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

Erik Portelius,Kina Höglund,Åsa Sandelius,Ulf Andréasson ,Bob Olsson,Leslie M Shaw,Murray Grossman,Jon B Toledo,Henrik Zetterberg,Leo Mccluskey,Jennifer D Mcbride ,Hlin Kvartsberg,Virginia M.‐Y Lee ,Nicholas Cullen ,David A Wolk,Lauren Elman,David J Irwin,Alice Chen‐Plotkin ,John Q Trojanowski,Daniel Weintraub,Kaj Blennow

doi:10.1007/s00401-018-1851-x

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.

Highlights

Synaptic density, and synaptic protein expression, is highest in the associative cortical areas, probably reflecting cognitive processing [4]
cerebrospinal fluid (CSF) Ng concentrations were significantly higher in Alzheimer’s disease dementia (ADD) compared to both mild cognitive impairment (MCI) (p < 0.0001) and CTRL (p = 0.0001) while the concentrations were similar in CTRL and MCI (Fig. 1a)
Since Ng is highly expressed in the cerebral cortex, hippocampus and amygdala, which are the same brain regions that are affected in ADD [42], we investigated the relationship between CSF Ng concentrations and neuropathology findings in amygdala and hippocampus

Summary

Introduction

Synaptic protein expression, is highest in the associative cortical areas, probably reflecting cognitive processing [4]. Extended author information available on the last page of the article (ADD) these brain regions show synaptic dysfunction, degeneration, and loss; synaptic pathology occurs early in the disease process, perhaps even earlier than neuronal degeneration and loss [2, 10], which is supported by studies of a tauopathy mouse model [56]. Neurogranin (Ng) is a neuronal protein that is highly expressed in the cortex, hippocampus, and amygdala, with the highest concentrations at the dendritic spines [16, 42]. Since the discovery that Ng is present in CSF [8], and that levels are increased in ADD [50], several recent studies have

Methods

Results

Conclusion