. The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis. PLoS ONE. 2014; 9(1): e87398. 24475283 PMC3903651
  114. [125]Jia R, Shepheard S, Jin J, et al Urinary extracellular domain of neurotrophin receptor p75 as a biomarker for amyotrophic lateral sclerosis in a Chinese cohort. Sci Rep. 2017; 7(1): 5127. 28698670 PMC5506052
  115. [126]Shi G, Shao S, Zhou J, Huang K, Bi FF. Urinary p75(ECD) levels in patients with amyotrophic lateral sclerosis: A meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2021: 1– 8. 34726989
  116. [127]Leonenko G, Baker E, Stevenson-Hoare J, et al Identifying individuals with high risk of Alzheimer's disease using polygenic risk scores. Nat Commun. 2021; 12(1): 4506. 34301930 PMC8302739
  117. [128]Hagenaars SP, Radakovic R, Crockford C, et al Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function. PLoS ONE. 2018; 13(6): e0198187. 29856801 PMC5983413
  118. [129]Hosp F, Mann M. A primer on concepts and applications of proteomics in neuroscience. Neuron. 2017; 96(3): 558– 571. 29096073
  119. [131]Lu W, Wan X, Liu B, et al Specific changes of serum proteins in Parkinson's disease patients. PLoS ONE. 2014; 9(4): e95684. 24769800 PMC4000217
  120. [132]Davidsson P, Sjogren M, Andreasen N, et al Studies of the pathophysiological mechanisms in frontotemporal dementia by proteome analysis of CSF proteins. Brain Res Mol Brain Res. 2002; 109(1–2): 128– 33. 12531522
  121. [133]Ruetschi U, Zetterberg H, Podust VN, et al Identification of CSF biomarkers for frontotemporal dementia using SELDI-TOF. Exp Neurol. 2005; 196(2): 273– 281. 16154129
  122. [134]van der Ende EL, Meeter LH, Stingl C, et al Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics. Ann Clin Transl Neurol. 2019; 6(4): 698– 707. 31019994 PMC6469343
  123. [135]Barschke P, Oeckl P, Steinacker P, Ludolph A, Otto M. Proteomic studies in the discovery of cerebrospinal fluid biomarkers for amyotrophic lateral sclerosis. Expert Rev Proteomics. 2017; 14(9): 769– 777. 28799854
  124. [136]Pasinetti GM, Ungar LH, Lange DJ, et al Identification of potential CSF biomarkers in ALS. Neurology. Apr. 2006; 66(8): 1218– 1222. 16481598
  125. [137]von Neuhoff N, Oumeraci T, Wolf T, et al Monitoring CSF proteome alterations in amyotrophic lateral sclerosis: Obstacles and perspectives in translating a novel marker panel to the clinic. PLoS ONE. 2012; 7(9): e44401. 22970211 PMC3435306
  126. [138]Ryberg H, An J, Darko S, et al Discovery and verification of amyotrophic lateral sclerosis biomarkers by proteomics. Muscle Nerve 2010; 42(1): 104– 111. 20583124 PMC2975276
  127. [139]Collins MA, An J, Hood BL, Conrads TP, Bowser RP. Label-free LC-MS/MS proteomic analysis of cerebrospinal fluid identifies protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis. J Proteome Res. 2015; 14(11): 4486– 4501. 26401960 PMC5592736
  128. [140]Brettschneider J, Mogel H, Lehmensiek V, et al Proteome analysis of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS). Neurochem Res. 2008; 33(11): 2358– 2363. 18481174
  129. [141]Chen Y, Liu XH, Wu JJ, et al Proteomic analysis of cerebrospinal fluid in amyotrophic lateral sclerosis. Exp Ther Med. 2016; 11(6): 2095– 2106. 27284291 PMC4887813
  130. [142]Ranganathan S, Nicholl GC, Henry S, et al Comparative proteomic profiling of cerebrospinal fluid between living and post mortem ALS and control subjects. Amyotroph Lateral Scler. 2007; 8(6): 373– 379. 17852009 PMC2829467
  131. [143]Brettschneider J, Lehmensiek V, Mogel H, et al Proteome analysis reveals candidate markers of disease progression in amyotrophic lateral sclerosis (ALS). Neurosci Lett. 2010; 468(1): 23– 27. 19853641
  132. [144]Xu Z, Lee A, Nouwens A, Henderson RD, McCombe PA. Mass spectrometry analysis of plasma from amyotrophic lateral sclerosis and control subjects. Amyotroph Lateral Scler Frontotemporal Degener. 2018; 19(5–6): 362– 376. 29384411
  133. [145]Bereman MS, Beri J, Enders JR, Nash T. Machine learning reveals protein signatures in CSF and plasma fluids of clinical value for ALS. Sci Rep. 2018; 8(1): 16334. 30397248 PMC6218542
  134. [146]Oeckl P, Weydt P, Thal DR, Weishaupt JH, Ludolph AC, Otto M. Proteomics in cerebrospinal fluid and spinal cord suggests UCHL1, MAP2 and GPNMB as biomarkers and underpins importance of transcriptional pathways in amyotrophic lateral sclerosis. Acta Neuropathol. 2020; 139(1): 119– 134. 31701227
  135. [148]Katzeff JS, Bright F, Lo K, et al Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation. Sci Rep. 2020; 10(1): 13741. 32792518 PMC7426269
  136. [149]Kim WS, Jary E, Pickford R, et al Lipidomics analysis of behavioral variant frontotemporal dementia: A scope for biomarker development. Front Neurol. 2018; 9: 104. 29541056 PMC5835505
  137. [150]Sol J, Jove M, Povedano M, et al Lipidomic traits of plasma and cerebrospinal fluid in amyotrophic lateral sclerosis correlate with disease progression. Brain Commun. 2021; 3(3): fcab143. 34396104 PMC8361390
  138. [151]FernAndez-Eulate G, Ruiz-Sanz JI, Riancho J, et al A comprehensive serum lipidome profiling of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2020; 21(3–4): 252– 262. 32106710
  139. [153]Santos ALM, Vitório JG, de Paiva MJN, et al Frontotemporal dementia: Plasma metabolomic signature using gas chromatography-mass spectrometry. J Pharm Biomed Anal. 2020; 189: 113424. 32619729
  140. [154]Jia R, Chen Q, Zhou Q, et al Characteristics of serum metabolites in sporadic amyotrophic lateral sclerosis patients based on gas chromatography-mass spectrometry. Sci Rep. 2021; 11(1): 20786. 34675267 PMC8531355

Cited by

Sorted by citations

Authors
Katzeff, J. S., Bright, F., Phan, K., Kril, J. J., Ittner, L. M., Kassiou, M., Hodges, J. R., Piguet, O., Kiernan, M. C., Halliday, G. M., & Kim, W. S.
Affiliations
  • The University of Sydney (AU)
  • Macquarie University (AU)
Corresponding author
Kim, Woojin Scott
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2022-02-24
Volume
145
Issue
5
Pages
1598-1609
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awac077
PMC
PMC9166557
OpenAlex
W4213428434
Cited by
48
References
14
Citations by year
2026: 7 · 2025: 10 · 2024: 15 · 2023: 14 · 2022: 2
FWCI
1.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Health and Medical Research Council of Australia (#1132524, #1095127, #1153439)
  • NHMRC Leadership Fellow (#1176607)
  • NHMRC Practitioner Fellow (#1156093)
  • NHMRC Principal Research Fellow (#1136241)
  • NHMRC Senior Research Fellow (#1103258)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
frontotemporal dementia, amyotrophic lateral sclerosis, biomarkers, C9orf72 repeat expansion, TDP-43 aggregates, biofluid biomarkers, proteomics, disease progression monitoring, neurodegeneration, immune system proteins, disease spectrum
MeSH terms
C9orf72 Protein, Amyotrophic Lateral Sclerosis, Humans, Neurodegenerative Diseases, Pick Disease of the Brain, DNA Repeat Expansion, Frontotemporal Dementia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review