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

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.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1851-x) contains supplementary material, which is available to authorized users.

The intact postsynaptic protein neurogranin is reduced in brain tissue from patients with familial and sporadic Alzheimer’s disease

“…In conclusion, our data shows that Ng is much more closely associated with plaque load compared to the spreading of Aβ pathology. This is in line with previous findings that CSF Ng is positively correlated with CERAD scores in autopsy-confirmed cases of AD [45]. Evaluating the levels of Ng in CSF from patients with primary tauopathies, without amyloid plaque pathology, might give us further insight into the association with tau as previous studies on CSF Ng have shown strong correlations with CSF tau [17, 24, 30, 33, 38, 61].…”

“…We previously showed a strong association between CSF Ng and degree of AD neuropathology independent of diagnosis in a study containing several neurodegenerative diseases [45]. In the present study, we confirmed the CSF study as brain Ng levels were increasing with both Braak stage, CERAD score and to some extent Thal phase, meaning that Ng is associated with both Aβ and tau pathology.…”

“…It is well established that cerebrospinal fluid (CSF) Ng is increased in sAD compared to healthy controls [17, 24, 28, 30, 32, 33, 45, 46]. Increased CSF Ng concentrations can also be used to distinguish patients with mild cognitive impairment (MCI) that will convert to sAD from those that remain stable [30, 32, 38, 46].…”

Cerebrospinal Fluid Levels of Neurogranin in Parkinsonian Disorders

“…CSF Ng levels have been extensively investigated in Alzheimer's disease (AD), where they are increased compared to controls, increased in amyloid‐beta (Aβ) + mild cognitive impairment (MCI), and linked to cognitive decline and progression from MCI to AD dementia . A recent postmortem, human brain proteome study on patiens with and without dementia found that synaptic proteins, but not any individual protein, could differentiate PD with dementia (PDD) and dementia with Lewy bodies (DLB) from controls and AD and that cognitive impairment and decline in life correlated with loss of synaptic proteins …”

“…Few studies have examined CSF Ng in PD, finding unchanged or decreased levels of Ng compared to controls . Even scarcer are studies on Ng and cognitive decline or motor dysfunction, and results are conflicting .…”