Full-length and C-terminal neurogranin in Alzheimer's disease cerebrospinal fluid analyzed by novel ultrasensitive immunoassays.

Alzheimer Disease / diagnostic imaging Amyloid beta-Peptides Biomarkers Cognitive Dysfunction Humans Immunoassay Neurogranin Peptide Fragments tau Proteins
Alzheimer’s disease Biomarkers Cerebrospinal fluid Mild cognitive impairment Neurogranin SNAP-25 Single molecule array Synaptic Synaptotagmin-1

Journal

Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643

Informations de publication

Date de publication:
22 12 2020
Historique:
received: 13 07 2020
accepted: 10 12 2020
entrez: 23 12 2020
pubmed: 24 12 2020
medline: 25 6 2021
Statut: epublish

Résumé

Neurogranin (Ng) is a neuron-specific and postsynaptic protein that is abundantly expressed in the brain, particularly in the dendritic spine of the hippocampus and cerebral cortex. The enzymatic cleavage of Ng produces fragments that are released into cerebrospinal (CSF), which have been shown to be elevated in Alzheimer's disease (AD) patients and predict cognitive decline. Thus, quantification of distinctive cleavage products of Ng could elucidate different features of the disease. In this study, we developed novel ultrasensitive single molecule array (Simoa) assays for measurement of full-length neurogranin (FL-Ng) and C-terminal neurogranin (CT-Ng) fragments in CSF. The Ng Simoa assays were evaluated in CSF samples from AD patients (N = 23), mild cognitive impairment due to AD (MCI-AD) (N = 18), and from neurological controls (N = 26). The intra-assay repeatability and inter-assay precision of the novel methods had coefficients of variation below 7% and 14%, respectively. CSF FL-Ng and CSF CT-Ng median concentrations were increased in AD patients (6.02 ng/L, P < 0.00001 and 452 ng/L, P = 0.00001, respectively) and in patients with MCI-AD (5.69 ng/L, P < 0.00001 and 566 ng/L, P < 0.00001) compared to neurological controls (0.644 ng/L and 145 ng/L). The median CSF ratio of CT-Ng/FL-Ng were decreased in AD patients (ratio = 101, P = 0.008) and in patients with MCI-AD (ratio = 115, P = 0.016) compared to neurological controls (ratio = 180). CSF of FL-Ng, CT-Ng, and ratio of CT-Ng/FL-Ng could each significantly differentiate AD patients from controls (FL-Ng, AUC = 0.907; CT-Ng, AUC = 0.913; CT-Ng/FL-Ng, AUC = 0.775) and patients with MCI-AD from controls (FL-Ng, AUC = 0.937; CT-Ng, AUC = 0.963; CT-Ng/FL-Ng, AUC = 0.785). Assessments of the FL-Ng and CT-Ng levels in CSF with the novel sensitive immunoassays provide a high separation of AD from controls, even in early phase of the disease. The novel Ng assays are robust and highly sensitive and may be valuable tools to study synaptic alteration in AD, as well as to monitor the effect on synaptic integrity of novel drug candidates in clinical trials.

Sections du résumé

BACKGROUND
Neurogranin (Ng) is a neuron-specific and postsynaptic protein that is abundantly expressed in the brain, particularly in the dendritic spine of the hippocampus and cerebral cortex. The enzymatic cleavage of Ng produces fragments that are released into cerebrospinal (CSF), which have been shown to be elevated in Alzheimer's disease (AD) patients and predict cognitive decline. Thus, quantification of distinctive cleavage products of Ng could elucidate different features of the disease.
METHODS
In this study, we developed novel ultrasensitive single molecule array (Simoa) assays for measurement of full-length neurogranin (FL-Ng) and C-terminal neurogranin (CT-Ng) fragments in CSF. The Ng Simoa assays were evaluated in CSF samples from AD patients (N = 23), mild cognitive impairment due to AD (MCI-AD) (N = 18), and from neurological controls (N = 26).
RESULTS
The intra-assay repeatability and inter-assay precision of the novel methods had coefficients of variation below 7% and 14%, respectively. CSF FL-Ng and CSF CT-Ng median concentrations were increased in AD patients (6.02 ng/L, P < 0.00001 and 452 ng/L, P = 0.00001, respectively) and in patients with MCI-AD (5.69 ng/L, P < 0.00001 and 566 ng/L, P < 0.00001) compared to neurological controls (0.644 ng/L and 145 ng/L). The median CSF ratio of CT-Ng/FL-Ng were decreased in AD patients (ratio = 101, P = 0.008) and in patients with MCI-AD (ratio = 115, P = 0.016) compared to neurological controls (ratio = 180). CSF of FL-Ng, CT-Ng, and ratio of CT-Ng/FL-Ng could each significantly differentiate AD patients from controls (FL-Ng, AUC = 0.907; CT-Ng, AUC = 0.913; CT-Ng/FL-Ng, AUC = 0.775) and patients with MCI-AD from controls (FL-Ng, AUC = 0.937; CT-Ng, AUC = 0.963; CT-Ng/FL-Ng, AUC = 0.785).
CONCLUSIONS
Assessments of the FL-Ng and CT-Ng levels in CSF with the novel sensitive immunoassays provide a high separation of AD from controls, even in early phase of the disease. The novel Ng assays are robust and highly sensitive and may be valuable tools to study synaptic alteration in AD, as well as to monitor the effect on synaptic integrity of novel drug candidates in clinical trials.

Identifiants

DOI: 10.1186/s13195-020-00748-6 PMID: 33353563 PMC: PMC7756958
pubmed: 33353563
doi: 10.1186/s13195-020-00748-6
pii: 10.1186/s13195-020-00748-6
pmc: PMC7756958
doi:

Substances chimiques

Amyloid beta-Peptides 0
Biomarkers 0
Peptide Fragments 0
tau Proteins 0
Neurogranin 132654-77-4

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

168

Subventions

Organisme : European Research Council
ID : 681712
Pays : International

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Auteurs

Annika Öhrfelt (A)

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital/Mölndal, SE-431 80, Mölndal, Sweden. annika.ohrfelt@neuro.gu.se.
ORCID: 0000-0001-8942-4181

Julien Dumurgier (J)

Université de Paris, INSERM U1144, Center of Cognitive Neurology, Lariboisière - Fernand-Widal Hospital, APHP, Paris, France.

Henrik Zetterberg (H)

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital/Mölndal, SE-431 80, Mölndal, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
UK Dementia Research Institute, London, UK.

Agathe Vrillon (A)

Université de Paris, INSERM U1144, Center of Cognitive Neurology, Lariboisière - Fernand-Widal Hospital, APHP, Paris, France.

Nicholas J Ashton (NJ)

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital/Mölndal, SE-431 80, Mölndal, Sweden.
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.

Hlin Kvartsberg (H)

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital/Mölndal, SE-431 80, Mölndal, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

Elodie Bouaziz-Amar (E)

Department of Biochemistry, Lariboisière - Fernand-Widal Hospital, Université de Paris, INSERMU1144, APHP, Paris, France.

Jacques Hugon (J)

Université de Paris, INSERM U1144, Center of Cognitive Neurology, Lariboisière - Fernand-Widal Hospital, APHP, Paris, France.

Claire Paquet (C)

Université de Paris, INSERM U1144, Center of Cognitive Neurology, Lariboisière - Fernand-Widal Hospital, APHP, Paris, France.

Kaj Blennow (K)

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital/Mölndal, SE-431 80, Mölndal, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

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Classifications MeSH

questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Full-length and C-terminal neurogranin in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Peptides bêta-amyloïdes › Full-length and C-terminal neurogranin in...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Full-length and C-terminal neurogranin in...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Troubles de la cognition › Dysfonctionnement cognitif › Full-length and C-terminal neurogranin in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Full-length and C-terminal neurogranin in...
questionsmedicales.fr › Techniques d'investigation › Techniques de sonde moléculaire › Dosage immunologique › Full-length and C-terminal neurogranin in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Neurogranine › Full-length and C-terminal neurogranin in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Fragments peptidiques › Full-length and C-terminal neurogranin in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Protéines associées aux microtubules › Protéines tau › Full-length and C-terminal neurogranin in...