Objective To investigate whether cerebrospinal fluid (CSF) neurogranin concentrations are altered in sporadic Creutzfeldt-Jakob disease (CJD), comparatively with Alzheimer’s disease (AD), and associated with neuronal degeneration in brain tissue.
Methods CSF neurogranin, total tau, neurofilament light (NFL) and 14-3-3 protein were measured in neurological controls (NCs, n=64), AD (n=46) and CJD (n=81). The accuracy of neurogranin discriminating the three diagnostic groups was evaluated. Correlations between neurogranin and neurodegeneration biomarkers, demographic, genetic and clinical data were assessed. Additionally, neurogranin expression in postmortem brain tissue was studied.
Results Compared with NC, CSF neurogranin concentrations were increased in CJD (4.75 times of NC; p<0.001, area under curve (AUC), 0.96 (95% CI 0.93 to 0.99) and AD (1.94 times of NC; p<0.01, AUC 0.73, 95% CI 0.62 to 0.82), and were able to differentiate CJD from AD (p<0.001, AUC 0.85, 95% CI 0.78 to 0.92). CSF tau was increased in CJD (41 times of NC) and in AD (3.1 times of NC), both at p<0.001. In CJD, neurogranin positively correlated with tau (r=0.55, p<0.001) and was higher in 14-3-3-positivity (p<0.05), but showed no association with NFL (r=0.08, p=0.46). CJD-MM1/MV1 cases displayed higher neurogranin levels than VV2 cases. Neurogranin was increased at early CJD disease stages and was a good prognostic marker of survival time in CJD. In brain tissue, neurogranin was detected in the cytoplasm, membrane and postsynaptic density fractions of neurons, with reduced levels in AD, and more significantly in CJD, where they correlated with synaptic and axonal markers.
Conclusions Neurogranin is a new biomarker of prion pathogenesis with diagnostic and prognostic abilities, which reflects the degree of neuronal damage in brain tissue in a CJD subtype manner.
- alzheimer’s disease
- neurofilament light
- neurodegenerative dementias
- creutzfeldt-jakob disease
- cerebrospinal fluid
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IFA, IZ and FL are joint senior authors.
KB and DD-L contributed equally.
Contributors IZ, IFA and FL designed the study. KB, DDL, HZ, IFA and FL performed experiments. KB, DDL, HZ, AV-P, AK, MS, IFA and FL analysed data and interpreted the results. EV provided reagents and technical expertise. FL wrote the manuscript draft. All authors critically revised the manuscript and approved its content before submission.
Funding This study was funded by the Spanish Ministry of Health—Instituto Carlos III (Miguel Servet programme—CP16/00041) to FL and by the Robert Koch Institute through funds from the Federal Ministry of Health (grant No, 1369-341) to IZ. KB is supported by the Torsten Söderberg Foundation, and by grants from the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and ALF/LUA Västra Götalandsregionen. HZ is supported by the European Research Council, the Swedish Research Council, the Knut and Alice Wallenberg Foundation and the UK Dementia Research Institute. This project has been funded at 65% by the Fondo Europeo de Desarrollo Regional (FEDER) through the Interreg V-A España-Francia-Andorra (POCTEFA 2014-2020) programme.
Competing interests KB has served as a consultant or at advisory boards for Alzheon, CogRx, Biogen, Novartis, and Roche Diagnostics, unrelated to this work. HZ has served at scientific advisory boards for Eli Lilly, Roche Diagnostics, Samumed, CogRx and Wave and has received travel support from Teva. KB and HZ are cofounders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. The other authors report no conflicts of interest related to the present study.
Ethics approval The study was conducted according to the revised Declaration of Helsinki and Good Clinical Practice guidelines, and approved by local Ethics committees (Reference numbers 11/11/93, 9/06/08, Universitaetsmedizin Göttingen, Germany).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.