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

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.