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.

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.

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.

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.

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.