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Brinkmalm A, Brinkmalm G, Honer WG, Frölich L, Hausner L, Minthon L, Hansson O, Wallin A, Zetterberg H, Blennow K, Öhrfelt A. SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease. Mol Neurodegener. 2014 Nov 23;9:53. PubMed.
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Ionis Pharmaceuticals
In my view, high methodological rigor was applied in both studies. The use of three separate cohorts with good clinical characterization and the technical characterization and validation of the methods used are quite exemplary. I have high confidence that the core findings of both papers are valid, i.e., CSF SNAP-25 and CSF-NG are, on average, increased in AD patients versus controls. The studies also demonstrate that it is possible to use moderate sample sizes and still draw solid conclusions. The higher correlation with CSF-tau and CSF-phospho-tau versus CSF-Aβ supports the hypothesis that both biomarkers are indicators of structural degeneration. How far they are indicators of degeneration specifically at synapses, as opposed to general neuronal degeneration, remains unclear. In this regard it may be of interest to compare the newly characterized biomarkers with CSF-NSE (neuron-specific enolase), a cytosolic protein believed to leak from structurally damaged neurons and reported to also be increased in CSF of AD patients (Schmidt et al., 2014; Palumbo et al., 2008; Bahl et al., 2009; Blennow et al., 1994).
Both CSF-SNAP25 and CSF-Ng are welcome additions to the existing CSF biomarkers and further use and characterization is warranted. The results of additional, larger, and prospective studies will inform us about the value of both biomarkers in the field of Alzheimer’s disease. Potential uses include clinical studies aimed at reducing neuronal and synaptic degeneration with therapeutic intervention. However, at this point no therapy has conclusively demonstrated reduction of neuronal degeneration or clinical progression in Alzheimer’s disease, and until this has been achieved there is a bit of a Catch-22 for biomarkers aimed at measuring the efficacy of therapeutic interventions.
Diagnosis and differential diagnosis are other potential uses for these markers and it remains to be seen if the addition of CSF-SNAP25 and CSF-Ng to CSF-(p)tau and CSF-Aβ will significantly increase sensitivity or specificity of AD (differential) diagnosis. The hurdle in this area is quite high, however, and from the papers it is quite clear that normal levels of CSF-SNAP25 or CSF-Ng do not rule out a diagnosis of AD. Also, in the future it may be worthwhile to test the biomarkers in other neurodegenerative diseases and dementia, to better characterize how specific the markers are for AD versus neurodegeneration in general. I see the best potential for these biomarkers in helping to further refine prognosis in individuals with MCI. Depending on the outcome of larger prospective studies with MCI patients, the biomarkers may also be used for selecting clinical trial populations in preventive studies. CSF-Ng can be measured by ELISA, which may facilitate wider use and spread of the method when compared with the more demanding mass spectroscopy methods. Before seeing data from larger MCI cohorts, it seems premature to me to judge which, if either, of the two biomarkers holds more potential.
References:
Schmidt FM, Mergl R, Stach B, Jahn I, Gertz HJ, Schönknecht P. Elevated levels of cerebrospinal fluid neuron-specific enolase (NSE) in Alzheimer's disease. Neurosci Lett. 2014 Jun 6;570:81-5. Epub 2014 Apr 16 PubMed.
Palumbo B, Siepi D, Sabalich I, Tranfaglia C, Parnetti L. Cerebrospinal fluid neuron-specific enolase: a further marker of Alzheimer's disease?. Funct Neurol. 2008 Apr-Jun;23(2):93-6. PubMed.
Bahl JM, Heegaard NH, Falkenhorst G, Laursen H, Høgenhaven H, Mølbak K, Jespersgaard C, Hougs L, Waldemar G, Johannsen P, Christiansen M. The diagnostic efficiency of biomarkers in sporadic Creutzfeldt-Jakob disease compared to Alzheimer's disease. Neurobiol Aging. 2009 Nov;30(11):1834-41. PubMed.
Blennow K, Wallin A, Ekman R. Neuron specific enolase in cerebrospinal fluid: a biochemical marker for neuronal degeneration in dementia disorders?. J Neural Transm Park Dis Dement Sect. 1994;8(3):183-91. PubMed.
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