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.

Fig. 1. Forest plot of random-effects meta-analysis of cerebrospinal fluid Ng levels between AD patients and HC subjects.

Data include 2891 individuals from 19 studies. The squares indicate individual study SMD and their corresponding 95% CIs and the sizes of the squares are proportional to study weight. Ng neurogranin, SMD standard mean difference, CI confidence interval, AD Alzheimer’s disease, HC healthy control.

Fig. 2. Forest plot of random-effects meta-analysis of cerebrospinal fluid Ng levels between MCI patients and HC subjects.

Data include 2203 individuals from 15 studies. The squares indicate individual study SMD and their corresponding 95% CIs and the sizes of the squares are proportional to study weight. Ng neurogranin, SMD standard mean difference, CI confidence interval, MCI mild cognitive impairment, HC healthy control.

Fig. 3. Forest plot of random-effects meta-analysis of cerebrospinal fluid Ng levels between AD and MCI patients.

Data include 2216 individuals from 14 studies. The squares indicate individual study SMD and their corresponding 95% CIs and the sizes of the squares are proportional to study weight. Ng neurogranin, SMD standard mean difference, CI confidence interval, AD Alzheimer’s disease, MCI mild cognitive impairment.

Fig. 4. Forest plot of random-effects meta-analysis of CSF neurogranin levels between MCI-AD and sMCI patients.

Data include 360 individuals from four studies. The squares indicate individual study SMD and their corresponding 95% CIs and the sizes of the squares are proportional to study weight. MCI-AD mild cognitive impairment patients who progressed to Alzheimer’s disease, sMCI stable mild cognitive impairment, CSF cerebrospinal fluid, SMD standard mean difference, CI confidence interval.

Fig. 5. Forest plot of random-effects meta-analysis of blood plasma neuronal derived exosomes Ng levels between AD, MCI patients and HC subjects.

a Data include 62 individuals from two studies (Goetzl’s study reports results from two groups of AD patients and HC subjects) for meta-analysis of exosomes Ng levels between AD and HC. b Data include 187 individuals from two studies for meta-analysis of exosomes Ng levels between MCI and HC. The squares indicate individual study SMD and their corresponding 95% CIs and the sizes of the squares are proportional to study weight. SMD standard mean difference, CI confidence interval, AD Alzheimer’s disease, MCI mild cognitive impairment, HC healthy control.