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Open Access 01-12-2018 | Research

Cerebrospinal fluid synaptosomal-associated protein 25 is a key player in synaptic degeneration in mild cognitive impairment and Alzheimer’s disease

Authors: Hua Zhang, Joseph Therriault, Min Su Kang, Kok Pin Ng, Tharick A. Pascoal, Pedro Rosa-Neto, Serge Gauthier, the Alzheimer’s Disease Neuroimaging Initiative

Published in: Alzheimer's Research & Therapy | Issue 1/2018

Abstract

Background

There is accumulating evidence that synaptic loss precedes neuronal loss and correlates best with impaired memory formation in Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) is a newly discovered marker indicating synaptic damage. We here test CSF SNAP-25 and SNAP-25/amyloid-β42 (Aβ42) ratio as a diagnostic marker for predicting cognitive decline and brain structural change in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.

Methods

We stratified 139 participants from the ADNI database into cognitively normal (CN; n = 52), stable mild cognitive impairment (sMCI; n = 22), progressive MCI (pMCI; n = 47), and dementia due to AD (n = 18). Spearman correlation was performed to test the relationships between biomarkers. Overall diagnostic accuracy (area under the curve (AUC)) was obtained from receiver operating curve (ROC) analyses. Cox proportional hazard models tested the effect of CSF SNAP-25 and SNAP-25/Aβ42 measures on the conversion from MCI to AD. Relationships between the CSF SNAP-25 levels, SNAP-25/Aβ42 ratio, and diagnostic groups were tested with linear regressions. Linear mixed-effects models and linear regression models were used to evaluate CSF SNAP-25 and SNAP-25/Aβ42 as predictors of AD features, including cognition measured by the Mini-Mental State Examination (MMSE) and brain structure and white matter hyperintensity (WMH) measured by magnetic resonance imaging (MRI).

Results

CSF SNAP-25 and SNAP-25/Aβ42 were increased in patients with pMCI and AD compared with CN, and in pMCI and AD compared with sMCI. Cognitively normal subjects who progressed to MCI or AD during follow-up had increased SNAP-25/Aβ42 ratio compared with nonprogressors. CSF SNAP-25, especially SNAP-25/Aβ42, offers diagnostic utility for pMCI and AD. CSF SNAP-25 and SNAP-25/Aβ42 significantly predicted conversion from MCI to AD. In addition, elevated SNAP-25/Aβ42 ratio was associated with the rate of hippocampal atrophy in pMCI and the rate of change of cognitive impairment in CN over the follow-up period.

Conclusions

These data suggest that both CSF SNAP-25 and SNAP-25/Aβ42 ratio are already increased at the early clinical stage of AD, and indicate the promise of CSF SNAP-25 and SNAP-25/Aβ42 ratio as diagnostic and prognostic biomarkers for the earliest symptomatic stage of AD.

DeKosky ST, Scheff SW, Styren SD. Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration. 1996;5:417–21.CrossRefPubMed

Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–80.CrossRefPubMed

DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol. 1990;27:457–64.CrossRefPubMed

Furuya TK, Silva PN, Payao SL, Bertolucci PH, Rasmussen LT, De Labio RW, Braga IL, Chen ES, Turecki G, Mechawar N, Mill J, Smith MA. Analysis of SNAP25 mRNA expression and promoter DNA methylation in brain areas of Alzheimer's disease patients. Neuroscience. 2012;220:41–6.CrossRefPubMed

Lista S, Hampel H. Synaptic degeneration and neurogranin in the pathophysiology of Alzheimer’s disease. Expert Rev Neurother. 2017;17:47–57.CrossRefPubMed

Scheff SW, DeKosky ST, Price DA. Quantitative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiol Aging. 1990;11:29–37.CrossRefPubMed

Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 2004;62:925–31.CrossRefPubMed

Scheff SW, Sparks L, Price DA. Quantitative assessment of synaptic density in the entorhinal cortex in Alzheimer’s disease. Ann Neurol. 1993;34:356–61.CrossRefPubMed

Overk CR, Masliah E. Pathogenesis of synaptic degeneration in Alzheimer’s disease and Lewy body disease. Biochem Pharmacol. 2014;88:508–16.CrossRefPubMedPubMedCentral

10.

Counts SE, Alldred MJ, Che S, Ginsberg SD, Mufson EJ. Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology. 2014;79:172–9.CrossRefPubMed

11.

Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology. 2007;68:1501–8.CrossRefPubMed

12.

Portelius E, Zetterberg H, Skillback T, Tornqvist U, Andreasson U, Trojanowski JQ, Weiner MW, Shaw LM, Mattsson N, Blennow K. Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease. Brain. 2015;138:3373–85.CrossRefPubMedPubMedCentral

13.

Pham E, Crews L, Ubhi K, Hansen L, Adame A, Cartier A, Salmon D, Galasko D, Michael S, Savas JN, Yates JR, Glabe C, Masliah E. Progressive accumulation of amyloid-beta oligomers in Alzheimer’s disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins. FEBS J. 2010;277:3051–67.CrossRefPubMedPubMedCentral

14.

Greber S, Lubec G, Cairns N, Fountoulakis M. Decreased levels of synaptosomal associated protein 25 in the brain of patients with Down syndrome and Alzheimer’s disease. Electrophoresis. 1999;20:928–34.CrossRefPubMed

15.

Brinkmalm A, Brinkmalm G, Honer WG, Frolich L, Hausner L, Minthon L, Hansson O, Wallin A, Zetterberg H, Blennow K, Ohrfelt A. SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer’s disease. Mol Neurodegener. 2014;9:53.CrossRefPubMedPubMedCentral

16.

Berg L. Clinical dementia rating (CDR). Psychopharmacol Bull. 1988;24:637–9.PubMed

17.

Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.CrossRefPubMed

18.

Aisen PS, Petersen RC, Donohue MC, Gamst A, Raman R, Thomas RG, Walter S, Trojanowski JQ, Shaw LM, Beckett LA, Jack CR Jr, Jagust W, Toga AW, Saykin AJ, Morris JC, Green RC, Weiner MW. Clinical core of the Alzheimer’s disease neuroimaging initiative: progress and plans. Alzheimers Dement. 2010;6:239–46.CrossRefPubMedPubMedCentral

19.

Tierney MC, Fisher RH, Lewis AJ, Zorzitto ML, Snow WG, Reid DW, Nieuwstraten P. The NINCDS-ADRDA work group criteria for the clinical diagnosis of probable Alzheimer’s disease: a clinicopathologic study of 57 cases. Neurology. 1988;38:359–64.CrossRefPubMed

20.

Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VM, Trojanowski JQ. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol. 2009;65:403–13.CrossRefPubMedPubMedCentral

21.

Risacher SL, Saykin AJ. Neuroimaging and other biomarkers for Alzheimer’s disease: the changing landscape of early detection. Annu Rev Clin Psychol. 2013;9:621–48.CrossRefPubMedPubMedCentral

22.

Arendt T. Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol. 2009;118:167–79.CrossRefPubMed

23.

Bark IC, Hahn KM, Ryabinin AE, Wilson MC. Differential expression of SNAP-25 protein isoforms during divergent vesicle fusion events of neural development. Proc Natl Acad Sci U S A. 1995;92:1510–4.CrossRefPubMedPubMedCentral

24.

Walch-Solimena C, Blasi J, Edelmann L, Chapman ER, von Mollard GF, Jahn R. The t-SNAREs syntaxin 1 and SNAP-25 are present on organelles that participate in synaptic vesicle recycling. J Cell Biol. 1995;128:637–45.CrossRefPubMed

25.

Hou QL, Gao X, Lu Q, Zhang XH, Tu YY, Jin ML, Zhao GP, Yu L, Jing NH, Li BM. SNAP-25 in hippocampal CA3 region is required for long-term memory formation. Biochem Biophys Res Commun. 2006;347:955–62.CrossRefPubMed

26.

Davidsson P, Puchades M, Blennow K. Identification of synaptic vesicle, pre- and postsynaptic proteins in human cerebrospinal fluid using liquid-phase isoelectric focusing. Electrophoresis. 1999;20:431–7.CrossRefPubMed

27.

Mattsson N, Insel PS, Palmqvist S, Portelius E, Zetterberg H, Weiner M, Blennow K, Hansson O. Cerebrospinal fluid tau, neurogranin, and neurofilament light in Alzheimer’s disease. EMBO Mol Med. 2016;8:1184–96.CrossRefPubMedPubMedCentral

28.

Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F. New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease modifying drugs. Br J Clin Pharmacol. 2012;73:504–17.CrossRefPubMed

Title: Cerebrospinal fluid synaptosomal-associated protein 25 is a key player in synaptic degeneration in mild cognitive impairment and Alzheimer’s disease
Authors: Hua Zhang
Joseph Therriault
Min Su Kang
Kok Pin Ng
Tharick A. Pascoal
Pedro Rosa-Neto
Serge Gauthier
the Alzheimer’s Disease Neuroimaging Initiative
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Alzheimer's Research & Therapy / Issue 1/2018
Electronic ISSN: 1758-9193
DOI: https://doi.org/10.1186/s13195-018-0407-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Cerebrospinal fluid synaptosomal-associated protein 25 is a key player in synaptic degeneration in mild cognitive impairment and Alzheimer’s disease

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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