Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer’s disease patients and healthy controls

Kvartsberg, Hlin; Portelius, Erik; Andréasson, Ulf; Brinkmalm, Gunnar; Hellwig, Konstantin; Lelental, Natalia; Kornhuber, Johannes; Hansson, Oskar; Minthon, Lennart; Spitzer, Philipp; Maler, Juan Manuel; Zetterberg, Henrik; Blennow, Kaj; Lewczuk, Piotr

doi:10.1186/s13195-015-0124-3

Cited by 119 publications

(108 citation statements)

References 20 publications

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“…No changes were seen in plasma neurogranin indicating that it is not associated with Aβ‐induced synaptic dysfunction. This was an expected result given the lack of correlation of CSF with plasma neurogranin concentrations, and that plasma neurogranin concentration probably reflects extra‐cerebral expression of the protein (Kvartsberg et al , ). Plasma NfL and T‐tau were barely significant in the models ( P = 0.02 and P = 0.04, respectively; ).…”

Section: Discussionmentioning

confidence: 80%

Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

et al. 2019

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Failures in Alzheimer's disease (AD) drug trials highlight the need to further explore disease mechanisms and alterations of biomarkers during the development of AD. Using cross‐sectional data from 377 participants in the BioFINDER study, we examined seven cerebrospinal fluid (CSF) and six plasma biomarkers in relation to β‐amyloid (Aβ) PET uptake to understand their evolution during AD. In CSF, Aβ42 changed first, closely followed by Aβ42/Aβ40, phosphorylated‐tau (P‐tau), and total‐tau (T‐tau). CSF neurogranin, YKL‐40, and neurofilament light increased after the point of Aβ PET positivity. The findings were replicated using Aβ42, Aβ40, P‐tau, and T‐tau assays from five different manufacturers. Changes were seen approximately simultaneously for CSF and plasma biomarkers. Overall, plasma biomarkers had smaller dynamic ranges, except for CSF and plasma P‐tau which were similar. In conclusion, using state‐of‐the‐art biomarkers, we identified the first changes in Aβ, closely followed by soluble tau. Only after Aβ PET became abnormal, biomarkers of neuroinflammation, synaptic dysfunction, and neurodegeneration were altered. These findings lend in vivo support of the amyloid cascade hypotheses in humans.

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Section: Discussionmentioning

confidence: 80%

Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

et al. 2019

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“…After developing novel monoclonal antibodies to measure neurogranin by ELISA, high CSF levels were found to predict prodromal AD in MCI [44]. High CSF neurogranin in AD dementia and prodromal AD has been confirmed in several subsequent papers [45, 46], including in the ADNI study [47]. High CSF neurogranin also correlates with the future rate of hippocampal trophy measured by MRI and rate of metabolic reductions on FDG-PET [47].…”

Section: Novel Biomarkers For Synaptic Dysfunction and Degenerationmentioning

confidence: 99%

A Review of Fluid Biomarkers for Alzheimer’s Disease: Moving from CSF to Blood

2017

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A set of core cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) includes total tau (T-tau), phosphorylated tau (P-tau) and β-amyloid 42 (Aβ42). These biomarkers reflect some of the key aspects of AD pathophysiology, including neuronal degeneration, tau phosphorylation with tangle formation, and Aβ aggregation with deposition of the peptide into plaques. The core AD CSF biomarkers have been validated clinically in numerous studies, and found to have a very high diagnostic performance to identify AD, both in the dementia and in the mild cognitive impairment stages of the disease. CSF Aβ42 has also been found to show very high concordance with amyloid PET to identify brain amyloid deposition. The synaptic protein neurogranin is a novel candidate CSF biomarker for AD and prodromal AD. High CSF neurogranin predicts future cognitive decline and seems to be more specific for AD than, for example, T-tau. Importantly, technical developments have given ultrasensitive measurement techniques that allow measurement of brain-specific proteins such as tau and neurofilament light (NFL) in blood samples. Both plasma tau and NFL are increased in AD, and a recent study showed that plasma NFL has a diagnostic performance comparable to the core AD CSF biomarkers, and predicted future cognitive decline. Future large longitudinal clinical studies are warranted to determine the potential for plasma tau and NFL to serve as first-in-line screening tools for neurodegeneration in primary care.

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“…CSF Ng concentration was measured using a previously published in-house Meso Scale Discovery assay as published in Kvastberg et al [21] and De Vos et al [22]. Commercially available kits were used for measuring the concentrations of VILIP-1 (Human VILIP-1 ELISA; BioVendor GmbH, Heidelberg, Germany), NFL (NF-light ELISA; IBL international, Hamburg, Germany), and YKL-40 (Quantikine ELISA Human Chitinase-3-like 1; R&D systems, MN, USA) by following the manufactures enclosed procedure, in technical duplicates.…”

Section: Assaysmentioning

confidence: 99%

[P3–174]: EFFECT OF PHYSICAL EXERCISE ON MARKERS OF NEURONAL DYSFUNCTION IN CEREBROSPINAL FLUID IN PATIENTS WITH ALZHEIMER's DISEASE

Jensen

Portelius

Høgh

et al. 2017

Alzheimer's & Dementia

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Introduction: Physical exercise has gained increasing focus as a potential mean to maintain cognitive function in patients with Alzheimer's disease (AD). Alongside the markers of specific AD pathology (amyloid b and tau), other pathologies such as neuronal damage and synaptic loss have been proposed as markers of the disease. Here, we study the effect of physical exercise on biomarkers of neuronal and synaptic integrity. Methods: Cerebrospinal fluid (CSF) from 51 AD subjects who participated in the randomized controlled trial Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) was analyzed for the concentration of neurofilament light (NFL), neurogranin (Ng), visinin-like protein-1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Participants were subjected to either 16 weeks of moderate-to highintensity exercise (n 5 25) or treatment as usual (control group, n 5 26), and CSF was collected before and after intervention. Results: No significant differences in CSF concentrations of VILIP-1, YKL-40, NFL, and Ng were observed when comparing mean change from baseline between the exercise and control groups. Similarly, when classifying subjects based on their exercise levels, no significant changes were observed for the biomarkers in the control group compared with the high-exercise group (attending 80% of the exercise sessions with an intensity of 70% of maximum heart rate or above). Discussion: These results are not supportive of a modulatory effect of physical exercise on the selected biomarkers of neuronal and synaptic integrity in patients with AD.

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Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer’s disease patients and healthy controls

Cited by 119 publications

References 20 publications

Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

A Review of Fluid Biomarkers for Alzheimer’s Disease: Moving from CSF to Blood

[P3–174]: EFFECT OF PHYSICAL EXERCISE ON MARKERS OF NEURONAL DYSFUNCTION IN CEREBROSPINAL FLUID IN PATIENTS WITH ALZHEIMER's DISEASE

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