Document Type : Original Article

Authors

1 Neuroscience Research Group, Universal Scientific Education and Research Network, Tehran, Iran School of Medicine, Iran University of Medical Sciences, Tehran, Iran

2 Center for the Study of Emotion and Attention, University of Florida, Florida, USA Department of Psychology, University of Florida, Florida, USA

3 Neuroscience Research Group, Universal Scientific Education and Research Network, Tehran, Iran

4 School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

5 Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran

Abstract

Background: Recent findings suggest that the plasma axonal structural protein, neurofilament light (NFL) chain, may serve as a potential blood biomarker for early signs of neurodegenerative diseases, such as Alzheimer’s disease (AD). Given the need for early detection of neurodegenerative disorders, the current study investigated the associations between regional cerebral blood flow (rCBF) in brain regions associated with neurodegenerative disorders and memory function with plasma NFL in AD, mild cognitive impairment (MCI), and healthy controls (HCs).
Methods: We recruited 29 AD, 76 MCI, and 39 HCs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database in the current cross-sectional study. We used Pearson’s correlation models adjusted for the effect of age, sex, and APOE genotype to investigate the association between plasma NFL and rCBF.
Results: We found non-significant differences in age (F(2, 141) = 1.304; P = 0.275) and years of education (F(2, 141) = 0.013; P = 0.987). Additionally, we found significant differences between groups in terms of MMSE scores (F(2, 141) = 100.953; P < 0.001). Despite the observation of significantly reduced rCBF in AD and MCI groups versus HCs, we did not detect significant differences in plasma NFL between these groups. We found significant negative associations between plasma NFL and rCBF in various AD-related regions, these findings were only observed after analyses in all participants, and were observed in HCs alone and no significant associations were observed in the AD or MCI groups.
Conclusion: These outcomes add to our current understanding surrounding the use of rCBF and plasma NFL biomarkers as tools for early detection and diagnosis of neurodegenerative diseases. A conclusion might be that the association between NFL and impaired rCBF exists before the clinical symptoms appear. Further longitudinal studies with a large sample size should be performed to examine the correlation between plasma NFL and rCBF in order to understand these complex relationships.

Keywords

  1. Stomrud E, Forsberg A, Hagerstrom D, Ryding E, Blennow K, Zetterberg H, et al. CSF biomarkers correlate with cerebral blood flow on SPECT in healthy elderly. Dement Geriatr Cogn Disord 2012; 33(2-3): 156-63.
  2. Meek PD, McKeithan K, Schumock GT. Economic considerations in Alzheimer's disease. Pharmacotherapy 1998; 18(2 Pt 2): 68-73.
  3. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, 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(3): 270-9.
  4. Kelley BJ, Petersen RC. Alzheimer's disease and mild cognitive impairment. Neurol Clin 2007; 25(3): 577-609, v.
  5. Mimura M, Yano M. Memory impairment and awareness of memory deficits in early-stage Alzheimer's disease. Rev Neurosci 2006; 17(1-2): 253-66.
  6. Pennanen C, Kivipelto M, Tuomainen S, Hartikainen P, Hanninen T, Laakso MP, et al. Hippocampus and entorhinal cortex in mild cognitive impairment and early AD. Neurobiol Aging 2004; 25(3): 303-10.
  7. Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol 2012; 71(4): 266-73.
  8. Olsson B, Lautner R, Andreasson U, Ohrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: A systematic review and meta-analysis. Lancet Neurol 2016; 15(7): 673-84.
  9. Khalil M, Pirpamer L, Hofer E, Voortman MM, Barro C, Leppert D, et al. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun 2020; 11(1): 812.
  10. Forgrave LM, Ma M, Best JR, DeMarco ML. The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis: A systematic review and meta-analysis. Alzheimers Dement (Amst) 2019; 11: 730-43.
  11. Ashton NJ, Leuzy A, Lim YM, Troakes C, Hortobagyi T, Hoglund K, et al. Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration. Acta Neuropathol Commun 2019; 7(1): 5.
  12. de Wolf F, Ghanbari M, Licher S, McRae-McKee K, Gras L, Weverling GJ, et al. Plasma tau, neurofilament light chain and amyloid-beta levels and risk of dementia; a population-based cohort study. Brain 2020; 143(4): 1220-32.
  13. Blennow K, Zetterberg H. Biomarkers for Alzheimer's disease: Current status and prospects for the future. J Intern Med 2018; 284(6): 643-63.
  14. Altuna-Azkargorta M, Mendioroz-Iriarte M. Blood biomarkers in Alzheimer's disease. Neurologia (Engl Ed) 2021; 36(9): 704-10.
  15. Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Perez JM, Evans AC. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat Commun 2016; 7: 11934.
  16. Pini L, Pievani M, Bocchetta M, Altomare D, Bosco P, Cavedo E, et al. Brain atrophy in Alzheimer's Disease and aging. Ageing Res Rev 2016; 30: 25-48.
  17. Petersen RC, Aisen PS, Beckett LA, Donohue MC, Gamst AC, Harvey DJ, et al. Alzheimer's Disease Neuroimaging Initiative (ADNI): Clinical characterization. Neurology 2010; 74(3): 201-9.
  18. Arevalo-Rodriguez I, Smailagic N, Roque-Figuls M, Ciapponi A, Sanchez-Perez E, Giannakou A, et al. Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev 2021; 7(7): CD010783.
  19. Mattsson N, Zetterberg H, Janelidze S, Insel PS, Andreasson U, Stomrud E, et al. Plasma tau in Alzheimer disease. Neurology 2016; 87(17): 1827-35.
  20. Tao R, Fletcher PT, Gerber S, Whitaker RT. A variational image-based approach to the correction of susceptibility artifacts in the alignment of diffusion weighted and structural MRI. Inf Process Med Imaging 2009; 21: 664-75.
  21. Yoo TS, Ackerman MJ, Lorensen WE, Schroeder W, Chalana V, Aylward S, et al. Engineering and algorithm design for an image processing Api: A technical report on ITK--the Insight Toolkit. Stud Health Technol Inform 2002; 85: 586-92.
  22. Wang FK, Yang SW. Applying Bootstrap method to the types III errors in the measurement system. Qual Reliab Engng Int 2008; 24(1): 83-97.
  23. Parra-Frutos I. Controlling the Type I error rate by using the nonparametric bootstrap when comparing means. Br J Math Stat Psychol 2013; 67(1): 117-32.
  24. Asllani I, Habeck C, Scarmeas N, Borogovac A, Brown TR, Stern Y. Multivariate and univariate analysis of continuous arterial spin labeling perfusion MRI in Alzheimer's disease. J Cereb Blood Flow Metab 2008; 28(4): 725-36.
  25. Korte N, Nortley R, Attwell D. Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease. Acta Neuropathol 2020; 140(6): 793-810.
  26. Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 2001; 21(10): 1133-45.
  27. Thiebaut AM, Hedou E, Marciniak SJ, Vivien D, Roussel BD. Proteostasis During Cerebral Ischemia. Front Neurosci 2019; 13: 637.
  28. Mattsson N, Tosun D, Insel PS, Simonson A, Jack CR, Beckett LA, et al. Association of brain amyloid-beta with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment. Brain 2014; 137(Pt 5): 1550-61.
  29. Wierenga CE, Hays CC, Zlatar ZZ. Cerebral blood flow measured by arterial spin labeling MRI as a preclinical marker of Alzheimer's disease. J Alzheimers Dis 2014; 42 Suppl 4(Suppl 4): S411-9.
  30. Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer disease. JAMA Neurol 2019; 76(7): 791-9.
  31. Zheng W, Cui B, Han Y, Song H, Li K, He Y, et al. Disrupted regional cerebral blood flow, functional activity and connectivity in Alzheimer's disease: A combined ASL perfusion and resting state fMRI Study. Front Neurosci 2019; 13: 738.
  32. Alsop DC, Casement M, de Bazelaire C, Fong T, Press DZ. Hippocampal hyperperfusion in Alzheimer's disease. Neuroimage 2008; 42(4): 1267-74.
  33. Zhang N, Gordon ML, Goldberg TE. Cerebral blood flow measured by arterial spin labeling MRI at resting state in normal aging and Alzheimer's disease. Neurosci Biobehav Rev 2017; 72: 168-75.
  34. Park KW, Yoon HJ, Kang DY, Kim BC, Kim S, Kim JW. Regional cerebral blood flow differences in patients with mild cognitive impairment between those who did and did not develop Alzheimer's disease. Psychiatry Res 2012; 203(2-3): 201-6.
  35. Rondina JM, Ferreira LK, de Souza Duran FL, Kubo R, Ono CR, Leite CC, et al. Selecting the most relevant brain regions to discriminate Alzheimer's disease patients from healthy controls using multiple kernel learning: A comparison across functional and structural imaging modalities and atlases. Neuroimage Clin 2018; 17: 628-41.
  36. Horie K, Barthelemy NR, Sato C, Bateman RJ. CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer's disease. Brain 2021; 144(2): 515-27.
  37. Chen B. Abnormal cortical regions and subsystems in whole brain functional connectivity of mild cognitive impairment and Alzheimer's disease: A preliminary study. Aging Clin Exp Res 2021; 33(2): 367-81.
  38. Yu E, Liao Z, Mao D, Zhang Q, Ji G, Li Y, et al. Directed functional connectivity of posterior cingulate cortex and whole brain in alzheimer's disease and mild cognitive impairment. Curr Alzheimer Res 2017; 14(6): 628-35.
  39. Huang C, Wahlund LO, Svensson L, Winblad B, Julin P. Cingulate cortex hypoperfusion predicts Alzheimer's disease in mild cognitive impairment. BMC Neurol 2002; 2: 9.
  40. Eberling JL, Jagust WJ, Reed BR, Baker MG. Reduced temporal lobe blood flow in Alzheimer's disease. Neurobiol Aging 1992; 13(4): 483-91.
  41. Onitsuka T, Shenton ME, Salisbury DF, Dickey CC, Kasai K, Toner SK, et al. Middle and inferior temporal gyrus gray matter volume abnormalities in chronic schizophrenia: An MRI study. Am J Psychiatry 2004; 161(9): 1603-11.
  42. Chayer C, Freedman M. Frontal lobe functions. Curr Neurol Neurosci Rep 2001; 1(6): 547-52.
  43. Leech R, Sharp DJ. The role of the posterior cingulate cortex in cognition and disease. Brain 2014; 137(Pt 1): 12-32.
  44. Xiong YL, Meng T, Luo J, Zhang H. The potential of neurofilament light as a biomarker in Alzheimer's disease. Eur Neurol 2021; 84(1): 6-15.
  45. 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(1): 17368.
  46. Zhao Y, Xin Y, Meng S, He Z, Hu W. Neurofilament light chain protein in neurodegenerative dementia: A systematic review and network meta-analysis. Neurosci Biobehav Rev 2019; 102: 123-38.
  47. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement 2018; 14(4): 535-62.
  48. Skillback T, Farahmand B, Bartlett JW, Rosen C, Mattsson N, Nagga K, et al. CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival. Neurology 2014; 83(21): 1945-53.
  49. Gaiottino J, Norgren N, Dobson R, Topping J, Nissim A, Malaspina A, et al. Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One 2013; 8(9): e75091.
  50. Mayeli M, Mirshahvalad SM, Aghamollaii V, Tafakhori A, Abdolalizadeh A, Rahmani F. Plasma neurofilament light chain levels are associated with cortical hypometabolism in Alzheimer disease signature regions. J Neuropathol Exp Neurol 2019; 78(8): 709-16.
  51. Chen Y, Therriault J, Luo J, Ba M, Zhang H, Initiative ADN. Neurofilament light as a biomarker of axonal degeneration in patients with mild cognitive impairment and Alzheimer's disease. J Integr Neurosci 2021; 20(4): 861-70.
  52. Hu H, Chen KL, Ou YN, Cao XP, Chen SD, Cui M, et al. Neurofilament light chain plasma concentration predicts neurodegeneration and clinical progression in nondemented elderly adults. Aging (Albany NY) 2019; 11(17): 6904-14.
  53. Benedet AL, Leuzy A, Pascoal TA, Ashton NJ, Mathotaarachchi S, Savard M, et al. Stage-specific links between plasma neurofilament light and imaging biomarkers of Alzheimer's disease. Brain 2020; 143(12): 3793-804.