CSF neurogranin as a neuronal damage marker in CJD: a comparative study with AD

Abstract

ObjectiveTo 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.MethodsCSF 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.ResultsCompared 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.ConclusionsNeurogranin 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.

Contribution of CSF biomarkers to early‐onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures

“…Unexpectedly 14‐3‐3 resulted a significant predictor of CTh values while other neurodegeneration markers as T‐tau, NfL, and Ng did not. Previous studies have analyzed the contribution of Aβ and T‐tau to structural changes in AD (Blennow et al, ; Li et al, ; Tosun, Schuff, Shaw, et al, ). The relevant contribution of Aβ in the CTh AD signature in the present study is plausible given its main role in AD pathophysiology.…”

“…CSF NfL levels have proved especially useful differentiating FTLD from early‐onset AD given that NfL levels in AD are lower in early onset compared to those in late onset presentations (Alcolea, Vilaplana, Suárez‐Calvet, et al, ; Olsson, Portelius, Cullen, et al, ; Portelius et al, ; Sjögren, Rosengren, Minthon, et al, ). Neurogranin (Ng) is a synaptic (dendritic) marker that has been suggested to be specific for AD although increased levels are also found in Creutzfeldt–Jakob diseases (Blennow, Diaz‐Lucena, Zetterberg, et al, ; Gaetani, Blennow, Calabresi, et al, ; Wellington et al, ). The 14‐3‐3 protein has been extensively studied in Creutzfeldt–Jakob disease, but its participation on the AD neuropathological process has also been described (Burkhard, Sanchez, Landis, et al, ; Chohan et al, ; McFerrin, Chi, Cutter, et al, ).…”

Neurogranin: A Potential Biomarker of Neurological and Mental Diseases

“…Of note, synaptic integrity and function are both the growing concerns in the pathogenesis of a wide variety of neurological and mental diseases ( Fyfe, 2015 ; Hellwig et al, 2015 ; Yang et al, 2015 ; Zetterberg and Blennow, 2015 ; Bereczki et al, 2017 ; De Vos et al, 2017 ; Guha et al, 2018 ; Blennow et al, 2019 ). In animal experiments, it showed that mice lacking NRGN show a remarkable decline in hippocampus-dependent spatial memory and deficits in hippocampal long-term potentiation ( Pak et al, 2000 ).…”

Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course—a joint PhD student course at University College London and University of Gothenburg

“…The elevation of CSF Ng seems to be specific for AD and is not seen in other neurodegenerative disorders beside CJD [52,63,64]. A recent study examining postmortem parietal and temporal cortex tissues found that the ratio of peptide-to-total full-length Ng was higher in patients with AD compared to controls, suggesting increased processing of Ng into peptides [65].…”

“…High levels of NfL are also seen in other neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), HIV-associated dementia (HAD) and Creutzfeldt-Jakob disease (CJD) [51]. In addition to very high NfL levels seen in CJD, the rapidly progressive disease exhibits unique, multi-fold increase in concentration of multiple other CSF biomarkers, including total tau, alpha-synuclein and neurogranin [52][53][54].…”