Suman Kushwaha

Meta-analysis of apolipoprotein E levels in the cerebrospinal fluid of patients with Alzheimer's disease

The possible association between Apolipoprotein E (ApoE) levels in the cerebrospinal fluid (CSF) and Alzheimers disease (AD) has been studied extensively. However, previous findings have been inconsistent. We conducted a meta-analysis of observational studies, seeking to provide insights into ApoEs potential as a biomarker for AD. A systematic literature search of PubMed (MEDLINE), EMBASE, and Web of Science was performed to retrieve relevant studies evaluating ApoE levels in CSF from AD subjects and controls. The association between ApoE levels in the CSF and AD was estimated by the weighted mean difference (WMD) and 95% confidence interval (CI) using a random-effect model. We identified 24 studies that included 1064AD cases and 1338 non-demented controls. Although the pooled WMD did not indicate a significant association between AD and ApoE levels (-0.30mg/l; 95% CI: -0.69 to 0.09; P=0.13), sub-group analysis controlling for patient sample size (n≥43) revealed significantly lower ApoE levels (WMD: -0.66mg/l; 95% CI: -1.02 to -0.31; P=0.0002) among patients with AD than in controls. Publication bias was absent and sensitivity analysis did not result in any significant change in the pooled estimates, indicating highly stable results. The present meta-analysis indicates the potential of CSF ApoE levels as a predictor of AD association.

Evaluation of Geno Type MTBDRplus Line Probe Assay for Early Detection of Drug Resistance in Tuberculous Meningitis Patients in India

Background: Molecular methods which allow for rapid and reliable detection of drug resistance have yet not been sufficiently evaluated for timely management of patients with tuberculous meningitis. Aims: We aimed to evaluate Geno Type MTBDRplus line probe assay for early detection of drug resistance in Mycobacterium tuberculosis isolates and CSF samples of confirmed tuberculous meningitis patients. Settings and Design: This was a multicentric prospective study carried out from July 2011 to December 2013 in tertiary care hospitals of Delhi. Materials and Methods: The assay was performed on 89 M. tuberculosis isolates and 31 direct CSF samples from microbiologically confirmed tuberculous meningitis patients. The sensitivity and specificity of this assay was calculated in comparison to drug susceptibility testing by BACTEC MGIT 960 system. Results: The sensitivity, specificity for detection of resistance to Isoniazid was 93%, 97% and to Rifampicin was 80%, 98.8%, respectively by this assay in comparison with the phenotypic drug susceptibility testing. The line probe assay could detect M. tuberculosis in 55% of CSF samples from patients with microbiologically confirmed tuberculous meningitis. Only 5/89 isolates (5.6%) were resistant to both Isoniazid and Rifampicin while 9/89 (10%) isolates were additionally resistant to Isoniazid. Resistance to any of the drugs, namely Isoniazid, Rifampicin, Streptomycin or Ethambutol, was seen in 24.7% of strains. Conclusion: The line probe assay has a good sensitivity and specificity for detection of drug resistance to Isoniazid and Rifampicin in M. tuberculosis culture isolates. However, this assay has limited role in detection of M. tuberculosis and drug resistance from direct samples with confirmed diagnosis of tuberculous meningitis.

Multifactorial Analysis of a Biomarker Pool for Alzheimer Disease Risk in a North Indian Population

Background: Alzheimer disease (AD) is a progressive neurodegenerative disease with a complex multifactorial etiology. Here, we aim to identify a biomarker pool comprised of genetic variants and blood biomarkers as predictor of AD risk. Methods: We performed a case-control study involving 108 cases and 159 non-demented healthy controls to examine the association of multiple biomarkers with AD risk. Results: The APOE genotyping revealed that ε4 allele frequency was significantly high (p value = 0.0001, OR = 2.66, 95% CI 1.58-4.46) in AD as compared to controls, whereas ε2 (p = 0.0430, OR = 0.29, CI 0.07-1.10) was overrepresented in controls. In biochemical assays, significant differences in levels of total copper, free copper, zinc, copper/zinc ratio, iron, epidermal growth factor receptor (EGFR), leptin, and albumin were also observed. The AD risk score (ADRS) as a linear combination of 6 candidate markers involving age, education status, APOE ε4 allele, levels of iron, Cu/Zn ratio, and EGFR was created using stepwise linear discriminant analysis. The area under the ROC curve of the ADRS panel for predicting AD risk was significantly high (AUC = 0.84, p < 0.0001, 95% CI 0.78-0.89, sensitivity = 70.0%, specificity = 83.8%) compared to individual parameters. Conclusion: These findings support the multifactorial etiology of AD and demonstrate the ability of a panel involving 6 biomarkers to discriminate AD cases from non-demented healthy controls.

Genetic contribution of CYP1A1 variant on treatment outcome in epilepsy patients: a functional and interethnic perspective.

CYP1A1 gene is involved in estrogen metabolism, and previously, we have reported association of variant rs2606345 with altered anti-epileptic drugs (AED) response in North Indian women with epilepsy (WWE). The present study aims to replicate the pharmacogenetic association, perform functional characterization and study its distribution within ethnically diverse Indian population. The variant was genotyped in 351 patients to assess the pharmacogenetic association and 552 healthy individuals belonging to 24 different ethnic groups to examine the distribution in Indian population. We observed significant overrepresentation of ‘A’ allele and ‘AA’ genotype in poor responders in WWE at Bonferroni-corrected significance levels. The recessive allele was found to lower the promoter activity by ~70–80% which was further substantiated by thermally less stable hairpin formed by it (ΔTm=7 °C). Among all ethnic groups, west Indo–European (IE-W-LP2) subpopulation showed highest genotypic frequency of the variant making women from this community more prone to poor AED response. Our results indicate that rs2606345 influences drug response in WWE by lowering CYP1A1 expression.

Effect of apolipoprotein E (APO E) polymorphism on leptin in Alzheimer's disease

Background: Leptin, a 16 kDa peptide hormone synthesized and secreted specifically from white adipose cells protects neurons against amyloid β-induced toxicity, by increasing Apolipoprotein E (APO E)-dependent uptake of β amyloid into the cells, thereby, protect individuals from developing Alzheimer′s disease (AD). The APO E ε4 allele is a known genetic risk factor for AD by accelerating onset. It is estimated that the lifetime risk of developing AD increases to 29% for carriers with one ε4 allele and 9% for those with no ε4 allele. Objectives: To determine the levels of serum leptin, cholesterol, low density lipoprotein (LDL-C), and high density lipoprotein (HDL-C) in the diagnosed cases of AD and the association of them with cognitive decline and Apolipoprotein E (APO E) genotypes in AD. Materials and Methods: Serum levels of serum leptin, cholesterol, LDL-C, and HDL-C along with APO E polymorphism were studied in 39 subjects with probable AD and 42 cognitive normal individuals. Results: AD group showed significantly lower levels of leptin (P = 0.00) as compared to control group. However, there was no significant difference in cholesterol, triglycerides, LDL-C, and HDL-C levels in AD and control groups. The frequency of ε4 allele in AD (38.5%) was found to be significantly higher than in control (10.3%). ε3 allele was more frequent than ε4 allele in AD and control group.

Predictors of adverse outcome in patients of tuberculous meningitis in a multi-centric study from India

INTRODUCTION This study aimed to investigate the factors which may predict mortality and neurological disability at one year follow up in patients of tuberculous meningitis (TBM) in India. METHODOLOGY Patients with TBM were prospectively enrolled from July 2012 to September 2014 from four tertiary care hospitals of Delhi. The demographic characteristics, clinical features and laboratory findings were collected and patients were followed up till 1 year. These were analyzed by univariate and multivariate multinomial logistic regression analysis to identify predictors of adverse patient outcome at 1 year follow up. RESULTS Out of 478 patients enrolled, 391 patients could be followed up to 1 year. Sixty-four patients (16.3%) died and 150 patients (39%) survived with one or more neurological disability. Altered sensorium, motor deficit, cranial nerve palsy, seizures, isolation of M. tuberculosis and presence of multi-drug resistance were independently associated with any adverse outcome (death or disability) but by multivariate analysis only motor deficit, altered sensorium and isolation of M. tuberculosis on culture produced a statistically significant model for prediction of patient outcome. CONCLUSION The three-predictor model with motor deficit, altered sensorium and isolation of M. tuberculosis produced a statistically significant model with correct prediction rate of 60.4%. These three variables predicted death with odds ratio of 39.2, 6.7 and 2.1 respectively in comparison to recovery whereas only motor deficit and isolation of M. tuberculosis predicted neurological disability at 1 year with odds ratio of 3.9, 2.4 respectively.

Evaluating the Role of Genetic Variants on first-line antiepileptic drug response in North India: Significance of SCN1A and GABRA1 Gene Variants in Phenytoin Monotherapy and its Serum Drug Levels.

The present study aimed to evaluate association of genetic variants on drug response and therapy optimization parameters in patients treated with first‐line antiepileptic drugs (AEDs). Genetic variants from ion channels, their functionally related genes, and synaptic vesicle cycle (SVC) genes with a potential role in epilepsy pathophysiology were thus prioritized.

Synergistic association of STX1A and VAMP2 with cryptogenic epilepsy in North Indian population.

“Common epilepsies”, merely explored for genetics are the most frequent, nonfamilial, sporadic cases in hospitals. Because of their much debated molecular pathology, there is a need to focus on other neuronal pathways including the existing ion channels.

Intravascular lymphoma: an unusual cause of rapid cognitive decline and the role of brain biopsy

Intravascular lymphoma (IVL) is a rare extra nodal variant of non Hodgkins lymphoma characterised by neoplastic lymphoid cells growing inside the lumina of medium and small vessels. IVL limited to the central nervous system (CNS) is an extremely rare condition as IVL is usually found with systemic lesions. Most cases of IVL are not diagnosed until post mortem because of variable clinical presentation and non-specific laboratory findings. Even if diagnosed early the disease is clinically aggressive and usually fatal, even with early detection and treatment. We present a case of a 37-year-old woman with a short history of behavioural abnormality, rapidly progressive cognitive decline and seizures. There were no cutaneous manifestations. Diagnosis was established only after the brain biopsy. The case is presented for the rarity of its presentation and role of brain biopsy in diagnosis.

Post-traumatic dissecting aneurysms of bilateral cervical carotid arteries with delayed complications

Carotid dissection is an uncommon complication of trauma. They can present with immediate or delayed complications. We describe the case of a young patient with bilateral carotid dissections and acute infarcts. Brief review of literature and treatment options are discussed.