Hippocampal glutathione depletion with enhanced iron level in patients with mild cognitive impairment and Alzheimer's disease compared with healthy elderly participants.

Oxidative stress has been implicated in Alzheimer's disease, and it is potentially driven by the depletion of primary antioxidant, glutathione, as well as elevation of the pro-oxidant, iron. Present study evaluates glutathione level by magnetic resonance spectroscopy, iron deposition by quantitative susceptibility mapping in left hippocampus, as well as the neuropsychological scores of healthy old participants (N = 25), mild cognitive impairment (N = 16) and Alzheimer's disease patients (N = 31). Glutathione was found to be significantly depleted in mild cognitive impaired (P < 0.05) and Alzheimer's disease patients (P < 0.001) as compared with healthy old participants. A significant higher level of iron was observed in left hippocampus region for Alzheimer's disease patients as compared with healthy old (P < 0.05) and mild cognitive impairment (P < 0.05). Multivariate receiver-operating curve analysis for combined glutathione and iron in left hippocampus region provided diagnostic accuracy of 82.1%, with 81.8% sensitivity and 82.4% specificity for diagnosing Alzheimer's disease patients from healthy old participants. We conclude that tandem glutathione and iron provides novel avenue to investigate further research in Alzheimer's disease.

Hippocampal Glutathione Depletion and pH Increment in Alzheimer's Disease: An in vivo MRS Study.

BACKGROUND: Oxidative stress plays a major role in Alzheimer's disease (AD) pathogenesis, and thus, antioxidant glutathione (GSH) has been actively investigated in mitigating the oxidative load. Significant hippocampal GSH depletion has been correlated with cognitive impairment in AD. Furthermore, postmortem studies indicated alterations in cellular-energy metabolism and hippocampal pH change toward alkalinity in AD. OBJECTIVE: Concurrent analysis of hippocampal GSH and pH interplay in vivo on the same individual is quite unclear and hence requires investigation to understand the pathological events in AD. METHODS: Total 39 healthy old (HO), 22 mild cognitive impairment (MCI), and 37 AD patients were recruited for hippocampal GSH using 1H-MRS MEGA-PRESS and pH using 2D 31P-MRSI with dual tuned (1H/31P) transmit/receive volume head coil on 3T-Philips scanner. All MRS data processing using KALPANA package and statistical analysis were performed MedCalc, respectively and NINS-STAT package. RESULTS: Significant GSH depletion in the left and right hippocampus (LH and RH) among MCI and AD study groups as compared to HO was observed, whereas pH increased significantly in the LH region between HO and AD. Hippocampal GSH level negatively correlated with pH in both patient groups. The ROC analysis on the combined effect of GSH and pH in both hippocampal regions give accuracy for MCI (LH: 78.27%; RH: 86.96%) and AD (LH: 88%; RH: 78.26%) groups differentiating from HO. CONCLUSION: Outcomes from this study provide further insights to metabolic alterations in terms of concurrent assessment of hippocampal GSH and pH levels in AD pathogenesis, aiding in early diagnosis of MCI and AD.

PRATEEK: Integration of Multimodal Neuroimaging Data to Facilitate Advanced Brain Research.

BACKGROUND: In vivo neuroimaging modalities such as magnetic resonance imaging (MRI), functional MRI (fMRI), magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), and quantitative susceptibility mapping (QSM) are useful techniques to understand brain anatomical structure, functional activity, source localization, neurochemical profiles, and tissue susceptibility respectively. Integrating unique and distinct information from these neuroimaging modalities will further help to enhance the understanding of complex neurological diseases. OBJECTIVE: To develop a processing scheme for multimodal data integration in a seamless manner on healthy young population, thus establishing a generalized framework for various clinical conditions (e.g., Alzheimer's disease). METHODS: A multimodal data integration scheme has been developed to integrate the outcomes from multiple neuroimaging data (fMRI, MEG, MRS, and QSM) spatially. Furthermore, the entire scheme has been incorporated into a user-friendly toolbox- "PRATEEK". RESULTS: The proposed methodology and toolbox has been tested for viability among fourteen healthy young participants. The data-integration scheme was tested for bilateral occipital cortices as the regions of interest and can also be extended to other anatomical regions. Overlap percentage from each combination of two modalities (fMRI-MRS, MEG-MRS, fMRI-QSM, and fMRI-MEG) has been computed and also been qualitatively assessed for combinations of the three (MEG-MRS-QSM) and four (fMRI-MEG-MRS-QSM) modalities. CONCLUSION: This user-friendly toolbox minimizes the need of an expertise in handling different neuroimaging tools for processing and analyzing multimodal data. The proposed scheme will be beneficial for clinical studies where geometric information plays a crucial role for advance brain research.

Glutathione in Brain: Overview of Its Conformations, Functions, Biochemical Characteristics, Quantitation and Potential Therapeutic Role in Brain Disorders.

Glutathione (GSH) is an important antioxidant found abundantly and synthesized intracellularly in the cytosol in a tightly regulated fashion. It has diverse physiological functions, including protection against reactive oxygen species and nitrogen species, antioxidant defense as well as maintenance of cellular thiol status. The human brain due to the high oxygen consumption is extremely susceptible to the generation of reactive oxygen species. GSH plays a paramount role in brain antioxidant defense, maintaining redox homeostasis. The depletion of brain GSH has also been observed from both autopsies as well as in vivo MRS studies with aging and varied neurological disorders (Alzheimer's disease, Parkinson's disease, etc.). Therefore, GSH enrichment using supplementation is a promising avenue in the therapeutic development for these neurological disorders. This review will enrich the information on the importance of GSH synthesis, metabolism, functions, compartmentation and inter-organ transport, structural conformations and its quantitation via different techniques. The transportation of GSH in the brain via different interventional routes and its potential role in the development of therapeutic strategies for various brain disorders is also addressed. Very recent study found significant improvement of behavioral deficits including cognitive decline, depressive-like behaviors, in APP (NL-G-F/NL-G-FG-) mice due to oral GSH administration. This animal model study put an emergent need to complete GSH supplementation trial in MCI and AD patients for cognitive improvement as proposed earlier.

BRAHMA: Population specific T1, T2, and FLAIR weighted brain templates and their impact in structural and functional imaging studies.

Differences in brain morphology across population groups necessitate creation of population-specific Magnetic Resonance Imaging (MRI) brain templates for interpretation of neuroimaging data. Variations in the neuroanatomy in a genetically heterogeneous population make the development of a population-specific brain template for the Indian subcontinent imperative. A dataset of high-resolution 3D T1, T2-weighted, and FLAIR images acquired from a group of 113 volunteers (M/F - 56/57, mean age-28.96 ±â€¯7.80 years) are used to construct T1, T2-weighted, and FLAIR templates, collectively referred to as Indian Brain Template, "BRAHMA". A processing pipeline is developed and implemented in a MATLAB based toolbox for template construction and generation of tissue probability maps and segmentation atlases, with additional labels for deep brain regions such as the Substantia Nigra generated from the T2-weighted and FLAIR templates. The use of BRAHMA template for analysis of structural and functional neuroimaging data obtained from Indian participants, provides improved accuracy with statistically significant results over that obtained using the ICBM-152 (International Consortium for Brain Mapping) template. Our results indicate that segmentations generated on structural images are closer in volume to those obtained from registration to the BRAHMA template than to the ICBM-152. Furthermore, functional MRI data obtained for Working Memory and Finger Tapping paradigms processed using the BRAHMA template show a significantly higher percentage of the activation area than ICBM-152 in relevant brain regions, i.e. the left middle frontal gyrus, and the left and right precentral gyri, respectively. The availability of different image contrasts, tissue maps, and segmentation atlases makes the BRAHMA template a comprehensive tool for multi-modal image analysis in laboratory and clinical settings.

Quantitation of in vivo brain glutathione conformers in cingulate cortex among age-matched control, MCI, and AD patients using MEGA-PRESS.

Oxidative stress (OS) plays an important role in Alzheimer's disease (AD) and glutathione (GSH) mitigates this effect by maintaining redox-imbalance and free-radical neutralization. Quantified brain GSH concentration provides distinct information about OS among age-matched normal control (NC), mild cognitive impairment (MCI) and AD patients. We report alterations of in vivo GSH conformers, along with the choline, creatine, and N-acetylaspartate levels in the cingulate cortex (CC) containing anterior (ACC) and posterior (PCC) regions of 64 (27 NC, 19 MCI, and 18 AD) participants using MEscher-GArwood-Point-RESolved spectroscopy sequence. Result indicated, tissue corrected GSH depletion in PCC among MCI (p = .001) and AD (p = .028) and in ACC among MCI (p = .194) and AD (p = .025) as compared to NC. Effects of the group, region, and group × region on GSH with age and gender as covariates were analyzed using a generalized linear model with Bonferroni correction for multiple comparisons. A significant effect of group with GSH depletion in AD and MCI was observed as compared to NC. Receiver operator characteristic (ROC) analysis of GSH level in CC differentiated between MCI and NC groups with an accuracy of 82.8% and 73.5% between AD and NC groups. Multivariate ROC analysis for the combined effect of the GSH alteration in both ACC and PCC regions provided improved diagnostic accuracy of 86.6% for NC to MCI conversion and 76.4% for NC to AD conversion. We conclude that only closed GSH conformer depletion in the ACC and PCC regions is critical and constitute a potential biomarker for AD.