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Open Access 01-09-2018 | Original Paper

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Authors: Erik Portelius, Bob Olsson, Kina Höglund, Nicholas C. Cullen, Hlin Kvartsberg, Ulf Andreasson, Henrik Zetterberg, Åsa Sandelius, Leslie M. Shaw, Virginia M. Y. Lee, David J. Irwin, Murray Grossman, Daniel Weintraub, Alice Chen-Plotkin, David A. Wolk, Leo McCluskey, Lauren Elman, Jennifer McBride, Jon B. Toledo, John Q. Trojanowski, Kaj Blennow

Published in: Acta Neuropathologica | Issue 3/2018

Abstract

Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.

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Title: Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology
Authors: Erik Portelius
Bob Olsson
Kina Höglund
Nicholas C. Cullen
Hlin Kvartsberg
Ulf Andreasson
Henrik Zetterberg
Åsa Sandelius
Leslie M. Shaw
Virginia M. Y. Lee
David J. Irwin
Murray Grossman
Daniel Weintraub
Alice Chen-Plotkin
David A. Wolk
Leo McCluskey
Lauren Elman
Jennifer McBride
Jon B. Toledo
John Q. Trojanowski
Kaj Blennow
Publication date: 01-09-2018
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 3/2018
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1851-x

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Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

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