Pravat K. Mandal

Interaction between Aβ Peptide and α Synuclein: Molecular Mechanisms in Overlapping Pathology of Alzheimer’s and Parkinson’s in Dementia with Lewy Body Disease

Amyloidogenic proteins (Aβ peptide) in Alzheimer’s disease (AD) and alpha-synuclein (α-Syn) in Parkinson’s disease (PD) are typically soluble monomeric precursors, which undergo remarkable conformational changes and culminate in the form of aggregates in diseased condition. Overlap of clinical and neuropathological features of both AD and PD are observed in dementia with Lewy body (DLB) disease, the second most common form of dementia after AD. The identification of a 35-amino acid fragment of α-Syn in the amyloid plaques in DLB brain have raised the possibility that Aβ and α-Syn interact with each other. In this report, the molecular interaction of α-Syn with Aβ40 and/or Aβ42 are investigated using multidimensional NMR spectroscopy. NMR data in the membrane mimic environment indicate specific sites of interaction between membrane-bound α-Syn with Aβ peptide and vice versa. These Aβ–α-Syn interactions are demonstrated by reduced amide peak intensity or change in chemical shift of amide proton of the interacting proteins. Based on NMR results, the plausible molecular mechanism of overlapping pathocascade of AD and PD in DLB due to interactions between α-Syn and Aβ is described. To the best of our knowledge, it is the first report using multidimensional NMR spectroscopy that elucidates molecular interactions between Aβ and α-Syn which may lead to onset of DLB.

Brain oxidative stress: Detection and mapping of anti-oxidant marker 'Glutathione' in different brain regions of healthy male/female, MCI and Alzheimer patients using non-invasive magnetic resonance spectroscopy

Glutathione (GSH) serves as an important anti-oxidant in the brain by scavenging harmful reactive oxygen species that are generated during different molecular processes. The GSH level in the brain provides indirect information on oxidative stress of the brain. We report in vivo detection of GSH non-invasively from various brain regions (frontal cortex, parietal cortex, hippocampus and cerebellum) in bilateral hemispheres of healthy male and female subjects and from bi-lateral frontal cortices in patients with mild cognitive impairment (MCI) and Alzheimers disease (AD). All AD patients who participated in this study were on medication with cholinesterase inhibitors. Healthy young male (age 26.4±3.0) and healthy young female (age 23.6±2.1) subjects have higher amount of GSH in the parietal cortical region and a specific GSH distribution pattern (parietal cortex>frontal cortex>hippocampus ~ cerebellum) has been found. Overall mean GSH content is higher in healthy young female compared to healthy young male subjects and GSH is distributed differently in two hemispheres among male and female subjects. In both young female and male subjects, statistically significant (p=0.02 for young female and p=0.001 for young male) difference in mean GSH content is found when compared between left frontal cortex (LFC) and right frontal cortex (RFC). In healthy young female subjects, we report statistically significant positive correlation of GSH content between RFC and LFC (r=0.641, p=0.004) as well as right parietal cortex (RPC) and left parietal cortex (LPC) (r=0.797, p=0.000) regions. In healthy young male subjects, statistically significant positive correlation of GSH content was observed between LFC and LPC (r=0.481, p=0.032) regions. This statistical analysis implicates that in case of a high GSH content in LPC of a young male, his LFC region would also contain high GSH and vice versa. The difference in mean of GSH content between healthy young female control and female AD patients in RFC region (p=0.003) and difference in mean of GSH content between healthy young male control and male AD patients (p=0.05) in LFC region is found to be statistically significant. It is the first scientific report correlating alteration (in selective brain regions) of GSH level with clinical status of male and female subjects using non-invasive imaging technique.

Anaesthetics and postoperative cognitive dysfunction: a pathological mechanism mimicking Alzheimer’s disease

With longevity, postoperative cognitive decline in the elderly has emerged as a major health concern for which several factors have been implicated, one of the most recent being the role of anaesthetics. Interactions of anaesthetic agents and different targets have been studied at the molecular, cellular and structural anatomical levels. Recent in vitro nuclear magnetic resonance spectroscopy studies have shown that several anaesthetics act on the oligomerisation of amyloid β peptide. Uncontrolled production, oligomerisation and deposition of amyloid β peptide, with subsequent development of amyloid plaques, are fundamental steps in the generation of Alzheimer’s disease. Amyloid β peptide is naturally present in the central nervous system, and is found at higher tissue concentrations in the elderly. We argue that administering certain general anaesthetics to elderly patients may worsen amyloid β peptide oligomerisation and deposition and thus increase the risk of developing postoperative cognitive dysfunction. The aim of this review is to highlight the clinical aspects of postoperative cognitive dysfunction and to find plausible links between possible anaesthetic effects and the molecular pathological mechanism of Alzheimer’s disease. It is hoped that our hypothesis will stimulate further enquiry, especially triggering research into elucidating those anaesthetics that may be more suitable when cognitive dysfunction is a particular concern.

Isoflurane and desflurane at clinically relevant concentrations induce amyloid beta-peptide oligomerization: an NMR study.

Current understanding on Alzheimers disease (AD) reveals that soluble amyloid beta-peptide (Abeta) oligomeric formation plays an important role in AD pathophysiology. A potential role for several inhaled anesthetics in promoting Abeta oligomer formation has been suggested. Using a nuclear magnetic resonance (NMR) study, we previously demonstrated that at a high concentration (higher than clinically relevant concentrations), the inhaled anesthetics halothane and isoflurane, interact with specific amino acid residues (G29, A30, and I31) and induce Abeta oligomerization. The present study confirms this is true at a clinically relevant concentration. Isoflurane and desflurane induce Abeta oligomerization by inducing chemical shift changes of the critical amino acid residues (G29, A30, and I31), reinforcing the evidence that perturbation of these three crucial residues indeed plays an important role in oligomerization. These findings support the emerging hypothesis that several commonly used inhaled anesthetics could be involved in neurodegeneration, as well as risk factor for accelerating the onset of AD.

Alzheimer's disease: Soluble oligomeric aβ(1-40) peptide in membrane mimic environment from solution NMR and circular dichroism studies

Amyloid beta peptide (Aβ) is a small peptide present in normal cells and aggregated Aβ is the main constituent of the extracellular amyloid plaques found in Alzheimer’s disease (AD) brain. Recent studies suggest that soluble Aβ oligomers are neurotoxic rather than amyloid fibrils found in amyloid plaques. This study using multidimensional NMR spectroscopy and circular dichroism (CD) provides the first direct evidence that alterations in membrane structure can trigger the conversion of soluble α-helical monomeric Aβ into oligomeric Aβ in a β-sheet conformation.

In vivo proton magnetic resonance spectroscopic signal processing for the absolute quantitation of brain metabolites

Magnetic resonance spectroscopy (MRS) is a non-invasive imaging modality for metabolite detection in different parts of the body (e.g. brain, liver, prostate, breast, kidney, skeletal muscle, and heart) for normal person as well as in various disorders. It aids in providing valuable information for both diagnosis as well as therapeutic monitoring. Though there has been tremendous progress in MRS signal processing techniques for the quantitation of neurometabolites, variability in the absolute quantitation of metabolites persists due to various experimental conditions. In this article, we present in-depth discussion on (1)H MRS data processing and quantitation using different software packages both in frequency (e.g. LCModel) and time domain (e.g. jMRUI). We have included comparative analysis of precision and accuracy of MRS data processing using LCModel and jMRUI (AMARES). Special emphasis has been provided for the handling of macromolecules and lipid in LCModel and jMRUI methods. The author also suggests certain points to be noted while opting for above software packages.

The Emerging Role of Glutathione in Alzheimer's Disease

With millions of older individuals presently suffering from Alzheimers disease (AD) worldwide, AD is an unduly common form of dementia that exacts a heavy toll on affected individuals and their families. One of the emerging causative factors associated with AD pathology is oxidative stress. This AD-related increase in oxidative stress has been attributed to decreased levels of the brain antioxidant, glutathione (GSH). In this article, we review the role of GSH in AD from a pathological as well as a diagnostic point of view. We recapitulate the literature that has assessed the role of GSH in AD onset and progression. We discuss the various methodologies through which alterations in GSH levels might be monitored, and highlight the yet uncharted potential of assaying GSH levels in vivo with magnetic resonance spectroscopy in AD therapeutics and prognostics. Finally, the present manuscript integrates findings from various studies to elucidate the possible molecular mechanisms through which disruptions in GSH homeostasis may contribute to AD pathology.

Automatic classification and prediction models for early Parkinson's disease diagnosis from SPECT imaging

Propose methods for very accurate classification of early PD using only 4 features.Used public database which is large and diverse making the developed models robust.First study to develop accurate prognostic model based on SBR features for early PD. Early and accurate diagnosis of Parkinsons disease (PD) is important for early management, proper prognostication and for initiating neuroprotective therapies once they become available. Recent neuroimaging techniques such as dopaminergic imaging using single photon emission computed tomography (SPECT) with 123I-Ioflupane (DaTSCAN) have shown to detect even early stages of the disease. In this paper, we use the striatal binding ratio (SBR) values that are calculated from the 123I-Ioflupane SPECT scans (as obtained from the Parkinsons progression markers initiative (PPMI) database) for developing automatic classification and prediction/prognostic models for early PD. We used support vector machine (SVM) and logistic regression in the model building process. We observe that the SVM classifier with RBF kernel produced a high accuracy of more than 96% in classifying subjects into early PD and healthy normal; and the logistic model for estimating the risk of PD also produced high degree of fitting with statistical significance indicating its usefulness in PD risk estimation. Hence, we infer that such models have the potential to aid the clinicians in the PD diagnostic process.

Alzheimer's Disease: NMR Studies of Asialo (GM1) and Trisialo (GT1b) Ganglioside Interactions with Aβ(1-40) Peptide in a Membrane Mimic Environment

Amyloid peptide (Aβ) is the major protein constituent of neuritic plaques in Alzheimers disease (AD). This peptide is an amphipathic molecule that perturbs membranes and binds to raft-like membranes composed of gangliosides. Ganglioside GM1 binds tightly with Aβ and it is speculated that GM1 inhibits Aβ from undergoing α-helix to β-sheet conformational changes. Although the role of gangliosides in conformational changes of Aβ have been studied, the specific nature of these interactions have not been reported. In the present report multidimensional NMR studies of ganglioside-Aβ interactions were conducted in sodium dodecyl sulphate (SDS) micelles, a membrane-mimicking environment. These studies reveal that asialoGM1 binds specifically with Aβ in a manner which could prevent β-sheet formation, but that ganglioside GT1b does not bind Aβ. Plausible pathways for the involvement of gangliosides in amyloidogenesis are discussed.

Brain Glutathione Levels – A Novel Biomarker for Mild Cognitive Impairment and Alzheimer’s Disease

BACKGROUND Extant data from in vivo animal models and postmortem studies indicate that Alzheimers disease (AD) pathology is associated with reduction of the brain antioxidant glutathione (GSH), yet direct clinical evidence has been lacking. In this study, we investigated GSH modulation in the brain with AD and assessed the diagnostic potential of GSH estimation in hippocampi (HP) and frontal cortices (FC) as a biomarker for AD and its prodromal stage, mild cognitive impairment (MCI). METHODS Brain GSH levels were measured in HP of 21 AD, 22 MCI, and 21 healthy old controls (HC) and FC of 19 AD, 19 MCI, and 28 HC with in vivo proton magnetic resonance spectroscopy. The association between GSH levels and clinical measures of AD progression was tested. Linear regression models were used to determine the best combination of GSH estimation in these brain regions for discrimination between AD, MCI, and HC. RESULTS AD-dependent reduction of GSH was observed in both HP and FC (p < .001). Furthermore, GSH reduction in these regions correlated with decline in cognitive functions. Receiver operator characteristics analyses evidenced that hippocampal GSH robustly discriminates between MCI and healthy controls with 87.5% sensitivity, 100% specificity, and positive and negative likelihood ratios of 8.76/.13, whereas cortical GSH differentiates MCI and AD with 91.7% sensitivity, 100% specificity, and positive and negative likelihood ratios of 9.17/.08. CONCLUSIONS The present study provides compelling in vivo evidence that estimation of GSH levels in specific brain regions with magnetic resonance spectroscopy constitutes a clinically relevant biomarker for MCI and AD.