Increased neurogranin concentrations in cerebrospinal fluid of Alzheimer’s disease and in mild cognitive impairment due to AD

Abstract

Synaptic dysfunction is linked to both major depressive disorder (MDD) and Alzheimer's disease (AD). Synapse protein concentrations in cerebrospinal fluid (CSF) may be useful biomarkers to monitor synaptic dysfunction and degeneration that lead to depressive symptoms and AD, respectively. CSF neurogranin (Ng), a post-synaptic protein, has emerged as a promising tool to measure synaptic dysfunction and/or loss in AD. The aim of this study was to test the specific hypothesis that CSF neurogranin (Ng) is able to differentiate AD from MDD and cognitively normal controls. CSF samples from 44 healthy control individuals (CTRL), 86 patients with mild cognitive impairment (MCI), 36 of whom had prodromal AD as defined by a positive CSF AD biomarker signature, 25 AD dementia and 6 patients with MDD were analysed using an in house enzyme-linked immunosorbent assay for Ng. CSF Ng levels were significantly higher in AD patients and in prodromal AD (MCI patients with an "AD-like" CSF tau and Aβ42 profile) compared with CTRL individuals (p < 0.0001 for both groups) and MDD patients (p < 0.001 and p < 0.01, respectively). Significantly higher CSF Ng concentration was also seen in prodromal AD patients as compared to MCI patients without biomarker evidence of underlying AD pathology (p < 0.0001). CSF Ng correlated positively with the classical axonal injury markers CSF T-tau and P-tau (p < 0.0001), whereas correlation to plaque pathology as reflected by CSF Aβ42 was less clear. Negative correlations of CSF Ng with cognitive evaluation scores (MMSE and CAMCOG) were observed. This study strengthens the clinical utility of CSF Ng as a CSF biomarker for AD. AD patients in both MCI and dementia stages of the disease had increased CSF Ng concentrations compared with cognitively normal control individuals, patients with non-AD MCI and patients with MDD. The lowest CSF Ng concentrations were seen in patients with MDD, a finding that warrants validation in further studies.

Neurogranin and BACE1 in CSF as Potential Biomarkers Differentiating Depression with Cognitive Deficits from Early Alzheimer’s Disease: A Pilot Study

“…Likewise, high Aβ(1–42) levels were found in depressed patients compared to a nondepressed group in another study [9]. In our study, these associations were also rather weak, which may explain why other reports failed to find the same correlations with CSF t-tau, Aβ(1–42), and/or neurogranin in the different diagnostic groups [7, 8, 33]. Yet, because of the overlap of some of the cognitive symptoms between AD and depression, the question arises as to whether, at some level, the pathophysiological mechanisms responsible for these diseases might interact or overlap - particularly among MDD patients who will later develop AD.…”

“…Changes in neurogranin levels have been reported to occur in the brain [31] and in CSF [33]. Interestingly, the study reporting the latter result found lower CSF neurogranin levels in depressed patients than in healthy controls.…”

Current state of Alzheimer’s fluid biomarkers

“…CSF neurogranin levels are higher in AD [63, 175, 190, 221, 242, 291, 310, 347, 354, 361] or MCI patients [291, 347] compared with controls or non-AD dementia patients [354]. Higher levels of CSF neurogranin have been reported in AD compared with MCI [138, 291], although there was no significant difference between AD and MCI Aβ-positive (based on CSF Aβ42) groups in a recent study of the ADNI cohort [347].…”

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

“…It is a postsynaptic protein that is mainly expressed in the cortex and hippocampus, where it is concentrated in dendritic spines, and has a major role in regulating LTP and learning. Cerebrospinal (CSF) Ng is elevated in patients fulfilling clinical criteria for AD compared to mild cognitive impairment (MCI) patients as well as controls, a finding that has been replicated using different assays and across clinical sites 4, 5, 6, 7. Importantly, it has not yet been determined if it is also elevated in atypical forms of AD.…”