Abstract
Alpha 1-antichymotrypsin (ACT), an acute-phase protein, has been reported to be increased in the brain and blood of Alzheimer’s disease (AD) patients. However, few previous studies have focused on amnestic mild cognitive impairment (aMCI) patients. The aim of our study was to investigate the changing trend in ACT concentrations during the progression of aMCI. Hence, we measured the cerebrospinal fluid (CSF) and serum levels of ACT in aMCI subjects and normal controls (NC) at 2-year follow-up assessments using ELISA and Western blot. Forty-four NCs, 28 stable aMCI (sMCI) patients, and 20 progressive aMCI (pMCI) patients finished the follow-up assessments, and their data were used for analysis. We found that CSF and serum ACT levels of both sMCI and pMCI patients increased over time, while those of NCs remained stable; CSF and serum ACT levels were significantly higher in both sMCI and pMCI patients than in NCs, except for baseline serum ACT. In pMCI patients prior to developing AD, CSF and serum ACT levels were already significantly higher than those in sMCI patients. The ROC curve results demonstrated that combining CSF and serum ACT levels can distinguish aMCI patients from NCs with high specificity and sensitivity. Our data suggest that ACT may be a biomarker for diagnosing aMCI.
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Abbreviations
- aMCI:
-
Amnestic mild cognitive impairment
- AD:
-
Alzheimer’s disease
- NC:
-
Normal control
- ACT:
-
Alpha 1-antichymotrypsin
- sMCI:
-
Stable amnestic mild cognitive impairment
- pMCI:
-
Progressive amnestic mild cognitive impairment
- Aβ:
-
Beta-amyloid
- CSF:
-
Cerebrospinal fluid
- MMSE:
-
Mini-mental state examination
- CDR:
-
Clinical dementia rating
- ANOVA:
-
Analysis of variance
- BBB:
-
Blood–brain barrier
- ROC:
-
Receiver-operating characteristic
- AUC:
-
The area under the curve
References
Loehfelm A, Boucsein A, Pretz D, Tups A (2019) Timing matters: Circadian effects on energy homeostasis and Alzheimer’s disease. Trends Endocrinol Metab 30(2):132–143
Lu R, Wang J, Tao R, Wang J, Zhu T, Guo W, Sun Y, Li H et al (2018) Reduced TRPC6 mRNA levels in the blood cells of patients with Alzheimer’s disease and mild cognitive impairment. Mol Psychiatry 23(3):767–776
Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 3(3):186–191
De Simone MS, Perri R, Fadda L, Caltagirone C, Carlesimo GA (2018) Predicting progression to Alzheimer’s disease in subjects with amnestic mild cognitive impairment using performance on recall and recognition tests. J Neurol 266(1):102–111
Manenti R, Sandrini M, Gobbi E, Binetti G, Cotelli M (2018) Effects of transcranial direct current stimulation on episodic memory in amnestic mild cognitive impairment: a pilot study. J Gerontol B Psychol Sci Soc Sci. https://doi.org/10.1093/geronb/gby134
Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P et al (2014) Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med 275(3):251–283
Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M (2010) Alzheimer’s disease: clinical trials and drug development. Lancet Neurol 9(7):702–716
Karran E, De Strooper B (2016) The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem 139(Suppl 2):237–252
Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 256(3):183–194
Forsyth S, Horvath A, Coughlin P (2003) A review and comparison of the murine alpha1-antitrypsin and alpha1-antichymotrypsin multigene clusters with the human clade A serpins. Genomics 81(3):336–345
Martin-Rojas T, Mourino-Alvarez L, Gil-Dones F, de la Cuesta F, Rosello-Lleti E, Laborde CM, Rivera M, Lopez-Almodovar LF et al (2017) A clinical perspective on the utility of alpha 1 antichymotrypsin for the early diagnosis of calcific aortic stenosis. Clin Proteomics 14:12
Nicola F, Marques MR, Odorcyk F, Petenuzzo L, Aristimunha D, Vizuete A, Sanches EF, Pereira DP et al (2019) Stem cells from human exfoliated deciduous teeth modulate early astrocyte response after spinal cord contusion. Mol Neurobiol 56(1):748–760
Ries M, Sastre M (2016) Mechanisms of Aβ clearance and degradation by glial cells. Front Aging Neurosci 8:160
Han Y, Jia J, Jia X, Qin W, Wang S (2012) Combination of plasma biomarkers and clinical data for the detection of sporadic Alzheimer’s disease. Neurosci Lett 516(2):232–236
DeKosky ST, Ikonomovic MD, Wang X, Farlow M, Wisniewski S, Lopez OL, Becker JT, Saxton J et al (2003) Plasma and cerebrospinal fluid α-1-antichymotrypsin levels in Alzheimer’s disease: Correlation with cognitive impairment. Ann Neurol 53(1):81–90
Nielsen HM, Minthon L, Londos E, Blennow K, Miranda E, Perez J, Crowther DC, Lomas DA et al (2007) Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies. Neurology 69(16):1569–1579
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Publishing, Washington
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CJ, Kawas CH, Klunk WE, Koroshetz WJ et al (2011) 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 7(3):263–269
Hamilton M (1967) Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 4(6):278–296
Gunn DG, Naismith SL, Terpening Z, Lewis SJ (2014) The relationships between poor sleep efficiency and mild cognitive impairment in Parkinson disease. J Geriatr Psychiatry Neurol 27(2):77–84
Roberts RO, Knopman DS, Geda YE, Cha RH, Roger VL, Petersen RC (2010) Coronary heart disease is associated with non-amnestic mild cognitive impairment. Neurobiol Aging 31(11):1894–1902
Coutinho AMN, Porto FHG, Duran FLS, Prando S, Ono CR, Feitosa EAAF, Spíndola L, de Oliveira MO, et al (2015) Brain metabolism and cerebrospinal fluid biomarkers profile of non-amnestic mild cognitive impairment in comparison to amnestic mild cognitive impairment and normal older subjects. Alzheimer’s Res Therapy 7(1):58–67
Koen JD, Yonelinas AP (2014) The Effects of healthy aging, amnestic mild cognitive impairment, and Alzheimer’s disease on recollection and familiarity: a meta-analytic review. Neuropsychol Rev 24(3):332–354
Insel PS, Hansson O, Mackin RS, Weiner M, Mattsson N (2018) Amyloid pathology in the progression to mild cognitive impairment. Neurobiol Aging 64:76–84
Pyun JM, Park YH, Kim HR, Suh J, Kang MJ, Kim BJ, Youn YC, Jang JW et al (2017) Posterior atrophy predicts time to dementia in patients with amyloid-positive mild cognitive impairment. Alzheimers Res Ther 9(1):99
Zabel M, Schrag M, Mueller C, Zhou W, Crofton A, Petersen F, Dickson A, Kirsch WM (2012) Assessing candidate serum biomarkers for alzheimer’s disease: a longitudinal study. J Alzheimer’s Dis 30(2):311–321
Sardi F, Fassina L, Venturini L, Inguscio M, Guerriero F, Rolfo E, Ricevuti G (2011) Alzheimer’s disease, autoimmunity and inflammation The good, the bad and the ugly. Autoimmun Rev 11(2):149–153
Wang J, Song Y, Chen Z, Leng SX (2018) Connection between systemic inflammation and neuroinflammation underlies neuroprotective mechanism of several phytochemicals in neurodegenerative diseases. Oxid Med Cell Longev 2018:1–16
King EO, Brien JT, Donaghy P, Morris C, Barnett N, Olsen K, Martin-Ruiz C, Taylor J et al (2018) Peripheral inflammation in prodromal Alzheimer’s and Lewy body dementias. J Neurol Neurosurg Psychiatry 89(4):339–345
Su C, Zhao K, Xia H, Xu Y (2019) Peripheral inflammatory biomarkers in Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis. Psychogeriatrics
Newcombe EA, Camats-Perna J, Silva ML, Valmas N, Huat TJ, Medeiros R (2018) Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease. J Neuroinflammation 15(1):276–301
Wang LY, Raskind MA, Wilkinson CW, Shofer JB, Sikkema C, Szot P, Quinn JF, Galasko DR et al (2018) Associations between CSF cortisol and CSF norepinephrine in cognitively normal controls and patients with amnestic MCI and AD dementia. Int J Geriatr Psychiatry 33(5):763–768
Tyagi E, Fiorelli T, Norden M, Padmanabhan J (2013) Alpha 1-antichymotrypsin, an inflammatory protein overexpressed in the brains of patients with Alzheimer’s disease, induces tau hyperphosphorylation through c-Jun N-terminal kinase activation. Int J Alzheimers Dis 2013:606083
Padmanabhan J, Levy M, Dickson DW, Potter H (2006) Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer’s disease brain, induces tau phosphorylation in neurons. Brain 129(11):3020–3034
Porcellini E, Davis E, Chiappelli M, Ianni E, Stefano GD, Forti P, Ravaglia G, Licastro F (2008) Elevated plasma levels of α-1-anti-chymotrypsin in age-related cognitive decline and Alzheimers disease: a potential therapeutic target. Curr Pharm Des 14(26):2659–2664
Acknowledgements
We thank all the subjects for participating in this study and the support by The Sixth Affiliated Hospital of Sun Yat-Sen University.
Funding
This study was financially supported by The Natural Science Foundation of Guangdong Province, China (No: Z20140701201710181).
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The ethical committee of The Sixth Affiliated Hospital of Sun Yat-Sen University approved this study and all subjects gave their written informed consent in accord with established human subject research procedures expressed in Declaration of Helsinki.
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Liu, S., Pan, J., Tang, K. et al. Alpha 1-antichymotrypsin may be a biomarker for the progression of amnestic mild cognitive impairment. Acta Neurol Belg 121, 451–464 (2021). https://doi.org/10.1007/s13760-019-01206-3
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DOI: https://doi.org/10.1007/s13760-019-01206-3