Glutathione Depletion and Concomitant Elevation of Susceptibility in Patients with Parkinson's Disease: State-of-the-Art MR Spectroscopy and Neuropsychological Study.

Parkinson's disease (PD) is characterized by extrapyramidal motor disturbances and nonmotor cognitive impairments which impact activities of daily living. Although the etiology of PD is still obscure, autopsy reports suggest that oxidative stress (OS) is one of the important factors in the pathophysiology of PD. In the current study, we have investigated the impact of OS in PD by measuring the antioxidant glutathione (GSH) levels from the substantia nigra (SN), left hippocampus (LH) and neurotransmitter γ-amino butyric acid (GABA) levels from SN region. Concomitant quantitative susceptibility mapping (QSM) from SN and LH was also acquired from thirty-eight PD patients and 30 age-matched healthy controls (HC). Glutathione levels in the SN region decreased significantly and susceptibility increased significantly in PD compared to HC. Nonsignificant depletion of GABA was observed in the SN region. GSH levels in the LH region were depleted significantly, but LH susceptibility did not alter in the PD cohort compared to HC. Neuropsychological and physical assessment demonstrated significant impairment of cognitive functioning in PD patients compared to HC. GSH depletion was negatively correlated to motor function performance. Multivariate receiver operating characteristic (ROC) curve analysis on the combined effect of GSH, GABA, and susceptibility in the SN region yielded an improved diagnostic accuracy of 86.1% compared to individual diagnostic accuracy based on GSH (65.8%), GABA (57.5%), and susceptibility (69.6%). This is the first comprehensive report in PD demonstrating significant GSH depletion as well as concomitant iron enhancement in the SN region.

SWADESH: a multimodal multi-disease brain imaging and neuropsychological database and data analytics platform.

Multimodal neuroimaging data of various brain disorders provides valuable information to understand brain function in health and disease. Various neuroimaging-based databases have been developed that mainly consist of volumetric magnetic resonance imaging (MRI) data. We present the comprehensive web-based neuroimaging platform "SWADESH" for hosting multi-disease, multimodal neuroimaging, and neuropsychological data along with analytical pipelines. This novel initiative includes neurochemical and magnetic susceptibility data for healthy and diseased conditions, acquired using MR spectroscopy (MRS) and quantitative susceptibility mapping (QSM) respectively. The SWADESH architecture also provides a neuroimaging database which includes MRI, MRS, functional MRI (fMRI), diffusion weighted imaging (DWI), QSM, neuropsychological data and associated data analysis pipelines. Our final objective is to provide a master database of major brain disease states (neurodegenerative, neuropsychiatric, neurodevelopmental, and others) and to identify characteristic features and biomarkers associated with such disorders.

Blood Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. The characteristic pathological manifestation of AD includes the deposition of extracellular insoluble ß amyloid plaques and intracellular neurofibrillary tangles formed from hyperphosphorylated tau protein. Cost effective and minimally invasive peripheral blood-based biomarkers are critical for early AD diagnosis. Currently, the plasma based two fraction of ß amyloid peptide ratio (Aß42/40) and phosphorylated tau (p-tau) are considered as blood-based biomarkers for AD diagnosis. Recent research indicates that oxidative stress (OS) occurs prior to amyloid plaque (Aß) formation and abnormal tau phosphorylation in AD. The imbalance of the master antioxidant, glutathione (GSH), and prooxidants (iron, zinc, and copper)─plays a crucial role in AD neurodegeneration. We present peripheral blood-based OS related biomarkers that are mechanistically involved in the disease process and may serve as a novel screening tool for early detection of AD onset. This OS based approach may also provide a quick and cost efficient method to monitor the effects of disease-modifying therapies in AD clinical trials.

Oxidative Stress Occurs Prior to Amyloid Aß Plaque Formation and Tau Phosphorylation in Alzheimer's Disease: Role of Glutathione and Metal Ions.

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder that affects millions of people worldwide. Although the pathogenesis remains obscure, there are two dominant causal hypotheses. Since last three decades, amyloid beta (Aß) deposition was the most prominent hypothesis, and the other is the tau hyperphosphorylation hypothesis. The confirmed diagnostic criterion for AD is the presence of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and the deposition of toxic oligomeric Aß in the autopsied brain. Consistent with these hypotheses, oxidative stress (OS) is garnering major attention in AD research. OS results from an imbalance of pro-oxidants and antioxidants. There is a considerable debate in the scientific community on which process occurs first, OS or plaque deposition/tau hyperphosphorylation. Based on recent scientific observations of various laboratories including ours along with critical analysis of those information, we believe that OS is the early event that leads to oligomeric Aß deposition as well as dimerization of tau protein and its subsequent hyperphosphorylation. This OS hypothesis immediately suggests the consideration of novel therapeutic approaches to include antioxidants involving glutathione enrichment in the brain by supplementation with or without an iron chelator.

Brain Imaging Databases.

The availability of neuroimaging-based databases is helping immensely to understand the brain function in healthy and diseased conditions. This viewpoint highlights the objectives, commonalities, and differences within these existing databases and pointers for researchers to choose a particular database. We introduce a multimodal multidisease database, SWADESH, and its comparison with the existing databases. A futuristic database blueprint is proposed for housing multidisease, multimodal, and longitudinal brain imaging data systematically organized in a matrix form along with neuropsychological assessment scores for the identification of causal disease processes. The information-rich databases will ultimately assist with the systematic identification of prime features linked to causal disease processes, leading to the design of appropriate clinical trials for successful therapeutic interventions.

Quantitation of Brain and Blood Glutathione and Iron in Healthy Age Groups Using Biophysical and In Vivo MR Spectroscopy: Potential Clinical Application.

The antioxidant glutathione (GSH) and pro-oxidant iron levels play a balancing role in the modulation of oxidative stress (OS). There is a significant depletion of GSH in the left hippocampus (LH) in patients with Alzheimer's disease (AD) with concomitant elevation of iron level. However, the correlation of GSH and iron distribution patterns between the brain and the peripheral system (blood) is not yet known. We measured GSH and magnetic susceptibility (e.g., iron) in the LH region along with GSH in plasma and iron in serum across four age groups consisting of healthy volunteers (age range 18-72 y, n = 70). We report non-variability of the mean GSH in the plasma and LH region across mentioned age groups. The mean iron level in the LH region does not change, but the iron level in the serum in the 51-72 y age group increases non-significantly. Regression analysis of our data indicated that GSH and iron levels (both in blood and in brain) are not related to age. This research pave the way for the identification of a risk/susceptibility biomarker for AD and Parkinson's disease from the evaluation of GSH (in plasma) and iron (in serum) levels concomitantly.

Distribution Pattern of Closed and Extended Forms of Glutathione in the Human Brain: MR Spectroscopic Study.

Glutathione (GSH) is a potent antioxidant synthesized de novo in cells and helps to detoxify free radicals in the brain and other organs. In vitro NMR studies from various research groups have reported primarily two sets of chemical shifts (2.80 or 2.96 ppm) of Cys-ßCH2 depending on GSH sample preparation in either inert or oxygenated environments. A multi-center in vivo MRS human study has also validated the presence of two types of GSH conformer in the human brain. Our study is aimed at investigating the distribution patterns of the two GSH conformers from five brain regions, namely, ACC (anterior cingulate cortex), PCC (posterior cingulate cortex), LPC (left parietal cortex), LH (left hippocampus), and CER (cerebellum). GSH was measured using a 3T MRI scanner using MEGA-PRESS pulse sequence in healthy young male and female populations (M/F = 5/9; age 32.8 ± 5.27 years). We conclude that the closed GSH conformer (characteristic NMR shift signature: Cys Hα 4.40-Hß 2.80 ppm) is more abundant than the extended GSH form (characteristic NMR shift signature Cys Hα 4.56-Hß 2.95 ppm). Closed conformer has a non-uniform distribution (ACC < CER < LH < PCC < LPC) in the healthy brain. On the contrary, the extended form of GSH has a uniform distribution in various anatomical regions.

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.

Schizophrenia, Bipolar and Major Depressive Disorders: Overview of Clinical Features, Neurotransmitter Alterations, Pharmacological Interventions, and Impact of Oxidative Stress in the Disease Process.

Psychiatric disorders are one of the leading causes of disability worldwide and affect the quality of life of both individuals and the society. The current understanding of these disorders points toward receptor dysfunction and neurotransmitter imbalances in the brain. Treatment protocols are hence oriented toward normalizing these imbalances and ameliorating the symptoms. However, recent literature has indicated the possible role of depleted levels of antioxidants like glutathione (GSH) as well as an alteration in the levels of the pro-oxidant, iron in the pathogenesis of major psychiatric diseases, viz., schizophrenia (Sz), bipolar disorder (BD), and major depressive disorder (MDD). This review aims to highlight the involvement of oxidative stress (OS) in these psychiatric disorders. An overview of the clinical features, neurotransmitter abnormalities, and pharmacological treatments concerning these psychiatric disorders has also been presented. Furthermore, it attempts to synthesize literature from existing magnetic resonance spectroscopy (MRS) and quantitative susceptibility mapping (QSM) studies for these disorders, assessing GSH and iron, respectively. This manuscript is a sincere attempt to stimulate research discussion to advance the knowledge base for further understanding of the pathoetiology of Sz, BD, and MDD.

Oxidative Stress: Glutathione and Its Potential to Protect Methionine-35 of Aß Peptide from Oxidation.

Alzheimer's disease (AD) is the most common neurodegenerative disorder with heterogeneous etiology. Intracellular neurofibrillary tangles caused by tau (τ) protein phosphorylation and extracellular senile plaques caused by aggregation of amyloid-beta (Aß) peptide are characteristic histopathological hallmarks of AD. Oxidative stress (OS) is also suggested to play a role in the pathophysiology of AD. The antioxidant glutathione (GSH) is able to mitigate OS through the detoxification of free radicals. The clearance of these free radicals is reported to be affected when there is a decline in GSH levels in AD. These radicals further react with the methionine-35 (M-35) residue of Aß and facilitate its subsequent oligomerization. This review presents a plausible model indicating the role of master antioxidant GSH to protect M35 of Aß1-40/Aß1-42 from oxidation in pathological conditions as compared to healthy controls.

Interplay Between Hippocampal Glutathione Depletion and pH Increment in Alzheimer's Disease.

Oxidative stress (OS) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Elevated OS in AD lowers the level of glutathione (GSH), a brain antioxidant. Currently, GSH is under examination in the clinical population for understanding its association with oxidative load in AD research. Significant depletion in hippocampal GSH, as observed using in vivo magnetic resonance spectroscopy (MRS), reportedly correlates with cognitive impairment in AD. Alterations in cellular-energy metabolism and increased hippocampal pH have also been reported in AD. Hence, this combined molecular interplay between hippocampal GSH and pH must be studied longitudinally for advancing AD research. Herein, we propose a schematic model depicting the molecular events in AD pathogenesis and provide a possible link between OS, GSH depletion, and pH alterations in the hippocampus. The model would further potentiate the need for in vivo longitudinal studies to confirm the interlinked mechanism between OS, hippocampal GSH depletion, and pH increment in an AD patient brain.

Comprehensive Account of Sodium Imaging and Spectroscopy for Brain Research.

Sodium (23Na) is a vital component of neuronal cells and plays a key role in various signal transmission processes. Hence, information on sodium distribution in the brain using magnetic resonance imaging (MRI) provides useful information on neuronal health. 23Na MRI and MR spectroscopy (MRS) improve the diagnosis, prognosis, and clinical monitoring of neurological diseases but confront some inherent limitations that lead to low signal-to-noise ratio, longer scan time, and diminished partial volume effects. Recent advancements in multinuclear MR technology have helped in further exploration in this domain. We aim to provide a comprehensive description of 23Na MRI and MRS for brain research including the following aspects: (a) theoretical background for understanding 23Na MRI and MRS fundamentals; (b) technological advancements of 23Na MRI with respect to pulse sequences, RF coils, and sodium compartmentalization; (c) applications of 23Na MRI in the early diagnosis and prognosis of various neurological disorders; (d) structural-chronological evolution of sodium spectroscopy in terms of its numerous applications in human studies; (e) the data-processing tools utilized in the quantitation of sodium in the respective anatomical regions.

In Vivo 13C Magnetic Resonance Spectroscopy for Assessing Brain Biochemistry in Health and Disease.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique that contributes to the elucidation of brain biochemistry. 13C MRS enables the detection of specific neurochemicals and their neuroenergetic correlation with neuronal function. The synergistic outcome of 13C MRS and the infusion of 13C-labeled substrates provide an understanding of neurometabolism and the role of glutamate/gamma-aminobutyric acid (GABA) neurotransmission in diseases, such as Alzheimer's disease, schizophrenia, and bipolar disorder. Moreover, 13C MRS provides a window into the altered flux rate of different pathways, including the tricarboxylic acid cycle (TCA) and the glutamate/glutamine/GABA cycle, in health and in various diseases. Notably, the metabolic flux rate of the TCA cycle often decreases in neurodegenerative diseases. Additionally, 13C MRS can be used to investigate several psychiatric and neurological disorders as it directly reflects the real-time production and alterations of key brain metabolites. This review aims to highlight the chronology, the technological advancements, and the applications of 13C MRS in various brain diseases.

Comparison of seven modelling algorithms for γ-aminobutyric acid-edited proton magnetic resonance spectroscopy.

Edited MRS sequences are widely used for studying γ-aminobutyric acid (GABA) in the human brain. Several algorithms are available for modelling these data, deriving metabolite concentration estimates through peak fitting or a linear combination of basis spectra. The present study compares seven such algorithms, using data obtained in a large multisite study. GABA-edited (GABA+, TE = 68 ms MEGA-PRESS) data from 222 subjects at 20 sites were processed via a standardised pipeline, before modelling with FSL-MRS, Gannet, AMARES, QUEST, LCModel, Osprey and Tarquin, using standardised vendor-specific basis sets (for GE, Philips and Siemens) where appropriate. After referencing metabolite estimates (to water or creatine), systematic differences in scale were observed between datasets acquired on different vendors' hardware, presenting across algorithms. Scale differences across algorithms were also observed. Using the correlation between metabolite estimates and voxel tissue fraction as a benchmark, most algorithms were found to be similarly effective in detecting differences in GABA+. An interclass correlation across all algorithms showed single-rater consistency for GABA+ estimates of around 0.38, indicating moderate agreement. Upon inclusion of a basis set component explicitly modelling the macromolecule signal underlying the observed 3.0 ppm GABA peaks, single-rater consistency improved to 0.44. Correlation between discrete pairs of algorithms varied, and was concerningly weak in some cases. Our findings highlight the need for consensus on appropriate modelling parameters across different algorithms, and for detailed reporting of the parameters adopted in individual studies to ensure reproducibility and meaningful comparison of outcomes between different studies.

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.

AD Hypotheses and Suggested Clinical Trials.

Alzheimer's disease (AD) is a major neurodegenerative disorder that impairs cognitive reserve impacting activities of daily living. The prime pathological characteristics of AD include the deposition of neurofibrillary tangles of hyperphosphorylated tau (τ) proteins, accumulation of amyloid-ß (Aß), and neuronal loss. Expanding literature suggests that oxidative stress (OS) is a vital factor contributing to the pathogenesis of AD such that biometals (e.g., iron, zinc, copper) are believed to play a crucial role in Aß formation and neurodegeneration. Growing evidence indicates the impact of OS in AD, and clinical trials with antioxidative therapeutic interventions are in the frontline of AD research. We discuss various AD hypotheses and associated clinical trials. We present a case for future therapeutic intervention for AD by putting forth postulated hypotheses and trials.

Brain Imaging in COVID-19.

Considering the neurological and neuropsychiatric manifestations of coronavirus disease 2019 (COVID-19), its early diagnosis is crucial. This Viewpoint aims to highlight these manifestations through multimodal neuroimaging studies reflecting neurochemical and structural impairment.