Altered central and blood glutathione in Alzheimer Disease and Mild Cognitive Impairment: a meta-analysis

Abstract

Background: Increasing evidence implicates oxidative stress (OS) in Alzheimer Disease (AD) and Mild Cognitive Impairment (MCI). Depletion of the brain antioxidant glutathione (GSH) may be important in OS-mediated neurodegeneration, though studies of post-mortem brain GSH changes in AD have been inconclusive. Recent in vivo measurements of brain and blood GSH may shed light on GSH changes earlier in the disease.Aim: To quantitatively review in vivo GSH in AD and MCI compared to healthy controls (HC) using meta-analyses. Method: Studies with in vivo brain or blood GSH levels in MCI or AD with a HC group were identified using Medline, PsychInfo, and Embase (1947-June 2020). Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. Outcome measures included brain GSH (Meshcher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) versus non-MEGA-PRESS), and blood GSH (intracellular versus extracellular) in AD and MCI. The Q statistic and Egger’s test were used to assess heterogeneity and risk of publication bias, respectively. Results: For brain GSH, 4 AD (AD=135, HC=223) and 4 MCI (MCI=213, HC=211) studies were included. For blood GSH, 26 AD (AD=1203, HC=1135) and 7 MCI (MCI=434, HC=408) studies were included. Brain GSH overall did not differ in AD or MCI compared to HC; however, the subgroup of studies using MEGA-PRESS reported lower brain GSH in AD (SMD [95%CI] -1.45 [-1.83, -1.06], p<0.001) and MCI (-1.15 [-1.71, -0.59], z=4.0, p<0.001). AD had lower intracellular and extracellular blood GSH overall (-1.10 [-1.58, -0.62], z=4.46, p<0.001). In a subgroup analysis, intracellular GSH was lower in MCI (-0.66 [-1.11, -0.21], p=0.025). Heterogeneity was observed throughout (I2 >85%) and not fully accounted by subgroup analysis. Egger’s test indicated risk of publication bias.Conclusion: Blood intracellular GSH decrease is seen in MCI, while both intra- and extracellular decreases were seen in AD. Brain GSH is decreased in AD and MCI in subgroup analysis. Potential bias and heterogeneity suggest the need for measurement standardization and additional studies to explore sources of heterogeneity.

Ellagic Acid Modulates the Amyloid Precursor Protein Gene via Superoxide Dismutase Regulation in the Entorhinal Cortex in an Experimental Alzheimer’s Model

“…Cu, Zn-SOD are fatally affected by the oxidative damage to the brain in AD and Parkinson’s disease [ 43 ]. In addition, GSH was proved to be low in brain tissue and blood in cases of AD and mild cognitive impairment [ 44 ], but higher plasma GSH levels were associated with a decreased risk of developing AD [ 45 ].…”

Functionalization strategies of polymeric nanoparticles for drug delivery in Alzheimer’s disease: Current trends and future perspectives

“…In a normal condition, ROS are kept at low levels by antioxidant molecules, such as glutathione and vitamins, but during aging these antioxidant defense mechanisms decrease their activity. For example, glutathione is a ROS scavenger and its concentration was observed to be reduced both in experimental models ( Chen et al, 1989 ; Iantomasi et al, 1993 ; Sasaki et al, 2001 ; Liu, 2002 ; Wang et al, 2003 ) and in AD patients ( Gsell et al, 1995 ; Zhu et al, 2006 ; Chen et al, 2022 ). In this way, the rate of ROS production exceeds the antioxidant ability of ROS buffering, leading to increased oxidative stress.…”