Role of Imaging Genetics in Alzheimer's Disease: A Systematic Review and Current Update.

BACKGROUND: Alzheimer's disease is a neurodegenerative disorder characterized by severe cognitive, behavioral, and psychological symptoms, such as dementia, cognitive decline, apathy, and depression. There are no accurate methods to diagnose the disease or proper therapeutic interventions to treat AD. Therefore, there is a need for novel diagnostic methods and markers to identify AD efficiently before its onset. Recently, there has been a rise in the use of imaging techniques like Magnetic Resonance Imaging (MRI) and functional Magnetic Resonance Imaging (fMRI) as diagnostic approaches in detecting the structural and functional changes in the brain, which help in the early and accurate diagnosis of AD. In addition, these changes in the brain have been reported to be affected by variations in genes involved in different pathways involved in the pathophysiology of AD. METHODOLOGY: A literature review was carried out to identify studies that reported the association of genetic variants with structural and functional changes in the brain in AD patients. Databases like PubMed, Google Scholar, and Web of Science were accessed to retrieve relevant studies. Keywords like 'fMRI', 'Alzheimer's', 'SNP', and 'imaging' were used, and the studies were screened using different inclusion and exclusion criteria. RESULTS: 15 studies that found an association of genetic variations with structural and functional changes in the brain were retrieved from the literature. Based on this, 33 genes were identified to play a role in the development of disease. These genes were mainly involved in neurogenesis, cell proliferation, neural differentiation, inflammation and apoptosis. Few genes like FAS, TOM40, APOE, TRIB3 and SIRT1 were found to have a high association with AD. In addition, other genes that could be potential candidates were also identified. CONCLUSION: Imaging genetics is a powerful tool in diagnosing and predicting AD and has the potential to identify genetic biomarkers and endophenotypes associated with the development of the disorder.

Current Update on Categorization of Migraine Subtypes on the Basis of Genetic Variation: a Systematic Review.

Migraine is a complex neurovascular disorder that is characterized by severe behavioral, sensory, visual, and/or auditory symptoms. It has been labeled as one of the ten most disabling medical illnesses in the world by the World Health Organization (Aagaard et al Sci Transl Med 6(237):237ra65, 2014). According to a recent report by the American Migraine Foundation (Shoulson et al Ann Neurol 25(3):252-9, 1989), around 148 million people in the world currently suffer from migraine. On the basis of presence of aura, migraine is classified into two major subtypes: migraine with aura (Aagaard et al Sci Transl Med 6(237):237ra65, 2014) and migraine without aura. (Aagaard K et al Sci Transl Med 6(237):237ra65, 2014) Many complex genetic mechanisms have been proposed in the pathophysiology of migraine but specific pathways associated with the different subtypes of migraine have not yet been explored. Various approaches including candidate gene association studies (CGAS) and genome-wide association studies (Fan et al Headache: J Head Face Pain 54(4):709-715, 2014). have identified the genetic markers associated with migraine and its subtypes. Several single nucleotide polymorphisms (Kaur et al Egyp J Neurol, Psychiatry Neurosurg 55(1):1-7, 2019) within genes involved in ion homeostasis, solute transport, synaptic transmission, cortical excitability, and vascular function have been associated with the disorder. Currently, the diagnosis of migraine is majorly behavioral with no focus on the genetic markers and thereby the therapeutic intervention specific to subtypes. Therefore, there is a need to explore genetic variants significantly associated with MA and MO as susceptibility markers in the diagnosis and targets for therapeutic interventions in the specific subtypes of migraine. Although the proper characterization of pathways based on different subtypes is yet to be studied, this review aims to make a first attempt to compile the information available on various genetic variants and the molecular mechanisms involved with the development of MA and MO. An attempt has also been made to suggest novel candidate genes based on their function to be explored by future research.

Neuroimaging Genomics a Predictor of Major Depressive Disorder (MDD).

Depression is a complex psychiatric disorder influenced by various genetic and environmental factors. Strong evidence has established the contribution of genetic factors in depression through twin studies and the heritability rate for depression has been reported to be 37%. Genetic studies have identified genetic variations associated with an increased risk of developing depression. Imaging genetics is an integrated approach where imaging measures are combined with genetic information to explore how specific genetic variants contribute to brain abnormalities. Neuroimaging studies allow us to examine both structural and functional abnormalities in individuals with depression. This review has been designed to study the correlation of the significant genetic variants with different regions of neural activity, connectivity, and structural alteration in the brain as detected by imaging techniques to understand the scope of biomarkers in depression. This might help in developing novel therapeutic interventions targeting specific genetic pathways or brain circuits and the underlying pathophysiology of depression based on this integrated approach can be established at length.

Genomic Variation Affecting MPV and PLT Count in Association with Development of Ischemic Stroke and Its Subtypes.

Platelets play a significant role in the pathophysiology of ischemic stroke since they are involved in the formation of intravascular thrombus after erosion or rupture of the atherosclerotic plaques. Platelet (PLT) count and mean platelet volume (MPV) are the two significant parameters that affect the functions of platelets. In the current study, MPV and PLT count was evaluated using flow cytometry and a cell counter. SonoClot analysis was carried out to evaluate activated clot timing (ACT), clot rate (CR), and platelet function (PF). Genotyping was carried out using GSA and Sanger sequencing, and expression analysis was performed using RT-PCR. In silico analysis was carried out using the GROMACS tool and UNAFold. The interaction of significant proteins with other proteins was predicted using the STRING database. Ninety-six genes were analyzed, and a significant association of THPO (rs6141) and ARHGEF3 (rs1354034) was observed with the disease and its subtypes. Altered genotypes were associated significantly with increased MPV, decreased PLT count, and CR. Expression analysis revealed a higher expression in patients bearing the variant genotypes of both genes. In silico analysis revealed that mutation in the THPO gene leads to the reduced compactness of protein structure. mRNA encoded by mutated ARHGEF3 gene increases the half-life of mRNA. The two significant proteins interact with many other proteins, especially the ones involved in platelet activation, aggregation, erythropoiesis, megakaryocyte maturation, and cytoskeleton rearrangements, suggesting that they could be important players in the determination of MPV values. In conclusion, the current study demonstrated the role of higher MPV affected by genetic variation in the development of IS and its subtypes. The results of the current study also indicate that higher MPV can be used as a biomarker for the disease and altered genotypes, and higher MPV can be targeted for better therapeutic outcomes.

Common microRNAs in Epilepsy and Migraine: Their Possibility as Candidates for Biomarkers and Therapeutic Targets during Comorbid Onset of Both Conditions.

Epilepsy and migraine are chronic neurological disorders with shared clinical as well as pathophysiological mechanisms. Epileptic patients are at a higher risk of developing migraine compared to normal individuals and vice versa. Several genetic and environmental risk factors have been reported to be associated with the development of both diseases. Previous studies have already established standard genetic markers involved in various pathways implicated in the pathogenesis of both these comorbid conditions. In addition to genetic markers, epigenetic markers have also been found to be involved in the pathogenesis of epilepsy and migraine. Among the epigenetic markers, miRNAs have been explored at length and have emerged as significant players in regulating the expression of their target genes. miRNAs like miR-22, miR-34a, miR-155, miR-211, and Let-7b play a significant role in neuronal differentiation and seem to be associated with epilepsy and migraine as comorbid conditions. However, the exact shared mechanisms underlying the role of these miRNAs in these comorbid conditions are still unclear. The current review has been compiled with an aim to explore common microRNAs targeting the genes involved in shared molecular pathways leading to epilepsy and migraine as comorbid conditions. The new class of ncRNAs, i.e., tRNA transfer fragments, are also discussed. In addition, their role as potential biomarkers and therapeutic targets has also been evaluated. However, limitations exist, and based on the current literature available, only a few microRNAs seem to be involved in the pathogenesis of both these disorders.

COVID-19 induced ischemic stroke and mechanisms of viral entry in brain and clot formation: a systematic review and current update.

Background: Coronavirus disease 2019, caused by SARS-CoV-2 (SCV-2) was stated as a pandemic on March 11 2020 by World Health Organization (WHO), and since then, it has become a major health issue worldwide. It mainly attacks the respiratory system with various accompanying complications, including cardiac injury, renal failure, encephalitis and Stroke.Materials and Methods: The current systematic review has been compiled to summarize the available literature on SCV-2 induced ischemic Stroke and its subtypes. Further, the mechanisms by which the virus crosses the blood-brain barrier (BBB) to enter the brain have also been explored. The role of CRP and D-dimer as potent prognostic markers was also explored. The literature search was carried out comprehensively on Google scholar, PubMed, SCOP US, Embase and Cochrane databases by following guidelines.Results: All the studies were reviewed thoroughly by authors and disagreements were resolved by consensus and help of the senior authors. The most common subtype of the IS was found to be large artery atherosclerosis in SCV-2 induced IS. Hypertension emerged as the most significant risk factor. The mechanism resulting in elevated levels of CRP and D-dimer have also been discussed. However, there is a scarcity of definitive evidence on how SCV-2 enters the human brain. The available literature based on various studies demonstrated that SCV-2 enters through the nasopharyngeal tract via olfactory cells to olfactory neurons, astrocytes and via choroid plexus through endothelial cells. Further, disruption of gut-brain axis has been also discussed.Conclusion: Data available in the literature is not adequate to come to a conclusion. Therefore, there is a need to carry out further studies to delineate the possible association between SCV-2 induced IS.

Advanced molecular therapies for neurological diseases: focus on stroke, alzheimer's disease, and parkinson's disease.

Neurological diseases (NDs) are one of the leading causes of disability and the second leading cause of death globally. Among these stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) are the most common NDs. A rise in the absolute number of individuals affected with these diseases indicates that the current treatment strategies in management and prevention of these debilitating diseases are not effective sufficiently. Therefore, novel treatment strategies are being explored to cure these diseases by addressing the causative mechanisms at the molecular level. Advanced therapies like gene therapy (gene editing and gene silencing) and stem cell therapies aim to cure diseases by gene editing, gene silencing and tissue regeneration, respectively. Gene editing results in the deletion of the aberrant gene or insertion of the corrected gene which can be executed using the CRISPR/Cas gene editing tool a promising treatment strategy being explored for many other prevalent diseases. Gene silencing using siRNA silences the gene by inhibiting protein translation, thereby silencing its expression. Stem cell therapy aims to regenerate damaged cells or tissues because of their ability to divide into any type of cell in the human body. Among these approaches, gene editing and gene silencing have currently been applied in vitro and to animal models, while stem cell therapy has reached the clinical trial stage for the treatment of NDs. The current status of these strategies suggests a promising outcome in their clinical translation.

Role of tRNA-Derived Fragments in Neurological Disorders: a Review.

tRFs are small tRNA derived fragments that are emerging as novel therapeutic targets and regulatory molecules in the pathophysiology of various neurological disorders. These are derived from precursor or mature tRNA, forming different subtypes that have been reported to be involved in neurological disorders like stroke, Alzheimer's, epilepsy, Parkinson's, MELAS, autism, and Huntington's disorder. tRFs were earlier believed to be random degradation debris of tRNAs. The significant variation in the expression level of tRFs in disease conditions indicates their salient role as key players in regulation of these disorders. Various animal studies are being carried out to decipher their exact role; however, more inputs are required to transform this research knowledge into clinical application. Future investigations also call for high-throughput technologies that could help to bring out the other hidden aspects of these entities. However, studies on tRFs require further research efforts to overcome the challenges posed in quantifying tRFs, their interactions with other molecules, and the exact mechanism of function. In this review, we are abridging the current understanding of tRFs, including their biogenesis, function, relevance in clinical therapies, and potential as diagnostic and prognostic biomarkers of these neurological disorders.

Evaluation of mean platelet volume and platelet count in ischemic stroke and its subtypes: focus on degree of disability and thrombus formation.

Background: Platelets are crucial players in thrombus formation during ischemic stroke. Platelet (PLT) count and Mean platelet volume (MPV) are important parameters that affect platelet functions. The current study has been carried out with an aim to evaluate the association of MPV and PLT count with ischemic stroke in a population from the Malwa region of Punjab.Material and Methods: The study included one hundred and fifty ischemic stroke patients. The extent of disability occurs by stroke was measured by mRS. MPV and PLT was evaluated using cell counter. Further, PLT count was confirmed in 50% of patients using flow cytometer. Clot formation rate was evaluated using Sonoclot Coagulation and Platelet Function Analyzer. All the statistical analysis was carried out using SPSS.Results: A significant association of increased MPV (p < 0.02) was found with the ischemic stroke. However, PLT count did not show a significant association with the disease (p < 0.07). Further, a stepwise multiple logistic regression (MLR) analysis controlling the other confounding risk factors evaluated the association of hypertension and MPV with the disease. Patients with higher mRS were found to have high MPV values confirming that higher MPV is correlated with disability occurs by ischemic stroke. MPV was also found to be significantly associated with large artery atherosclerosis (p < 0.001). Clot formation analysis revealed that ischemic stroke patients bear higher clot rate (CR) and Platelet function (PF) values.Conclusions: Elevated MPV is an independent risk factor for Ischemic stroke along with hypertension. In addition, higher MPV associated significantly with stroke disability as well.

Role of Omics in Migraine Research and Management: A Narrative Review.

Migraine is a neurological disorder defined by episodic attacks of chronic pain associated with nausea, photophobia, and phonophobia. It is known to be a complex disease with several environmental and genetic factors contributing to its susceptibility. Risk factors for migraine include head or neck injury (Arnold, Cephalalgia 38(1):1-211, 2018). Stress and high temperature are known to trigger migraine, while sleep disorders and anxiety are considered to be the comorbid conditions with migraine. Studies have reported various biomarkers, including genetic variants, proteins, and metabolites implicated in migraine's pathophysiology. Using the "omics" approach, which deals with genetics, transcriptomics, proteomics, and metabolomics, more specific biomarkers for various migraine can be identified. On account of its multifactorial nature, migraine is an ideal study model focusing on integrated omics approaches, including genomics, transcriptomics, proteomics, and metabolomics. The current review has been compiled with an aim to focus on the genomic alterations especially involved in the regulation of glutamatergic neurotransmission, cortical excitability, ion channels, solute carrier proteins, or receptors; their expression in migraine patients and also specific proteins and metabolites, including some inflammatory biomarkers that might represent the migraine phenotype at the molecular level. The systems biology approach holds the promise to understand the pathophysiology of the disease at length and also to identify the specific therapeutic targets for novel interventions.

Role of Calcium Homeostasis in Ischemic Stroke: A Review.

Stroke is the second most common cause of death worldwide. It occurs due to the insufficient supply of oxygen-rich blood to the brain. It is a complex disease with multiple associated risk factors, including smoking, alcoholism, age, sex, ethnicity, etc. Calcium ions are known to play a vital role in cell death pathways, which is a ubiquitous intracellular messenger during and immediately after an ischemic period. Disruption in normal calcium homeostasis is known to be a major initiator and activator of the ischemic cell death pathway. Under ischemic stroke conditions, glutamate is released from the neurons and glia, which further activates the N-methyl-D-aspartate (NMDA) receptor and triggers the rapid translocation of Ca2+ from extracellular to intracellular spaces in cerebral tissues and vice versa. Various studies indicated that Ca2+ could have harmful effects on neurons under acute ischemic conditions. Mitochondrial dysfunction also contributes to delayed neuronal death, and it was established decades ago that massive calcium accumulation triggers mitochondrial damage. Elevated Ca2+ levels cause mitochondria to swell and release their contents. As a result, oxidative stress and mitochondrial calcium accumulation activate mitochondrial permeability transition and lead to depolarization-coupled production of reactive oxygen species. This association between calcium levels and mitochondrial death suggests that elevated calcium levels might have a role in the neurological outcome in ischemic stroke. Previous studies have also reported that elevated Ca2+ levels play a role in the determination of infarct size, outcome, and recurrence of ischemic stroke. The current review has been compiled to understand the multidimensional role of altered Ca2+ levels in the initiation and alteration of neuronal death after an ischemic attack. The underlying mechanisms understood to date have also been discussed.

Epilepsy and Migraine Shared Genetic and Molecular Mechanisms: Focus on Therapeutic Strategies.

Epilepsy and migraine are both episodic disorders and share clinical as well as pathophysiological mechanisms. The prevalence of epilepsy in migraine patients is generally higher than normal as compared to general population and vice versa. Various environmental risk factors and genetic factors have been reported to be associated with susceptibility of these comorbid diseases. Specific genes have been implicated in the pathogenesis of the two diseases. However, the shared genetic susceptibility has not been explored extensively. Previous studies have reported that the alterations in the genes encoding ion channel proteins are common risk factors for both the diseases. The alterations in ion channel-encoding genes CACNAIA (T666M) and SCNIA (Q1489K and L1649Q) have been found to be involved in the development of familial hemiplegic migraine (FHM) as well as generalized epilepsy and some cases of focal epilepsy as well. The fact that both these disorders are treated with anti-epileptic drugs (AEDs) strongly supports common underlying mechanisms. This review has been compiled with an aim to explore the alterations in common genes involved in various pathways regulating neuronal hyperexcitability, a common risk factor for both these conditions. The avenue for future treatment strategies targeting common genes and molecular mechanisms has also been discussed.

Establishing molecular signatures of stroke focusing on omic approaches: a narrative review.

Stroke or 'brain attack' is considered to be the major cause of mortality and morbidity worldwide after myocardial infraction. Inspite of the years of research and clinical practice, the pathogenesis of stroke still remains incompletely understood. Omics approaches not only enable the description of a huge number of molecular platforms but also have a potential to recognize new factors associated with various complex disorders including stroke. The most significant development among all other omics technologies over the recent years has been seen by genomics which is a powerful tool for exploring the genetic architecture of stroke. Genomics has decisively established itself in stroke research and by now wealth of data has been generated providing new insights into the physiology and pathophysiology of stroke. However, the efficacy of genomic data is restricted to risk prediction only. Omics approaches not only enable the description of a huge number of molecular platforms but also have a potential to recognize new factors associated with various complex disorders including stroke. The data generated by omics technologies enables clinicians to provide detailed insight into the makeup of stroke in individual patients, which will further help in developing diagnostic procedures to direct therapies. Present review has been compiled with an aim to understand the potential of integrated omics approach to help in characterization of mechanisms leading to stroke, to predict the patient risk of getting stroke by analyzing signature biomarkers and to develop targeted therapeutic strategies.

The molecular basis of platelet biogenesis, activation, aggregation and implications in neurological disorders.

Platelets are anucleated blood constituents, vital for hemostasis and involved in the pathophysiology of several cardiovascular, neurovascular diseases as well as inflammatory processes and metastasis. Over the past few years, the molecular processes that regulate the function of platelets in hemostasis and thrombosis have emerged revealing platelets to be perhaps more complex than may have been expected. The most understood part of platelets is to respond to a blood vessel injury by altering shape, secreting granule contents, and aggregating. These responses, while advantageous for hemostasis, can become detrimental when they root ischemia or infarction. Only a few transcription and signaling factors involved in platelet biogenesis have been identified till date. Platelets encompass an astonishingly complete array of organelles and storage granules including mitochondria, lysosomes, alpha granules, dense granules, a dense tubular system (analogous to the endoplasmic reticulum of nucleated cells); a highly invaginated plasma membrane system known as the open canalicular system (OCS) and large fields of glycogen. Platelets as a model cells to study neurological disorders have been recommended by several researchers since several counterparts exist between platelets and the brain, which make them interesting for studying the neurobiology of various neurological disorders. This review has been compiled with an aim to integrate the latest research on platelet biogenesis, activation and aggregation focusing on the molecular pathways that power and regulate these processes. The dysregulation of important molecular players affecting fluctuating platelet biology and thereby resulting in neurovascular diseases has also been discussed.

Association of CYP2C19*2 and ALDH1A1*1/*2 variants with disease outcome in breast cancer patients: results of a global screening array.

PURPOSE: Cyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab. METHODS: A total of 250 confirmed breast cancer patients were involved in the study. Genotyping was performed on an Illumina Infinium HD assay platform using a Global Screening Array (GSA) microchip. GenomeStudio (Illumina, Inc.) was used for data preprocessing and a p value less than or equal to 5 × 10-8 was considered statistically significant. To rule out the influence of confounding risk factors, a step-wise multivariate regression analysis was carried out to evaluate the association of genotype with overall clinical outcome. RESULTS: Two gene variants, CYP2C19 (G681A) and ALDH1A1*2 (17 bp deletion), were found to be significantly associated with the disease outcome, including overall survival, recurrence and metastasis, in breast cancer patients on adjuvant therapy. Both these genes are involved in the pharmacokinetics of cyclophosphamide. However, none of the variants in the genes involved in pharmacokinetics and pharmacodynamics of doxorubicin were found to have any significant impact on disease outcome in the studied group. CONCLUSION: CYP2C19 (G681A) variant and ALDH1A1*2 emerged as two important biomarkers associated with bad outcome in breast cancer patients on adjuvant therapy.

Recent advances in HER2 positive breast cancer epigenetics: Susceptibility and therapeutic strategies.

HER2 amplification/overexpression accounts for aggressive clinical features of HER2 positive breast cancer. Epigenetic changes including DNA methylation, histone modifications and ncRNAs/miRNAs are associated with regulation of DNA chromatin and specifically, gene transcription. Hence, these produce eminent effects upon proto-oncogenes, tumor-suppressors and key cancer-regulatory signaling pathways. Understanding of epigenomic regulation of HER2 overexpression and signaling may help uncover the unmatchable physiology of HER2 gene/protein. Moreover, this may also aid in resolving the major issue of resistance-development towards HER2 targeted agents (trastuzumab and lapatinib), since epigenetic alterations are important therapeutic markers and modulate the response towards HER2 targeted therapy. Therefore, in this review the information regarding various epigenetic markers implicated in HER2 positive breast cancer susceptibility and therapeutic-strategies has been compiled.