Vesicular Glutamate Transporter Changes in the Cortical Default Mode Network During the Clinical and Pathological Progression of Alzheimer’s Disease

Abstract

Background: Altered glutamatergic neurotransmission may contribute to impaired default mode network (DMN) function in Alzheimer’s disease (AD). Among the DMN hub regions, frontal cortex (FC) was suggested to undergo a glutamatergic plasticity response in prodromal AD, while the status of glutamatergic synapses in the precuneus (PreC) during clinical-neuropathological AD progression is not known. Objective: To quantify vesicular glutamate transporter VGluT1- and VGluT2-containing synaptic terminals in PreC and FC across clinical stages of AD. Methods: Unbiased sampling and quantitative confocal immunofluorescence of cortical VGluT1- and VGluT2-immunoreactive profiles and spinophilin-labeled dendritic spines were performed in cases with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or moderate-severe AD (sAD). Results: In both regions, loss of VGluT1-positive profile density was seen in sAD compared to NCI, MCI, and mAD. VGluT1-positive profile intensity in PreC did not differ across groups, while in FC it was greater in MCI, mAD, and sAD compared to NCI. VGluT2 measures were stable in PreC while FC had greater VGluT2-positive profile density in MCI compared to sAD, but not NCI or mAD. Spinophilin measures in PreC were lower in mAD and sAD compared to NCI, while in FC they were stable across groups. Lower VGluT1 and spinophilin measures in PreC, but not FC, correlated with greater neuropathology. Conclusion: Frank loss of VGluT1 in advanced AD relative to NCI occurs in both DMN regions. In FC, an upregulation of VGluT1 protein content in remaining glutamatergic terminals may contribute to this region’s plasticity response in AD.

Application of robust regression in translational neuroscience studies with non-Gaussian outcome data

“…It should be noted that the analyses in Mi et al (2023) used the MMSE as the dependent variable with cyano-PiB and X-34 as independent variables. Here, we used cyano-PiB and X-34 as the dependent variables since their distributions are more like those of other biological variables used in neuroscience studies.…”

“…Using two different independent datasets from published postmortem neurodegenerative disease studies ( Ginsberg et al, 2019 ; Mi et al, 2023 ), we demonstrated how robust regression can be used as an alternative to linear regression when the error distribution of a dependent variable does not meet the assumption of normality. The examples used in the present study show how estimates for regression coefficients, SE, p -values, and R 2 values can be significantly biased using linear regression models when the dependent variable does not meet the assumption of normality.…”

“…Dataset 2 was derived from a study investigating the association between vesicular glutamate transporters and spinophilin with last ante-mortem clinical and postmortem neuropathological diagnoses as well as quantitative cyano-PiB- and X-34-stained amyloid plaque loads in the precuneus ( Mi et al, 2023 ). Antemortem clinical, demographic, APOE information and exclusion criteria were same as for Dataset 1.…”

“…For Dataset 2, cyano-PiB- and X-34-stained amyloid plaque loads in precuneus were used as dependent variables with MMSE score as the independent variable ( Mi et al, 2023 ). The Shapiro–Wilk test was used to determine whether each of the dependent variables met the assumption of normality.…”

Glaucoma Animal Models beyond Chronic IOP Increase

“…In addition, glutamate also performs neurobiological tasks by regulating motor as well as brain functions [78,79]. However, glutamate overstimulation can also cause neurotoxic processes, which are also observed in some neurodegenerative diseases, including Alzheimer's and Parkinson's disease [80][81][82][83].…”