Neurogranin as a cognitive biomarker in cerebrospinal fluid and blood exosomes for Alzheimer’s disease and mild cognitive impairment

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with clinical, biological, and pathological features occurring along a continuum from normal to end-stage disease. Currently, the diagnosis of AD depends on clinical assessments and post-mortem neuropathology, which is unbenefited early diagnosis and progressive monitoring. In recent years, clinical studies have reported that the level of cerebrospinal fluid (CSF) and blood neurogranin (Ng) are closely related to the occurrence and subsequent progression of AD. Therefore, the study used meta-analysis to identify the CSF and blood Ng levels for the development of diagnosis biomarker of patients with AD and mild cognitive impairment (MCI). We searched the Pubmed, Embase, Cochrane Library, and Web of Science databases. A total of 24 articles eligible for inclusion and exclusion criteria were assessed, including 4661 individuals, consisting of 1518 AD patients, 1501 MCI patients, and 1642 healthy control subjects. The level of CSF Ng significantly increased in patients with AD and MCI compared with healthy control subjects (SMD: 0.84 [95% CI: 0.70–0.98], P < 0.001; SMD: 0.53 [95% CI: 0.40–0.66], P = 0.008), and higher in AD patients than in MCI patients (SMD: 0.18 [95% CI: 0.07–0.30], P = 0.002), and CSF Ng level of patients with MCI-AD who progressed from MCI to AD was significantly higher than that of patients with stable MCI (sMCI) (SMD: 0.71 [95% CI: 0.25–1.16], P = 0.002). Moreover, the concentration of Ng in blood plasma exosomes of patients with AD and MCI was lower than that of healthy control subjects (SMD: −6.657 [95% CI: −10.558 to −2.755], P = 0.001; and SMD: −3.64 [95% CI: −6.50 to −0.78], P = 0.013), and which in patients with AD and MCI-AD were also lower than those in patients with sMCI (P < 0.001). Furthermore, regression analysis showed a negative relationship between MMSE scores and CSF Ng levels in MCI patients (slope = −0.249 [95% CI: −0.003 to −0.495], P = 0.047). Therefore, the Ng levels increased in CSF, but decreased in blood plasma exosomes of patients with AD and MCI-AD, and highly associated with cognitive declines. These findings provide the clinical evidence that CSF and blood exosomes Ng can be used as a cognitive biomarker for AD and MCI-AD, and further studies are needed to define the specific range of Ng values for diagnosis at the different stages of AD.

Neurogranin: A Potential Biomarker of Neurological and Mental Diseases

“…In that regard, a pilot study investigated the blood-derived Ng and revealed that the concentrations of Ng in the plasmatic NDEs are significantly lower in AD compared with the controls and correlate with the progression from MCI to AD ( Winston et al, 2016 ). A recent meta-analysis uncovered that compared with the cognitively normal controls, the levels of plasmatic NDEs Ng in AD patients have an obvious decrease ( Liu et al, 2020 ). Moreover, a recent study confirmed the difference in plasmatic NDEs Ng between AD patients and controls ( Jia et al, 2020 ).…”

Fluid Candidate Biomarkers for Alzheimer’s Disease: A Precision Medicine Approach

“…Elevated CSF MCP-1 levels were found in AD patients compared to controls [185]. Noteworthy, also in blood, MCP-1 could be higher in MCI subjects than in controls [185].…”

“…Another interesting candidate inflammatory biomarker is the monocyte chemoattractant protein-1 (MCP-1), which is a member of the C-C chemokine family and a potent chemotactic factor for monocytes [184]. Elevated CSF MCP-1 levels were found in AD patients compared to controls [185]. Noteworthy, also in blood, MCP-1 could be higher in MCI subjects than in controls [185].…”

Extracellular Vesicles in Liquid Biopsies: Potential for Disease Diagnosis

“…Blood-derived EVs have shown potential for the diagnosis of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease [ 139 ]. The calmodulin-binding protein neurogranin, expressed primarily in the brain, is downregulated in plasma EVs from Alzheimer's patients, and its levels correlate with those of cognitive biomarkers [ 140 ]. Identifying reliable biomarkers of Parkinson's disease may be particularly beneficial because treatments exist that can alter the disease and improve prognosis [ 141 ].…”